EA039114B1 - Use of insulin glargine/lixisenatide fixed ratio composition in the treatment of diabetes mellitus type 2 - Google Patents

Abstract

The invention relates to the use of a composition of (a) 33 g/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof, and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, for the preparation of a composition for the treatment of diabetes mellitus type 2, wherein the composition is administered to a patient in need thereof in combination with metformin and/or a pharmaceutically acceptable salt thereof. Furthermore, the invention relates to a method of treating diabetes mellitus type 2 comprising administering to a patient in need thereof the above stated composition, and to the use of a combination comprising the above stated composition and a composition comprising a) 50 g/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof, and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of diabetes mellitus type 2, which is administered in combination with metformin and/or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to the use of a fixed ratio pharmaceutical composition of insulin glargine/lixisenatide for the treatment of type 2 diabetes mellitus.

In healthy individuals, the release of insulin by the pancreas is strongly related to the concentration of glucose in the blood. Elevated blood glucose that occurs after a meal is quickly balanced by a corresponding increase in insulin secretion. In the fasted state, plasma insulin levels fall to basal levels, which is sufficient to provide a continuous supply of glucose to insulin-sensitive organs and tissues and to keep hepatic glucose production low at night.

In contrast to type 1 diabetes, in type 2 diabetes there is usually no lack of insulin, but in many cases, in particular in cases of progression, insulin treatment is considered the most appropriate therapy, if necessary in combination with orally administered antidiabetic drugs.

Elevated blood glucose for several years without initial symptoms poses a significant health risk. This can be clearly demonstrated by the large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986), according to which chronically elevated blood glucose levels are the main cause of complications. diabetes. Examples of complications of diabetes are micro- and macrovascular damage, which often manifests as retinopathy, nephropathies or neuropathies and leads to blindness, kidney failure and loss of limbs and is accompanied by an increased risk of cardiovascular disease. Thus, it can be concluded that improved diabetes therapy should primarily be aimed at maintaining blood glucose levels in the physiological range as much as possible.

A certain risk exists for overweight patients suffering from type 2 diabetes, such as patients with a body mass index (BMI) >30 kg/m ² . In these patients, the risks of diabetes overlap with the risks associated with being overweight, leading, for example, to an increased risk of cardiovascular disease compared to patients with type 2 diabetes who are of normal weight. Thus, it is particularly necessary to treat diabetes in these patients concomitantly with weight loss.

Metformin is a biguanide hypoglycemic agent used in the treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) that cannot be corrected by dietary modification. Metformin improves glycemic control by increasing insulin sensitivity and reducing intestinal absorption of glucose. Metformin is usually administered orally. However, control of type 2 diabetes mellitus in obese patients with metformin may not be sufficient. Therefore, these patients may require additional measures to control type 2 diabetes.

Connection des-Pro ³⁶ -exendin-4(1-39)-Lys ₆ -NH ₂ (AVE0010, lixisenatide) is a derivative of exendin-4. Lixisenatide is disclosed as SEQ ID NO: 93 in WO 01/04156:

SEQ ID NO: 1: Lixisenatide (44 amino acids)

HGEGTFTSDLSKQMEEEAVRL-FIEWLKN-Gg-pssgappskkkkkk-nh ₂ .

SEQ ID NO: 2: exendin-4 (39 amino acids)

HGEGTFTSDLSKQMEEEAVRL-FIEWLKN-Gg-pssgappps-nh ₂ .

Exendins are a group of peptides that can lower blood glucose levels. The exendin analog lixisenatide is characterized by a C-terminal truncation of the native exendin-4 sequence. Lixisenatide contains six C-terminal lysine residues not present in exendin-4.

In the context of the present invention, lixisenatide includes its pharmaceutically acceptable salts. The person skilled in the art is aware of the pharmaceutically acceptable salts of lixisenatide. The preferred pharmaceutically acceptable salt of lixisenatide useful in the present invention is an acetate.

Insulin glargine is a human insulin 31 ^B -32 ^B -di-Arg analog of human insulin with the additional replacement of the asparagine at position A21 with glycine. Insulin glargine is also called Gly(A21)-Arg(B31)-Arg(B32)-human insulin. According to the present invention, insulin glargine includes pharmaceutically acceptable salts thereof.

Insulin glargine is disclosed in US 5656722.

Lantus® is an insulin based product containing insulin glargine that provides a 24-hour supply of basal insulin after a single dose subcutaneous injection.

A dose of 100 units of insulin glargine requires an injection of 1 ml of Lantus® U100 because each ml of Lantus® U100 contains 100 units of insulin glargine. 100 units of insulin glargine corresponds to 3.6378 mg of insulin glargine.

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WO 2011/147980 discloses a pre-use mixture containing a constant concentration of insulin glargine and a variable concentration of lixisenatide. This document also discloses an exemplary pre-use formulation containing 100 U/mL insulin glargine and 66.67 µg/mL (or 800/300x25 µg/mL) lixisenatide, 60.6 µg/mL (or 800/330x25 µg /ml) lixisenatide, 55.56 µg/ml (or 800/360x25 µg/ml) lixisenatide, 51.28 µg/ml lixisenatide (or 800/390x25 µg/ml lixisenatide), 47.62 µg/ml (or 800/ml) 420x25mcg/mL) lixisenatide, 44.44mcg/mL (or 800/450x25mcg/mL) lixisenatide, 41.67mcg/mL (or 800/480x25mcg/mL) lixisenatide, 39.22mcg/mL (or 800 /510x25 µg/ml) lixisenatide, 37.04 µg/ml (or 800/540x25 µg/ml) lixisenatide, 35.09 µg/ml (or 800/570x25 µg/ml) lixisenatide or 33.33 µg/ml (or 800/600x25 µg/ml) lixisenatide.

The present invention relates to the use of a composition of:

(a) 33 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof; and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, to obtain a composition for the treatment of type 2 diabetes mellitus, wherein the composition is administered to a patient in need thereof at combinations with metformin and/or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the age of the patient to be treated is at least 50 years old.

In one embodiment of the present invention, the patient to be treated is obese.

In one embodiment of the present invention, the patient to be treated has a body mass index of at least 30 kg/m ² , at least 31 kg/m ² , at least 32 kg/m ² or at least 33 kg/ m ² .

In one embodiment of the present invention, type 2 diabetes mellitus is not adequately controlled with metformin alone.

In one embodiment of the present invention, treatment with at least 1.5 g/day of metformin does not adequately control type 2 diabetes mellitus.

In one embodiment of the present invention, the patient to be treated has an HbA1c value in the range of at least 7%, at least 8%, or at least 9% within one month prior to treatment with the composition.

In one embodiment of the present invention, the patient to be treated has a fasting plasma glucose concentration of at least 7 mmol/l, at least 8 mmol/l, at least 9 mmol/l, at least 10 mmol/ l or at least 11 mmol/l within one month prior to treatment with the composition.

In one embodiment of the present invention, the patient to be treated has a self-monitoring plasma glucose concentration of at least 8 mmol/L, at least 9 mmol/L, at least 10 mmol/L, or at least 11 mmol /l within one month prior to treatment with the composition.

In one embodiment of the present invention, the patient to be treated has a plasma glucose level 2 hours after a meal of at least 12 mmol/L, at least 13 mmol/L, at least 14 mmol/L, at least 15 mmol/l, at least 16 mmol/l or at least 17 mmol/l within one month prior to treatment with the composition.

In one embodiment of the present invention, the patient to be treated has a difference between the concentration of glucose in blood plasma 2 hours after a meal and the concentration of glucose in blood plasma 30 minutes before a test meal of at least 5 mmol/l, at least 5 .5 mmol/l, at least 6 mmol/l, at least 6.5 mmol/l or at least 7 mmol/l within one month prior to treatment with the composition.

In one embodiment of the present invention, the patient to be treated is not receiving a GLP-1 receptor agonist and/or insulin.

In another aspect, the present invention relates to a method of treating type 2 diabetes mellitus comprising administering to a patient in need thereof a composition comprising:

(a) 33 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof; and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, where the composition is administered in combination with metformin and/or a pharmaceutically acceptable salt thereof.

In one embodiment of the proposed method, the dose of insulin glargine is from 0.25 to 1.5 U/kg of body weight.

In one embodiment of the proposed method, the dose of lixisenatide is from 0.05 to 0.5 μg/kg of body weight.

In one of the variants of the proposed method, the composition is administered parenterally.

In yet another aspect, the present invention relates to the use of a combination comprising:

(I) a pharmaceutical composition containing:

- 2 039114 (a) 50 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof; and (II) a pharmaceutical composition containing:

(a) 33 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of type 2 diabetes mellitus, which is administered in combination with metformin and/or a pharmaceutically acceptable salt thereof.

Example 1 illustrating the present invention describes a randomized, 30-week, active-drug-controlled, open-label, 2-treatment, parallel-group, multicenter study comparing the efficacy and safety of a fixed ratio combination of insulin glargine/lixisenatide with insulin glargine. , with or without metformin, in patients with T2DM. In this study, (I) a pharmaceutical composition containing 100 U/ml insulin glargine and 50 μg/ml lixisenatide, and (II) a pharmaceutical composition containing 100 U/ml insulin glargine and 33 μg/ml lixisenatide are used. In addition, a combination of (I) and (II) is used.

Example 2 illustrating the present invention describes a 3-treatment randomized clinical trial comparing the efficacy and safety of a fixed ratio combination of insulin glargine/lixisenatide with insulin glargine alone and with lixisenatide alone along with metformin in patients with type 2 diabetes mellitus. .

Example 2 demonstrated a statistical advantage of the fixed ratio combination over insulin glargine in changing HbA1c levels, as well as a statistical advantage of the fixed ratio combination over lixisenatide (Table 9 of Example 2).

Example 2 demonstrated that significantly more patients treated with the fixed ratio combination achieved levels of HbA1c<7% and HbA1c<6.5% compared to those treated with insulin glargine or lixisenatide (Table 10 of Example 2).

Example 2 demonstrated that treatment with a fixed ratio formulation significantly improved postprandial glycemic control, glucose drift was largely normalized after 2 hours compared to treatment with insulin glargine (Table 11 of Example 2). Improvement with the fixed dose ratio formulation was also observed for 2 h postprandial (PPG) plasma glucose compared with lixisenatide and insulin glargine (Table 12).

Body weight decreased in the fixed ratio/lixisenatide combination groups and increased in the insulin glargine group. A statistically significant difference in body weight change was found between the fixed ratio combination group and the insulin glargine group (Table 13).

The reductions in fasting plasma glucose (FPG) levels were similar in the fixed ratio combination group and the insulin glargine group, and they were significantly lower in the lixisenatide group (Table 14).

Patients treated with the fixed ratio combination had a statistically significant greater decrease in mean SMPG concentration in the 7 time point profile compared to patients treated with insulin glargine and patients treated with lixisenatide, respectively (Table 15).

In the clinical study described in Example 2, a higher proportion of patients achieved the combined endpoint of HbA1 <7.0% without body weight gain in the fixed ratio combination group compared to the insulin glargine and lixisenatide groups (Table 16). More patients achieved the triple composite endpoint of HbA1c <7.0% without gaining body weight and without documented (plasma glucose concentration <70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia during the study in the formulation group with a constant dose ratio compared to the insulin glargine group and the lixisenatide group, respectively (Table 17).

Thus, a fixed ratio combination added to metformin for patients in whom metformin with or without a second oral antidiabetic drug (OAD) does not provide adequate control significantly normalized HbA1c levels and reduced 2-hour glucose and PPG fluctuations. after 2 hours, mean SMPG concentration profile over 7 time points and body weight compared with insulin glargine. The combination also significantly normalized HbA1c, FPG levels, and mean SMPG concentration in a 7-point profile compared to lixisenatide.

The benefits of initiating treatment with a fixed ratio combination compared with initiating treatment with either component alone in patients in whom an oral antidiabetic drug is not adequately controlled is therefore supported based on the benefits demonstrated for HbA1c levels and body weight in

- 3 039114 versus insulin glargine and for HbAlc, FPG and gastrointestinal tolerance versus lixisenatide.

Example 3, illustrating the present invention, describes a 2-treatment randomized clinical trial comparing the efficacy and safety of a fixed ratio combination of insulin glargine/lixisenatide and insulin glargine with or without metformin in patients with type 2 diabetes mellitus.

Fixed-ratio combination with or without metformin for patients in whom basal insulin with or without oral antidiabetic drugs is not adequately controlled significantly improved HbA1c levels (Table 8 of Example 3), allowed more patients to achieve target HbA1c levels during treatment (Table 9), reduced deviations in glucose levels after 2 hours (Table 10) and PPG after 2 hours (Table 11), the average value of the concentration of SMPG in the profile over 7 time points (Table 13) and body weight (Table 12) versus insulin glargine.

A pharmaceutical composition or combination as described herein may be administered in combination with metformin and/or a pharmaceutically acceptable salt thereof, particularly as an adjunct to treatment with metformin and/or a pharmaceutically acceptable salt thereof. Metformin is the international nonproprietary name for 1,1-dimethylbiguanide (CAS number 657-24-9). According to the present invention, the term metformin includes any pharmaceutically acceptable salt thereof.

According to the present invention, metformin can be administered orally. Metformin formulations suitable for the treatment of type 2 diabetes by oral administration are known to one skilled in the art. Metformin can be administered to a patient in need thereof in an amount sufficient to induce a therapeutic effect. Metformin can be administered at a dose of at least 1.0 g/day or at least 1.5 g/day. For oral administration, metformin may be formulated into a solid dosage form such as a tablet or pill. Metformin may be formulated with suitable pharmaceutically acceptable carriers, adjuvants and/or excipients.

According to the present invention, the terms supplement, additional treatment, additional therapy and along with refer to the treatment of type 2 diabetes mellitus with metformin and the composition of the present invention as described herein. The composition of the present invention and metformin can be administered via different routes of administration. Metformin can be administered orally, and the composition of the present invention can be administered parenterally.

Self-Monitoring Plasma Glucose Concentration (SMPG) as used herein specifically represents the self-monitoring plasma glucose concentration at 7 time points. The 7-point self-monitoring plasma glucose concentration specifically refers to measuring the blood plasma glucose level seven times a day and calculating the mean plasma glucose concentration value from that. The 7-point self-monitoring plasma glucose value is, in particular, the mean plasma glucose concentration including fasting and postprandial states. In particular, plasma glucose measurements are taken before breakfast, after breakfast (for example, 2 hours after breakfast), before lunch, after lunch (for example, 2 hours after lunch), before lunch, after dinner (for example, after 2 after dinner) and before bed. Treatment with the combination of the present invention described herein can provide normalization of plasma glucose concentration under self-monitoring.

According to the present invention, the glucose deviation is, in particular, the difference between the plasma glucose concentration 2 hours after a meal and the plasma glucose concentration 30 minutes before a test meal (glucose deviation 2 hours after a meal). According to the present invention, the glucose deviation can also be calculated as the difference between the plasma glucose concentration 30 minutes or 1 hour after a meal and the plasma glucose concentration 30 minutes before a test meal (glucose deviation after 30 minutes or 1 hour). after eating). Preferably, the glucose deviation is the glucose deviation 2 hours after a meal.

After a meal is a term that is well known to those skilled in the art of diabetology. The term postprandial describes, in particular, the phase after ingestion and/or exposure to glucose under experimental conditions. In a healthy person, this phase is characterized by an increase and subsequent decrease in the concentration of glucose in the blood. The postprandial term or postprandial phase typically ends within 2 hours of ingestion and/or glucose exposure. According to the present invention, the term postprandial plasma glucose level is, in particular, the plasma glucose level 30 minutes, 1 hour or 2 hours after a meal, i. the level of glucose in the blood plasma after a meal, determined after 30 minutes, 1 hour or 2 hours after a meal and / or exposure to glucose. In particular, the concentration of glucose in blood plasma after a meal is the concentration of glucose in blood plasma after 2 hours

- 4 039114 after eating.

According to the present invention, the composition described herein may contain at least one of suitable pharmaceutically acceptable carriers, adjuvants and/or excipients.

The composition described herein can be administered parenterally, for example by injection (such as intramuscular or subcutaneous injection). Suitable injection devices, also referred to as pens, are known, comprising a cartridge containing the active ingredient and an injection needle.

The pharmaceutical composition described herein may be provided within a container, such as an ampoule, vial or pen, as described herein, for use by a patient. For example, a pharmaceutical composition that is a liquid formulation may be provided within a vial. From such a vial, the patient can draw the required dose into a syringe (in particular, a single-use syringe). In particular, the combination of the present invention may be provided in a pen.

The composition described herein can be administered by one injection per day.

According to the present invention, the composition described in this document may be a liquid composition. Liquid compositions of lixisenatide suitable for parenteral administration are known to those skilled in the art. The person skilled in the art is also aware of liquid formulations of insulin glargine suitable for parenteral administration. The liquid composition of the present invention may have an acidic or physiological pH. The acidic pH is preferably in the range of pH 1-6.8, pH 3.5-6.8 or pH 3.5-5. The physiological pH is preferably in the range of pH 2.5-8.5, pH 4.0-8.5 or pH 6.0-8.5. The pH can be adjusted with a pharmaceutically acceptable dilute acid (typically HCl) or a pharmaceutically acceptable dilute base (typically NaOH).

The liquid composition of the present invention may contain a suitable preservative. A suitable preservative may be selected from phenol, m-cresol, benzyl alcohol and parahydroxybenzoic acid ester. The preferred preservative is m-cresol.

The liquid composition of the present invention may contain a tonicity agent. A suitable tonicity agent may be selected from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium containing compounds such as CaCl ₂ . The concentration of glycerol, lactose, sorbitol, mannitol and glucose can be in the range of 100-250 mm. The NaCl concentration can be up to 150 mM. A preferred tonicity agent is glycerol.

The liquid composition of the present invention may contain methionine at a concentration of 0.5 to 20 μg/ml, preferably 1 to 5 μg/ml. Preferably the liquid composition contains L-methionine.

The present invention is further illustrated by the following figures and examples.

Explanation of conventions (example 2).

Fig. 1. Mean HbA1c (%) at visit - mITT population. S - screening (week -6), R - introductory phase (week -1), B - start time, LOCF - carry forward last observation. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIX - lixisenatide. Note: The graph includes all planned measurements taken during the study, including those taken after the IMP has been discontinued or the rescue agent has been administered.

Fig. 2. Mean change in HbA1c (%) from baseline at visit - mITT population. B is the start time, LOCF is the carry forward of last observation data. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIXI - lixisenatide. Note: The graph includes all planned measurements taken during the study, including those taken after the IMP has been discontinued or the rescue agent has been administered.

Fig. 3. Average body weight (kg). B is the start time, LOCF is the carry forward of last observation data. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIXI lixisenatide. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 4. Mean fasting plasma glucose (mmol/L/[mg/dL]) at the mITT population visit. S - screening (week -6), R - introductory phase (week -1), B - start time, LOCF - carry forward last observation. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIXI - lixisenatide. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 5. Mean fasting plasma glucose (mmol/L/[mg/dL]) from baseline time at visit - mITT population. B is the start time, LOCF is the carry forward of last observation data. INS/LIXI - Fixed Ratio Combination, INS - Insulin

- 5 039114 glargine, LIXI - lixisenatide. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 6. Mean value of the SMPG level in the profile for 7 time points (mmol/l/[mg/dl]) at the initial time point and at week 30. SMPG is the concentration of glucose in the blood plasma during self-monitoring. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIXI - lixisenatide. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 7. Mean value of the average daily dose of insulin glargine (ED) at the visit. LOCF carries the data of the last observation forward. INS/LIXI - fixed ratio combination, INS - insulin glargine, LIXI - lixisenatide. The analysis included scheduled measurements taken up to the date of the last IMP injection, including those taken after the administration of rescue therapy.

Fig. 8. Graphical representation of the study plan from example 2:

* - Sulfonylurea, glinide, SGLT-2i or DPP4 inhibitor will be discontinued at V2; the daily dose of metformin will be increased during the run-in phase to a final daily dose of at least 2000 mg or to a tolerated dose;

* * - Insulin glargine will be started at 10 units during the first week and then optimized and individually titrated throughout the study to achieve and maintain fasting SMPG levels: 80-100 mg/dL (4.4-5.6 mmol /l) without hypoglycemia;

* ** - treatment with fixed ratio combination insulin glargine/lixisenatide will be initiated using pen A. The initial daily dose of insulin glargine to be administered during the first week of treatment will be 10 units: this corresponds to an initial associated dose of 5 mcg lixisenatide according to the fixed ratio of 2 U/1 mcg used in pen A. Thereafter, doses will be individually titrated throughout the study to achieve and maintain fasting SMPG levels: 80-100 mg/dL (4.4-5 .6 mmol/l) without hypoglycemia.

Fig. 9. Graph of mean HbA1c (%) at visit - mITT population. S - screening (week -8), R - introductory phase (week -1), B - start time, LOCF - carry forward last observation. INS/LIXI is a fixed ratio combination, INS is insulin glargine. Note: The graph includes all planned measurements taken during the study, including those taken after the IMP has been discontinued or the rescue agent has been administered.

Fig. 10. Plot of mean change in HbA1c (%) from baseline at visit - mITT population. B is the start time, LOCF is the carry forward of last observation data. INS/LIXI is a fixed ratio combination, INS is insulin glargine. Note: The graph includes all planned measurements taken during the study, including those taken after the IMP has been discontinued or the rescue agent has been administered.

Fig. 11. Graph of the mean change in body weight (kg) from baseline at the mITT population visit. B is the start time, LOCF is the carry forward of last observation data. INS/LIXI is a fixed ratio combination, INS is insulin glargine. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 12. Graph of average SMPG levels in the profile for 7 time points at the initial time point and at week 30 - mITT population. SMPG is the concentration of glucose in blood plasma during self-monitoring. INS/LIXI is a fixed ratio combination, INS is insulin glargine. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 13. Graph of mean daily dose of insulin glargine (ED) at visit - mITT population. Week 6 is the first week of the introductory phase, B is the start time, LOCF is the last observation carried forward. INS/LIXI is a fixed ratio combination, INS is insulin glargine. The analysis included scheduled measurements taken up to the date of the last IMP injection, including those taken after the administration of rescue therapy.

Fig. 14. Plot of Mean Fasting Plasma Glucose at Visit - mITT Population. S - screening (week -8), R - introductory phase (week -1), B - start time, LOCF - carry forward last observation. INS/LIXI is a fixed ratio combination, INS is insulin glargine. The analysis included all planned measurements taken during the study, including those taken after IMP was discontinued or rescue therapy was introduced.

Fig. 15. Graphical representation of the study plan from example 1.

¹ - insulin glargine should be administered by subcutaneous injection once a day. The timing of the injection (any time of day, the same time every day) will be determined at visit 2 and should remain approximately the same throughout the study (during the run-in phase for all patients and also during the randomized treatment period for patients , randomisi

- 6,039,114 assigned to the insulin glargine treatment group);

² - fixed ratio combination insulin glargine/lixisenatide should be administered by injection once a day within one hour before breakfast;

³ - treatment with any oral anti-diabetic agent other than metformin, if any, will be discontinued at visit 2.

Example 1

Randomized, 30-week, active-drug-controlled, open-label, 2-treatment, parallel-group, multicenter study comparing the efficacy and safety of a fixed-ratio combination of insulin glargine/lixisenatide with insulin glargine, with or without metformin, in patients with type 2 diabetes

COMPOUND: HOE901 (insulin and argin) / AVE0010 (.shxisenatide) combinations HEADING Rshdomizirovashk, ZO-isdslyus, controlled by the active drug; An open-label, 2-treatment, parallel-group, multicenter study comparing the efficacy and safety of a constant-ratio combination of insulin glargine and insulin glargine with or without metformin in patients with T2DM INVESTIGATOR / TEST LOCATION international DEVELOPMENT PHASE Phase III WHOLE) RESEARCH Target goal; Demonstrating for over 30 weeks the superiority of a combination with a constant stroke ratio! glargshlixnsenatide compared with insulin glargine with or without metformin in terms of reduction in 1 IbA । in patients with type 2 diabetes. Target(|·) □ Consistent over 30 weeks of the effects of a constant ratio combination of insulin gfgnshliksmeenatad versus insulin glarpsh with: • Percentage of patients who achieved NLL target levels । ; • Glycemic control in relation to lichen intakes, assessed by plasma glucose level ι plasma glucose level 2 hours after a meal (PPG) at the entrance of a standardized food intake test; Body weight determinations: Self-monitoring plasma glucose concentration profile at 7 SMPG time points; • Percentage of patients who achieved target levels of HLA] _C without gaining body weight had documented symptomatic hypoglycemia; * Dose of insulin ktirshna; • Fasting plasma glucose concentrations (FPG). Assess the safety and tolerability of each ipyiuie treatment. □ Let's push the chain to insulin and anipel to lixissnat (tpyiiiia .with the help of combination 2 with a constant ratio of the latter). □Chain of total and active plasma concentrations of lnkeisenatnd before and after nggyektsin (treatment group πρι aid combination about a constant ratio). Assessing the effects ^of the course in each treatment group on patient reported outcomes (PRO), and measured by the following questionnaires: IWQoL-Llte) Evaluation of the overall response of patients to treatment in each treatment group using a rating scale for the effectiveness of treatment, designed for the patient and the doctor

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Brief description of the clinical study

RESEARCH PLAN Open-label, randomized L:1, active-drug com- glargkna. Randomization will be stratified by HNL j at visit 5 (week -1) (<8% 8%} and using metformin or screening (Y, N). Research budsg count from 3 periods: * 1 [screening period up to 8 weeks, which includes - a phase of sgfshshtgga lasting up to 2 weeks: The initial visit can be carried out by a pug than 2 weeks after the screening visit if laboratory data are available. - the current phase of the dgtatslnnsssto b nedol: 1 dose optimization of insulin rjEprwna, supplementation of metformin (if necessary), and stop of sula|tonilmochsvi1-1a (SU), glynsc in1kbiura sodium-glucose collapsrtir 2 tin (SGLT-2i), or dipeptindyl-pegtndase-4 inhibitor (ΠΡΡ-4Ϊ) ), sat down previously taken on V2. • 30-week open-label randomized treatment period - At the end of the screening period, patients in whom HAADc is > 7% and < 10% whose mean fasting SMIXj value, calculated from self-measurement responses 7 days prior to randomization, is < 140 mg/dL (7.8 mmol/L) and whose daily dose of insus.shna glargyl is 20 IU or <50 IU, will include® a 30-period open-label randomized treatment comparing a fixed-ratio combination of gxxisenntide/insugpsh with insulin glargine (: 1stformin for both treatments) * A 3-day follow-up period is observed from post-cooking for all patients after IMP (for withdrawal of study medication prematurely [[relapsed study treatment: patients should continue their participation in the study until hccjüdoespin ia). INVESTIGATED POPULATION Main selection criteria Inclusion criteria; * Patients with diabetes mellitus! 2, up to 1 post-mortem and at least 1 year before the screening visit. * Patients treated with .basal insulin for at least 6 months prior to the visit. * Patients., ggo.tuchaypis treatment on stable achsms acadian basal insulin high at least 3 months prior to the screening visit (ts. * (Highest dry dose of basal insulin should be stable (21)%) and set aside from d 15 to 41) E DA days at least 2 months before the screening visit. * 1 [patients who are on half-healthy basal insulin at a distance or in combination with a stable dsp of 1 to 2 DDDs for at least 3 months prior to the critical wheeze, which may be: tolerable sulphyl-dipsynthidase inhibitor or inhibitor SGJ /T-2 * 1 [assessment with ΙΊΚτ < ¹ JOmg/dl (10.0 m >cnn";g) at the written informed visit. Exclusion Criteria: ⁴ Age below the upper stage for adults at the time of the screening visit Fri ⁴ Hb1spa1/k>mst[tcrnn}11mg vzmta<7.5% and> 10% ⁴ Pregnancy ww j.activation, women of childbearing potential * 1 [previous use of other oral or intravenous glucose-lowering blood glucose-lowering drugs, as opposed to oral glucocorticosteroids in 3-month screening criteria *1 [previously using an insulin regimen different from that of basal IEculish ( for example , regular or premixed insulin) more than 3 months ago

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L/shlgechoyude.. Short-term treatment with ν intercurrent treatment, waw including gestational diabetes. allowed at the discretion of the researcher • Discontinuation of previous treatment with GLP-l RA due to safety/tolerability or lack of femininity Results of laboratory tests at the screening visit, including: • Amylase and/or lipase greater than 3 times the upper limit of the normal .taborshore range fULN); * ALT or ASP-3ULN, * Calcitonin - 20 pg / ml (5.9 pmolStX * Positive pregnancy test. • Any contraindications to the use of metformin according to the regional version of the instructions for use (for example, renal failure, defined by the level of creatinine > 1.4 mg/dl in women, > L5 mg/di in men, or creatinine clearance <60 lmin and ί. if the patient is prescribed metformin. • A patient suffering from renal insufficiency with creatinine clearance <30 op. (with the use of Cockcroft and Gault formulas) mln end-stage renal failure in patients who did not receive metformin. • Contraindications to the use of insulin glargip or lixisenatide. History of icerchuvsgvi'gelnos'1i reaction to insulin g largine. lixisenatide m;w any of the excipients. • A history of allergic reaction to your GLP-1 KA or insulin glargen or to Mstacrzol. • A history of personal or closely related family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTS (eg, multiple endocrine syndromes of neoplasia). • Cases of pancreatitis (except in cases where pancreatitis was associated with gallstone disease and cholecystectomy has already been a history of chronic pancreatitis, pancreatitis during previous treatment with increpe therapy, pancreatitis, gastric and gastric surgery in history. Exclusion criteria for randomization at the end of the screening period: HbA or > 1 ϋ% at visit 5 (week -1). • Mean fasting SMPG calculated according to self-measurement 7 days of the week prior to the randomization visit (V6) is >140 hgg dl (7.8 mmol/l). • Mean daily dose of insulin glargine <20 U or >50 U calculated for the last three days of the week prior to Visit 6. • Amylase or lipase level >3 ULN at visit 5 (week -1). Total expected number of patients 11 Approximately 700 randomized patients (350 per group). RESEARCH PURPOSE® Investigated medical project Investigated medical products): Study drug: Combination with a fixed ratio of insulin gl^syn / lixisenitide A combination with a constant ratio of insulin [dargik'.shkeisenashts lredostakyu! in the form of a sterile aqueous solution in a pre-filled single-use injector of the type SoloStaKS tgpritspen (100 gAst of insulin tlargine with lixisatatide 33 or 50 μg / ml, depending on the syringe pen) Pen type injector: The combination drug will be self-injected using a pre-filled, disposable SoloSlar& pen type injector. The dose of the combination will be titrated based on the patient's insulin requirements. 11a, the dose indicator in the pen only indicates the dose of insulin glargine. The dose (pg) of lixisenatide does not appear on the dose index despite the fact that lixisenatnd is premixed in a cartridge.

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To ensure titration of insulin glargine from 10 to 60 units using a limiting dose of lixisenatide up to 20 mcg/day, two syringes with different constant ratios of insulin glargine/lixisenatide will be used; ♦ Pen A (yellow label, yellow dispenser button): SoloStar® pre-filled disposable pen injector containing 3 ml of a sterile solution of 100 U/ml insulin glargine and 50 µg/ml lixisenatide in a 2:1 ratio (2 units insulin glargine per 1 mcg lixisenatide). This pen allows you to administer daily doses of the combination from 10 U/5 µg to 40 U/20 µg. ♦ Pen B (red label, red dispenser button): SoloStar® pre-filled disposable pen injector containing 3 ml of a sterile solution of 100 U/ml insulin glargine and 33 µg/ml lixisenatide in a 3:1 ratio (3 units insulin glargine per 1 mcg lixisenatide). This pen allows you to administer daily doses of the combination from 30 U/10 µg to 60 U/20 µg. It is intended primarily for patients requiring daily doses of insulin glargine between 40 and 60 units. However, it can also be used to administer daily doses of 30 to 40 units of insulin glargine either at the start of treatment (see below) or during the treatment phase to reduce the dose, for example in the event of hypoglycemia, without requiring a return to the syringe -handle A. Patients who started treatment with pen A and require a daily dose of insulin glargine above 40 units will be switched to pen B. Control drug: Insulin glargine (Lcaitus) Insulin glargine is supplied as a sterile aqueous solution in a SoloStar® pre-filled disposable pen injector (100 U/ml insulin glargine). Pen type injector: The SoloStar® pre-filled pen injector is specifically labeled for study use and contains a total of 300 units/3 ml of insulin glargine. Disposable pre-filled Lantus® SoloSTAR® pen-type injectors are provided to all patients during V2 and patients randomized to insulin glargine during V6 (week 0, day 1) and then for IMP injection. Route(s) of administration: Subcutaneous injection of both IMPs Dosing regimen During the introductory phase: Starting dose of insulin glargine From the start of administration (Visit 2), the only approved basal insulin is insulin glargine. Patients on any basal insulin other than pre-screening insulin glargine will be switched to once daily insulin glargine at the start of Visit 2. The starting dose of insulin glargine will be the same as the previous basal insulin dose if they received 1 daily injection, or the total daily dose of the previous insulin minus 20% if they received more than 1 daily injection. Patients who received insulin glargine prior to the start of the study will begin to receive doses that are the same as those before the start of the study. Insulin glargine can be given at any time of the day, but at the same time each day. The timing of the single daily injection is at the discretion of the patient and investigator and will be fixed at Visit 2 and should remain approximately the same throughout the study (during the run-in phase for all patients and also during the randomized treatment period for patients randomized to insulin treatment). glargine). Dose adjustment of insulin glargine During the run-in phase, doses will be adjusted based on daily measured fasting SMPG to improve fasting glycemic control and provide patients with randomization criteria (HbAlc at visit 5 > 7% and <10%, mean fasting SMPG < 140 mg/dl [7, 8 mmol/l] measured within 7 days of the week prior to visit 6). The titration procedure to achieve these criteria while avoiding hypoglycemia is at the discretion of the investigator. Small dose reduction

- 10 039114 allowed in the case of ι shyuishkzdshi and at the discretion of ishgdedovage.sh.

During the period of the randomized course in the open mode:

Group. treated with a fixed ratio combination of insulin glargnin/lnxisenyatide

Patients who received insush glprgin {ij/ntux) in the morning

Patients [finimanmcpe a day before dogwood* 6 (G>1) daily ;viy of insulin glargine • < 30 ί will start treatment with the combination using pen A at 20 U insulin glargip/10 mcg lixisenatide* > 30 U will start treatment with the combination using prn1 (-pen B at a dose of 30 units of insulin g. srg nnl N)

The first blood injection will be given at the study center on the morning of randomization.

Patients who received insulin gdrgin at other times of the day than in the morning, d? introductory phase

Patients should switch to administration within one hour before breakfast. The following is the procedure for switching to a different injection time, alternative transition schemes can be used if necessary:

• Morning of visit at midnight time point (TW) after randomization: injection during patient stay, study ηεπηχ: dose of insulin glargine equal to 1/2 - 23 (to be determined by the investigator) of the desh dose administered prior to randomization (D -1) • The next morning (D2) taking the day before Visit 6 (D-1) the daily dose of insulin [.[apt ina < 30 U will start treatment with the combination using ngrnc pen A at a dose of 20 U of insulin ι larginiU mcg lixisenatide

-> 30 U will begin treatment with a combination using pen B at a dose of 30 U insulin glargine/10 µg lixisenatide.

scea nuifuestmoft (20 11D'10 mcg or 31 U/10 mcg) will be drained continuously for 2 weeks. For two additional weeks, increasing the dose, if necessary, will be a tyrannical incremental increase in I 2 U and ns more often than once a week.

After the first 4 weeks, doses will be titrated once a week according to the algorithm described in the table below to achieve target glycemic levels (fasting SMPG in the range of στ 80 to 100 yg'dl [4.4-5.6 mmol]) without hypoglycemia. Thereafter, until the end of the study, the dose will be adjusted as needed to maintain the highest target levels of SXfPG.

Ltgorithm utpEkgmtyut doses

Median fasting SMK1 values for previous 3 days Dose adjustments for insulin glargine (EDdsn) 140 mg/dl C'7.8 mmol l:) + 4 >100 and <140 mg/dl (5.6 and 1.7.8 mpm) + 2 Calculated glycemic level: 80 and 100 sh^dl (4.4 and 5.6 mmol!.) INCLUDED Without changes >60 and <80 mg/dL [>3.3 and <4.4 mmol) -2 <60 mg d.t ('o.3 mmol'l) or the appearance of 2 (or more) episodes of symptomatic hypoglycemia or one episode of severe hypoglycemia (requiring assistance) documented in the previous week. - from 2 to -4 or at the discretion of the researcher or qualified on that sheet

Insulin group gls11ptnz11l]L15X)

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Patients who are randomized to insulin glargino/g are given the same daily dose of insulin glargine on the day of randomization as the day before the randomization visit, and then continue to titrate the insulin dose as needed during the open-label randomized treatment period. The injection time should remain the same as the time set during Visit 2 and was used during the run-in phase. The dose will be adjusted weekly according to the same algorithm as described above for the Copby Nation at a constant ratio. Both treatment groups Dose adjustments are based on the median of the last 3 days of upper body SMPG measured by the patient using blood glucose meters and equipment provided by the sponsor for this study. Doses may be reduced or changed at any time in the event of hypoglycemia and according to the investigator's best clinical judgement. The total daily ¹ dose of insulin glargine will be limited to 60 U. In the event that a dose of > 60 U of insulin glargine is required to maintain IlbAlc below predefined thresholds, the dose should be maintained at 60 U and rescue therapy should be initiated (see section Rescue Therapy " below). All assessments scheduled for the end-of-course visit should be carried out prior to initiation of emergency therapy. Composition of non-essential drugs Background treatment with metformin (Metformin tablet for sale) and emergency treatment will be considered as NIMP PathPush) introductions Oral administration of metformin Dosing regimen Background therapy with metformin (if necessary) should be administered in accordance with the regional version of the instructions for use. If Nazis are taking metformin, it must be given at a stable dose not less than 1500 mg/day or the maximum tolerated dose for at least 3 months prior to screening. This regimen should be continued and the dose should remain stable throughout the study unless there is a specific safety concern associated with this treatment. Treatment with sulfonylurea, clay, SGLT-2 inhibitors, and DHM inhibitors has previously been treated with these. should be stopped from the beginning of the introductory period (visit 2), emergency therapy To ensure that glycemic parameter results remain within predetermined thresholds, regular SMPG test and hPU and HbAlc readings from a central laboratory are required. In the event that ΓΚΉ1>Α1ο exceed the threshold signs (see Section 7.4), if the source of explanations for insufficient control of the level of thluchosa or if appropriate actions do not lead to success, or if for an emergency, EKEN; short-acting insulin may be added to therapy, starting with a single daily injection, which should be given at times other than breakfast in the constant sun group, and with any meal for funia and targin insulin. In any cadaver, no other OAD or basal insulin should be taken as emergency medications. All evaluations scheduled for the end-of-treatment visit should be followed by Proves™ before pumping emergency care. Once these assessments have been completed and rescue therapy has begun, the patient will remain in the study and will continue to be treated in the study (including background

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therapy). Scheduled visits and assessments (staplement of the last meal) do not be completed until the last toned squeal. END POINTS!) Primary endpoint * Change in level I ]bA1o from baseline to week 30, Secondary endpoint(s) tpchkya(-1|) 'Efficacy: * Percentage of patients. dosleep NAK! <6 _? 5% by week 30 • Change in PPG after 2 las and glucose levels during a standardized PN trial at baseline by week 30; * Change in body tesa from the initial point in time to 30 weeks; • 7-point change in SMKi or baseline profiles by week 30 (at each time point and daily mean): * Percentage of patients achieving HbAlc <7% without body weight gain by week 30; • Change in daily insulin dose from baseline to week 30; • Change in the level of FPG οι of the initial moment of time to week 30; * Percentage of patients. reaching HbAlc < 7% by week 30 without documented symptomatic hypoglycemia [PC<70 mg'dl (3.9 mmol/l)] during the 30 second period of raidomized treatment; * Percentage of patients achieving PLA1 with <7% RR of body weight gain by week 30 and RR of symptomatic hypoglycemia [PG <70 mg/dL (3.9 mmol/L)] during a 30-day randomized treatment period; *Change in PPG at 30 minutes and 1 hour and in glucose levels during a standardized food trial from baseline to week 30; * Percentage of patients requiring emergency care during a 3-week open treatment period. 1st danger: * Symptomatic hypoglycemia (documented, probable, severe symptomatic hypoglycemia * Uncommon events, serious adverse events and AF.SL anti-lixisenatide and/or anti-insulin antibodies (depending on treatment group) will be measured on day 1 of the treatment phase and at week 30. Other end point(s) Pharmacokinetic parameters * General and active Plasma concentrations of lixissnatide will be assessed over a period of 1 to 4 hours post-injection on day 1 of the treatment phase and prior to injection, and 1 to 4 hours post-injection at week 30 (for patients with a constant insulin glargip ratio). /lnksnSepatnd). Patient-reported outcomes (PRO) • Changes in patient-reported outcomes (PRO) will be assessed from time base to week 30 for the treatment-related impact measure, diabetes (TRIM-D). EnroQol-iD (EQ5D) and the effect of weight on quality of life (IWQoL-Lite); 'At the end of the study will also be considered a rating scale for the effectiveness of treatment, designed for the patient and the doctor. SCHEME OSH LPShLNIA Ganit scheme:

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The outline of procedures/assessments associated with the study is detailed in the Study Procedures Schedule (Section 1.2). Early termination: Patients who discontinue IMPs prematurely and permanently for any reason should make an assessment visit as soon as possible, which is typically scheduled on the last day of IMP dosing, i. PK and antibody scores, meal trials, and PRO scores if available. Note: Patients who terminate IMP administration prematurely must continue their participation in the study until the scheduled end date of the study. They must follow the study procedures specified in the protocol (with the exception of the 3-day post-treatment follow-up period, PK and antibody assessment, food trial, and PRO assessment). STATISTICAL FEATURES Determining the sample size A sample size of 350 patients per arm would provide over 95% power to detect a 0.4% difference in HbAlc change from baseline to week 30 when comparing a fixed ratio combination of insulin glargine/lixisenatide and insulin glargine. This calculation assumes an overall standard deviation of 1.1% at a 5% significance level (2-tailed). Population for analysis: The population for primary efficacy analysis will be the Modified Intention-to-Treat (mITT) population, which includes all randomized patients who received at least one dose of the investigational drug and were assessed at baseline and at least one assessment after baseline. point in time at any of the primary or secondary efficacy points, regardless of compliance with study protocol and procedures. Patients will be analyzed for efficacy according to the IVRS/IWRS treatment regimen according to the randomization schedule at the randomization visit (according to randomization). Safety analyzes will be performed on a safety population, defined as all randomized patients exposed to at least one dose of investigational drug, regardless of the amount of drug administered. Patients will be analyzed according to the actual treatment regimen. Primary efficacy endpoint analysis Analysis of the primary efficacy endpoint (change in HbAlc from time base to week 30) will be performed on the mITT population using HbAlc values obtained at scheduled visits during the treatment period. The treatment period for HbAlc is defined as the time from the first dose of investigational drug to 14 days after the last dose or to rescue therapy, whichever comes first. The statistical test will be two-tailed at an alpha level of 0.05. The primary analysis method for the primary efficacy endpoint would be a repeated measures mixed effects model (MMRM) with missing data assigned randomly. The MMRM model will include treatment groups, randomization strata, visits, interaction with treatment factor effect by visit, and country as fixed effects factors, and interaction with HbAlc factor effect at baseline by visit as covariates. The initial time value is defined as the last available value prior to the first dose of investigational medicinal product. The adjusted mean change in HbAlc at baseline to week 30 for each treatment group will be assessed within this model, as well as the difference between groups and 95% C1 for the adjusted mean. The MMRM model will be run using the SAS® (version 9.2 or higher) MIXED (PROC MIXED) procedure with an unstructured correlation matrix to model errors within a single patient evaluation. The parameters will be estimated using the constrained maximum likelihood method with the Newton-Raphson algorithm. The degree of freedom of the denominator will be estimated using the Canward-Roger approximation by fitting values from scheduled visits after randomization during treatment. This model will use only scheduled HbAlc measurements obtained during the treatment period.

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For the primary efficacy endpoint, sensitivity dialysis will be performed as needed to explore different methods for handling missing data. Secondary Endpoint Analysis of Efficacy Subsequent secondary efficacy endpoints will be analyzed using a similar MMRM-based method. Differences between treatment groups and confidence intervals will be assessed within the MMRNL. The endpoints of tactic efficiency will be analyzed by the Cochrane-Man tel-Hsnze stratified randomization strata. Security Analysis The safety analysis of the 3()-week treatment period will be descriptive, based on a population e.1 safety assessment (randomized and open). Treatment-related adverse events (ΊΈΑΕ) are defined as adverse events (AEs) that developed or worsened or became serious during the period from the first dose of the study treatments to 3 days after the last dose. Pharmacokinetic parameters Plasma concentrations of lixisenatide (total and active) in patients in the constant ratio insulin glartine-lixisenatide combination group will be listed and summarized by visit and analysis period and by anti-lixisenatide antibody status in the PK population, using descriptive statistics N. geometric mean, coefficient variation, median, minimum and maximum. Patient Reported Outcomes Descriptive statistics (mean, median, standard deviation, and range) for absolute values and for change from baseline (ΊΊΒΝΗ, I X)-5D n IWQOE Lite) will be represented by treatment group per visit for the global indicator, sub-indicators, and as well as each indicator of the three PRO scorers. Descriptive statistic (mean, median, standard deviation to range) for treatment effectiveness rating scales calculated on the basis of the patient and the doctor of the same® will be presented pears! treatment at the end of the study. DURATION OF THE STUDY PERIOD (for the patient) The maximum duration of the study will be approximately 39 weeks: a screening period of up to 8 weeks (with r(za screening of up to 2 weeks and 1 week of introductory photon), a 30-week randomized treatment period, and an S-two period |[(tsdsduk)| observations to assess safety after treatment.

1. Schedules of procedures.

1.1. Graphical representation of the study plan.

A graphical representation of the study plan is shown in Fig. fifteen.

1.2. Schedule of examination procedures

Study period Screenshot of the non-original ° Pepiop pan-remembrance treatment η open mode Vnmp during the subsequent Screening phase Introductory phase observation ijouic treatment VISIT: Time frame: V3 5: + 3 days: V7-15:-.3 days VI6-21 : ±5 days one .5 four 5 6 7 S 9 ten and 12 in fourteen fifteen 16 17 IN 19 twenty 21 V21+3 days 5’22: -1 -3 days S5 E S S S To in limit LA Infuriated consent ί ri <rnm 1 1 Yu (k, IMH Ht f "uch „niya ^X 1 CLsCH. hMltl JU IIUBO hir \ pi a ¹ ate ss hch.sha _w luio. dm"<x cС^ occ .i/uibu t a ϊ kr "nchel ns to bervanin B4HIW v mi :re* cnrs t 1mcho wx me "kmo J" and | * sYa r ( "1 Si and" a yiy> y k 'ovshis Ros g Weight gs.sh hipc ic ν "not tja"'and ii-ki gisino important Functions IT ><12 he. - neither K. n p. G RS IVI1S Ran domi kshiya 'anis * s nm, v''Chyi. yal ar", wasp ip. SJ foreign gemny Vnct! 1 T'M ^ Mcrp > F. (IR t 1|book{ of kg H'Mt rhenium glucose1 -S X X X X X X X X X -b X X X X X -2 X 0 X X X X X X X one k>CTOj -one X JHHO with 3 appreciating. four X X X a yut and 5 record! b mwayug a X X V on pr ten heavy 12 X X V Research Institute of the Armed Forces fifteen STO IS one" X X X SLSDO1 21 ^any 24 X X X' 27 thirty X χ X X X X Wii l shni^ia -o p (r kma iyan ί 1ri lzhdom vn t- L LKC WK'eaiV ibvt N sL ιρ 1 X X X X X X BUT' X X X Grennrsvta sg'chm dli ϊ ri lohk shchi Lantns'-iv SolosiariV X

The issuance of Xu lenses

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Training introduction about the use of tprtsh-pen. ^prefilled combination; X Issuance of syringe-handle with ks?.unietsen with a constant ratio X X X X X X Daily measurement of fasting SMPG SMPG in profile io 7 time points 102 times per week prior to visit) Insulin dot adjustment i.iapi ina Dose adjustment of fixed ratio combination Recording of IMP fractions (per day | days \ 3 times of each week to the week 12 and son-in-law for the last 3 days of the week prior to each visit) ³ Count of returned fathers-hands; Compliance Checks PRO Questionnaires (TRIM-D. EQ-51X IWQol.-l.ite) Treatment Effectiveness™ Scale. ryassch1yammsh1 Ni liaHUuaia Evaluation scale.sh FKk1nkn' *whether treatment, designed for the doctor Researches in imtrplynti labor 1 IbA^ (in the central laboratory) Plasma glucose level imuiapiHted ΊροόΐΗιΐΗ meal ioryn .X X .X X X X X X X X X X |_A X X X X X X X X X X X X X X X G* X X X H: X X X X X X X X X X X X X X X H X X X X X X' X X X X X X X X X X X V .X X X X X X X X X X X La X .X X b X X X La X X X X X X X X X X M X X X X X X X X X X X X X X X Levels of general-; IDL-: HDL(olsl^rina trngli1yuridon X X Urinalysis' and test for the surface antigen of the virus gene m ha B and anshte.yu to miivcv leiiam ta C X '' ratio of 1buminecreel1nninya '1st morning urine) X X Women only: Levels I S] 1. tstradiol (if necessary; X Women only: Pregnancy guest! b 'in case of fertility) X X X X Laboratory data’: general analysis of trovn. biochemical ana.piece of serum t exactly X X X X amylase levels. lipases X X X X X X X X Serum calcitonin level X X X X The level of antibodies to lixissnagidui or antibodies to insulin (depending on the ruin .current / X Ebtaya and active concentration of tnxiseiatnd in plasma (treatment group ιρκ assistance combination with constant animal relief) X X Optional sampling for pharmacological research X

^a - additional phone calls for dose titration should be scheduled as often as deemed necessary by the investigator; the introductory visit (V2) can be done less than 2 weeks after the screening visit (V1). if laboratory data are available;

^b - in the case of emergency therapy, all assessments (including the 2-hour standardized food trial, but excluding PK and antibody assessments) scheduled for visit V21 should be performed before the start of emergency therapy, patients then continue treatment with IMP, and all visits and assessments (including PK and antibody assessments, but excluding food trials and PRO assessments) should be performed as scheduled.

In the event of premature discontinuation of IMPs, all evaluations (including the 2-hour standardized food trial only if the patient received IMP on the day of the food trial) scheduled for the V21 visit should be performed prior to premature discontinuation of the IMP, patients should continue their participation in the study until the planned end date of the study, and all assessments (except for the 3-day post-treatment follow-up period, food trial, PK and antibody assessment, and PRO assessment) should be performed as: ^c - repeat as needed;

^d - the missed injection of IMP should be recorded in the e-CRF;

^e - screening analysis of urine: (pH, glucose, ketones, leukocytes, blood, protein);

^f - laboratory data: complete blood count - WBC, RBC, hemoglobin, hematocrit, platelets, differential count of leukocytes (neutrophils, lymphocytes, monocytes, eosinophils, basophils). Biochemical analysis of blood serum - total bilirubin, G-GT, AST, ALT, ALP, creatinine, uric acid, sodium, potassium, phosphorus, calcium;

^g - one additional sampling will be done at week 30 for potential additional immunogenicity measurements;

^h - Samples for antibody evaluation should be taken prior to injection;

I - Samples may also be collected at any follow-up visit.

2. List of abbreviations.

ADA - American Diabetes Association,

AE is an undesirable phenomenon,

AESI is an Adverse Event of Special Interest,

ALP - alkaline phosphatase,

ALT - alanine aminotransferase,

ANCOVA - analysis of covariance,

ARAC - Allergy Assessment Committee,

AST - aspartate aminotransferase,

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BID - Bis in die = gea times a day, BMI - body mass index, bpm - beats per minute, CAC - expert committee on cardiovascular diseases, CRF - individual registration card, CSR - clinical study report, CI - confidence interval,

CMN - Cochran-Mantel-Hansel test,

CMRS - committee on patented medical products, CT - computed tomography, D - day,

DBP - diastolic blood pressure dl - deciliter,

DNA - deoxyribonucleic acid,

DMC - Data Monitoring Committee,

DRF - Discrepancy Resolution Protocol e.g.=for example,

EASD - European Association for the Study of Diabetes,

ECG - electrocardiogram, e-CRF - electronic individual registration card, EQ-5D - European questionnaire for assessing the quality of life in five areas, EDTA - ethylenediaminetetraacetic acid, ELISA - enzyme-linked immunosorbent assay, FPG - fasting plasma glucose, FSH - follicle-stimulating hormone , FU - follow-up, GCP - good clinical practice, G-GT - gamma-glutamyl transpeptidase, GI - gastrointestinal,

GLP-1 - glucagon-like peptide-1,

GSO - General Security Specialist,

HbA1c - glycated hemoglobin Ale,

HBsAg - hepatitis B surface antigen,

HCAb - antibody to hepatitis C virus,

HDL - high density lipoprotein,

HLGT - high-level generic term, HLT - high-level term,

HRQoL - health-related quality of life, ICH - international conference on harmonization, i.e. - that is,

IEC is an independent ethics committee,

IMP is an investigational medical product,

IND - investigational new drug, INR - international normalization ratio, IRB - Institutional Review Board, ITT - depending on the prescribed treatment, IVRS / IWRS - interactive system providing access by voice response and via the Internet,

IWQOL-lite - the effect of weight on the quality of life, kg - kilogram,

LDL - low density lipoprotein,

LOCF - carry forward last observation, LLOQ - lower limit of quantitation, LLT - low level term, MTS - medullary thyroid cancer,

MedDRA - Medicines Regulatory Dictionary,

Met - metformin,

MMRM - repeated measures mixed effects model,

MRI - magnetic resonance imaging, mcg - microgram, mITT - modified population depending on the prescribed treatment, ml - milliliter, mm Hg. Art. - millimeters of mercury,

- 17 039114 mmol - millimoles, ms - milliseconds, N - number, NGSP - national glycohemoglobin standardization program, OAD - oral antidiabetic agent, OS - observed cases,

PCSA - potentially clinically significant abnormalities, pg - picogram, PK - pharmacokinetics, pmol - picomole,

PPG - Postprandial Plasma Glucose, PRO - Patient Reported Outcome, PSAC - Pancreatic Safety Review Committee, PT - Preferred Term, PTC - Quality Complaint, QD - Once Daily, QoL - quality of life, RBC - erythrocyte count, s - second, s.c. - subcutaneous, SAE - serious adverse event, SAS - statistical analysis system, SBP - systolic blood pressure, SD - standard deviation,

SMPG - self-measured plasma glucose, SOC - system organ class, SU - sulfonylurea, T2DM - type 2 diabetes mellitus, TEAE - treatment-related adverse event, TRIM-D - treatment-related measure of effect on diabetes, TSH - thyroid stimulating hormone, ULN - upper limit of normal range, V - visit, VAS - visual analogue scale, WBC - white blood cell count, WHO - World Health Organization, WHO-DD - World Health Organization Dictionary of Medicines. 3. Introduction and explanation.

In this example, the efficacy and safety of the combination of the basal insulin glargine (Lantus®) and the GLP-1 receptor agonist lixisenatide will be evaluated in patients with T2DM that is not adequately controlled by basal insulin.

Lixisenatide (AVE0010) is a polypeptide with potent GLP-1 receptor agonist activity that was approved in 2013 in the European Union, Japan, Mexico and Australia (under the trade name Lyxumia®) and is under consideration in several other countries. The currently approved indication in the EU for Lyxumia is the treatment of adult patients with type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when the latter, together with diet and exercise, do not provide adequate glycemic control. control.

Insulin glargine (HOE901 or Lantus®), a human insulin analogue, provides a 24-hour supply of basal insulin after a single dose subcutaneous injection. Lantus® has been on the market since June 2000 in Europe and since May 2001 in the US and other parts of the world. Lantus® is indicated for the treatment of adult and pediatric patients with T1DM or adult patients with T2DM who require basal (long acting) insulin to control hyperglycemia.

Because both lixisenatide and insulin glargine are effective once daily and have similar physicochemical properties such as good low pH solubility, both components can be mixed as a fixed ratio formulation for single injection delivery.

Type 2 diabetes mellitus (T2DM) is characterized by a gradual deterioration in glucose control. Even when taking multiple oral antidiabetic drugs (OAD), a significant proportion of patients eventually need the addition of insulin therapy to achieve and maintain target levels of glycated hemoglobin (HbA _1c ). Switching from OAD to insulin

- 18 039114 but is done by adding basal insulin to existing OADs and is usually an effective step in controlling fasting plasma glucose (FPG) levels when the beta cell still has sufficient function to ensure endogenous insulin synthesis or secretion at meals . Approximately 60% of T2DM patients treated with basal insulin do not reach the HbA1c target of <7%. Subsequent increases in basal insulin or the addition of other agents that also target FPG are often associated with weight gain and hypoglycemia. These and other factors lead to poor resistance and adherence in a significant proportion of patients.

The combination of basal insulin with a GLP-1 receptor agonist (GLP-1RA) may provide a significant advantage over current treatment intensification for patients unable to achieve good glycemic control with basal insulin. In addition, to improve glycemic control in patients who are already on basal insulin treatment, the association of the two may maximize other benefits while minimizing some of the limitations of each. Since the studies conducted to date are heterogeneous in study design, overall the combination portends an increase in the number of patients at the target level with minimal weight gain or even weight loss, while maintaining a manageable hypoglycemia profile. Therefore, the combination of basal insulin with a GLP-1 receptor agonist may provide an improved risk/benefit ratio over either used alone.

Since basal insulin based products target primarily, though not exclusively, fasting hyperglycemia and are often given once daily, a combination with a GLP-1RA such as lixisenatide, which when given once a day, is most desirable. 24 hours is still effective on postprandial glycemia by slowing down gastric emptying, even when the ability to restore glucose-sensitive insulin secretion is exhausted or limited.

Despite basal insulin, there is still an unmet need in patients with uncontrolled type 2 diabetes. A very significant proportion of patients were able to achieve target FPG levels but not target HbA1c levels. A therapeutic strategy targeting the HbA1c components, both FPG and PPG, could help address this unmet medical need. This example is intended to demonstrate this for the combination of insulin glargine and lixisenatide.

A lixisenatide-based product has been separately developed and approved in the EU at a constant dose of 20 µg QD. Dosing of lixisenatide in combination will vary and will range from 5 to 20 µg QD.

In this combination, insulin glargine and lixisenatide will be mixed in two fixed ratio solutions delivered using pre-filled disposable pen-type injectors. The dose of the combination will be titrated according to the patient's insulin requirement from 10 units of insulin glargine/5 µg lixisenatide to 60 units of insulin glargine/20 µg lixisenatide. 2 constant ratios of components are offered to obtain a good pharmacological effect within the established tolerance limits. The lower end of the dosing range for lixisenatide is determined by the lowest effective dose, the upper end is determined by the available safety database. Data from studies in T2DM patients and healthy subjects demonstrated that doses of 5-10 μg of lixisenatide could provide concentrations sufficient to stimulate glucose-sensitive insulin release and demonstrated efficacy on HbA1c levels, while doses of 10 μg also showed a strong effect on inhibition of gastric emptying.

Based on the above discussion, in this example, the following two pens with 2 different dosage combinations will be used: Pen A will deliver a dose of 10 U insulin glargine/5 µg lixisenatide to 40 U insulin glargine/20 µg lixisenatide [ratio 2 ( units) to 1 (µg)], while Pen B will deliver a dose of 30 U insulin glargine/10 µg lixisenatide to 60 U insulin glargine/20 µg lixisenatide [a ratio of 3 (units) to 1 (µg)] .

The dose of the combination will be titrated based on the patient's need for insulin glargine. The dose indicator in the pen only indicates the dose of insulin glargine. The dose (mcg) of lixisenatide is not listed on the dose index, although lixisenatide is premixed in a cartridge. The dose of lixisenatide is increased or decreased with any change in the dose of insulin glargine and also depends on the constant insulin glargine/lixisenatide ratio in the combination product. Pen A is intended for patients requiring doses of insulin glargine from 10 to 40 units, pen B is intended for use in patients requiring doses of insulin glargine from 40 to 60 units. It can also be used to administer insulin glargine doses of 30 to 40 units either at the start of treatment or during the treatment phase to provide a temporary (<5

- 19 039114 days) dose reduction, for example, in case of hypoglycemia, without the need to return to pen A.

The primary goal of this example is to demonstrate, over 30 weeks, the benefit of insulin glargine/lixisenatide combination over insulin glargine (± metformin for both treatments) in reducing HbA1c in patients who are not well controlled by basal insulin. ±types of oral antidiabetic treatment.

Secondary objectives are to evaluate the effects of the insulin glargine/lixisenatide combination versus insulin glargine on the percentage of patients reaching target HbA1c levels, glycemic control during a standardized meal trial, body weight, the combined endpoints of the percentage of patients reaching target HbA1c levels (< 7%) without weight gain and/or documented symptomatic hypoglycemia, 7-point self-monitored plasma glucose profile (SMPG), insulin glargine dose, and fasting plasma glucose. Other endpoints include health-related quality of life.

These endpoints, focusing not only on glucose and HbA1c lowering effects but also on other parameters such as weight and hypoglycemia, are considered appropriate to demonstrate the expected benefits of a constant ratio combination of insulin glargine/lixisenatide.

Screened patients who meet all inclusion criteria will begin a 6-week run-in phase to administer and/or adjust doses of insulin glargine (tailored according to investigator judgment based on results of fasting SMPG levels). Anti-diabetic treatment other than metformin will be discontinued upon entry into the run-in phase. Treatment with metformin, if previously taken place, will be continued.

At the end of this run-in phase, patients with HbA1c levels >7% and <10%, mean fasting SMPG levels calculated from self-measurements during the 7 days prior to the randomization visit of <140 mg/dL (7.8 mmol/L) , and a daily dose of insulin glargine >20 U or <50 U, will be administered in a 30-week open-label randomized treatment period to compare the fixed ratio combination with insulin glargine. The duration of this treatment period is considered sufficient to provide an appropriate assessment of the effect on HbA1c levels, plasma glucose levels, body weight and other secondary endpoints.

Patients with a daily dose of insulin glargine <30 U at randomization will start treatment with the combination using pen A at a dose of 20 U insulin glargine/10 mcg lixisenatide, patients receiving 30 U or more will start treatment with the combination using pen A. Pens B based on a dose of 30 units of insulin glargine/10 mcg of lixisenatide. After the transition phase during the first 4 weeks of treatment (see section 7.2.4), doses will be titrated once a week to achieve target glycemic levels [self-monitored fasting plasma glucose (SMPG) in the range of 80 to 100 mg/dL (from 4.4 to 5.6 mmol / l)] without hypoglycemia. To avoid exceeding the daily dose of 20 mcg lixisenatide, the maximum daily dose of insulin glargine that can be administered in the fixed ratio combination treatment group is 60 units. Therefore, the maximum dose of insulin glargine that can be tolerated in the insulin glargine alone group will also be 60 U/day to better explore the additional effect of the lixisenatide component in combination with a constant insulin glargine/lixisenatide ratio on glucose control.

Both treatments should be administered once daily by deep subcutaneous injection. The fixed ratio insulin glargine/lixisenatide combination should be administered by injection within one hour before breakfast. Insulin glargine can be given by injection at any time of the day (but at about the same time each day). The timing of the injection will be determined at Visit 2. This timing of the injection should remain the same throughout the study period (during the run-in phase for all patients and also throughout the randomized treatment period for patients randomized to insulin glargine). Patients randomized to the fixed ratio combination group and those previously treated with insulin glargine at other times of the day than in the morning will need to switch to administration within one hour before breakfast. The procedure for changing to another insertion time is suggested in section 7.2.4.

Reports of potential safety concerns regarding acute pancreatitis have been identified in post-marketing experience with other GLP-1 receptor agonists (subject to confirmation by GSO Elisabete). Therefore, patients enrolled in this study should be monitored for any suspicion of pancreatitis, such as those with symptoms and/or signs of acute abdominal distress or abnormal pancreatic enzyme levels. Serum amylase and lipase concentrations are monitored in the usual manner at screening, at baseline, and periodically throughout the study treatment period. Since this monitoring can be difficult for

- 20 039114 patients who already have high amylase or lipase levels, patients with values 3 times the upper limit of the normal range at the time of screening will not be included in this study. Recommendations for investigators regarding follow-up in case of suspected pancreatitis are noted in the protocol. In addition, selected events related to the pancreas, including pancreatitis, pancreatic neoplasms, and abnormal amylase or lipase levels, will be reviewed by a panel of invited experts working with anonymized data (Pancreatic Safety Assessment Committee).

Information derived from preclinical studies on the carcinogenicity of Victoza® has raised the question of a potential increased risk of C-cell hyperplasia and thyroid neoplasms. Following the requirement of the public health authorities for any clinical trial lasting more than 3 months using a GLP-1 receptor agonist, serum calcitonin levels will be monitored in this example as a marker of C-cell hyperplasia and thyroid neoplasms, with specific monitoring being performed for patients with a value >20 pg/ml (5.9 pmol/l). Because this monitoring may be difficult in patients who already have high values, patients with calcitonin levels equal to or greater than 20 pg/mL (5.9 pmol/L) at the time of screening will not be included in this study.

Conclusion on the assessment of the benefit / risk ratio in this study:

The fixed ratio insulin glargine/lixisenatide combination is a combination of two products with demonstrated glucose lowering properties approved in Europe for the treatment of adult patients with T2DM to improve glycemic control.

Type and frequency of adverse events observed in previous clinical trials of lixisenatide covering daily doses up to 60 mcg and in the phase 2 study of Example 1 using a fixed ratio combination of insulin glargine/lixisenatide with daily doses up to 60 units of insulin glargine/ 30 mcg of lixisenatide showed no results or problems preventing the continuation of the clinical trial. Given the safety profile observed in the completed studies, combination treatment with insulin glargine and lixisenatide in fixed ratio solution can be considered well tolerated and no specific risk has been identified in the population to be included in this example. Therefore, the risk profile for patients participating in this study using daily doses up to 60 units of insulin glargine/20 mcg lixisenatide is considered limited.

All patients enrolled in this study will receive fixed-ratio insulin glargine/lixisenatide or insulin glargine combination treatment, which should improve their glycemic control. In addition, all patients will benefit from good management of their T2DM treatment.

Emergency therapy is planned and described in the clinical study protocol for patients whose glycemia is poorly controlled.

Given the expected improvement in metabolic control and additional measures to improve the control of diabetes management, these benefits are believed to outweigh the limited risk associated with the fixed ratio insulin glargine/lixisenatide combination drug. Therefore, the benefit/risk ratio for the patients participating in this example is considered to be favorable.

4. Research objectives.

4.1. Primary.

The primary goal of this study is to demonstrate, over 30 weeks, the superiority of a fixed ratio combination of insulin glargine/lixisenatide over insulin glargine with or without metformin in reducing HbA1c in patients with type 2 diabetes mellitus.

4.2. Secondary.

The secondary objectives of this study are as follows.

To evaluate, over 30 weeks, the effects of a fixed ratio combination of insulin glargine/lixisenatide versus insulin glargine on the percentage of patients achieving target HbA1c levels;

glycemic control in connection with food intake, assessed by the deviation of the level of glucose in blood plasma and the level of glucose in blood plasma 2 hours after a meal (PPG) during a standardized test meal;

body weight;

7-point self-monitoring plasma glucose profile (SMPG);

- 21 039114 percentage of patients reaching target HbAlc levels without weight gain and/or documented symptomatic hypoglycemia;

dose of insulin glargine;

fasting plasma glucose (FPG).

To assess safety and tolerability in each treatment group.

To assess the production of antibodies to insulin and antibodies to lixisenatide (the latter in the fixed ratio combination treatment group).

To assess total and active plasma concentrations of lixisenatide before and after injection (constant ratio combination treatment group).

To evaluate the effects of treatment in each treatment group on patient-reported treatment outcomes (PRO) as measured by the following questionnaires:

treatment-related measure of influence - diabetes (TRIM-D),

EuroQol-5D (EQ-5D), impact of weight on quality of life - simplified (IWQoL-Lite).

To assess the overall response of patients to treatment in each treatment group using a global patient and clinician rating scale for treatment efficacy.

5. Research plan.

5.1. Description of the protocol.

This study is an open-label, randomised, 1:1, active-drug-controlled, two-treatment, 30-week, parallel-group, international, and multicentre Phase III study.

This study will recruit outpatients with T2DM. At the time of the initial visit, the patient will be randomized to one of the following two treatment groups:

insulin glargine/lixisenatide fixed ratio combination group, insulin glargine group.

Patients will be stratified by HbA1c at visit 5 (week -1) (<8%, >8%) and metformin use at screening (Y, N).

The study will consist of 3 periods.

screening period of up to 8 weeks, which includes the following:

screening phase of up to 2 weeks: the introductory visit can be done less than 2 weeks after the screening visit if laboratory data are available;

6-week run-in phase: switching (if needed) and/or dose optimization of insulin glargine, continuing metformin (if needed), and stopping sulfonylurea, glinide, SGLT-2 inhibitor, or DPP-4 inhibitor if previously taken at V2 ;

30-week open-label randomized treatment period.

At the end of the screening period, patients with an HbA1c level of >7% and <10% who have a self-monitored mean plasma glucose (SMPG) calculated from self-measurements during the 7 days prior to the randomization visit is <140 mg /dL (7.8 mmol/L) and whose daily dose of insulin glargine is >20 U or <50 U will be administered in a 30-week open-label randomized treatment period to compare the combination with a fixed ratio of lixisenatide/insulin glargine with insulin glargine (±metformin for both treatments).

A 3-day post-treatment safety follow-up period for all patients after definitively discontinuing IMPs (except for patients who discontinued study treatment prematurely; these patients must remain under study observation until the scheduled end date of the study).

5.2. Duration of participation in the study.

5.2.1. Duration of participation in the study for each patient.

The maximum duration of the study for a patient will be approximately 39 weeks: a screening period of up to 8 weeks (with a screening phase of up to 2 weeks and a 6-week run-in phase), a 30-week randomized treatment period, and a 3-day follow-up period to assess safety after treatment.

5.2.2. Determining the end of a clinical trial (for all patients).

The end of the study is defined as the last visit of the last patient scheduled in the protocol, including the follow-up visit.

5.3. Intermediate analysis.

Please refer to section 10.5.

5.4. Research Committees.

5.4.1. Data Monitoring Committee.

A Data Monitoring Committee (DMC), with representatives independent of the sponsor and investigators, will be used to make appropriate clinical recommendations.

- 22 039114 study to ensure the protection and safety of patients included in the study. The DMC reviews and analyzes on a regular basis unblinded safety data provided by an independent statistical panel throughout the study, as well as safety data from other ongoing clinical studies conducted with lixisenatide (excluding the cardiovascular study). Detailed regulations describe the activities of the DMC.

5.4.2. Allergy Assessment Committee.

Because lixisenatide is a peptide that has the potential to cause allergic reactions, the Allergy Assessment Committee (ARAC) has been established. The ARAC is a committee of experts in the field of allergic reactions, independent of the sponsor and investigators, that evaluates allergic or allergic-like reactions that may occur during the study. The purpose of the ARAC activity will be to identify, without delay, all allergic or possible allergic phenomena. The ARAC will blindly review these cases for treatment in the study.

The ARAC will review reported cases, determine the nature of the events, and confirm the allergic nature or make an alternative diagnosis based on the information provided by the investigator. The detailed regulation describes the ARAC procedures.

5.4.3. Expert Committee on Cardiovascular Diseases.

Following the requirements of the regulatory authority to better assess the impact of newly developed treatments for diabetes mellitus on cardiovascular events and to establish significant cardiovascular events, an independent expert committee on cardiovascular disease (CAC) was created. The CAS is a committee of experts in the field of cardiovascular or cerebrovascular disease, independent of the sponsor and investigators, which determines the main cardiovascular events that may occur during the course of the study. The CAS will review cases in a blinded manner to treatment within the study, no later than closing access to the database. The detailed procedure manual describes the CAS procedures.

5.4.4. Pancreatic safety assessment committee.

Reports of potential safety concerns regarding acute pancreatitis have been identified in post-marketing experience with other GLP-1 receptor agonists. In this study, specific monitoring was planned for events related to the pancreas (see section 9.6.4) and a Pancreatic Safety Assessment Committee (PSAC) was established. This is a committee of experts in the field of pancreatitis and pancreatic neoplasms, independent of the sponsor and investigators, that evaluates events related to the pancreas that may occur during the course of the study. The PSAC will consider selected events related to the pancreas, including pancreatitis, pancreatic neoplasms, and abnormal amylase or lipase levels. This review will be conducted in a blinded fashion regarding the treatments within the study. The detailed regulation describes the PSAC procedures.

6. Patient selection.

6.1. Inclusion Criteria.

Patients who meet all of the following inclusion criteria will be screened.

I 01. Patients with type 2 diabetes mellitus diagnosed at least 1 year before the screening visit.

I 02. Patients treated with basal insulin for at least 6 months prior to Screening Visit.

I 03. Patients treated with a stable basal insulin regimen (i.e. type of insulin and time/frequency of injection) for at least 3 months prior to Screening Visit.

I 04. The total daily dose of basal insulin should be stable (±20%) and range from 15 to 40 units/day for at least 2 months prior to the screening visit.

I 05. Patients treated with basal insulin alone or in combination with 1-2 stable dose OADs for at least 3 months prior to screening visit, which may be: Metformin (>1500 mg/day or maximum tolerated dose ), sulfonylurea (SU), glinide, dipeptidyl peptidase-4 (DPP-4) inhibitor, or SGLT-2 inhibitors.

I 06. Patients with an FPG level <180 mg/dl (10.0 mmol/l) at the time of the screening visit.

I 07. Signatories of written informed consent.

6.2. exclusion criteria.

Patients who meet all of the above inclusion criteria listed in Section 6.1 will be screened for the following exclusion criteria, which are ordered and numbered in the following subsections:

6.2.1. Exclusion criteria related to study methodology.

- 23 039114

E 01. At screening visit, under legal age of majority.

E 02. At the time of the screening visit, HbA1c: <7.5% and >10.0%.

E 03. At the time of the screening visit, body mass index (BMI) <20 or >40 kg/m ² .

E 04. No history of early warning signs of hypoglycemia.

E 05. History of metabolic acidosis, including diabetic ketoacidosis, within 1 year prior to screening visit.

E 06 Use of other oral or injectable glucose-lowering agents than those specified in the inclusion criteria in the 3 months prior to screening.

E 07. Previous use of an insulin regimen other than basal insulin (eg, prandial or premixed insulin) more than 3 months ago.

Note: Short-term treatment for intercurrent disease, including gestational diabetes, is at the discretion of the investigator.

E 08. Previous use of an insulin regimen other than basal insulin (eg, prandial or premixed insulin) more than 3 months ago.

Note: Short-term treatment for intercurrent disease, including gestational diabetes, is at the discretion of the investigator.

E 09. Discontinuation of previous treatment with GLP-1 RA due to safety/tolerability issue or lack of efficacy.

E 10. Use of systemic glucocorticoids (excluding topical or inhaled forms) for a total period of 1 week or more within 3 months prior to the screening visit.

E 11. Use of weight loss drugs within 3 months prior to the screening visit.

E 12 Use of any investigational medicinal product within 1 month or 5 half-lives, whichever was longer, prior to the screening visit.

E 13. A patient who has or has previously participated in any clinical trial with lixisenatide or a fixed-ratio insulin glargine/lixisenatide combination has received lixisenatide.

E 14. Within the last 6 months before the screening visit: a history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization.

E 15. Planned coronary, carotid or peripheral revascularization procedures to be performed during the treatment period.

F 16. Known history of drug or alcohol dependence within 6 months prior to the time of the screening visit.

E 17. Uncontrolled or insufficiently controlled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >95 mmHg) at the time of the screening visit.

E 18. Conditions/situations, such as patients with conditions/comorbidities that do not allow patients to assess the primary endpoint of efficacy (eg, hemoglobinopathy or hemolytic anemia, receiving blood or plasma products within the last 3 months prior to the screening visit);

Patients with conditions/comorbidities that preclude their safe participation in this study (e.g., actively growing malignancy, underlying systemic disease, presence of clinically significant diabetic retinopathy, or presence of macular edema likely to require treatment within the study period, etc.) d.);

failure to meet specific protocol requirements (eg, scheduled visits, patients unable to fully understand and complete study documents for a patient, etc.);

non-contact or any condition that could render the patient non-compliant with study procedures (eg, patient unable or unwilling to self-inject or monitor blood glucose levels using a sponsor-supplied home glucometer, etc.);

the patient is a researcher or any junior researcher, research assistant, pharmacist, research coordinator, other employee or their relative directly involved in completing the protocol.

E 19. Results of laboratory tests at the time of the screening visit:

amylase and/or lipase level: >3 times the upper limit of normal (ULN) laboratory range, ALT or AST level: >3 ULN, total bilirubin level >1.5 ULN (except in the case of Gilbert's syndrome),

- 24 039114 calcitonin level >20 pg/ml (5.9 pmol/l), hemoglobin level <10.5 g/dl, or neutrophils <1500/mm ³ , or platelets <100000/mm ³ , surface antigen positive hepatitis B virus and / or antibody to hepatitis C virus, a positive blood serum test for pregnancy.

E 20. Any technical/administrative reason that prevents a patient from being randomized in the study.

E 21. Patient who withdraws consent during the screening period (screening phase and lead-in phase).

E 22. Target number of randomized patients reached.

6.2.2. Exclusion criteria related to therapy with the active comparator and/or background therapy.

E 23. Any contraindication to the use of metformin according to the regional version of the instructions for use (for example, renal failure, defined by the level of creatinine > 1.4 mg / dl in women, > 1.5 mg / dl in men, or creatinine clearance < 60 ml / min, etc.) provided that the patient is taking metformin.

E 24. Contraindication to the use of insulin glargine in accordance with the regional version of the instructions for use. History of hypersensitivity reactions to insulin glargine or to any of the excipients.

6.2.3. Exclusion criteria related to the tested IMP (constant ratio insulin glargine/lixisenatide combination).

E 25. Pregnancy or lactation.

E 26. Women of childbearing potential who are not protected by a highly effective method of contraception (as defined for contraception in the informed consent form and/or in the application of the local protocol) and/or who are unwilling or unable to undergo a pregnancy test.

Women of childbearing potential who are not protected by highly effective contraceptive method(s) (as defined for contraception in the informed consent form and/or modified regional protocol in the case of a specific regional requirement) and/or who are unwilling or unable to undergo a pregnancy test , -whether it will be changed - under confirmation.

E 27. A clinically significant case of gastrointestinal disease associated with prolonged nausea and vomiting, including (but not limited to) gastroparesis, unstable (i.e. worsening) or uncontrolled (i.e. with prolonged nausea and vomiting) gastroesophageal reflux disease requiring medical treatment within 6 months prior to the screening visit.

E 28. Cases of pancreatitis (except when pancreatitis was associated with gallstone disease and cholecystectomy has already been performed), chronic pancreatitis, pancreatitis during previous treatment with incretin therapy, pancreatectomy, history of gastric / gastric surgery in anamnesis.

E 29. Cases of medullary thyroid cancer (MTS) or a genetic condition that predisposes to MTS (for example, multiple endocrine neoplasia syndromes), in a personal or closely related family history.

E 30. A patient with renal insufficiency with creatine clearance <30 ml / min (using the Cockcroft-Gault formula) or end-stage renal disease for patients not treated with metformin.

E 31. Contraindication to the use of lixisenatide (according to the regional version of the instructions for use, if necessary). Allergic reaction to any GLP-1 receptor agonists, including lixisenatide, in the past or history of metacresol.

6.2.4. Additional exclusion criteria at the end of the screening period before randomization.

E 32. Application of sulfonylurea, glinide, SGLT-2 inhibitor and DPP-4 inhibitor after the start of the run-in phase (from visit 2).

E 33. HbA _1c <7% or >10% at visit 5 (week -1).

E 34. The mean fasting SMPG level calculated from self-measurements during the 7 days of the week prior to the randomization visit (V6) is >140 mg/dL (7.8 mmol/L).

E 35. Mean daily dose of insulin glargine <20 U or >50 U calculated during the last three days of the week prior to Visit 6.

E 36. Amylase and/or lipase levels >3 ULN at visit 5 (week -1).

E 37. Patient with any AE that, in the judge's judgment, would preclude enrollment in randomized open-label treatment.

The patient should not enter the run-in phase or be randomized more than once. In cases where the initial screening dropout was due to reasons that are expected to change on rescreening and based on the clinical judgment of the study

- 25 039114, the patient may be rescreened once for this study.

7. Types of treatment within the study.

7.1. Diet and exercise.

Lifestyle and dietary therapy provided prior to the time of screening should be continued during the study in a similar manner. Dietary and lifestyle advice will be provided by a healthcare professional at the time of visit 2 and visit 6, which should be in line with international or local guidelines (regarding the distribution of calories between carbohydrates, proteins and fats, exercise, etc.) for patients with type 2 diabetes.

Compliance with dietary and lifestyle advice will be assessed in case of inadequate glucose control (please refer to section 7.4).

7.2. Investigational medical product(s).

The fixed ratio combination of insulin glargine/lixisenatide and insulin glargine are considered investigational medicinal products (IMPs).

7.2.1. Compositions.

Fixed ratio combination insulin glargine/lixisenatide.

The fixed ratio insulin glargine/lixisenatide combination is provided as a sterile aqueous solution for subcutaneous (s.c.) injection in a SoloStar® pre-filled disposable pen injector (100 U/mL insulin glargine with 50 µg/mL or 33 µg/mL lixisenatide in depending on the syringe pen (syringe pen A or B, respectively).

insulin glargine.

Insulin glargine is provided as a sterile aqueous solution for subcutaneous (s.c.) injection in a pre-filled SoloStar® disposable pen injector (100 U/ml insulin glargine).

7.2.2. Injection devices and training in the use of injection devices.

7.2.2.1. injection devices.

Insulin glargine/lixisenatide fixed ratio combination (pen A or pen B).

The combination product will be self-injected using a pre-filled SoloStar® disposable pen injector.

The dose of the combination is titrated according to the patient's need for insulin glargine. Please note that the dose indicator in the pen only indicates the dose of insulin glargine. The dose (mcg) of lixisenatide is not listed on the dose index, although lixisenatide is premixed in a cartridge.

Two pens (A and B) with different fixed ratios of insulin glargine/lixisenatide are available to provide insulin glargine titration ranging from 10 to 60 U/day, while limiting the dose of lixisenatide to a maximum dose of 20 mcg/day.

Pen A (yellow label, yellow dispenser button): SoloStar® pre-filled disposable pen injector containing 3 ml of a sterile solution with 100 U/ml insulin glargine and 50 µg/ml lixisenatide in a 2:1 ratio (2 units insulin glargine per 1 mcg lixisenatide). Each pen is specifically labeled for study use and each contains a total of 300 units of insulin glargine and 150 micrograms of lixisenatide per 3 ml. The inscriptions printed on the digital drum indicate the degree of filling of the syringe pen and the dose from 10 to 40 IU, which is the specified dose range for the syringe pen A (see image drawing below).

Shn|)11ts-|pchk'a A ; ratio 2:1 t I

Doses can be set from 10 to 40 units in increments of one unit. Pen A allows administration of daily doses of the combination ranging from 10 U/5 µg to 40 U/20 µg.

It is theoretically possible to draw more than 40 U or less than 10 U of insulin glargine (no mechanical top or bottom cap), but the dose is not labeled on the pen outside the predetermined range of 10 to 40 U.

Pen B (red label, red dispenser button): SoloStar® pre-filled disposable pen injector containing 3 ml sterile solution with 100 U/ml insulin glargine and 33 µg/ml lixisenatide in a 3:1 ratio (3 units insulin glargine per 1 mcg lixisenatide). Each pen is specifically labeled for study use and contains a total of 300 units of insulin glargine and 99 µg of lixisenatide per 3 ml. The inscriptions printed on the digital drum show the measure of filling and doses from 30 to 60 IU (see image drawing below).

Doses can be set from 30 to 60 units in increments of one unit. Pen B allows administration of daily doses of the combination ranging from 30 U/10 µg to 60 U/20 µg.

It is theoretically possible to draw more than 60 U or less than 30 U of insulin glargine (no mechanical top or bottom cap), but the dose is not labeled on the pen outside the predetermined range of 30 to 60 U.

Pen B is primarily intended for use by patients requiring a daily dose of 40 to 60 units of insulin glargine. However, it may also be used in patients requiring daily doses of 30 to 40 units of insulin glargine either at the start of treatment (see section 7.2.4) or during the treatment phase to provide a temporary (<5 or 7 days?) dose reduction. e.g. in the case of hypoglycemia, so as not to cause inconvenience when changing to pen A. But if the dose remains below 40 units for more than X days, then the patient should return to using pen A.

Patients who started treatment with pen A and require a daily dose of insulin glargine greater than 40 units will be switched to pen B.

The dose of lixisenatide is increased or decreased simultaneously with changes in the dose of insulin glargine and also depends on which pen (A or B) is being used. For example, when the dose indicator in pen A (2:1 ratio) shows 30 units, this is a dose of 30 units of insulin glargine and 15 mcg of lixisenatide, while for pen B (3:1 ratio) when the dose indicator shows 30 units, this is a dose of 30 units of insulin glargine and 10 mcg of lixisenatide. Detailed dose descriptions for pen A and pen B are shown below:

Pen A Pen B

ten 5 12 6 fourteen 7 16 eight eighteen 9 twenty ^ten 22 eleven 24 12 26 13 28 fourteen thirty fifteen 32 16 34 17 36 eighteen 38 19 40 twenty

thirty ten 32 10.7 34 11.3 36 12 38 12.7 40 13.3 " fourteen 44 14.7 46 15.3 48 16 fifty 16.7 52 17.3 54 eighteen 56 18.7 58 19.3 ___6 0 Z0

Insulin glargine only (Lantus® SoloStar®).

Lantus® SoloSTAR® disposable pre-filled pen injectors are provided to all patients at V2 and patients randomized to insulin glargine at V6 (week 0, day 1) and thereafter. Each pen is specifically labeled for study use and contains 300 units of insulin glargine per 3 ml. Doses can be set from 1 to 80 units in 1 unit increments. However, in this study, the maximum daily dose of insulin glargine is 60 units.

7.2.2.2. Training in the use of injection devices.

An instruction leaflet (including an IMP? leaflet) will be provided that explains how to use disposable pen type injectors. The study staff member will train all patients on how to use the pen correctly, how to store it, and how to change the needle in both of the following devices, which are syringe type injectors

- 27 039114 handle.

At time V2 (week -6): all patients are training using training disposable Lantus®, Solostar®.

At V6 (Day 1): Patients randomized to receive treatment with the combination are trained using training disposable pen A and pen B.

The study staff member at the study center will repeat the training as needed throughout the run-in phase and the treatment period.

The pens and leaflet that the patient will need to use during the introductory phase and the treatment period will be distributed according to the visit. Each patient is provided with an appropriate number of pen-type injectors in accordance with the dispensing schedule indicated in the schedule of study procedures (see section 1.2).

The following commercial pen needles will be provided for use with disposable pen type injection devices

BD Micro-Fine+31 Gx8 mm

Problems with the pen device (malfunctions) must be reported to the sponsor in the Quality Complaint (PMC) form, which is described in a separate manual.

7.2.3. Dosing schedule.

Fixed ratio combination insulin glargine/lixisenatide.

The fixed-ratio insulin glargine/lixisenatide combination should be administered alone once daily in the morning within one hour (0 to 60 minutes) before breakfast using Pen A or Pen B, depending on the daily dose of insulin glargine.

insulin glargine.

Insulin glargine should be self-administered once daily at any time during the day, but at approximately the same time each day, using Lantus® SoloSTAR®, during the run-in phase (all patients) and the open-label randomized treatment period ( only for patients randomized to insulin glargine). The timing of the injection will be at the discretion of the patients and investigators at V2.

Site of injection.

IMP should be administered by deep subcutaneous injection, alternating left and right anterolateral and left and right posterolateral abdominal wall or thighs or upper arms. Within a given area, the location should be changed (alternate) each time to avoid skin reactions at the injection site.

On study site visit days, IMP, to be administered before breakfast, should be self-administered at the study site under the supervision of a staff member of the study site.

7.2.4. Starting dose and dose adjustments.

7.2.4.1. During the introductory phase.

Initial dose of insulin glargine.

From the start of the run-in phase (Visit 2), the only basal insulin approved is insulin glargine. Patients on any basal insulin other than insulin glargine prior to screening will be switched to once-daily insulin glargine at Visit 2.

Recommendations for converting a patient's basal insulin doses from their pre-study regimen to their in-study regimen at V2 are provided below. These are only guidelines and other transition schemes may be used if desired.

Patients should be advised at the Screening Visit (V1) not to administer their morning basal dose on V2, if at all possible.

Patients receiving more than once daily basal insulin injection will be switched to once daily injection at V2.

The total basal insulin dose on the day before V2 will be used to calculate the starting dose according to the rules described in Table 1. one.

Table 1

Initial dose of insulin glargine at entry visit

Patients taking The daily dose (ED) of insulin glargine will be equal to insulin glargine total daily dose on the day preceding visit day 2 basal insulin other than insulin glargine once daily total daily dose on the day preceding visit day 2 basal insulin other than insulin glargine more than once a day 80% of the total daily dose (= total daily dose reduced by 20%) on the day before visit day 2

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Insulin glargine can be injected at any time during the day, but at the same time each day. The timing of once daily injection is at the discretion of the patient and investigator and will be determined at Visit 2 and should remain approximately the same throughout the study (during the run-in phase for all patients and throughout the randomized treatment period for patients randomized to insulin glargine).

Dose adjustment of insulin glargine.

Doses will be adjusted based on daily measured fasting SMPG to improve fasting glycemic control and ensure patients meet randomization criteria (HbA1c at visit 5 >7% and <10%; mean fasting SMPG <140 mg/dL [7, 8 mmol/l] measured within 7 days prior to visit 6). The titration procedure to meet these criteria while avoiding hypoglycemia is at the discretion of the investigator. Small dose reductions are allowed if hypoglycemia occurs and at the discretion of the investigator.

7.2.4.2. During the open-label randomized treatment period.

7.2.4.2.1. Fixed ratio combination group insulin glargine/lixisenatide.

Patients who received insulin glargine (Lantus) in the morning during the run-in phase: Patients taking a daily dose of insulin glargine < 30 units the day before Visit 6 (D-1) will begin treatment with the pen A combination at dose 20 U insulin glargine/10 µg lixisenatide, >30 U will start treatment with pen B combination at 30 U insulin glargine/10 µg lixisenatide.

The first injection will be given at the study site on the morning of randomization.

Patients who received insulin glargine at times of the day other than the morning during the run-in phase.

These patients will need to switch to administration within one hour before breakfast. The following is the procedure for switching to a different insertion time, but other transition schemes can be used if desired:

morning of visit at initial time point after randomization (D1): injection during the patient's stay at the study site of a dose of insulin glargine equal to 1/2-2/3 (to be determined by the investigator) of the dose administered the day before randomization (D-1);

the next morning (D2), patients on the day prior to Visit 6 (D-1) taking a daily dose of insulin glargine < 30 U will start treatment with the pen A combination at 20 U insulin glargine/10 mcg lixisenatide, > 30 U will start treatment with the pen B combination at a dose of 30 U insulin glargine/10 mcg lixisenatide.

For all patients, this first dose (either 20 U/10 mcg or 30 U/10 mcg) will remain constant for 2 weeks. For the next two weeks, any necessary dose increase will be limited to a maximum increase of +2 U, no more than once a week.

After the first 4 weeks, doses will be titrated once a week according to the algorithm described in Table 1. 2 until the patient reaches the target fasting SMPG level (80 to 100 mg/dL [4.4 to 5.6 mmol/L]) without hypoglycemia. Thereafter, the dose will be adjusted as necessary until the end of the study to maintain these target fasting SMPG levels.

Patients who started treatment with a fixed ratio combination using pen A and then required a daily dose of >40 U will be instructed to switch from pen A to pen B: for example, a patient receiving 40 U with using pen A and having a median self-monitoring plasma glucose (SMPG) based on the previous 3 days >140 mg/dL (>7.8 mmol/L) will require a dose adjustment of +4 U/ day (according to table. 1) to a daily dose of 44 IU. Since the maximum dose provided for delivery with pen A is 40 IU, the patient will use pen B to self-inject the adjusted daily dose of 44 IU.

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table 2

Dose Adjustment Algorithm

Median fasting SMPG values in the previous 3 days Dose adjustments for insulin glargine (U/stump)* >140 mg/dL (>7.8 mmol/L) four >100 and < 140 mg/dl (>5.6 and < 7.8 mmol/l) 2 Target glycemic level: 80 and 100 mg/dL (4.4 and 5.6 mmol/L) inclusive Without changes >60 and < NR mg/dl (>3.3 and < 4.4 mmol/L) -2 <60 mg/dL (<3.3 mmol/L) or 2 (or more) episodes of symptomatic hypoglycemia or one episode of severe hypoglycemia (requiring assistance) documented in the previous week. - 2 to -4 or at the discretion of the investigator or qualified specialist

* - dose adjustment should not be carried out more than once a week.

7.2.4.2.2. Insulin glargine group.

The injection time should remain the same as determined at the time of visit 2 for the run-in phase.

Patients randomized to the insulin glargine arm will receive the same daily dose of insulin glargine on the day of randomization as on the day before randomization and then titrate the insulin dose as needed throughout the open-label randomized treatment period.

The dose will be titrated once a week, following the same algorithm as for the fixed ratio combination group (Table 2), until the patient reaches the target fasting SMPG level (80 to 100 mg/dL [4.4 to 5 .6 mmol/l]) without hypoglycemia. Thereafter, the dose will be adjusted as necessary until the end of the study to maintain these target fasting SMPG levels.

7.2.4.2.3. In both groups.

Dose changes are based on the median fasting SMPG values over the last 3 days measured by the patient using blood glucose meters and equipment provided by the sponsor for this purpose.

The total daily dose of insulin glargine will be limited to 60 units. If a dose >60 U of insulin glargine is required to maintain HbA1c levels below a predetermined threshold, the dose should be maintained at 60 U and rescue therapy should be initiated (see section 7.4). All assessments scheduled for the end-of-treatment visit should be completed prior to initiation of emergency therapy.

An in-depth clinical judgment should be made when titrating doses in patients. Investigators may adjust or stop dose titration, or temporarily reduce the dose, if they believe that further dose titration would be unsafe at this time.

Patients will be educated about the dose titration regimen so that they can monitor it with the help of a researcher or qualified medical representative. Patients will be allowed to increase the dose on their own as needed (i.e., median fasting SMPG values obtained in the previous 3 days >100 mg/dL), but no more than +2 U and no more than once a week. All other dose increases must be agreed by the patient and appropriate study site personnel. All discussions must be properly documented in the patient's medical record. Additional contacts will be made available to patients as needed to discuss dose adjustments between scheduled visits. At the discretion of the Investigator, it is acceptable for experienced patients to adjust insulin IMP doses between scheduled visits without prior consultation with study site staff.

Doses may be reduced or modified at any time in the event of hypoglycemia and in accordance with the medical judgment of the investigator. Patients who experience moderate to severe hypoglycemia as a result of a missed meal, unusual exercise, or alcohol consumption will receive guidance on how to correct their behavior and optionally have their insulin dose reduced (decision to be based on clinical assessment of the investigator).

7.3. Unexplored medical products.

Metformin (when needed) is considered a non-investigational medical product (NIMP). It (commercially available metformin tablet) will be administered orally according to its regionally approved label.

If patients are taking metformin as background treatment, then it should be given at

- 30 039114 stable dose of at least 1500 mg/day or maximum tolerated dose for at least 3 months prior to screening. This regimen should be continued and the dose should remain constant throughout the study unless there is a specific safety issue associated with this treatment. Sulfonylureas, glinides, SGLT-2i and DPP4i, if present, will be discontinued at the start of the run-in phase (Visit 2) and should not be used during the run-in phase and treatment period.

Emergency care (section 7.4) will be considered as NIMP if necessary.

The dose of metformin treatment or emergency treatment will be reported in the e-CRF.

Metformin background treatment (if applicable) or emergency treatment that is not covered by health insurance will be reimbursed if permitted by local regulations.

7.4. Emergency therapy.

Regular fasting SMPG levels and FPG levels (and HbA1c levels after week 12) from a central laboratory are required to ensure that glycemic parameters remain below predetermined thresholds (see below). If all fasting SMPG values exceed the specified limit for three consecutive days, the patient should contact the investigator and a central laboratory FPG measurement (and HbA1c level after week 12) will be performed.

Thresholds are as follows, depending on the study period:

visit 13 (week 8) to visit 15 (week 12) (excluding V15): FPG level >240 mg/dL (13.3 mmol/L);

visit 15 (week 12) to visit 21 (week 30) (including V21): FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8%.

In the case of FPG or HbA1c levels above cut-offs, the investigator should ensure that there is no reasonable explanation for poor glucose control and, in particular, that:

plasma glucose levels were measured while the patient was fasting (i.e., after at least 8 hours of fasting);

doses of the treatment are properly titrated according to the protocol (up to a maximum daily dose of 60 IU for both groups);

there is no intercurrent illness that could impair glycemic control (eg, infection);

adherence to treatment is appropriate;

adherence to diet and lifestyle is appropriate.

If any of the above can reasonably explain poor glycemic control, the investigator should take appropriate action, i.e.:

assess the level of glucose in the blood plasma in a fasting state (i.e. after at least 8 hours of abstinence from food);

titrate doses of insulin glargine or fixed-ratio insulin glargine/lixisenatide combinations according to protocol (up to a maximum of 60 units for both groups);

initiate evaluation and treatment of any intercurrent disease (which must be reported in the AE/concomitant medication parts of the e-CRF and the patient's medical record);

emphasize the absolute need for adherence to treatment;

schedule a meeting with the patient and a qualified nutritionist to reinforce recommendations regarding the absolute need for dietary and lifestyle compliance;

schedule an assessment of FPG/HbA1c levels at the time of the next visit (if the next visit is a phone call, this should be replaced by a visit to the study center).

If none of the above causes can be found and/or appropriate actions have failed, or if the dose is >60 IU, FPG/HbA1c should be lowered below the cut-off level and rapid insulin may be added as a rescue therapy. short action; this should start with a once daily administration to be administered with a meal other than breakfast in the fixed ratio combination group and any meal for the insulin glargine group.

All assessments (including the 2-hour standardized food trial, but excluding PK and antibody assessments) scheduled for the end-of-treatment visit should be performed prior to initiation of rescue therapy. After such assessments are completed and emergency therapy is initiated, the patient will remain in the study and continue on study treatment (including background therapy). Scheduled visits and assessments (including PK and antibody assessments, but excluding food trials and PRO assessments) should be performed up to the last scheduled visit.

Note.

If the results of the central laboratory tests show FPG and/or HbA1c levels above the cut-off level(s), the investigator will receive an alert from the central laboratory.

The decision to initiate rescue therapy should not be based on a single laboratory value.

- 31 039114 indicators. If an FPG level above the threshold is inadvertently detected at a routine visit, the Investigator should ensure that the criteria for emergency treatment are met (i.e., 3 consecutive fasting SMPG levels above the threshold, confirmed by a score value from the central laboratory) prior to the start of the emergency. therapy.

Short-term (up to a maximum of 10 days) use of rapid/short-acting insulin therapy (eg, in connection with an acute illness or surgery) will not be considered emergency therapy. All such use of rapid/short-acting insulin therapy must be reported on the e-CRF and the patient's medical record.

7.5. blinding procedures.

7.5.1. Research blinding methods.

The design of this study is open.

Compensation for lack of glare.

The Investigator and Sponsor will not have access to either primary efficacy endpoint data (i.e. HbA1c level) or standardized food trial endpoint data obtained after the pre-V21 (week 30) baseline visit, or before the end-of-study visit in case of early discontinuation of treatment. However, the research team may review the data for the primary efficacy parameter in the masked-name IMP descriptive statistics during the data review meetings.

ARAC, CAS and PSAC representatives will review and decide events on a blind basis (please also refer to section 5.4).

The Data Monitoring Committee receives unblinded, closed reports from an independent statistician for review, which must be treated in strict confidence. None of these reports can be delivered to third parties (please also refer to section 5.4.1).

7.6. How patients are assigned to a treatment group.

Patients were randomized to receive, during a 30-week open-label treatment period, once daily, either a fixed ratio combination of insulin glargine/lixisenatide, or insulin glargine alone. The randomization ratio is 1:1. The randomization group was stratified by HbA1c (<8, >8%) at week -1 and metformin use at screening (Y, N).

Randomization and treatment assignment were performed centrally using an interactive system providing access by voice response and via the Internet (IVRS/IWRS). The randomized treatment kit number list is centrally generated by Sanofi and the study biostatistician provides a randomization chart (including stratifications) for IVRS/IWRS. The IVRS/IWRS then creates a patient randomization list, according to which patients are assigned to treatment groups.

IMP (fixed ratio insulin glargine/lixisenatide combination or insulin glargine alone) are provided in open boxes and are identified by treatment kit numbers.

At the time of the screening visit, the investigator or medically qualified representative should contact the IVRS/IWRS center to obtain a patient number. The patient identification number (patient number) consists of a 9-digit number containing the 3-digit country code, the 3-digit center code, and the 3-digit patient history number (which is 001 for the first patient screened at the center, 002 for the second patient screened at the same centre, etc.).

At V6 (week 0), after V5 (week -1), summarize the results of the assessments and complete the assessments at the initial time point, contact the IVRS/IWRS for randomization and distribution of treatment sets. For each randomized patient, IVRS/IWRS will allocate a treatment kit number and a number of kits to be dispensed corresponding to the same treatment group as determined by randomization. After V6 (week 0), the IVRS/IWRS are contacted again each time a new treatment kit(s) needs to be allocated. IVRS/IWRS will distribute treatment kits using their treatment kit numbers.

A randomized patient is defined as a patient who is enrolled and assigned to a randomized IVRS/IWRS treatment arm as described in the IVRS/IWRS logbook.

A patient cannot be randomized more than once per study. In addition, the patient cannot be entered into the introductory phase more than once.

7.7. Packaging and instructions for use.

The packaging corresponds to the mode of administration. The content of the instructions for use is in accordance with local regulatory specifications and requirements.

An appropriate number of kits will be distributed to cover the need for them until the next distribution visit. Storage conditions and expiration date are part of the label text.

- 32 039114

The labels on the treatment box will indicate the treatment number (used to prescribe the treatment and reported in the e-CRF). The patient number, visit number, and date of issue will be manually entered by a study site staff member on the label of the treatment box prior to issue.

Fixed ratio combination insulin glargine/lixisenatide.

Pens A containing 3 ml of a solution with insulin glargine 100 U/ml and lixisenatide 50 µg/ml were supplied as open treatment kits containing 3 pre-filled pens.

Pens B containing 3 ml of a solution with insulin glargine 100 U/ml and lixisenatide 33 µg/ml were supplied as open treatment kits containing 3 pre-filled pens.

Insulin glargine (Lantus® SoloSTAR®).

Insulin glargine pens (Lantus® SoloSTAR®) containing 3 ml insulin glargine solution at 100 U/mL were supplied as open treatment kits containing 3 Lantus® SoloSTAR® pens.

7.8. Storage conditions and shelf life.

Researchers or other authorized persons (eg, pharmacists) are responsible for storing IMP in a secure and secure location in accordance with local regulations, package leaflet specifications, policies, and procedures.

Control of IMP storage conditions, especially temperature control (eg, refrigeration), and information regarding stability in use, and instructions for handling the compound from Sanofi should be in accordance with the sponsor's guidelines.

The expiration date is written on the IMP labels, and the storage conditions are written on the IMP labels and in the instruction leaflet.

Fixed ratio combination insulin glargine/lixisenatide.

Before first use, disposable fixed ratio combination pens should be stored at 2 to 8°C protected from light and must not be frozen.

The used disposable pen-type injector should be stored below +30°C (without refrigeration) protected from light. Each pen should be replaced if it has not been completely used in 14 days.

Insulin glargine (Lantus® SoIoSTAR®).

Prior to first use, Lantus® SoIoSTAR® Disposable Pens should be stored at 2 to 8°C, protected from light, and must not be frozen.

Used Lantus® SoIoSTAR® disposable syringe pens should be stored below +25°C (without refrigeration) protected from light. Each pen should not be used for more than 28 days after first use.

7.9. A responsibility.

The investigator, hospital pharmacist, or other personnel authorized to store and dispense IMPs will be responsible for ensuring that the IMP used in a clinical trial is securely stored as directed by the sponsor and in accordance with applicable regulatory requirements.

All IMPs will be issued as assigned by the investigator, and it is the investigator's responsibility to ensure that an accurate record of issued and returned IMPs is maintained.

Any quality problem noted when receiving or using an IMP (lack of condition, appearance, proper documentation, instructions for use, expiration date, etc.) must be reported to the sponsor immediately. Some deficiencies may be recorded through the complaints procedure.

A potential quality defect in an IMP may be subject to a sponsor's recall procedure. In this case, the investigator will be responsible for promptly resolving any request made by the sponsor in order to withdraw the IMP and eliminate potential hazards.

Under no circumstances will the Investigator supply the IMP to third parties, authorize the IMP to be used in any other way than specified in the protocol for this clinical study, or dispose of the IMP in any other way.

7.9.1. Accounting and compliance.

The Investigator verifies compliance with the study treatments based on the patient's diary and by visual inspection of returned Fixed Ratio Pens or Lantus® SoloSTAR® Pens and completes the appropriate Treatment Registration Form. A visual check of the return must be performed by a staff member of the research facility. In addition, he/she also registers dosing information.

- 33 039114 on the relevant e-CRF pages.

For metformin (if applicable), name, start and end dates of treatment, total daily dose, etc. will be documented in primary documents. Metformin compliance (if required) will be verified by patient interview and examination diary at each visit and will be documented in primary documents and in the e-CRF.

7.9.2. Return and/or liquidation of funds for treatment.

Patients should return used and used IMPs (and related package inserts, if applicable) at each study site visit. Patients also return unused IMPs each time a restock is scheduled (see section 1.2).

Patients must return used, used, and unused IMPs at Visit 21 (or the Final Evaluation Visit upon receipt of treatment in case of definitive early termination).

All partially used or unused treatments will be returned to the sponsor. A detailed medication log for returned IMPs will be created by the investigator (or pharmacist) and signed by the investigator or monitoring team.

For non-sponsor-provided NIMPs, tracking and reconciliation should be achieved by the investigator in accordance with the sponsor-provided system.

7.10. Concomitant medication.

A concomitant medication is any treatment the patient is receiving at the same time as any open-label IMP (medications should also be reported during the screening and follow-up period).

7.10.1. Approved concomitant therapy.

Any therapies or medications other than prohibited concomitant therapy in addition to IMPs should be kept to a minimum throughout the study. However, if deemed necessary for the well-being of the patient and there is little chance of interfering with IMPs, they may be given at the investigator's discretion at a stable dose (if possible).

In the insulin glargine/lixisenatide fixed ratio combination treatment group, for oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take these medicinal products at least 1 hour before or 4 hours after after injection of lixisenatide. Enteric formulations containing substances susceptible to breakdown in the stomach should be administered 1 hour before or 4 hours after injection of lixisenatide.

Specific treatments that were continued prior to study entry and/or administered or changed during the course of the study should be recorded in the e-CRF and primary data (please refer to section 9.2).

7.10.2. Concomitant therapy for diabetes.

Patients are included on therapy with a stable basal insulin regimen alone or in combination with 1-2 OADs at a stable dose for at least 3 months prior to the Screening Visit, which may be: Metformin (>1500 mg/day or maximum tolerated dose), sulfonylurea (SU), glinide, dipeptidyl peptidase-4 (DPP-4) inhibitor, or SGLT-2 inhibitors.

Starting with V2, all patients receive insulin glargine as their basal insulin.

Previous use of OADs (SU, glinide, DPP-4i or SGLT-2i) other than metformin will be discontinued at Visit 2. Previous metformin treatment, if any, will continue throughout the study. Metformin should be continued at a stable dose throughout the study unless there is a specific safety concern associated with this treatment. Changes in metformin treatment doses should be properly reported in the patient's medical record and in the eCRF (see section 7.3).

No other concomitant antidiabetic treatment other than rescue therapy should be used in this study.

7.10.3. Prohibited concomitant therapy.

The following drugs are not allowed during the screening period (including the screening phase and the run-in phase) and randomized open-label treatment period:

any glucose-lowering agents other than IMP, approved background antidiabetic therapy (metformin, if needed), and rescue therapy, if needed;

note: short-term use (<10 days) of rapid/short-acting insulin in connection with an acute illness or surgical intervention (for example, an infectious disease) is acceptable; sulfonylurea, glinide, SGLT-2 inhibitor, or DPP-IV inhibitor, if present, should be discontinued at 42;

systemic glucocorticoids for more than 10 days (topically applied or inhaled forms are allowed);

- 34 039114 drugs for weight loss.

During the 3-day follow-up period, any treatment (other than GLP-1 receptor antagonists) is allowed at the discretion of the investigator.

8. Evaluation of the investigational medical product.

All biological efficacy and safety analyzes will be carried out in a central laboratory. Detailed information regarding the collection, control and analysis of samples will be provided in a separate manual.

8.1. primary endpoint.

8.1.1. Primary efficacy endpoint.

Change in HbA1c from baseline to week 30.

8.2. secondary endpoints.

8.2.1. Secondary endpoint(s) of effectiveness.

Quantitative secondary efficacy endpoints are:

change in PPG and glucose deviation at 2 h on a standardized meal trial from baseline to week 30, change in body weight from baseline to week 30, change in SMPG profiles across 7 time points from baseline to week 30 ( at each time point and averaged daily value), change in daily dose of insulin glargine from baseline to week 30, change in PPG from baseline to week 30, change in PPG and glucose fluctuations at 30 min and 1 h during standardized trial meal from start time to week 30.

Qualitative secondary efficacy endpoints are: percentage of patients achieving HbA1c <6.5% at week 30, percentage of patients achieving HbA1c <7% at week 30, percentage of patients achieving HbA1c <7% without supplementation body weight at week 30, percentage of patients achieving HbA1c<7% at week 30 without documented [PG<70 mg/dL (3.9 mmol/L)] symptomatic hypoglycemia during the 30-week randomized treatment period, percentage of patients achieving HbA1c<7% without weight gain at week 30 and without documented [PG<70 mg/dL (3.9 mmol/L)] symptomatic hypoglycemia during the 30-week randomized treatment period, percentage of patients requiring in emergency care for a 30-week open-label treatment period.

Follow-up period for efficacy endpoints.

The period of treatment in terms of efficacy endpoints (primary and secondary efficacy endpoints) is defined as the time from the first open-label IMP injection to 14 days for HbA1c levels; 0 days for parameters of standardized meal trial, SMPG level at 7 time points, and dose of insulin glargine; 1 day for FPG level and 3 days for body weight after the last IMP injection or until rescue therapy, whichever comes first.

The value at start time for efficacy endpoints is the last available value before the first IMP injection.

8.2.2. Security endpoints.

Safety endpoints are assessed by symptomatic hypoglycemia (documented, probable, severe symptomatic hypoglycemia), adverse events, serious adverse events and AESI, safety laboratory values, vital signs and physical examination, electrocardiogram (ECG), immunogenicity (variables for antibodies): antibodies to lixisenatide and/or antibodies to insulin (constant ratio combination group).

Monitoring period for security endpoints.

The security data monitoring period will be divided into 3 segments.

The pre-treatment period is defined as the time between the informed consent date and the first open-label IMP injection.

The treatment period is defined as the time from the first open-label IMP injection to 3 days (1 day for symptomatic hypoglycemia) after the last IMP injection, regardless of the introduction of rescue therapy. The 3-day interval is chosen based on the half-life of the IMP

- 35 039114 (approximately 5 times the half-life of lixisenatide).

The post-treatment period is defined as the time starting from day 4 after the last open IMP injection (post-treatment period).

The value at start time for security endpoints will be the last available value before the first IMP injection.

8.2.2.1. Symptomatic hypoglycemia.

Symptomatic hypoglycemia (documented, probable, severe symptomatic hypoglycemia) will be assessed. For details, please refer to section 9.6.1.

8.2.2.2. Undesirable phenomena.

AEs will be judged, including SAE and AESI. For details, please refer to section 9.4 and section 9.7.

Collection of information on adverse events: Information on adverse events and serious adverse events will be collected from the time of signing the informed consent and thereafter at each visit until the end of the study.

8.2.2.3. Laboratory variables for safety.

All laboratory data listed in this section will be measured at the central laboratory. Laboratory data will be collected during the visits outlined in section 1.2. Clinical laboratory values will be analyzed after conversion to standard international units. International units will be used in all lists and tables. If necessary, a standard unit will be provided.

The following laboratory safety variables will be analyzed:

hematology: complete blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet analysis;

clinical chemistry: levels of total bilirubin (and in the case of values above the normal range, differentiation into conjugated and unconjugated bilirubin), AST, ALT, ALP, G-GT, creatinine, uric acid, sodium, potassium, calcium, phosphorus;

lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides);

serum amylase and lipase levels;

serum calcitonin level;

assessment of the ratio of albumin / creatinine in the urine (should be carried out on the first morning urine sample).

In addition, the following laboratory data will also be collected at the screening visit, baseline visit, and site visits, depending on the task (see section 1.2) to identify patients with exclusion criteria, fertility, or safety considerations:

hepatitis B surface antigen and hepatitis C antibody (only at the time of screening);

urinalysis (analyzed in the central laboratory): pH, glucose, ketones, leukocytes, blood/hemoglobin content, protein (only at the time of screening);

a blood serum test for the presence of pregnancy in women, the ability to bear children;

the level of FSH and estradiol in the blood serum (only in women who need confirmation of postmenopausal status and only at the time of screening).

If acute pancreatitis is suspected, laboratory safety studies, including amylase and lipase levels, should be performed without delay. Please also refer to section 9.6.4.

For patients who are concomitantly treated with oral anticoagulants, International Normalization Ratio (INR) values (measured in the laboratory familiar to the patient) should be reported to the e-CRF whenever available, in conjunction with the actual anticoagulant dose.

Notes: Any abnormal laboratory value should be immediately rechecked (using a central laboratory if possible) for confirmation before a decision is made to permanently discontinue the IMP for the patient in question. Please also refer to section 9.3 and section 9.4.2.

8.2.2.4. Vital signs.

Clinical safety will be assessed by physical examination, vital signs (systolic and diastolic blood pressure, heart rate).

Blood pressure (mmHg) should be measured when the patient is calm and seated with the arm at mid-sternum level and supported. Measurements should be carried out at standard

- 36 039114 under controlled conditions, at approximately the same time of day, on the same arm, using the same device (after the patient has been comfortably rested for at least five minutes), and the values should be register in e-CRF. Both systolic blood pressure and diastolic blood pressure should be recorded. Blood pressure devices should be recalibrated regularly according to the manufacturer's instructions.

Definition of a hand for measuring blood pressure.

At the time of Screening Period Visit 1, blood pressure should be measured in both arms after 5 minutes in the sitting position and then again after 2 minutes in both arms in the sitting position. At this visit, the arm with the higher diastolic pressure will be determined, which will indicate the standard arm for future measurements throughout the study. The highest values will be recorded in the e-CRF (all blood pressure values should be recorded in the raw data).

Heart rate (bpm) will be measured during blood pressure measurement.

8.2.2.5. Electrocardiogram (ECG) variables.

Normal or abnormal ECG scores will be analyzed.

ECG is measured automatically using a device received from the researcher, in the form of an automatic 12-lead ECG. ECG status, normal or abnormal, will be reported on the e-CRF as determined by the investigator.

Perform a 12-lead ECG after at least 10 minutes of supine position. The electrodes should be placed in the same place for each ECG recording throughout the study.

Each entry is analyzed in comparison with the entry recorded during the screening. The original record is stored as primary data.

Notes: Each abnormal ECG parameter should be immediately rechecked for confirmation before a decision is made to permanently discontinue IMP treatment for the patient in question. Please also refer to section 9.3 and section 9.4.2.

8.2.2.6. Immunogenicity.

Variables for antibodies.

For the fixed ratio insulin glargine/lixisenatide combination group: anti-lixisenatide antibody status (positive, negative) and their concentration.

For both treatment groups: Insulin glargine antibody ratio status (positive, negative) and titer and change from baseline over the course of the clinical study with additional determination of human insulin cross-reactivity in insulin antibody positive patients glargine.

Anti-lixisenatide and/or anti-insulin levels will be measured on day 1 and week 30. Sample collection time.

Blood samples for insulin antibody and lixisenatide antibody determination will be taken prior to IMP injection, on day 1 and week 30, in both treatment arms for insulin antibody and in all patients treated with lixisenatide for anti-lixisenatide antibody. Samples will also be taken in the event of early termination of IMPs, if possible (see Section 9.3).

Note: One sample will also be collected at week 30 (V21) for potential additional immunogenicity measurements.

Anti-lixisenatide and insulin treatment procedures.

Detailed procedures for preparing, storing and shipping samples will be described in a specific laboratory manual.

bioanalytical method.

Anti-insulin and anti-lixisenatide antibodies will be determined in centralized laboratories using validated assays.

8.3. Other endpoint(s).

8.3.1. Pharmacokinetics.

8.3.1.1. pharmacokinetic parameters.

Plasma total and active concentrations of lixisenatide will be assessed over a period of 1 to 4 hours post-injection on day 1 of the treatment phase and before injection, and 1 to 4 hours post-injection at week 30 (for patients in the combination arm). with a constant ratio of insulin glargine/lixisenatide).

8.3.1.2. Time of sampling.

Sampling for determination of the PK of lixisenatide.

For total and active lixisenatide concentrations, respectively, three blood samples should be taken for patients in the fixed insulin glargine/lixisenatide ratio combination group: at the baseline visit and end-of-study visit, as described in the treatment schedule. One sample will be taken immediately prior to the IMP injection at week 30 and one sample will be taken over a period of 1 to 4 hours post-injection.

- 37 039114 units on day 1 and week 30. Samples will also be taken in case of early IMP discontinuation or in case of emergency treatment, if possible.

8.3.1.3. Processing procedure for PK determination.

Detailed procedures for preparing, storing, and shipping specimens are described in a separate laboratory manual.

8.3.1.4. bioanalytical method.

The total concentration of lixisenatide.

To determine total lixisenatide concentrations (anti-lixisenatide bound and not bound), plasma samples will be analyzed using a validated ELISA method with a lower limit of quantitation of 5.5 pg/mL.

Active concentration of lixisenatide.

To determine the active concentrations of lixisenatide, plasma samples will be analyzed using a validated cell assay with a lower limit of quantitation of 40 pg/mL.

Active concentrations will be analyzed for at least 100 patients in the fixed-ratio insulin glargine/lixisenatide combination group, although blood samples will be taken from all patients in this group.

8.3.2. Patient-reported treatment outcomes.

Patient Reported Outcome (PRO) questionnaires include TRIM-D, EQ-5D, and IWQoLLite, which are described later in this section. These three PRO scores will be applied at baseline, week 12, and end of treatment. Patient and clinician global treatment efficacy rating scales will be applied at the end of the study.

TRIM-D, EQ-5D, and IWQoL: Patients will be asked to complete self-administered questionnaires at selected clinical visits (see Study Procedure Schedule) in specific booklets, regardless of the investigator, study site staff, and any assistance from friends or relatives. To ensure validity, patients will be asked to complete all questions on these questionnaires at the start of the visit in a quiet location while still at the study site, in order to return completed questionnaires to the investigator or his/her staff the same day. The schedule for completing the questionnaires is specified in the survey procedures schedule (Section 1.2). Questionnaires are given in Appendix D.

PRO questionnaires will be analyzed using scores obtained over the period from the first open-label IMP injection according to randomization up to 3 days after the last IMP injection or before rescue therapy, whichever comes first.

8.3.2.1. Treatment-related intervention measure for diabetes (TRIM-D).

The overall treatment-related impact on patient health-related quality of life, treatment satisfaction, and treatment patterns will be assessed using the TRIM-D questionnaire.

The TRIM-D Questionnaire (Appendix D) is a 28-item, 5-domain test that assesses treatment difficulties, daily living, diabetes control, compliance, and mental health. This PRO test can be scored independently for each domain or as an overall score.

Response options on a 5-point Likert scale, for all items, range from (1) not at all happy/comfortable, never to extremely/almost always, always or extremely dissatisfied/uncomfortable to (5) extremely satisfied/comfortable depending on the primary points and are rated on a scale from 0 to 100, so a higher score indicates better health (less negative impact).

TRIM-D variables include the response to each item and the change in TRIM-D scores (overall score and individual score for each of the five domains) from start time to endpoint.

A domain score is calculated if the patient responds to at least half of the items in a multi-item domain (or half plus one in the case of odd-number domains).

8.3.2.2. European questionnaire for assessing the quality of life in five areas (EQ 5D).

Patients' health-related quality of life (HRQoL) will be assessed using the EQ-5D questionnaire.

The EQ-5D Questionnaire (Appendix E) is a 6-item self-administered measuring tool consisting of 2 components: a descriptive profile and a single index visual analogue scale (VAS). The descriptive profile assesses health status in 5 areas: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents were asked to indicate whether they had: 1) no problems; 2) some/moderate problems or 3) critical problems in each of the 5 areas. Their responses were then compared with previously obtained utility values for each of the 243 possible combinations.

- 38 039114 tsy. These utility measures are intended to represent society's assessments of the desirability of a given health condition. Utility values were obtained from the general population in the UK and USA.

VAS records according to the patient's personal opinion of their current health status on a vertical rating scale with scores ranging from 0 to 100, with 0 representing the worst health condition imaginable and 100 representing the best health condition imaginable . VAS is considered as a reflection of the patient's overall HRQoL.

The EQ-5D variables include the response to each item, the change in score in 5 directions from start time to end point, the change in the single utility index from start time to end point, and the change in perceived health status on the VAS from start time to end point.

The EQ-5D indicator and the unified utility index will be calculated only if the correct answers are given for all 5 directions of the descriptive profile.

8.3.2.3. Effect of weight on quality of life - simplified (IWQOL-Lite).

Body weight-related quality of life for patients will be assessed using the IWQOL-Lite questionnaire.

The IWQOL-Lite Questionnaire (Appendix F) is a 31-item self-assessment tool that provides a reliable measure of how a patient's weight affects his/her quality of life. The five domains of IWQOL-Lite are physical functioning, self-image, sex life, social distress, and work. The IQWOL-Lite scores (overall score and individual scores for each of the five domains) range from 0 to 100, with 0 being the worst and 100 being the best.

The IQWOL-Lite variable includes the response to each item and the change in IWQOL-Lite scores (overall score and individual score for each of the five domains) from start time to end point.

A score for each domain is calculated only if the patient responds to at least half of the items in the multi-item domain (or half plus one in the case of odd-number domains), and for the total score only if 75% of the items are answered.

8.3.2.4. Global rating scales for the effectiveness of treatment, designed for the patient and the doctor.

The Patient and Physician Global Treatment Efficiency Rating Scales are self-administered measurement tools that will measure whether patients' overall response to treatment is excellent, good, moderate, poor, or worsening. The variables associated with these patient and clinician global treatment effectiveness rating scales provide for the response to each question at the end of treatment.

8.3.3. Pharmacogenetic evaluation.

Taking samples for pharmacogenetic testing is optional for the patient. For those patients who have signed a specific informed consent form, a single 6 ml blood sample will be taken, preferably at the initial time point (V6; day 1), but the sample can also be taken at any follow-up visit.

Data derived from genetic material can be used to determine possible links between genes and responses to treatment with lixisenatide. DNA will be stored for 15 years from the date of completion of the clinical study report.

Procedures for collecting, storing and transporting pharmacogenetic samples are described in a specific document included in the central laboratory manual.

Sponsor has implemented security measures to protect the confidentiality of patient information. The blood sample and extracted DNA will be assigned a second number, a genetic ID (de-identifying code), which is different from the subject's ID. This dual coding is done to distinguish between the patient's medical information and the DNA data. The clinical study data (encoded with the Subject ID) will be stored in a separate database in a different location from the database containing the pharmacogenetic data (encoded with the Genetic ID). The key linking the subject ID and the genetic ID will be held by a third party, under appropriate access control. Comparison of clinical data and pharmacogenetic data for the purposes of data analysis will only be possible using this key, which will be under strict access control. All data will be communicated only in encrypted form in order to maintain the confidentiality of information.

8.4. Methods for evaluating effectiveness.

8.4.1. Measurement of the level of HbA1c.

To assess the acceptability and performance of this study, HbA1c levels are measured using the central laboratory of the National Glycohemoglobin Standardization Program

- 39 039114 (NGSP) Level I certified.

8.4.2. Standardized test meal.

Patients will be subjected to a standardized food challenge to assess fasting and postprandial glucose levels (central laboratory), as well as abnormal plasma glucose levels.

A standardized meal contains approximately 600 kcal and is composed of 50 to 55% carbohydrates, 15 to 20% protein, and 25 to 30% fat.

The composition and amount of the standardized meal should be identical throughout the study.

If a patient is in need of a rescue drug for diabetes, a standardized meal test should be performed prior to the administration of the rescue drug and will not be performed at the time of the final treatment visit.

In the event of definitive discontinuation of treatment with an IMP, a standardized meal test should only be performed if the patient received an IMP on the day of the visit.

On the day of the standardized meal trial, patients will arrive at the study center in the morning, fasted for at least 8 hours, and should not consume any food or drink other than water until the scheduled standardized meal trial. Insulin glargine/lixisenatide fixed ratio combination injection at V21 (week 30) should be given at the study site in the presence of study staff 30 min before the start of the standardized meal. A patient in the insulin glargine group will inject their insulin glargine at their usual injection time.

A standardized meal for all patients should be taken within a 15-minute period.

Blood sampling to measure the level of glucose in the blood plasma is carried out 5 times:

30 minutes before the start of the meal and before the administration of IMP, if the IMP is injected before breakfast, immediately before the start of the standardized meal (0 min), 30 min after the start of the standardized meal, 60 min after the start of the standardized meal, 120 min after the start of a standardized meal.

The exact timing of IMP injection and standardized meals and blood draws should be documented.

8.4.3. Self-monitoring plasma glucose (SMPG) profiles, as well as glucometer use, patient diaries, and exercise.

8.4.3.1. Self-monitoring plasma glucose profiles (SMPG).

SMPG measurements include the following.

Fasting SMPG level.

The fasting SMPG level will be used as needed by the investigator and patients to titrate and adjust the dose of insulin glargine or combination dose, and to monitor glycemic control (section 8.4). Fasting SMPG levels should be measured by the patient before breakfast and before administration of glucose lowering agents (IMP or metformin as needed) once daily from Visit 2 until the end of treatment.

Daily fasting SMPG values should be recorded in the patient's diary. The following daily fasting SMPG values will be entered into the e-CRF:

values from the last 3 days leading to a change in insulin dose, values measured during the 7 days in the week prior to Visit 6 (used to assess eligibility for randomization).

Profile of SMPG levels for 7 points in time.

The 7 time point profile of SMPG levels should be measured at the following 7 time points: pre-meal and 2 hours post-meal at breakfast, lunch, dinner and at bedtime. Two hours after a meal (breakfast, lunch or dinner) is defined as 2 hours after the start of a meal.

Patients are asked to profile SMPG levels at 7 time points over a single 24-hour period on 2 different days of the week up to V6 (week 0), V15 (week 12) and V21 (week 30, end-of-treatment assessment visit). All SMPG values measured on these days will be recorded in a diary and transferred to the e-CRF.

On 7-point profiling days, information regarding mealtimes and bedtimes, injection times, and IMP doses should be recorded in the patient diary and entered into the e-CRF.

SMPG levels during episodes of symptomatic hypoglycemia.

Whenever the patient experiences symptoms of hypoglycemia, the patient (or bystanders as appropriate) should have their plasma glucose measured if possible. Patient

- 40 039114 you should be instructed to measure plasma glucose levels before administering glucose or consuming carbohydrates in all cases where symptomatic hypoglycemia is suspected (section 9.6.1), unless immediate emergency administration of glucose/carbohydrates is necessary for safety reasons until confirmation.

SMPG values should be recorded in the patient diary and entered into the e-CRF.

Additional levels of SMPG.

The investigator may decide to request more frequent self-monitoring of plasma glucose if he/she deems it necessary for the patient. SMPG values should be recorded in the patient's diary.

8.4.3.2. Glucometer, patient diaries and training.

All patients are provided with a glucometer, appropriate medical supplies (lancets, test strips, etc.), package insert and diaries at the V2 visit (week -6) for self-measurement and recording of plasma glucose. Patients will be instructed to bring their blood glucose meters and patient diaries with them at each visit to the study site.

The meters must be calibrated according to the instructions on the package insert, and the study staff at the study site must also check the meters regularly using the provided control solutions to validate the data.

At visit V2 (week -6), patients are trained to accurately measure plasma glucose values with a glucometer and to correctly record values and other requested information in patient diaries. It is the investigator's responsibility to explain to patients the need to measure glucose levels at the requested time points and to correctly record all SMPG values in the patient's diaries. The training is repeated as needed at the time of study visits.

Instructions on how to complete the patient diary on a daily basis will be provided by the study site staff member. At each site visit, a study staff member at the site will review the patient's diary, and the SMPG values stored in the meter's memory will be downloaded, printed, dated, signed, and stored in the patient folder. This information will help the investigator evaluate treatment effects, adjust insulin doses, and assess compliance.

Note: The SMPG values recorded in the diary to be entered into the e-CRF must be checked against the information received from the meter. In case of nonconformity, the reason for the nonconformity shall be documented. If necessary, the resulting action (for example, training the patient to properly document values) should also be documented. Validated values will be entered into the e-CRF by the investigator or qualified representative based on the meter output values.

The patient diary includes, without limitation, the following information:

timing and dose of IMP injections (insulin glargine/lixisenatide combination or insulin glargine), missed IMP injection (including start date and end date), fasting SMPG time and value, meal start time and SMPG measurements, and plasma glucose values on the day of profiling by 7 time points, potential changes in metformin treatment, adverse events, including indicators and symptoms suggestive of hypoglycemia, and local reactions at the injection site, if any.

8.4.4. Body weight.

Body weight should be determined with the patient wearing underwear or very light clothing and no shoes, and with an empty bladder. The same balance should be used throughout the study and calibrated at regular intervals according to the manufacturer's recommendations.

Use of lever scales is recommended; if digital scales are used, test weight testing is of particular importance. The floor surface on which the balance is placed must be hard and must not be covered with carpet or other soft material. The balance must be balanced, both by setting the weights to zero and by aligning the balance sensor. The patient must stand in the center of the platform as off-center position may affect measurements. The weights are moved until the balance beam is balanced (arrows aligned). The weight index is read and recorded in the e-CRF and raw data. Patient-reported weights are not acceptable; patients do not have to read the scale information themselves.

8.4.5. Dose of IMP.

Patients document their IMP dose or any missed IMP injection daily in a patient diary.

The following values will be entered into the e-CRF:

daily doses of IMP applied during the last 3 days per week until week 12, and then the dose

- 41 039114 used during the last 3 days before each visit (including each visit in the form of a phone call);

daily doses of IMP applied on 7-point blood glucose profiling days;

missed IMP injections.

In the event of early termination of participation in a study or emergency treatment, data for the last 3 days of the week before the time of discontinuation of treatment or emergency therapy should be entered into the e-CRF.

8.4.6. Fasting plasma glucose level.

The FPG level is measured in a central laboratory. At V5 and V21, FPG measurement will be part of the standardized meal trial.

8.5. Suitability of measurements.

The combination of basal insulin with a GLP-1 receptor agonist (GLP-1RA) is expected to lower HbA1c levels as an additional effect on both fasting and postprandial glucose levels, without weight gain or even weight loss, and limited increased risk of hypoglycemia with once-daily injection.

The primary efficacy analysis of this study, which compares the fixed-ratio combination of insulin glargine to insulin glargine, will be based on the primary variable: HbA1c change from baseline to week 30.

The HbA1c concentration reflects glycemic changes over the previous 120 days and is thus the average glycemic index, documenting glycemic control over the past 2-3 month period.

HbA1c levels have also been shown to correlate with the development of long-term complications of diabetes, and lowering HbA1c levels is known to reduce the risk of long-term microvascular complications. Therefore, the HbA1c level is considered an appropriate primary endpoint to evaluate the effect of treatment on glycemic control. In addition to analyzing the change in HbA1c levels from baseline, responder analysis will demonstrate the clinical significance of the reduction in observed HbA1c levels. The duration of treatment within the study is considered to be sufficient to achieve steady state with IMP following insulin dose titration and to provide an adequate assessment of time-dependent changes in HbA1c levels and the associated risk of hypoglycemia.

The problem of weight gain in type 2 diabetes is well known. More than 80% of individuals with type 2 diabetes are overweight, many at the time of diagnosis. Therefore, iatrogenic weight gain is not only undesirable, but represents an important clinical problem that can become an obstacle to the successful organization of glycemic control. Body weight control is one of the reasons for choosing a GLP-1 receptor agonist over rapid-acting insulin to enhance basal insulin therapy for this population of diabetic 2 patients who are overweight or obese. Given the large impact of insulin-related body weight gain, it seems appropriate to include body weight change as a secondary efficacy endpoint.

Insulin glargine targets primarily, though not exclusively, fasting hyperglycemia, and lixisenatide is effective in postprandial glycemia, primarily by slowing gastric emptying. Therefore, assessment of both fasting and postprandial (after a standardized meal) glucose levels is appropriate for this study. These 2 blood glucose parameters are also considered by regulatory authorities as a concomitant measure of the effectiveness of an antidiabetic agent.

Safety will be assessed according to standard clinical and laboratory measurements. Specific safety parameters of interest for the injectable glucose lowering peptide will also be evaluated, such as symptomatic hypoglycemia, injection site reactions, and potential allergic reactions. In addition, since lixisenatide is a GLP1 receptor agonist, pancreatic enzyme levels (amylase and lipase) and serum calcitonin concentrations will be monitored and reported throughout the study according to specific procedures (section 9.6)

9. Research procedures.

This section is intended to summarize information not provided in the Study Procedures Schedule or Section 9.

9.1. Visit schedule.

This section does not repeat the visit and procedure/assessment scheduling information listed in the Study Procedures Schedule in Section 1.2. The purpose of this section is to provide detailed information on how to carry out certain procedures/assessments.

This study is performed on outpatients and consists of 11 visits.

- 42 039114 to the research center and 11 phone calls. In addition, optional phone call visits to monitor insulin titration should be scheduled whenever deemed necessary by the investigator.

The patient must be fasted during all visits to the study center. For all these visits, the patient should appear in the morning, at about the same time, as far as possible. The patient must take the metformin treatment and inject the fixed ratio insulin glargine/lixisenatide combination or insulin glargine (if needed) at the study center after a fasting blood sample has been taken. Insulin glargine will be injected at the usual time fixed at V2, even if it falls within an 8-hour fasting period.

Fasting is defined as fasting overnight, but not less than 8 hours, which includes the absence of food or liquid other than water. IMP and other glucose-lowering agents (i.e., metformin, if needed) should be administered after fasting blood sample collection for all laboratory tests at the study site.

Note: If the patient is not fasted at the time of the visits described above, no blood sample is taken and a new patient appointment should be scheduled the following day, if possible, with instructions to arrive fasted.

Visit Interval: For the introductory phase, a visit interval of ±3 days is acceptable using visit date 2 as the baseline. During the open treatment period, a visit interval of ±3 days for the time span from visit 7 to visit 15 and ±5 days for the time span from visit 16 to visit 21 is acceptable using day 1 (visit day 6) as a starting point. A visit interval of -1 day or +3 days for a post-treatment follow-up visit (V22) is acceptable, using visit day 21 as the starting point. If the date of one visit changes, then the next visit must occur according to the original schedule.

9.1.1. Screening period (week -8 to week 0).

Only patients who meet all of the inclusion criteria are candidates for screening. The screening period is approximately 8 weeks and includes the screening phase, which is up to two weeks from the screening visit (V1, week -8) to the run-in visit (V2, week -6), and the run-in phase, which is from the run-in visit (V2, week -6) before the visit at the initial time (V6, week 0).

Only patients who meet the inclusion criteria as noted in Section 6.1 may be screened. It is the investigator's responsibility to confirm the diagnosis of T2DM.

Background treatment with metformin (if needed) at a stable dose should be continued throughout the screening period.

All laboratory tests performed at the central laboratory that are necessary to validate patient exclusion criteria are performed at the time of the screening visit. At time V2 (week -6), depending on the availability of laboratory parameters, eligible patients may enter the run-in phase. The introduction visit (V2) can be done less than 2 weeks after the screening visit if laboratory data are available. After the screening period, patients who meet the eligibility criteria at the end of the screening period, as noted in section 6.2.4, may enter the open-label randomized treatment period.

9.1.1.1. Study site visits: V1 (screening visit, week -8); V2 (introductory visit, week -6); V5 (week -1).

For a complete list and content of the procedures/assessments planned during the visits, please refer to the Examination Procedures Schedule in Section 1.2, and for a detailed description of the assessments, please refer to Section 8 and Section 9.6.

The following are details of procedures/assessments to be performed at study site visits during the screening period that have not been described elsewhere.

informed consent.

The patient will receive verbal information about the purposes and methods of this study, its limitations and risks, and the duration of the study at the time of the screening visit. Written information will be provided to the patient and must be signed by the patient and investigator prior to any investigations.

Demographic information, history of diabetes and medical/surgical history, history of cardiovascular disease and allergies, alcohol abuse and smoking habit, and medications.

Demographic data will be collected, such as date of birth, gender, and race. Information regarding history of diabetes will include documentation of duration of diabetes, history of microvascular complications (retinopathy, neuropathy, and nephropathy), and gestational diabetes in

- 43 039114 history, if appropriate. The medical/surgical history will be recorded, including a history of cardiovascular disease and allergies and a family history of allergies in the patient. Will collect data on alcohol abuse during the last 12 months prior to the screening visit and smoking habits.

Previous medication checks refer to medication records, including glucose-lowering medications and over-the-counter medications. In women of childbearing potential, methods of contraception should be documented.

Diet and lifestyle advice.

Please refer to section 7.1.

Contact with IVRS/IWRS.

IVRS/IWRS will be contacted to notify of screening and allocation of patient numbers (Section 7.6). Please note that it is important to contact the IVRS/IWRS before any blood sample is taken, as the patient number is provided by the IVRS/IWRS and must be reported on the laboratory's request forms.

Self-injection device training and insulin glargine delivery.

Issue one injection device type syringe pen with a leaflet with instructions. The patient is instructed by study staff on how to properly use the pen, how to store it, and is also instructed on self-injection techniques. Please refer to section 7.2.2.

Compliance check.

Compliance checks include compliance with metformin (if needed), insulin treatment and meter use, review of daily fasted SMPG values, and patient diary.

Issuance of a glucometer and training.

Please refer to section 8.4.3.2.

Insulin glargine starting dose and dose adjustment.

Eligible patients will enter a 6-week run-in phase with conversion to insulin glargine (if needed) and/or dose optimization (see details in section 7.2.4).

Testing in the central laboratory.

Collect a blood sample for all central laboratory tests required to test the exclusion criteria.

Provide patients with a urine collection container and instruct them on how to collect their first morning urine at home in the morning and bring the urine sample to the study center at the time of the scheduled visit.

The patient is given a referral for the next visit (a visit to the research center or a visit in the form of a phone call). Patients are instructed to return to the study center in the morning and bring a glucometer, diary, and insulin glargine pens.

9.1.1.2. Phone call visits: V3 (week -4) and V4 (week -2).

The patient is called by the investigator or qualified representative at the scheduled time. If the call was made by non-investigator research site staff, the investigator should be consulted if AE/SAE is suspected and informed if AE/SAE is observed. The phone call visit may optionally be a clinical visit for symptomatic hypoglycemia/AE or other reasons.

During a phone call, ask the following questions:

Have you experienced any new medical event, illness, or symptom since your last visit?

Have you experienced any changes in a pre-existing medical condition, illness, or symptom since your last visit?

Have you stopped, changed, taken, or added any medications (including OAD, if applicable) since your last visit?

Have you experienced any symptoms or phenomena of hypoglycemia and AE?

Are you comfortable with the diary, glucometer, and IMP injection device, or do you need any further explanation?

Phone call visits will also include the following:

asking the patient about fasting SMPG before breakfast and insulin dose in the last 3 days, including the day of the visit;

dose adjustment of insulin glargine if necessary;

registration of AE and symptoms of symptomatic hypoglycemia (if any);

registration of the use or replacement of any medication.

The patient will be instructed on the following.

making the necessary SMPG measurements;

daily filling of the diary;

- 44 039114 once-daily self-injections of insulin glargine at the dose prescribed by the investigator;

contacting the study center in the event of an adverse event, recording the event in the patient's diary and returning to the study center if necessary.

The patient will be given a referral for follow-up visits (a study site visit or a phone call visit) and they will be reminded to come on an empty stomach for their next visit to the center if scheduled.

9.1.2. Open-label randomized treatment period (week 0 to week 30).

Patients who meet all inclusion criteria and do not have exclusion criteria at the end of the screening period are considered eligible to participate in the open-label randomized treatment period. The duration of the open treatment period is 30 weeks ± 5 days from the start time visit (V6, week 0) to the end of treatment visit (V21, week 30).

Each patient self-administers IMP once a day during the open treatment period. The dose of IMP will be adjusted according to the fasting SMPG values documented in the patient's diary (section 7.2.4.2).

9.1.2.1. Visit at start time (V6, week 0, day 1).

For a complete list and content of the procedures/assessments planned during the visit, please refer to the Examination Procedures Schedule in Section 1.2, and for a detailed description of the assessments, please refer to Section 8 and Section 9.6.

Below are the details of the procedures/assessments that will be performed during this visit that have not been described elsewhere.

During this visit, the patient must return to the study center in the morning after 8 hours of fasting without having their own insulin injection or metformin administration (if applicable) at home. Patients will come to the study center with a blood glucose meter, diary, and used, unused, and used insulin glargine pens.

Compliance check.

Compliance checks include compliance with insulin glargine and metformin treatment (if applicable) and meter use, viewing daily fasting SMPG values, as well as SMPG concentration values in a 7 time point profile and a patient diary. If the patient does not comply adequately with study procedures, the study site staff member will repeat the exercise.

Contact with IVRS/IWRS.

After completion of the initial time evaluations and confirmation of eligibility, the investigator contacts the IVRS/IWRS for randomization. The treatment group (i.e. fixed ratio combination insulin glargine/lixisenatide or insulin glargine) is declared by IVRS/IWRS.

Self-injection device training and IMP issuance.

A study staff member instructs patients randomized to the combination group on how to properly use and store Pen A and Combination Pen B. They are also instructed on the technique of self-injection. Issue an injection device such as a syringe pen with a leaflet with instructions.

Patients randomized to insulin glargine will continue to use the insulin glargine pen (SoloStar). If necessary, you can repeat the workout with the SoloStar syringe pen. Issue an injection device such as a syringe pen. Please refer to section 7.2.2.

Starting dose and dose adjustment of IMP.

Eligible patients will begin a 30-week open-label randomized treatment period with either a fixed ratio combination of insulin glargine/lixisenatide or insulin glargine (see Section 7.2.4 for details).

The patient is given a referral for the next visit in the form of a phone call, which will occur in one week.

9.1.2.2. Phone call visits: V1 (week 1); V9 (week 3); V11 (week 5); V12 (week 6); V14 (week 10); V16 (week 15); V18 (week 21); V20 (week 21).

The patient is called by the investigator or qualified representative at the scheduled time. If the call was made by non-investigator research site staff, the investigator should be consulted if AE/SAE is suspected and informed if AE/SAE is observed. A phone call visit may optionally be a clinical visit, in case of symptomatic hypoglycemia/AE, or for other reasons.

During a phone call, ask the following questions.

Have you experienced any new medical event, illness, or symptom since your last visit?

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Have you experienced any changes in a pre-existing medical condition, illness, or symptom since your last visit?

Have you stopped, changed, taken, or added any medications (including OAD, if applicable) since your last visit?

Have you experienced any symptoms or phenomena of hypoglycemia and AE?

Are you comfortable with the diary, glucometer, and IMP injection device, or do you need any further explanation?

Have you adjusted your IMP intake since your last visit? If applicable, what is your IMP dose?

Have you measured any fasting SMPG value outside the range of 80-100 mg/dL (4.4-5.6 mmol/L)?

Have you measured any fasting SMPG value greater than visit 13 (week 8) to visit 15 (week 12) (excluding V1 value 5):

FPG >240 mg/dL (13.3 mmol/L);

from visit 15 (week 12) to visit 21 (week 30) (including V21 value):

FPG >200 mg/dL (11.1 mmol/L).

Phone call visits will also include the following:

asking the patient about fasting SMPG before breakfast and insulin dose in the last 3 days, including the day of the visit;

adjusting the dose of IMP (insulin glargine or insulin glargine/lixisenatide combination) to continue treatment towards a target fasting SMPG of 100 to 80 mg/dl (5.6 to 4.4 mmol/l), inclusive;

registration of AE and symptoms of symptomatic hypoglycemia (if any);

registration of the use or replacement of any concomitant medication.

The patient will be instructed regarding the following:

making the necessary SMPG measurements;

daily filling of the diary;

self-injection once a day IMP at the dose prescribed by the investigator;

contacting the study center in the event of an adverse event, recording the event in the patient's diary and returning to the study center if necessary.

Patients will be given referrals for follow-up visits (a study site visit or a phone call visit) and will be reminded to come on an empty stomach for their next visit to the center if scheduled.

9.1.2.3. Research site visits: V8 (week 2); V10 (week 4); V13 (week 8); V15 (week 12); V11 (week 18); V19 (week 24).

For a complete list and content of the procedures/assessments planned during the visits, please refer to the Examination Procedures Schedule in Section 1.2, and for a detailed description of the assessments, please refer to Section 8 and Section 9.6.

Below are the details of the procedures/assessments that will be performed during the visits and which have not been described elsewhere.

Compliance check.

Compliance checks include compliance with IMP and metformin treatment (if applicable) and meter use, viewing daily fasting SMPG values, as well as SMPG concentration values in a 7 time point profile and a patient diary. If the patient does not fully comply with the requirements of the study, then a staff member of the study site must repeat the training.

Patients are instructed to return to the study center in the morning in a fasted state for all study center visits with a glucometer and diary for each study center visit. Patients will return used pens/used pens at each study site visit and unused pens at scheduled restocking visits.

At the end of each study site visit, a referral for the next visit (a study site visit or a phone call visit) will be issued.

9.1.2.4. Final evaluation visit upon receipt of treatment/end of treatment (V21, week 30).

For a complete list and content of the procedures/assessments planned during the visit, please refer to the Examination Procedures Schedule in Section 1.2, and for a detailed description of the assessments, please refer to Section 8 and Section 9.6.

The same procedures/assessments, including IVRS/IWRS contact scheduled for visit 21 (week 30), should be performed in the event of premature definitive treatment discontinuation (section 9.3.2). Contact with IVRS/IWRS should be made to record the end of treatment.

A referral for a visit in the form of a phone call should be issued during post-treatment follow-up.

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9.1.3. Phone call visit during post-treatment follow-up (V22).

Following the last injection of insulin glargine or fixed ratio insulin glargine/lixisenatide combination, either as scheduled or early, 3 (-1/+3) days post-treatment follow-up visit. This visit may be a phone call visit or, if necessary, a study site visit in the event of an ongoing or new adverse event during the post-treatment period.

The patient receives a call from a researcher or a qualified medical representative at a specific, pre-agreed point in time.

During a phone call, ask the following questions.

Have you experienced any new medical event, illness, or symptom since your last visit?

Have you experienced any changes in a pre-existing medical condition, illness, or symptom since your last visit?

Have you changed, taken or added any new medications since your last visit?

All reports of hypoglycemia (if any) or any adverse events are recorded. The use or replacement of any concomitant medications, including emergency therapy, is recorded.

Contact with IVRS/IWRS is made to notify of the end of the study.

9.2. Definition of primary data.

9.2.1. Primary data present in the patient folder.

Scores reported in the e-CRF must be supported by appropriately signed and identified source documentation, linked without limitation to the following: consent and informed consent signature with study identification number;

patient identification number, last participation in a clinical study, medical history, associated diseases and data related to the pathology under study;

method of contraception for women with the ability to bear children;

the reason for the inability to bear children for the women in question (eg, postmenopausal period, history of hysterectomy);

prior and concomitant medication (including background metformin and rescue therapy);

study identification number;

treatment kit number, date of administration, and dose of the fixed-ratio insulin glargine/lixisenatide combination or insulin glargine alone (Lantus®Solostar® Pen, Pen A, and Pen B);

Metformin compliance, as assessed through interviews and patient diaries, if needed;

dates of visits and evaluations, including a report on the results;

vital signs, height, body weight;

faxed reports from the central laboratory and original reports received at the study center (with date and signature of the principal investigator or junior investigator);

confirmation of IVRS/IWRS notification via fax or e-mail (screening, screening dropout, run-in period, run-in dropout, randomization, treatment reallocation, treatment/study termination, study termination, treatment change if necessary, etc. .);

ECG records with signature and date;

adverse events and follow-up;

in the case of SAE, lipase/amylase elevation >2 ULN, calcitonin elevation, the research site should file at least copies of hospitalization reports and any relevant study reports (e.g., imaging records, specialist reports, etc.) ) documenting the follow-up of SAE or AESI;

date and reason for premature discontinuation of treatment (if any).

Primary documentation can be found in the following documents: patient ID, medical history, temperature sheet, nutritionist's report, physician's report, patient diaries, dated and signed SMPG printouts, with data downloaded from the glucometer.

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9.2.2. Primary data validation requirements for patients not randomized.

For patients not randomized, the primary data that should be verified include details of patient identification, informed consent signed by the patient, study identification number, dates of study visits, and underlying reasons that prevent randomization.

9.3. Treatment of patients who temporarily or permanently stop treatment, or patients who stop the study.

IMP should be continued whenever possible. In the event that IMP reception is stopped, it should be determined whether the stop can be made temporary; permanent cessation of IMP use should be a last resort. Any discontinuation of the use of an IMP must be fully documented in the e-CRF. In any case, the patient should remain in the study as long as possible.

9.3.1. Suspension of treatment with an investigational medicinal product(s).

Temporary discontinuation of treatment may be contemplated by the investigator due to suspected AEs or for other reasons. In the event of interruption of treatment due to AE immediately after the investigator concludes, based on his/her fair medical opinion, that the IMP was unlikely to be responsible for the event in question, and if the eligibility criteria for the study are still met (refer to section 6) then resumption of treatment with IMP will be carried out with careful and appropriate monitoring in the clinic and/or laboratory.

All treatment interruption dates should be recorded by the investigator on the appropriate pages of the e-CRF, if deemed valid.

9.3.2. Definitive discontinuation of treatment with an investigational medical product(s).

Definitive discontinuation of treatment is any discontinuation of treatment associated with an irrevocable decision by either the investigator or the patient not to treat the patient with an IMP at any time.

9.3.3. List of criteria for permanent discontinuation of treatment.

Patients may choose not to be treated with an IMP if they choose to do so, at any time and for any reason, or it may be at the discretion of the investigator. Every attempt should be made to document the reasons for stopping treatment and this should be documented in the e-CRF.

Patients may refuse treatment with IMP if:

at the patient's own request;

if, in the opinion of the investigator, continued administration of the IMP would be detrimental to the patient's well-being;

at the specific request of the sponsor.

The patient should refuse treatment with IMP in any of the following cases:

an intercurrent medical condition requiring discontinuation of IMPs: e.g. laboratory abnormalities (see decision tree and general guidance for follow-up of laboratory abnormalities in Appendix B), diagnosis of acute pancreatitis confirmed by gastrointestinal examination and imaging (section 9.6.4), calcitonin level >50 pg/ml (see section 9.6.6);

pregnancy.

Any abnormal laboratory values or ECG parameter will be subject to immediate re-evaluation for confirmation before a decision is made to permanently discontinue the IMP for the patient in question.

9.3.4. Treatment of patients after the final cessation of treatment.

Patients will be retained in the study as long as possible and followed up according to the procedures listed in this protocol (excluding 3-day post-treatment follow-up safety assessment, PK and antibody assessment, food trial, and PRO assessment) until the planned end date of the study, or normalization or stabilization of any AE requiring follow-up as specified in this protocol, whichever is later.

If possible, after permanent discontinuation of treatment, regardless of cause, patients will be evaluated as soon as possible using the procedure normally scheduled for the last day of IMP dosing (end of treatment visit), including samples for PK and antibody, PRO scores, in the appropriate case.

A trial meal will only be performed if the IMP has not been stopped and if the patient is not receiving emergency treatment. The two PK samples normally scheduled for the end-of-treatment visit should only be taken if the last dose is given at the visit, otherwise one PK sample is sufficient.

All cases of permanent discontinuation of treatment should be recorded by the investigator according to the

- 48 039114 on the relevant CRF pages and on the patient's medical record, if validated. IVRS/IWRS should be alerted when a patient discontinues treatment prematurely.

9.3.5. Procedure and consequences of refusal of treatment for the patient.

Patients may withdraw from the study prior to completion of the study if they choose to do so, at any time and for any reason. If possible, patients are evaluated using the procedure normally scheduled for the end-of-study visit, including PK and antibody samples, and PRO assessment, as appropriate.

In the case of patients who refuse to return to the study site, the investigator should make the best attempt to re-establish contact with the patient (e.g., contact the patient's family or private physician, consult available health registers or databases) and determine his/her health status, including, at least information about whether he/she is alive. Attempts to establish contact with such patients should be documented in the patient's medical record (eg, times and dates of attempted telephone contact, receipt of registered mail).

The statistical analysis plan will specify how these patients lost to follow-up will be evaluated in terms of their primary endpoints.

Patients who withdraw from the study cannot be re-randomized (treated) in the study. Their inclusion and treatment numbers should not be reused.

9.4. Investigator's responsibility regarding the safety assessment report.

9.4.1. Definitions of adverse events.

9.4.1.1. Undesirable event.

An adverse event (AE) is any adverse medical event in a patient or a patient participating in a clinical trial who has been administered a pharmaceutical product and which is not necessarily causally related to the treatment.

9.4.1.2. Serious adverse event.

A serious adverse event (SAE) is any adverse medical event that, at any dose:

results in death, or is life-threatening, or (note: the term life-threatening in the definition serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that would hypothetically cause death if would be more severe) requires hospitalization in a hospital or continuation of an ongoing hospitalization, or results in permanent or significant disability/disability, or is a congenital anomaly/congenital malformation, is a medically significant event.

Medical and scientific opinion should be taken into account when deciding whether rapid reporting is appropriate in other situations, such as important medical events that may not be directly life-threatening or result in death or hospitalization, but may put the patient at risk or may require medical or surgical intervention (i.e. special measures or corrective therapy) to prevent one of the other outcomes listed in the definition above.

Note: The following list of medically important events is intended to serve as a guide for determining which condition should be considered a medically important event. The list is not intended to be exhaustive.

Intensive treatment in the emergency department or at home in case of: allergic bronchospasm, forms of blood dyscrasia (i.e. agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia, etc.), convulsions (convulsive seizures, epilepsy, epileptic seizure, short-term loss of consciousness, etc.), development of drug dependence or drug abuse,

ALT>3 ULN+total bilirubin >2 ULN or asymptomatic elevation of ALT>10 ULN, suicide attempt or any event suggestive of suicidal tendencies, syncope, loss of consciousness (unless documented as a consequence of blood sampling), bullous skin rashes, forms of cancer diagnosed during the study or aggravated during the study (only if considered unusual/significant in oncology studies by investigators), chronic neurodegenerative diseases (newly diagnosed), or aggravated

- 49 039114 during the study (only if they were considered unusual/significant by the investigators in studies that specifically assessed the effect of the investigational medicinal product on these diseases).

9.4.1.3. An undesirable phenomenon of particular interest.

An Adverse Event of Special Interest (AESI) is an AE (serious or non-serious) of concern to scientists and healthcare professionals that is specific to a sponsored product or program that requires ongoing monitoring and immediate notification by the sponsor investigator. Further research may be required to characterize and understand such phenomena. AESIs can be added or removed throughout the study by changing the protocol.

All AESIs will be reported to the sponsor at the same time as the SAE, ie. within 24 hours as detailed in section 10.4.1.2.

AESIs are listed below.

ALT increase (see appendix B).

Pregnancy in a female patient in the study and pregnancy in the female partner of a male patient in an IMP/NIMP study.

Pregnancy will be recorded as AESI in all cases.

It will only qualify as an SAE if it meets one of the severity criteria (see Section 9.4.1.2).

If a female participant is pregnant, IMP should be discontinued.

Pregnancy follow-up of a female participant or female partner of a male participant is mandatory until the outcome is determined.

Overdose of IMP/NIMP with clinical manifestations (serious or non-serious).

IMP/NIMP overdose (accidental or intentional) is an event suspected by the investigator or reported voluntarily by the patient (not based on systematic pill counts) and is defined as follows.

For insulin glargine/lixisenatide combination: any dose corresponding to a daily dose of lixisenatide greater than 40 mcg (i.e. >80 U for pen A, >120 U for pen B).

For insulin glargine: any dose administered that, in the opinion of the investigator, based on clinical judgement, is considered to be significantly higher than the prescribed dose of insulin.

An overdose of an OAD (eg, metformin) is defined as at least two times the intended dose within the intended/planned period of treatment.

The circumstances of the overdose (i.e., accidental or intentional) must be explicitly stated in specific words, and the symptoms, if any, recorded on separate AE forms.

Note: An overdose of IMP without clinical manifestations does not require immediate notification: the definition is the same as described above. Overdose without clinical manifestations should be reported on the standard AE page in the e-CRF.

9.4.1.4. Other AEs requiring special monitoring and reporting in dedicated e-CRFs.

The following AUs require special monitoring and should be reported in a dedicated e-CRF report. These AEs will only warrant a rapid report when they are severe (meet the SAE criteria):

suspected allergic reactions (please refer to section 9.6.3);

monitoring of patients with elevated pancreatic enzymes >2 ULN/suspected pancreatitis (please refer to section 9.6.4);

major cardiovascular events (please refer to section 9.6.5);

monitor patients with elevated calcitonin >20 pg/ml (please refer to section 9.6.6).

9.4.2. General guidance for reporting adverse events.

All AEs, regardless of severity or association with IMP/NIMP, covering the time span from signing the informed consent form to the end of the study, as defined by the protocol for that patient, should be recorded on the appropriate page(s) or window(s) e- CRF.

Where possible, the diagnosis or individual syndrome should be reported instead of symptoms. The investigator should state the date of onset, severity, action taken for the IMP, corrective treatment/therapy prescribed, additional studies performed, outcome and his/her opinion, whether there is a reasonable likelihood that the AE was caused by the IMP or NIMP or the procedure(s) research.

For IMP (lixisenatide/insulin glargine combination), causality assessment aims to evaluate the combination product.

The investigator should take appropriate measures to monitor all AEs until clinical recovery is complete and laboratory results return to normal, or until progression stabilizes or until death occurs, to ensure

- 50 039114 chit patient safety. This may imply that observations will continue beyond the last scheduled visit in the protocol, and that the monitoring team may request additional studies prior to notification from the sponsor.

If treatment is stopped prematurely, the patient will continue to be monitored until the end of the study, as determined by the protocol for that patient.

Abnormal laboratory values, vital signs or ECG should be recorded as AE only if they:

are symptomatic and/or require either corrective treatment or consultation, and/or result in IMP discontinuation or dosage changes, and/or meet the severity criteria, and/or are defined as AESI.

9.4.3. Instructions for reporting serious adverse events.

In the event of an SAE, the investigator should immediately take the following actions.

ENTER (within 24 hours) the SAE-related information into the appropriate e-CRF boxes; however, the system will automatically send a notification to the monitoring team after the investigator's e-CRF confirmation or after the standard delay.

SEND (preferably by fax or e-mail) a photocopy of all tests performed and the dates on which these tests were performed to a member of the monitoring team whose name, fax number and email address appear on the clinical trial protocol. Care must be taken to ensure that the identification of the patient is protected and that the patient's identity in the clinical trial is properly mentioned on the copy of the original documentation provided to the sponsor. For laboratory results, include normal laboratory ranges.

All further data updates, as appropriate, should be recorded in the e-CRF and additional documentation as well as additional information (regarding lab data, concomitant medications, patient status...) should be sent (via fax or email) to the monitoring team within 24 hours from receipt of information. In addition, any attempt should be made to further document each serious AE that is fatal or life-threatening within a week (7 days) of initial notification.

A fallback plan (using paper CRF maintenance) is available and should be applied when the e-CRF system is not operational (please see Appendix C).

Any SAE that comes to the investigator's attention at any point in time after the end of the study for the patient, and which he/she considers with reasonable probability to be caused by an IMP, should be reported to the monitoring team.

9.4.4. Guidelines for reporting adverse events of particular interest.

In the case of an AESI, the sponsor must be informed immediately (i.e. within 24 hours) as outlined in the SAE notification guidance described in section 9.4.3, even if they do not meet the severity criterion, using the appropriate CRF pages (subject to forward ) or windows in eCRF.

The instructions for reporting AE are summarized in Table 1. 3.

9.4.5. Guidelines for the control of deviations from the norm of specific laboratory parameters.

Sanofi developed decision trees for the control of certain laboratory abnormalities are provided in Appendix B. The following laboratory abnormalities should be tracked, documented and controlled in accordance with the associated procedure schedule in the Appendix B protocol:

Neutropenia

Thrombocytopenia, elevated ALT levels, acute renal failure, suspected rhabdomyolysis.

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Brief description of instructions regarding unwanted Table 3 < events Phenomenon category Reported Period Specific phenomena in this category Filling out an individual patient registration card Form Dogyulnntelnen Others AE chinese forms be'yuyasnosgi form Adverse event (not being SAE, not being AESI) Regularly Any AE. which is not SAE or AESI Yes Pet East Serious Adverse Event (Non-AESJ or AESI) Express Report (within 24 hours) Any AE severity criteria in accordance with section 9.4.1.2 d" Not really I [desirable phenomenon, I present shhh special ischeree (non-sweeping SAE) Express otchst (within 24 hours) Pregnancy female patient eyenshinubtskta Pregnancy of a woman-iargnerya mu: aiin s-iatsien ga'men ireu object Overdose of Ι^Π^/ΝΤΜΡ with clinical manifestations * Increasing the level of ALT Yes Yes Yes Yes East Yes Her Hei Yes ΛΕ. requiring special monitoring Regularly Suspected allergic reactions Elevated levels of amylase Elipase Yes No Yes (non-SCYE) >2ULX Major Cardiovascular Events Petyshpin-N calcitonin level > 20 pg/ml Yes Yes Yes No Yes No Yes No Yes Deviations from the stern of laboratory parameters. Regularly Neutropenia Yes No no Phenomenon category Reporting Period Specific events in this category Filling out an individual registration card of a patient

Additional Others

AE form special security form

Abnormal ECG, asymptomatic overdose, Thrombocytopenia Yes Not Not registered as AE (non-SAE, non-AESI) Acute renal failure Yes Not Not Suspicion of rhabdomyolysis Yes Not Not Others (eg leading to discontinuation of IMPs) Yes Not Not really

Hypoglycemia should be reported on the page dedicated to the phenomenon of hypoglycemia;

* - overdose without clinical manifestations is reported in the AE form, and express reporting is not required.

9.5. Sponsor Responsibilities.

During the course of the study, the sponsor will communicate in an expedited manner the following:

all SAEs that are both unanticipated and at least reasonably related to IMPs (SUSAR), to regulators, IEC/IRBs, as appropriate, and researchers;

about all SAEs that are expected and at least reasonably associated with the IMP, to regulatory authorities, in accordance with regional regulations.

Any other AE not listed as an expected event in the Investigator's Brochure (IB) for the lixisenatide/insulin glargine combination product will be considered an unexpected event.

In this study, some AEs that are believed to be related to the underlying pathological condition (eg, elevated blood glucose) will not be considered unexpected, as outlined in the investigator's brochure.

The Sponsor will report all safety assessment observations made during the course of the trial in the Clinical Study Report (CSR).

9.6. Instructions regarding safety measures.

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This section provides instructions regarding safety precautions specific to this study.

9.6.1. Symptomatic hypoglycemia.

Symptoms of symptomatic hypoglycemia will be categorized as follows.

Severe symptomatic hypoglycemia.

Severe symptomatic hypoglycemia is a phenomenon in which a person needs the help of another person to actively administer carbohydrate, glucagon, or perform other resuscitative actions. These episodes may be associated with neuroglycopenia sufficient to induce a seizure, loss of consciousness, or coma. Measurement of plasma glucose concentration may not be available during such an event, but normalization of neurological status associated with the restoration of normal plasma glucose concentration is considered sufficient evidence that the event was caused by low plasma glucose concentration.

The definition of severe symptomatic hypoglycemia includes all episodes in which the neurological impairment was severe enough to preclude self-treatment, and which is thereby considered to put patients at risk of harm to themselves or others.

It should be noted that in need of help means that the patient cannot help himself. Helping a patient out of kindness, when help is not needed, should not be considered a phenomenon in which help is needed.

Severe symptomatic hypoglycemia will only qualify as SAE if it meets the SAE criteria. All events of seizure, loss of consciousness or coma should be reported as SAE.

Documented symptomatic hypoglycemia.

Documented symptomatic hypoglycemia is a phenomenon in which the typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration of <70 mg/dL (3.9 mmol/L). In addition, episodes of hypoglycemia with plasma glucose <60 mg/dL (3.3 mmol/L) will be analyzed.

Clinical symptoms thought to be due to an episode of hypoglycemia may include (but are not necessarily limited to) increased sweating, nervousness, asthenia, tremors, dizziness, increased appetite, palpitations, headache, sleep disturbance, confusion, seizures, loss of consciousness and to whom.

Possible symptomatic hypoglycemia.

Probable symptomatic hypoglycemia is a phenomenon in which symptoms of hypoglycemia are not accompanied by a measurement of plasma glucose concentration, but which was presumably due to a plasma glucose concentration of less than or equal to 70 mg / dL (3.9 mmol / L); the symptoms are treated with oral administration of carbohydrates without a plasma glucose test.

Patients will be instructed to measure plasma glucose levels by finger prick prior to administration of carbohydrates in all cases where symptomatic hypoglycemia is suspected unless, for safety reasons, immediate emergency glucose administration prior to confirmation is necessary, in which case glucose measurement should be performed. as soon as it is safe to do so, with appropriate documentation in the diary. Details of episodes of hypoglycemia will be recorded in patient diaries and patients will contact study centers as soon as possible after severe events to provide details and determine any necessary action to be taken.

Episodes of symptomatic hypoglycemia will be documented on the hypoglycemia event page in the e-CRF. Symptomatic hypoglycemic events that meet SAE criteria will also be documented on supplemental AE and SAE forms in the e-CRF.

9.6.2. Local tolerance at the injection site.

In the event that the investigator or the patient determines any signs of local intolerance at the injection site, this should be recorded on the standard AE page in the e-CRF.

9.6.3. Allergic or similar allergic reaction.

In the event that a patient experiences an allergic reaction or a similar allergic reaction, this should be reported as an adverse event and recorded in the e-CRF on a special form AE for the suspected allergic event. Additional information is collected on a special additional form for allergic reactions. Recognition of an allergic reaction or a possible allergic reaction will be done by the ARAC (section 5.4.2).

Virtually all of the symptoms listed on the Allergic Reactions Supplementary Form are possible adverse reactions that may be allergic in nature and may require consideration after medical judgment ruling out an etiology other than allergy.

Sometimes there may be temporary reactions at the injection site, which are of the nature of irritation.

- 53 039114 statements that do not require intervention and are of dubious value. These reactions should not be considered allergic reactions. Adverse events that are clearly not allergic in nature (for example, local reactions at the injection site) should not be recorded on the supplementary form for allergic reactions.

9.6.4. Monitor patients with elevated lipase and/or amylase >2 ULN.

Potential safety signals for acute pancreatitis were identified in a study following the introduction of other GLP-1 receptor agonists into the market. Therefore, patients enrolled in this study should be monitored for any suspicion of pancreatitis, for example, with symptoms and/or signs of acute abdominal distress or abnormal levels of pancreatic enzymes. Serum amylase and lipase concentrations are monitored in the usual manner at screening at baseline and periodically during the study treatment period.

If there are clinical signs and/or symptoms associated with pancreatitis, such as persistent abdominal pain that may radiate to the back, often with positional features, with possible nausea, vomiting, fever, and leukocytosis, additional measurements of amylase levels should be performed. and lipases. Clinical signs and/or symptoms should be documented in the primary data.

(1) An increase in amylase and/or lipase levels >2 ULN without clinical signs and/or symptoms.

In any case, when amylase and/or lipase levels are >2 ULN, a repeat test (assessed in a central laboratory, if possible) should be performed as follows:

if value(s) is/are >2-3 ULN: repeat test within 7 days if value(s) are/are >3 ULN: repeat test within 48 hours if value(s) remain(s) >2 ULN after retest: Amylase and/or lipase levels should be retested weekly until values are <2 ULN.

In the event that a repeat test shows a value of >2 ULN, a gastrointestinal examination and imaging (ultrasound and/or CT or MRI with contrast, as appropriate) should be performed. Please document the absence of clinical signs and/or symptoms in the primary data (if clinical signs and/or symptoms develop, please see (2) below).

The best clinical judgment should be used when interpreting elevated serum amylase and lipase levels in asymptomatic patients. In these cases, a decision may be made to temporarily stop taking the IMP, if deemed necessary by the investigator.

(2) Elevation of amylase and/or lipase >2 ULN with clinical signs and/or symptoms.

In the presence of clinical signs and/or symptoms caused by pancreatitis (as described above) that are associated with elevated levels of amylase and/or lipase, treatment with IMP should be promptly and at least temporarily discontinued, pending further clinical evaluation and confirmation. diagnosis.

Clinical signs and/or symptoms are documented in the raw data. Laboratory determinations of amylase and lipase levels should be obtained at the time of the event and again within 48 hours or sooner as clinically indicated. If the value(s) remains(remain) >2 ULN, then amylase and/or lipase levels should be retested as described in (1) above, or more frequently if clinically indicated.

Gastroenterological examination and imaging (ultrasound and/or CT or MRI with contrast, as appropriate) should be performed. If the diagnosis of pancreatitis is confirmed, IMP should not be restarted and should be permanently discontinued.

In both cases, as described in (1) and (2) above, all laboratory or clinical documentation should be collected. If the repeat test confirms that lipase and/or amylase values are >2 ULN, the event should be reported to the eCRF in Special Form AE for Elevated Lipase and/or Amylase Levels >2 ULN and Special Forms using the appropriate specific words: for example, elevated amylase and/or lipase if a single enzyme is elevated, suspected pancreatitis if clinical signs due to pancreatitis are present, if the diagnosis is suspected but cannot be confirmed or ruled out, and pancreatitis if the diagnosis has been confirmed.

The PSAC will consider selected events related to the pancreas, including pancreatitis, pancreatic neoplasms, and abnormal amylase or lipase levels.

9.6.5. Major cardiovascular events.

In the event that a patient experiences a major CV event, the investigator, in addition to reporting adverse events on the dedicated AE form for CV events, should collect more detailed information on the dedicated supplementary forms. Recognition of major cardiovascular events will be carried out blindly by CAS no later than,

- 54 039114 than before closing access to the database. Please also refer to section 5.4.3.

9.6.6. Control of patients with elevated calcitonin values.

During the course of the study, if a calcitonin value is found to be >20 pg/ml (5.9 pmol/l), then the following should be done.

A repeat test should be performed at the central laboratory within 7 days. In addition, blood should be collected and sent to a central laboratory to measure the levels of: calcium, phosphorus, gastrin, thyroid stimulating hormone (TSH), and thyroid peroxidase antibodies (anti-TPO antibodies).

The clinical and laboratory records listed below should be collected and recorded in primary records as soon as possible:

circumstances potentially leading to false positive results: smoking status, proton pump inhibitor treatments (eg, omeprazole), autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease), differentiated thyroid cancer, hypercalcemia, hypergastrinemia, chronic renal failure (without dialysis), other neuroendocrine tumors (small cell lung cancer, intestinal carcinoid), acute inflammatory processes in the lungs or sepsis;

diseases of the thyroid gland or other endocrine glands in a specific personal and / or family history;

special physical examination (neck, thyroid gland).

If a repeat test confirms that the calcitonin value is >20 pg/ml, then the following should be done:

the event must be reported to e-CRF on a special form AE and a special supplementary form for Elevated calcitonin >20 pg/mL with all relevant clinical and laboratory documentation;

an ultrasound of the thyroid should be performed and the patient may be referred to a thyroid specialist if considered necessary;

the patient should continue to be monitored according to the protocol schedule (including scheduled calcitonin measurements). Special Form AE Elevated calcitonin >20 pg/mL (5.9 pmol/L) should be updated with any new information collected during follow-up;

if a calcitonin value >50 pg/ml (14.75 pmol/l) is detected at any time during further follow-up, then the patient should permanently stop taking IMP (see section 9.6.6) and consult a specialist. Where possible, blood should be collected 1–2 weeks after IMP has been discontinued and sent to a central laboratory for calcitonin measurement;

if at any time during follow-up a calcitonin value >20 pg/mL rises by 20% or more between 2 assessments (while remaining below 50 pg/mL), remeasurement should be performed earlier than scheduled in the protocol, i.e. . after 1 month. As soon as the results become available, discussions with the sponsor regarding further guidance should begin without delay.

9.6.7. Monitoring of renal function in case of prolonged and severe nausea and vomiting.

In case of prolonged or severe nausea and vomiting, if clinically indicated, serum creatinine should be measured in a central laboratory. In the event of an acute increase in serum creatinine, metformin (if administered) should be discontinued until renal dysfunction is normalized.

9.6.8. Follow-up observation of laboratory abnormalities.

Decision trees for the control of deviation from the norm of certain laboratory parameters are presented in Appendix B.

9.7. Monitoring of adverse events.

All events will be monitored and reported in accordance with all applicable regulations and will be included in the final clinical study report.

10. Statistical features.

10.1. Sample size determination.

Sample size calculations are based on the primary efficacy variable, change in HbA1c from time base to week 30, under the following assumptions:

the overall standard deviation is 1.1%,

0.4% mean difference between fixed ratio insulin glargine/lixisenatide combination and insulin glargine in HbA1c change from baseline to week 30, t-test at 2-tailed 5% significance level with at least 95% power.

Based on the above assumptions, this study requires 350 patients per

- 55 039114 group.

Calculations were performed using nQuery Advisor 7.0.

10.2. Distribution of patients.

The total number of patients for each of the following categories will be reported in the CSR: screened patients: patients who signed an informed consent, run-in phase patients: patients who had a run-in entry in the IVRS/IWRS database, randomized patients: patients with distributed and enrolled to the IVRS/IWRS database with the treatment kit number, and whether or not the treatment kit was used, the safety population (i.e. randomized and on-treatment patients), modified treatment-based population (mITT) (as defined in section 10.3.1.1 and analyzed as randomized), pharmacokinetic (PK) population (as defined in section 10.3.3), randomization stratum [HbA _1c level at visit 5 (<8%, >8%) and metformin use at screening (yes, no)], as determined by IVRS/IWRS, will be summarized. The discrepancy between IVRS/IWRS stratum and the information reported on the Electronic Individual Registration Form (eCRF) will be listed for all randomized patients, patients who have completed the 30-week treatment period, patients who have stopped IMPs for 30 -week period of treatment and reasons for stopping treatment.

For all patient categories, except screened and run-in patients, percentages will be calculated using the number of randomized patients as a divisor for each treatment group.

A list of patients who terminated treatment early will be presented, along with reasons for termination.

Patients treated but not randomized, patients randomized but not treated, and patients randomized but not treated as randomized will be identified and described in separate lists. Only patients in the third category (randomized and not treated as randomized) will form part of the efficacy and safety analyzes.

For any patient randomized more than once, only the data associated with the first randomization will be used in any analyzed population. Safety data associated with any later randomization will be evaluated separately.

Safety assessment data for treated and non-randomized patients will be reported separately and these patients will not be included in the safety population.

10.3. Analyzed populations.

10.3.1. Populations for performance evaluation.

Efficacy analyzes will be based on treatment groups assigned by IVRS/IWRS according to the randomization schedule at the time of the randomization visit (as randomized), regardless of the actual treatment group.

10.3.1.1. Modified population, formed depending on the prescribed treatment.

Efficacy analyzes will be based on a modified intent-to-treat (mITT) population, defined as all randomized patients who received at least one open-label dose of IMP and have both a baseline score and at least one assessment after the initial time point for the primary or secondary efficacy variable, regardless of adherence to protocol requirements and study procedures. Patients will be analyzed in efficacy analyzes according to the treatment group to which they are randomized.

10.3.2. Population for safety assessment.

Safety evaluation analyzes will be based on a safety evaluation population defined as all randomized patients who received at least one open-label dose of IMP (regardless of the amount of treatment administered). Patients will be analyzed in safety assessment analyzes according to the treatment actually received.

In addition:

non-randomized but treated patients will not be part of the safety assessment population, but safety assessment data for them will be presented separately;

randomized patients for whom it is not clear whether they took the study medication will be included in the population for safety assessment as randomized;

when a patient is exposed to both insulin glargine/lixisenatide fixed ratio combination and insulin glargine, the patient will be analyzed in the treatment arm (insulin glargine/lixisenatide fixed ratio combination or insulin glargine) in which he/she has been treated for longer ;

- 56 039114 patients will be excluded from the safety population only if there is documented evidence (i.e. for all study dates recorded that the medication was not taken) that the patients were not taking study medication.

10.3.3. Population for evaluation of pharmacokinetic parameters.

For pharmacokinetic (PK) analyzes, the PK population is defined as all randomized and treated patients who have submitted at least one valid plasma test for lixisenatide.

10.4. Statistical methods.

Quantitative data will be summarized by treatment group using the available number of observations (N), mean, standard deviation (SD), minimum, median, and maximum.

Qualitative data will be aggregated by treatment group using counts and percentages.

In general, descriptive statistics on the quantitative parameters of efficacy and safety (outcome and change from the initial time point) to the time of the scheduled visits will be provided for observed cases (OS), i.e. include only patients with non-missing evaluations at the time of a particular visit.

10.4.1. Demographic characteristics and characteristics at the initial point in time.

The initial time value is defined as the last available value before the first injection of the investigational medicinal product (IMP) in open mode. The derived parameters will be calculated by the sponsor.

The demographic characteristics to be aggregated are:

age (years) obtained as (date of informed consent - date of birth)/365.25, age categories (age <50, >50 to <65, >65 to <75, >75 years), sex (male, female), race (Caucasian/White, Black, Mongolian/Oriental, Other), ethnicity (Hispanic, non-Hispanic), HbA1c (%) at visit 5 (week -1), HbA1c randomization strata (<8, >8 %) at visit 5 (week -1), metformin randomization strata (yes, no) at screening, BMI (kg/m ² ) at baseline given as: (weight in kg)/(height in meters) ² , BMI category at the initial time (<30, >30 kg/m ² ), country.

A history of diabetes includes:

duration of diabetes (years) obtained as (date of informed consent - date of diagnosis of diabetes+1)/365.25, age at onset of diabetes (years) obtained as (date of diagnosis of diabetes - date of birth+1)/365, 25, duration of basal insulin treatment (years) derived as (date of informed consent - date of first basal insulin dose+1)/365.25, mean daily basal insulin dose at visit 2 (week -6) and mean daily insulin glargine dose at randomization, visit 6 (week 0), the average daily dose of basal insulin within 3 days immediately before screening at visit 2 (week - 6) and the average daily dose of insulin glargine within 3 days immediately before randomization at visit 6, percentage of patients using metformin at screening, duration of metformin treatment (years) (for patients using metformin at screening) given as (date of informed consent - date of first dose of metformin+1)/365.25, daily dose of metformin (mg) at baseline, categories for daily dose of metformin at baseline (<1500, >1500 to <2500, from > 2500 to <3000, >3000 mg), percentage of patients with number of OADs used at screening (no OAD, one OAD, two OADs), percentage of patients with OADs by class (i.e. metformin, sulfonylurea, glinide, dipeptidyl peptidase 4 inhibitor, or SGLT-2 inhibitor alone or in combination with any two of them), duration of first OAD (years) (for patients who used OAD at screening) obtained as (date of informed consent - date of first dose OAD+1)/365.25, duration of second OAD (years) (for patients using OAD at screening) obtained as (date of informed consent - date of first dose OAD+1)/365.25 , previous use of a GLP-1 receptor agonist (yes, no),

- 57 039114 microvascular complications of diabetes at initial time (yes, no) (i.e. diabetic retinopathy, diabetic sensory or motor neuropathy, diabetic autonomic neuropathy and diabetic nephropathy, including categories of most late events), urinary albumin/creatinine ratio categories at baseline (<30 mcg/mg [normal], >30 to <300 mcg/mg [microalbuminuria] and >300 mcg/mg [macroalbuminuria]), estimated creatinine clearance at screening (mL/min), categories by estimated creatinine clearance at screening (<30 mL/min, [severe renal impairment], >30 to <50 mL/min, [moderate renal impairment], >50 to <80 mL/min [mild renal impairment] and >80 ml/min [no renal insufficiency]).

Efficacy variables at baseline include HbA1c levels during a standardized meal trial:

the level of glucose in the blood plasma 2 hours after a meal (PPG) and the deviation of the glucose level,

PPG after 30 minutes and 1 hour and the corresponding deviation of the glucose level,

Note: Plasma glucose deviation at 30 min, 1 h or 2 h - value at 30 min, 1 h or 2 h after a meal - value obtained 30 min before a meal and before administration of IMP if IMP is injected before breakfast, 7-point self-monitoring plasma glucose (mean), body weight, fasting plasma glucose (central laboratory).

Medical history and medical findings include physical examination, medical or surgical history, medical history of cardiovascular and cerebrovascular events, medical history of allergies, subject's family history of allergies, alcohol abuse within the last 12 months, smoking habit.

Medical and surgical history will be coded using the version of the Medical Regulatory Dictionary (MedDRA) that is in effect at Sanofi at the time the database is closed.

No statistical criteria will be calculated for between-group differences in demographic and baseline characteristics (including medical history and efficacy data at baseline).

Demographic and disease characteristics at baseline, efficacy variables at baseline, and medical history and medical findings will be summarized with relevant descriptive statistics by treatment group and overall. Pathologies associated with past medical or surgical history will be summarized according to the main SOC and HLT. These generalizations will be provided for randomized patients.

10.4.2. Prior and concomitant medications.

All medicines will be coded using the version of the World Health Organization Dictionary of Medicines (WHO-DD) that is in effect at Sanofi at the time the database is closed.

Medications will be classified into the following three groups:

prior medications are medications that the patient took prior to the first injection of IMP in open mode;

concomitant medications are medications that the patient continued or started taking in the period after the first open-label IMP injection up to 3 days after the last IMP injection;

post-treatment medications during the follow-up period are medications that the patient continued or started taking 4 days after the last open-label IMP injection.

A certain medication can be classified into several groups. Medications will be summarized according to the WHO-DD dictionary, taking into account the first digit of the ATC class (anatomical category) and the first three digits of the ATC class (therapeutic category). All ATC codes associated with a drug will be aggregated, with patients counted once in each ATC category (anatomical or therapeutic) associated with the drug, so patients can be counted multiple times for the same drug.

Summary of previous concomitant medications and medications taken after the end of treatment will be presented for randomized patients in each treatment arm.

- 58 039114 cheniya (and in general for the generalization of previous medicines) using calculations and percentages. No statistical criteria for intergroup difference will be calculated.

10.4.3. Study treatment exposure volume and compliance.

Study treatment exposure volume and compliance will be assessed and aggregated according to actual treatment received in the population to assess safety.

10.4.3.1. Scope of exposure to an investigational medical product.

The amount of exposure to a treatment within a study will be assessed by the duration of drug exposure throughout the study.

The duration of treatment exposure will be equal to the total number of days of open-label administration of the investigational medical product, regardless of unplanned periodic interruptions. The duration of IMP exposure will be calculated as (date of last open-label IMP injection - date of first open-label IMP injection)+1.

The number (%) of patients randomized and exposed to open-label IMPs will be presented for specific time periods for each treatment arm in the population for safety assessment. The time periods of interest are grouped as follows: 1 to 14 days, 15 to 28 days, 29 to 56 days, 57 to 84 days, 85 to 126 days, 127 to 168 days, 169 to 210 days, >210 days.

Descriptive statistics on duration of treatment exposure (number, mean, SD, minimum, median, and maximum) and cumulative exposure in patient-years will also be presented by treatment group in the population to assess safety.

20.4.3.2. Compliance.

Overall treatment compliance is defined as the actual number of days with an IMP injection compared to the planned number of days with an IMP injection during the open-label treatment period until treatment is stopped. It is calculated according to the following formula:

Compliance rate (%)

Total number of days with at least one IMP injection

Planned number of days with IMP xIOO injection.

Treatment compliance will be summarized by treatment group using the mean, SD, median and population range to assess safety. In addition, the percentage of patients who are <60%, >60 to <80%, >80 to <100%, and >100% compliant will be aggregated by treatment group.

10.4.4. Efficiency endpoint analyses.

Efficacy analyzes will be performed on the mITT population using estimates of efficacy obtained over the treatment period (section 8.1 and section 8.2.1) unless otherwise noted.

For a patient to be included in an analysis of change from start time (endpoint - start time) or endpoint analysis corrected for start time, the patient must have both measurements of that endpoint, at start time and after start time at receiving treatment.

20.4.4.1. Analysis of the primary endpoint(s) of effectiveness.

The statistical test will be a two-tailed test with a nominal 5% significance level.

The primary endpoint, HbA1c change from baseline to week 30, will be analyzed using a repeated measures mixed effects model (MMRM) with missing data randomly assigned. The MMRM model will include treatment arm (fixed-ratio insulin glargine/lixisenatide combination or insulin glargine), HbA1c randomization strata (<8, >8%) at visit 5 (week -1), metformin randomization strata (yes, no) at screening, visit (week 8, week 12, week 24, and week 30), treatment-visit and country interaction as fixed effects, and HbA1c value interaction at baseline-visit as covariate. This model will evaluate the adjusted mean change in HbA1c levels from baseline to week 30 for each treatment group, as well as intergroup difference and 95% CI for the adjusted mean.

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The MMRM model will be implemented using the MIXED procedure (PROC MIXED) in SAS® (version 9.2 or higher) with an unstructured correlation matrix to model errors within a single patient. The parameters will be estimated using the constrained maximum likelihood method with the Newton-Raphson algorithm. The degrees of freedom of the denominator will be estimated using the Canward-Roger approximation by fitting values from scheduled visits after randomization throughout the treatment period.

The primary analysis will be performed using the mITT population and including all scheduled HbA1c measurements collected during the treatment period.

sensitivity analyses.

For the primary endpoint, the following sensitivity analyzes will be performed.

To evaluate the impact of rescue therapy, sensitivity analysis will be performed on a multilevel model with arbitrary slopes and intervals using all HbA1c level data collected up to the end of treatment plus 14 days (including data collected after the introduction of rescue therapy). A multilevel model with arbitrary slopes and intervals will be used to adjust for the effect of the rescue agent on the change in HbA _1c level from the initial time point. This model will include treatment (constant ratio insulin glargine/lixisenatide combination or insulin glargine), HbA1c randomization strata (<8, >8%) at visit 5 (week -1), metformin randomization strata (yes, no) at screening, visit (week 8, week 12, week 24, and week 30), treatment-visit interaction, country as fixed effect factors, and HbA _1c level interaction at baseline-visit and number of days spent at taking emergency medicines as a covariate. The layered model will be implemented using PROC MIXED. The parameters will be estimated using the constrained maximum likelihood method with the Newton-Raphson algorithm. The degrees of freedom of the denominator will be estimated using the Canward-Roger approximation by fitting values from all visits after randomization during the treatment period.

An analysis of covariance (ANCOVA) with data gap replacement by last observation forward (LOCF) will be performed on the primary efficacy variables. The last available measurement of HbA1c on treatment after the initial time point (before rescue medication in case of emergency) for each patient will be modeled with treatment groups (constant ratio insulin glargine/lixisenatide combination or insulin glargine), HbA1c randomization strata ( <8, >8%) at visit 5 (week -1), randomization strata for metformin use (yes, no) at screening and country as fixed effects, and using HbA1c value at baseline as covariate. Adjusted mean scores for the treatment and differences in these scores (constant ratio combination of insulin glargine/lixisenatide versus insulin glargine) will be presented along with the 95% confidence intervals (CI) of these differences and the p-value.

Sensitivity analyzes will also be performed for those who completed the 30-week period in the mITT population (i.e., all mITT patients who completed the 30-week open-label treatment period and did not start any rescue therapy before the end of the 30-week treatment period) using observed values for week 30 and the same MMRM pattern as described for the primary analysis above.

Evaluation of the effect of treatment by subgroups.

Descriptive analyzes of the primary endpoint will be performed to summarize treatment effects for subgroups defined by the following factors at baseline or at screening:

race, ethnicity (Hispanic, non-Hispanic), age group (age <50, >50 to <65, >65 years), sex, BMI at baseline (<30, >30 kg/ ^m2 ), level HbA1c at baseline (<8, >8%), metformin use (yes, no) at screening, country, number of OADs used at screening (no OAD, one OAD used, two OADs used).

Subgroup treatment effects determined for each of these factors will be assessed in terms of change in HbA1c levels from baseline to week 30 in the mITT population, excluding estimates made after rescue agent administration, and using an MMRM approach with treatment group (combination with constant insulin glargine/lixisenatide or insulin glargine ratio), HbA1c randomization strata (<8, >8%) at Visit 5 (week -1), ran

- 60 039114 domination strata for metformin use (yes, no) at screening, visit, subgroup factor, treatment-visit, treatment-subgroup factor, visit-subgroup factor, treatment-visit-subgroup factor and country as fixed effects and with applying the interaction value of HbA1c at the initial time-visit as a covariate. Adjusted mean difference estimates for treatment (constant ratio insulin glargine/lixisenatide combination versus insulin glargine alone and versus lixisenatide alone) with standard errors and 95% confidence intervals will be provided as appropriate for subgroups.

In the case where the subgroup factor is identical or similar to the randomization stratum factor (eg, HbA1c level category at baseline or metformin use), only the subgroup factor will be included in the model to avoid the problem of collinearity in the analysis.

A similar MMRM model will also be applied to assess the within-group treatment effect on HbA1c change from baseline to week 30 for the following subgroups:

anti-lixisenatide antibody status (positive, negative) at end of 30 weeks of treatment, anti-insulin glargine antibody status (positive, negative) at end of 30 weeks of treatment, anti-lixisenatide antibody concentration at end of 30 weeks of treatment: <lower limit of quantitation ( LLOQ), >LLOQ to 100, >100 nmol/l.

Adjusted means for each treatment group will be provided by subgroup as appropriate, as well as associated standard errors and 95% confidence intervals.

The change in HbA1c level from baseline versus time of visit will be assessed using descriptive statistics (mean, standard deviation, median and ranges).

20.4.4.2. Analyzes of secondary efficacy endpoints.

Descriptive statistics (number, mean, standard deviation, median, minimum and maximum) will be provided according to treatment for all quantitative secondary variables at the time of scheduled visits.

With the exception of PPG at 30 min, 1 h, 2 h and glucose deviation, all quantitative secondary efficacy endpoints at week 30 defined in Section 8.2.1 will be analyzed using the same MMRM approach described in Section 10.4.4.1 for comparison of a fixed ratio combination of insulin glargine/lixisenatide with insulin glargine. This model will include fixed effects parameters including treatment arm (fixed-ratio insulin glargine/lixisenatide combination or insulin glargine), HbA1c randomization strata (<8, >8%) at visit 5 (week -1), randomization strata for metformin use (yes, no) at screening, scheduled visit, treatment-visit interaction, and country and covariate, interaction value at baseline-visit (excluding dose of insulin glargine at week 30, for which the MMRM model will not be adjusted relative to the value at the initial time). Mean and adjusted mean values for the treatment group will be provided, as well as the adjusted mean and the associated two-sided 95% CI difference between treatment groups. Statistical tests for between-group differences will be two-tailed with a Type I error probability of 0.05. The analyzes include all planned measurements collected during the treatment period.

PPG at 30 min, 1 h, 2 h and glucose deviation, for which only one evaluation during treatment is scheduled, will be analyzed using a similar ANCOVA with data replacement by LOCF, as described in section 10.4.4.1, to compare the combination with a constant ratio of insulin glargine/lixisenatide to insulin glargine. This model will include fixed effects parameters, including treatment groups, randomization strata for HbA1c (<8, >8%) at visit 5 (week -1), randomization strata for metformin use (yes, no) at screening , and country, and covariate using the corresponding value at the start time. Mean and adjusted mean values for the treatment group will be provided, as well as the adjusted mean and the associated two-sided 95% CI difference between treatment groups. If study drug is discontinued prior to week 30 PPG at 30 min, 1 h, 2 h, glucose drift will be assessed at the time of discontinuation. The LOCF procedure will be applied by using this last available measurement when receiving treatment after the initial time point (before taking the rescue drug in the case of rescue therapy) as the value at week 30.

All qualitative secondary efficacy endpoints defined in section 8.2.1 will be analyzed using the Cochran-Mantel-Haenszel (CMH) method with stratification

- 61 039114 according to randomization strata for HbA _1c (<8, >8%) at visit 5 (week -1) and randomization strata for metformin use (yes, no) at the time of screening. The proportion in each treatment group will be provided, as well as the difference in proportions between groups with an associated 2-tailed 95% CI. For Week 30 HbA1c Responders (<6.5%, <7%, respectively), patients who had no Week 30 scores during the treatment period will be treated as negatives (nonresponders) in the analysis, including those who stopped study treatment before week 30, started rescue medication before week 30, or were not scored at all on treatment in the mITT population. For each qualitative composite endpoint, a patient will be treated as a responder only if the criterion is met for each component of the composite endpoint.

20.4.4.3. Features of multiple comparisons (which should be defined).

To control for Type I errors, a step-down testing procedure will be applied.

For the primary variable (HbA1c change from baseline to week 30), no adjustment for multiplicity of comparisons is required to control for Type I error, as only one comparison of the combination with a constant ratio of insulin glargine/lixisenatide versus insulin glargine will be performed.

If the primary variable is statistically significant at the 5% level, a hierarchical testing procedure will be performed to test the next secondary performance variables with the following order of precedence. Testing will be terminated when the endpoint is found not to be statistically significant at the 5% level:

1) change in blood glucose deviation after 2 hours during a standardized trial meal from the initial time point to week 30,

2) change in body weight from the initial time point to week 30,

3) change in the daily mean value of SMPG over 7 time points from the initial time point to week 30,

4) percentage of patients achieving HbA1c <7% without gaining body weight at week 30,

5) change in the daily dose of insulin glargine from the initial time point to week 30.

No adjustment for multiplicity of comparisons is made for secondary efficacy variables that are not included in the list above.

10.4.5. Safety assessment data analyzes.

Summarizations of the results of the safety assessment will be presented by treatment group.

All safety assessment analyzes will be conducted on safety populations as defined in section 10.3.2, applying the following general rules.

The value at the start time is usually defined as the last available value before randomization.

The following definitions will apply to laboratory parameters and vital signs.

Potentially Clinically Significant Abnormal Values (PCSAs) for clinical laboratory tests and vital signs are defined as abnormal values considered medically important by the sponsor's Central Pharmaceutical Safety and Epidemiology Unit and valid at the time of final SAP approval. PCSA criteria for parameters not mentioned in the protocol as safety assessment parameters will not be analyzed.

The PCSA criteria will determine which patients had at least 1 PCSA during the treatment period, taking into account all evaluations performed during the treatment period, including unscheduled or repeat evaluations. The number of all such patients will be the numerator for the percentage of PCSAs on treatment.

The follow-up period defined in Section 8.2.2 is applicable for classifying AEs, determining on-treatment PCSA values, and on-treatment last value for laboratory parameters, vital signs, and ECG parameters.

10.4.5.1. Symptomatic hypoglycemia tests.

The number (%) of patients and the rate in patient-years (2 types: number of patients with events or total events per 100 patient-years) for each type of symptomatic hypoglycemia (severe, documented and probable symptomatic hypoglycemia) will be summarized by treatment group. The pattern of occurrence of symptomatic hypoglycemia will also be assessed over time, as appropriate.

In addition to a cut-off value of less than or equal to 70 mg/dL (3.9 mmol/L) (please refer to section 9.6.1), episodes of symptomatic hypoglycemia with plasma glucose <60 mg/L will be analyzed separately. dl (3.3 mmol/l).

10.4.5.2. Adverse event analyses.

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Pre-treatment AEs are AEs that developed, or worsened, or became severe during the period prior to treatment.

Treatment-onset AEs (TEAEs) are AEs that developed, or worsened (according to the investigator), or became severe during the period of treatment.

Post-treatment AEs are AEs that have developed, or worsened, or become severe over the period following the end of treatment.

The focus of reporting AEs in the CSR will be on TEAE. AE before treatment and after treatment will be described separately.

All unwanted events.

Adverse event tables will be presented according to system organ class (SOC) (sorted according to internationally agreed order), high-level term (HLGT), high-level term (HLT), and preferred term (PT), sorted alphabetically for each treatment group, the number (n) and percentage (%) of patients who have AE. Multiple occurrences of the same event in the same patient will be counted only once in the tables within the treatment phase. The denominator for calculating percentages is the safety population within each treatment group.

Summary of all TEAEs in each treatment group would include the following:

review of AE summarizing the number (%) of patients with any

TEAE, serious TEAE,

TEAE, leading to death,

TEAE leading to permanent discontinuation of treatment.

Number (n) and percentage (%) of patients with at least one TEAE for major SOC, HLGT, HLT, and RT.

Summary of TEAE according to maximum severity (severe, moderate, mild) presented by major SOC and RT.

A generalization of TEAEs possibly associated with clear mode IMP reception presented on the main SOC, HLGT, HLT and PT.

A detailed list of TEAE generalizations will be provided in the statistical analysis plan.

Deaths and serious adverse events.

Deaths and SAEs occurring during treatment will be summarized and presented as the number and percentage of patients in each treatment group.

The following summaries of deaths will be obtained:

the number (%) of patients who died during the study period (TEAE, during the study period), generalized in the population to assess safety according to the treatment received, deaths in non-randomized patients or randomized and untreated patients,

TEAE resulting in death (death as an outcome on the e-CRF AE page reported by the investigator) according to the main SOC, HLGT, HLT and PT showing the number (%) of patients sorted by the internationally agreed SOC order, and alphabetical order HLGT, HLT and RT.

Adverse events leading to the final discontinuation of treatment.

TEAEs leading to permanent treatment discontinuation will be summarized and presented as the number and percentage of patients in each treatment group.

Local tolerance at the injection site.

AEs associated with local intolerance at the injection site will be identified by searching for the term injection site in both RTs coded based on Investigator-reported terms and RTs coded based on ARAC diagnostic terms. The number (%) of patients with associated events will be summarized by treatment group.

Allergic reactions.

The number (%) of patients with events recognized by the ARAC as allergic reactions and with events recognized by the ARAC as possibly related to IMPs will be summarized by treatment group. All allergic events reported by investigators on the AE form for the suspected allergic event and its associated additional forms (ARAC-validated or non-ARAC-validated) will be listed.

Elevated levels of pancreatic enzymes >2 times the ULN.

The number (%) of patients with events reported in the AE form for elevated levels of lipase and/or amylase >2 times the ULN and its associated additional forms will be summarized according to the RT for each treatment group.

Major cardiovascular events.

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Major CV events explicitly recognized and confirmed by the CAS will not be summarized in the CSR. All events reported by investigators on the AE Forms for CV Events and Associated Complementary Forms (confirmed or unconfirmed CAS) will be listed with the recognized outcome.

Increasing the values of calcitonin.

The number (%) of patients with events reported on the AE form for elevated calcitonin levels >20 pg/mL and its associated additional forms will be summarized according to the TA for each treatment group.

Increasing the level of ALT.

The number (%) of patients with events reported on the ALT-elevated AE form and its associated additional forms will be summarized according to the RT for each treatment group.

20.4.5.3. Analyzes of laboratory variables.

The number and percentage of PCSA patients at any assessment during the treatment period will be summarized for each clinical laboratory test within each treatment group. Generalizations will include patients in the safety population who have at least one laboratory test performed during the treatment period and, if required to determine abnormality, have an available value at baseline and available normal laboratory ranges.

Descriptive statistics will be used to summarize the results of laboratory tests and changes from the initial time point at the visit to the last value at the time of receipt of treatment within each treatment group.

Offset tables, as well as other tabular and graphical methods, can be used to present the results of laboratory tests of interest.

The listings will be flagged to indicate values outside the range of normal laboratory parameters, as well as PCSA values.

Drug-induced liver injury.

Liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin levels, are used to assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any visit after the initial time point relative to the status at the initial time point will be shown according to the treatment group for each parameter. The proportion of patients with PCSA values at any visit after the initial time point will also be shown according to duration of exposure for each treatment group, only if a tabular summary is needed.

A list of possible cases of High's law, identified by treatment group (e.g., patients with any elevated ALT >3xULN and associated with >2xULN total bilirubin), liver-related TEAE, ALT, AST, ALP, total bilirubin, and the following additional parameters, if available: conjugated bilirubin and clotting time/INR, creatine phosphokinase, serum creatinine, CBC, immunoglobulin M (IgM) antibodies to hepatitis A virus, IgMantibodies to hepatitis B core antigen, antibodies to the virus hepatitis C and hepatitis C virus ribonucleic acid, cytomegalovirus IgM antibodies and hepatitis E virus IgM antibodies, autoantibodies: to the nucleus, to deoxyribonucleic acid, to smooth muscle, Epstein-Barr virus, herpesviruses and to liver/kidney microsomes.

10.4.5.4. Analyzes of vital signs variables.

The number and percentage of patients with PCSA at any assessment during the treatment period will be summarized for each vital function parameter within each treatment group. The summaries will include patients in the safety population who had at least one parameter to be analyzed during the treatment period. When the PCSA definition provides for a change from initial time value, patients must also have initial time value to be included in the generalizations.

Descriptive statistics will be used to summarize the study results and changes from the initial time point at the visit to the last value at the time of receipt of treatment within each treatment group.

Tabular and graphical methods can be used to present the results of the parameters of interest.

The lists will be marked with the PCSA values.

10.4.5.5. 12-lead ECG status analyzes.

An offset table will be provided to present the status of the ECG on receipt of treatment according to the status at baseline within each treatment group.

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10.4.5.6. Variable analyzes for anti-drug antibodies.

Variable analyzes for antibodies will be performed on a population basis to evaluate safety (i.e. in patients in both treatment arms for anti-insulin glargine antibody; in patients in the constant insulin glargine/lixisenatide ratio combination arm for anti-lixisenatide antibody only).

The number and percentage of patients according to antibody status and the percentage of negative to positive transition from baseline to week 30 will be listed and summarized by treatment group and visit. In the case of insulin antibodies, the number and percentage of patients with cross-over human insulin reactivity will also be summarized by treatment group and visit in patients positive for antibodies to insulin glargine.

Antibody levels (titer or concentration) and corresponding percentage change from baseline for anti-insulin glargine antibodies will be listed and summarized by treatment group and visit using descriptive statistics for N, geometric mean, coefficient of variation, median, minimum, and maximum.

10.4.6. Analyzes of pharmacokinetic variables.

Plasma concentrations of lixisenatide (total and active) in patients in the fixed insulin glargine/lixisenatide ratio combination arm will be listed and summarized by visit and analysis periods and by anti-lixisenatide antibody status in the PK population using descriptive statistics for N, geometric mean value, coefficient of variation, median, minimum and maximum.

For research purposes, a simulation of the PK population could be performed.

10.4.7. Variable analyzes for patient-reported treatment outcomes.

TRIM-D, EQ-5D and IWQoL-Lite analyzes will be performed on the mITT population.

The change in all calculated PRO scores (global and for each domain from various questionnaires) from baseline to endpoint will be analyzed using an MMRM model similar to that of the primary endpoint.

Descriptive statistics (mean, median, standard deviation and range) for absolute values and for change from baseline will be presented by treatment group per visit for each score (global and for each domain of each questionnaire) as well as for each item.

Moreover, responses to each EQ-5D item will be presented per visit for each treatment group. The tables will contain information regarding the frequency and proportion of the population reporting level 1 (no problems), level 2 (some problems), and level 3 (severe problems), by item, by treatment group, and by visit.

Patient- and clinician-based global treatment rating scale analyzes will be conducted on the mITT population. Descriptive statistics (mean, median, standard deviation, and range) for the global patient and clinician rating scales will also be presented by treatment group at the end of the study.

10.5. Intermediate analysis.

No formal interim efficacy analysis is planned for this study. This study will not be terminated prematurely due to very good performance.

An Independent Data Monitoring Committee (DMC) will monitor and evaluate the safety of patients in this trial by periodically reviewing the collected safety data provided by an independent statistical team. Related details are provided in separate documents (DMC regulation and DMC statistical analysis plan).

11. Applications.

Appendix A. Calculation of creatinine clearance using the Cockcroft-Golt formula

Calculation name 1 Creatinine clearance Formula Units Number of signs Traditional: Men: [(140-age) x (wcc(kg)) / [(72 x serum creatinine (mg/dl)) Women: [0.85 x (140-age) x weight(kg)] / [72 x serum level of creativity (mg/dl)] chi ι/min. 0 Si: Men: | (140-age) x (weight(kg))] / [(72 x serum creatinine (µmol/l) x 0.6786) Women: [0.85 x (140-age) x (wcc(kg))] / [(72 x serum creatinine (µmol/L) x 0.6786) ml/ek. 2

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Appendix B. General guidance for the follow-up of laboratory abnormalities from Sanofi

Neutropenia

__________I

Neutrophils < 1 50 £) / mm ³ with confirmed irynacs

1. STOP administration of investigational medicinal product, hospitalization should be considered

2. PERFORM more logical studies on infection

In both situations ^- PRO1SHFORM OBT Regional Clinical Study Monitor

4. STUDY previous treatments, especially long-term, even long-standing, exposure to toxic agents, e.g. benzene, x-rays, etc.

5. PERFORM and collect data on the following studies (results):

RBC and platelet count

Serology; Eli V, (HIV), mumps, measles, rubella

6. DECISION regarding bone marrow aspiration: carry out in a specialized department

7. FREEZE serum (5 ml to 2) on Day 1 (suspension of study drug administration) and Day 5 (for additional studies)

8. TRACK white blood cell count 3 times a week for at least one Week, then Twice a Month until then. until oyo nc is true sya to normal

Note:

the procedures described in the flowchart above are only to be discussed with the patient if the event is present. If necessary (according to regional regulations), additional consent (for example, for an HIV test) will only be obtained if the event actually exists.

For individuals of African descent, the relevant value for consent is 1000 mm ³ .

Types of neutropenia are only eligible for registration as AE if they:

symptomatic, and/or require either corrective treatment or consultation, and/or result in discontinuation or dosage adjustment of the IMP, and/or meet the criteria for severity [in which case the SAE should be reported

MT within 24 h] and/or identified as an Adverse Event of Special Interest (AESI).

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Thrombocytopenia

Platelets < 100,000/mm ³

Repeat count immediately (excluding EDTA anticoagulant in sample)

Platelets about 100 000/mm ³ with confirmed bleeding

Platelets ' 100 000 / mm ¹ bel confirmed bleeding

STOP injection

one.

2.

investigational medicinal product HOSPITALIZATION should be considered

2.

STOP administration of investigational drug EXamine for bleeding

In both situations

3.

four.

5.

6.

7.

INFORM regional clinical trial monitor

ASK about recent use of quinine (in drinks), alcoholism.

administration of heparin

PERFORM or collect data for the following study:

* Carry out a blood test, schizocytes. creatinine • Blood clotting time test (fibrinogen. RT. aPTT). fibrin degradation product • Serological method of the day of gnostics and viral infections: ERV. HIV. mumps, measles, rubella FREEZE serum (5 mc x 2) on Day I (end of treatment) and Day 5 to test for drug-induced platelet antibodies

DECISION regarding bone marrow aspiration: carry out in a specialized department

On Day 1 in case of associated anemia and/or leukopenia • On Day 8 if platelet count remains < 50 000/mm’*

8. TRACK your platelet count every day for at least one week and then regularly until it returns to normal

Note:

the procedures described in the flowchart above are only to be discussed with the patient if the event is present. If necessary (according to regional regulations), additional consent (eg for H1V testing) will only be obtained if the event is actually present.

Types of thrombocytopenia should be recorded as AEs only if they are: symptomatic, and/or require either corrective treatment or consultation, and/or result in discontinuation or dosage adjustment of the IMP, and/or meet the criteria for severity [in which case, an SAE should be notify MT within 24 hours], and/or identified as an adverse event of special interest (AESI).

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Increasing the content of ALT

ALT ^3 ULN (if ALT " start time change L7..V/ Or. ALT 3 2 times the value at start time (if AL T at start time _ L7.A7 one FILL

ALT _ 5 ULX feciii ALT ALT _ 3 times the value at the start time "seat alt at the start time vrgyyash PLt (er'NG-I.T at the start time * ΙΊΜ Or, ALT 3 times the initial time at the start time

ALT at initial time t'LM special form CRF regarding liver injury” and INFORM MONI Goring Group within 24 hours

Total bilirubin 2 ΙΊ.Ν

.....-t___________

Total bilirubin 2 ΙΊ.Ν

Track LFT

If not possible every 48 hours

STOP TEST INTRODUCTION

MEDICINAL

DRUG

Administration of the investigational medicinal product may be continued provided that: when closely monitored, no stopping conditions are observed

IN THE VLKDYUM CASE. FOLLOW instructions ##1-6. listed in the box below

I STUDY, especially in case of malaise with loss of consciousness. dizziness and. or hypotension drank with or without arrhythmia. the previous 72 hours, excluding muscle damage

EXECUTE THE FOLLOWING

- LFT AST. ALT. alkaline phosphate. total and conjugated bnirubpn and clotting time INR

SRK. serum creatinine, complete blood count

- IgM to HAV. IgM to HBs. antibodies to HCV and HCV RNA. IgM to SMU and IgM to NU.

- Autoantibodies: to “.dram, to DNA. to smooth muscles, to LKM

Depending on the clinical context, screening for recent EVE infection. herpes viruses and toxoplasma

- Hepatobiliary ultrasonography I can be performed through other imaging studies at the required tn)

CONSIDER the issue of consultation v temrnJioia

CONSIDER hospitalization if INR 2 (inn PT- 50%) indicates central nervous system abnormalities suggest hepatic encephalopathy

TRACK!, FT ' '

- If study drug is continued every 4 hours until return to normal ( 21 I.Nl or baseline value) study protocol

- If the visdepis of the study drug is stopped.1drugs>P1<by the drug: with a frequency as close as possible to 48 hours, until stabilization, then every 2 weeks until the increase to the norm t 21 jI.ΝΊ shi to the value at the initial time titi of at least 3 month, depending on the οι of that, 'to comes last.

ΊΛΜΤTHZIT blood serum (5 ml X 2)

Note: In addition, once a severity criterion is observed, the event must be notified to the monitoring team within 24 hours.

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Acute renal failure

A sharp increase in serum creatinine above 150 µmol l or a sharp decrease in creatinine clearance below 50 ml mn

You can drastically change back:

• Saturation of the volume • Relief of obstruction of the urethra (according to the etiology)

Cannot be abruptly changed back:

• Incidence of exacerbation of life-threatening symptoms of ARF: anemia, hypercalsmia. hyperuricemia. meschbolic acidosis, heart failure, pulmonary edema, arrhythmias. D1C, etc.

• And or predominant elimination of study drug via the renal route

1. Investigational drug administration can be continued

2. TRACK your serum creatpin! ke of blood before returning to the value at __initial time__

2.

four.

11INFORM1SUPPLY pei clinical trial monitor STOP administration of investigational medicinal product

HOSPITALIZATION should be considered and the recommendation of a nephrologist should be sought

PERFORM the following examinations:

BP. H.R. hydration status. ECG

Blood analysis

Liver function test IBS

Biochemistry including urine

Analysis of urine

FREEZE blood serum (5 ml X

2) '

TRACK renal function until it returns to baseline (at first every day, then every week)

Acute renal failure should only be reported as an AE if it is: symptomatic, and/or requires either corrective treatment or consultation, and/or results in discontinuation or a change in IMP dosage. and either satisfies the severity criteria [in which case the event (SAE) must be reported to the MT within 24 hours] and/or is identified as an adverse event of special interest (AESI).

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Suspicion of rhabdomyolysis

You complete: b IBS ______ ... 1,—________

With an increase in the value of the SRC Ha equivalent to ULN)

Kechi will chime in. TC inform the regional monitor of the clinical trial and ___________ I ______________________

STUDY regarding origin:

- EXECUTE:

• ECG • IBS-MH-MM • Troponin • Creatinine

Analysis for the level of ions (K . Ca ^: I) * Transaminases ι Total and conjugated b i.tiru b and i • Myoglobin (in serum and urine)

- FREEZE BLOOD SERUM (5 ml x 2) for RK • INTERVIEW the patient about recent intense muscle effort, trauma. convulsions, electrical trauma.

skeletal muscle injury or stress, multiple intramuscular injections.

recent surgery, concomitant medications, alcohol, morphine, cocaine use.

- LOOK for alternative causes of cardiac or muscle toxicity, eg: stroke, pulmonary infarction, dermatomalosis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular dystrophies.

If the presence of either cardiac myolysis or rhabdomyolysis is confirmed. or if IBS is 10 CLN:

I [RESTORE administration of investigational medicinal product

MONITOR IBS every 3 days for the first week, then once a week until return to normal or at least 3 months

I OCI1ITALIZA1 (IR) to be considered

Ehln excluded the presence of mio.sh for the heart' ^Ί ' or rhabdomyolysis n if IBS 10 ULN:

MONITOR IBS every 3 days for the first week, then once a week until return to normal or less than 3 months

Suspicion of rhabdomyolysis should only be recorded as AE if it becomes: symptomatic, and/or requires either corrective treatment or consultation, and/or results in discontinuation or dosage changes of the IMP. and either satisfies the severity criteria [in which case the event (SAE) must be reported to the MT within 24 hours] and/or is identified as an adverse event of special interest (AESI).

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Appendix C. Fallback Plan for SAE and Other Investigator Rapid Reporting of Process Reported Events When the e-CRF System Is Not Working

Ise kushch mm rchtsrgkmgme! n slstesho ^; Ishg

N-ich’P ^ > chngyungn fprm SAL

Lkl for * GN |‘] and ‘MZHN1 1’ F ISH’P ff’|<1

ble x

And' IC'CEUK’ •w·

I Сг ^,р Π 1 Ш ' k^wi fewtftW·

^^featured ^! i iG-wp peshm Ί4ΐ tr re O'P1ILU.'' ιι

CRI'p j

GgPUSHISCHSH t'tsishsksh h m "'gchien ^ A nt

V^r "delak g * Upon receipt of the SAE and Friday or the first day before any I prt'ishidam, the SAF report must be sent to the S-A GPE on the same desh.

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Appendix D. Treatment-Related Measure of Influence for Diabetes (TRIM-D) (For informative purposes only)______________________________________________

Stravila Study ID: Nizit: Ichattafixxshoshzdj patient number Tsata (dd'mostpt) __1___J____

Liver-related measure of influence - diabetes (TRTM-D)

The following questions are related to the MEDICINE you are taking for diabetes. If you are taking more than one medication for diabetes, or if you are taking medication for other circumstances, please consider only your MEDICATION when answering these questions.

Please circle the answer that best describes how you have handled your MEDICATION for the PAST TWO WEEKS. Please mark only one number for each question. Remember, there are no right or wrong answers to these questions.

one. Nyasvdiso DOEIJDLI IMI E[^[W(1VM|sNybyO1 EC Skzdg Schooly to some extent rb®A1etfs)) Simplicity and convenience of receiving your ' meditative .................................................... one 2 3 four 5 Ί How comfortable or dissatisfied Sgmaam not iieAfjfWJjritt fgdo.ihkhmyu You: comfortable a. Carry Our Medicine And Materials medical appointment with Vann.................................................................. .. one four b. Store your medication .............................. one 2 3 four 5 With. Take your medication the right way ] 2 , four ................................................. ........... d. Prepare your medication for I -i -, four apply .................................. e. Monitor your blood sugar levels as often as needed.................. one 2 four 5

3 How often do you take your MNDICAMEMENTD mtragivdet tut>t ns aaTrappist OursGNazou): yamaha Agatha Z7«?4wn Atexio' a. Prima time planning one 3 four 5 food ......................................... b. social one 2 3 four 5 activity.......................

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Page Study ID: Vili: Patient identification number Tsat (dd ¹ mesp) I 1

In some

Not at all Slightly Degrees Very Extremely pleased / a) oooolen (a) aovolen<a> ooolen (a1 oolen (a) i !astzlk0 Are you satisfied or unhappy with the newobios p.u MEDI K AM EH ‘ J L:

Helping you control your diabetes ..............................................

b I Iomoibh. You Avoid High Blood Sugar (hyperglycemia) .............................................. c Help you avoid low blood sugar (hypoglycemia) .................... one one 2 3 3 four four $ 5 d Help you manage your one h four 5 the weight ......... f Help you prevent feeling set up GO INSUFFICIENT ^nerpsh...................... one four 5 5 Because of your MEDICATION. Nobody Almost Posti AVcW How HOUR THAT: Reska Much Often Nicoma Totala a. 11neither should you limit your h four 5 daily activities.............. b Are you doing less than you would like to one 3 four L would . . ... . ................... Do you feel tension in your relationships with friends or one 7 3 four h family....................... 6 When talking about your MEDICATION, how Never Nenki ί Chnogoa Often Nearly often you Nearly all 11 kohoa Totala a Proceeding DotA ............... ..... one Ί h four 5 b Delay or delay taking one Your medikampg.......... With. You are taking your medication at the wrong time the time that is written ___________ one 3 four d. Feel embarrassed type awkward while taking your medication. .. one 3 four S e. Worry about what you forgot TipillIKTb'lLTJI missed your one 2 3 four 5 last dose.............. Page [D studies: Visit: Idea ification Tzata (da'mes'tt) patient number . . I I 7. Kot yes I take MEDICATION against Nikogoa' Nearly diabetes, I feel: Nearly Rarely Inogoa Often always·' Never Is always a. Depressive........................ one I. 3 four 5 b. Those who are worried that the medication is not nowraei slow down or prevent one 7 3 four 5 complications from my Diabetes ............................................... With. Nervously cry one Ί 3 four 5 anxious ........................................ d. Worried about my control one 2 3 four 5 blood sugar level ............................... e. Unhealthy ................... one 7 .3 four 5 f. Evil...................... one 7 3 four 5 g. Worried about side effects pt of my medicine..................... one 2 3 four 5

Thank you!

Annex E. EuroQoL Quality of Life Questionnaire (EQ-5D).

(For informative purposes only).

By placing a check mark in one of the boxes in each group below, please indicate which statement best describes your current state of health.

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Mobility

I have no problem walking—1

I have some walking problems□

I'm bedridden

Self-servicing and using

I have no problems with self-service□

I have some problems with washing or dressing myself Q

I am unable to bathe or dress myself

Ordinary activities (e.g. work, study, OOM work, family or leisure activities)

I have no problem doing my normal activities

I have some problems running my normal Q activity

I am unable to perform normal activities

Pain/discomfort

I have no pain or discomfort

I have moderate pain or discomfort

I have extremely severe pain or discomfort

Anxiety/depression|jussia

I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed □

I was in the best state of health imaginable

To help people tell how good or bad a state of health is, the authors of this study drew a scale (rather like a thermometer) on which the best imaginable state is marked as 100 and the worst imaginable state is marked as 0.

The authors of this study would like to for you to indicate on this scale how good or bad your state of health is today, in your opinion. Please do it. by drawing a line from the box below to some point on the scale that indicates how good or bad health is today.

Worst imaginable consisted of health problems

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Appendix F. Effect of weight on quality of life (IWQOL-Lite).

(For informative purposes only).

Effect of weight on quality of life.

Please answer the following statements by circling the number that best applies to you in the past week. Be as honest as possible. There are no right or wrong answers here.____________________ ____

Physical functioning ALWAYS TRUE USUALLY TRUTH SOMETIMES TRUE RARELY TRUE TOTALLY IE TRUE one. 1 lo because of my weight i have problems in lifting objects 5 four 3 2 one 2. Due to my weight, I have trouble tying my shoelaces. four four 3 one 3. Because of my weight, I have difficulty getting up from chairs. 5 four 3 one four. Due to my weight I have problems in isiolzopamine steps. 5 four 3 2 one _< Due to my weight, I have difficulty putting on or taking off my clothes, $ four 3 2 one &. Because of my weight, I have problems with my mobility (movement). 5 four 3 2 one 7, Due to my weight, I have trouble crossing my legs, ? four 3 2 one eight. I feel short of breath only on light exertion [eg. up one flight of stairs). 5 four 3 2 one 9. I worry about sore or numb joints. 5 four 3 one It). My ankles and lower legs swell at the end of the day 5 four 3 2 one II. I'm worried about my health. 5 four 3 one Self-esteem ALWAYS TRUTH USUALLY TRUE SOMETIMES TRUE RARELY TRUTH TOTALLY NOT TRUE one. Tso the reason for my weight I am embarrassed myself. $ four 3 2 one Because of the weight loss, my self-esteem is not what it could be. 5 four 3 2 one 3. Due to my weight, I feel insecure. 5 four 3 one four. Because of my weight, I don't like myself. 5 four 3 2 one 5. Because of my weight, I am afraid of being rejected. 5 four 3 2 one 6. Due to my weight, I avoid looking at myself in the mirror or looking at myself in photographs. 5 four 3 2 one 7, Due to my weight, I am embarrassed to be seen in public places. 5 four 3 2 one

Copyright, 2000. Duke University. All rights reserved.

Send all requests to:

K. wing | ΕΉΙ,ηΓιΠ ¹ < ik-mp diidiju.iJm nl 1 it. i .gulling ΐΙ'Ί* ”i'-.l i-iiiil·ГЧ1Г1ШП. XT Г h \ ΟΗΙ,ιΐΙ ___у___b __

14QJI -Lit -T!high-.h 1h LKL

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sexy live ALWAYS TRUE USUALLY TRUE SOMETIMES TRUE RARELY TRUE TOTALLY NOT TRUE one. But because of my weight, I don't enjoy sexual intercourse, four 3 2 one Due to my weight, I have psbskshshos or lack of sexual desire. S four 3 one FROM. But due to my weight I have difficulty with sexual function. four 3 2 one four. Due to my weight, I don't give up sex cats. according to possible ιu. S four 3 one

Psychological stress in society ALWAYS TRUTH USUALLY TRUE SOMETIMES TRUE RARELY TRUE TOTALLY NOT TRUE one. By reason of weight, I am dealing with ridicule, teasing, or rather than positive attention. four 3 2 one 2. Because of the bridge about the weight, I'm worried about that. to fit into seats in public places (ex. icarpax. movies iea fuck, restaurants, mi spikes or S four 3 one - ¹ - But because of my weight, I worry about passing through the aisles in the salons or the turnstiles. S four 3 one four. Because of my weight, I'm worried about that. to find seats strong enough to support my weight. four 3 one 5. Because of my weight, I deal with discrimination by others. four 3 2 one Work (11note: For those who do not have a paid job, oibci refers to your regular lei ic.ilhoc ih. ) ALWAYS TRUE USUALLY TRUE SOMETIMES TRUE RARELY TRUE TOTALLY NOT TRUE one. But because of my weight, I have trouble getting things done or meeting my obligations. four 3 one 2. On account of my weight, I am less heroic. than mot would OY1 L*. four 3 one But because of my weight, I'm not getting the pay increases, promotions, or job recognition I deserve. four 3 one four. But because of my weight I am afraid to go to job interviews. four 3 2 one

Example 2

Randomized, 30-week, active-drug-controlled, open-label, 3-treatment, parallel-group, multicenter study comparing the efficacy and safety of a fixed ratio combination of insulin glargine/lixisenatide with insulin glargine alone and with lixisenatide alone along with metformin in patients with type 2 diabetes mellitus (T2DM).

1. Abbreviations.

AE is an undesirable phenomenon,

ALT - alanine aminotransferase,

ANCOVA - analysis of covariance,

ARAC - Allergy Assessment Committee,

BMI - body mass index,

CI - confidence interval,

CMN - Cochran-Mantel-Hansel test,

FPG - fasting plasma glucose level,

IMP is an investigational medical product,

LS - least squares method, mITT - modified population depending on the prescribed treatment,

PPG is the level of glucose in the blood plasma after a meal,

RT is the preferred term,

SAE is a serious adverse event,

SMPG - self-measurement plasma glucose level,

SOC - system organ class,

T2DM - type 2 diabetes mellitus,

TEAE is an adverse event that occurs during treatment.

Study Title: Randomized. A 30-week, active-drug-controlled, open-label, 3-treatment, parallel-arm, multicenter study comparing the efficacy and safety of the combination with a constant ratio of insulin glargine/lixieenatide with insulin glargine alone and with lixiesnatide alone along with metformin in patients with type 2 diabetes mellitus (T2DM) __________________________________________________________________________________________

2. Synopsis

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Development Phase: Phase 3

Goals

Primary goal:

Demonstration is superior to combinations with idone insulin r:iapi II/lixisenatide supralixiseiagides but the change in glycated hemoglobin Ak (HbAlc) from baseline to week 30.

Demonstration of the non-inferiority of a fixed ratio combination of insulin glargine/lixissnghyd with insulin glargine in changing HbAlc from baseline to week 30.

Secondary Goals:

Evaluation of the effect of a combination with a constant ratio of insulin glargine / lixisen-gide compared with insulin rnapi in and lixiepatin alone for more than 30 weeks on:

- Percentage who achieved target HbAlc levels;

- Meal glycemic control as assessed by deviation of plasma glucose and plasma glucose levels 2 hours after ingestion

- Body weight;

- Fasting plasma glucose level (FPG);

-] fofnl concentration of glucose in blood plasma during self-monitoring at 7 points in time;

- Percentage of patients reaching target HbAlc levels without gaining body weight and/million documented symptomatic hypoglycemia:

* Dose of insulin glargine (in the combination and insulin glargine groups).

To assess safety and tolerability in each treatment group.

Methods: This study was an open-label, 2:2:1 randomized, active drug cohort, three treatment arms, a 30-week long-term/long-term treatment, a multi-Gruil international, and a multi-cell health care system. Randomization was stratified by HbAlc values at Visit 4. (<ZNR, >8%) and on the use of a second oral antidiabetic drug (CAD) at screening (Yes, Pet).

The study consisted of 3 periods: (1) A screening phase of up to 6 weeks (including a screening phase of up to 2 weeks and a 4-week run-in phase where eulfonylurea (SIJJ, g.tnnmd, sodium glucose cotransport type 2 inhibitor) (8(.11 /1-2) or the inhibitor of schistidnl-cectidase-D (DPF-4), if taken previously, was canceled and treatment with mesformin was optimized for a daily dose of at least 2000 mg or up to the maximum tolerated dose (> 1500 mg/day)) (2) 30-day period of open-label randomized treatment, and (3) 3-day post-treatment follow-up period.

Number of patients: Planned: 1125

Randomized: 1170

Receive 8 healing: 1169

Rated: Efficiency: 1167

Security: 1169

Diagnosis and Inclusion Criteria: Inclusion Criteria: Patients with type 2 diabetes mellitus (T2DM) diagnosed at least 1 year prior to the screening visit who were treated for at least 3 months prior to the visit with 1 metformin per ward with Eugene or MSCYurmin and a second oral prescription means, καιαρικ can be 8P. ι lipid, SG1.T-2 inhibitors, or DPP-4 inhibitor, and which were not adequately controlled by treatment, Key Screening Exclusion Criteria! I IbA 1 with <7.5% or> 10.0% in patients previously treated with metformin alone; 1 [bAI o <7.[]% or >9.0% in patients previously treated with metformin and a second oral antidiabetic agent: body mass index (BMI) <2C or >40 kg/m.

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Investigated Treatments

Investigational drug(s) (IMP): Study drug: constant ratio insulin glargine/lixisenatide combinations; controlled drugs: Insulin glargine (Lantus®) and lixisenatide

Compound:

Fixed Ratio Insulin Glergan/Lixisenatide Combination

The fixed ratio insulin ιlargmn/lixisenate combination (referred to herein as fixed ratio combinations) was supplied as a sterile aqueous solution in a pre-filled SoloSUrK disposable pen injector.

Two pens (A and B) with different fixed ratios were available to allow titration of insulin glargip from 10 U/day to 60 U/dep, using a limiting dose of lixnsepatide to µg·'day;

* Pen A contained 100 U/mL of insulin glargine and 60 μg/mL of lixisenatide in a 2:1 ratio (2 units of insulin glargine per 1 μg of lixisenatide). Doses could range from 10 units to 40 units in 1 unit increments, allowing daily combination doses of 10 U5 µg to 40 U/20 µg.

* Pen B contained 1(10 U/mL insulin glargine and 33 µg/mL lixisenatide in a 3:1 ratio. Doses could range from 30 units to 60 units in 1 unit increments, allowing daily combination doses from 30 IU / 10 mcg to 60 IU / 20 mcg.

The maximum daily dose was 60 units (60 units of insulin glargine and 20 micrograms of lnxisenatide).

insulin glargine

Insulin glargine was supplied as a sterile aqueous solution in a pre-filled disposable Lantus® SoloStar® pen-type injector (100 IU/mL). Doses could range from 1 unit to 80 units in increments of 1 unit. However, in this study, the maximum allowable daily dose of insulin glargine was 60 units.

Lixisenatide

Lixisenatide was supplied as a disposable prefilled pen (lixisenatide pen):

« initial dose 10 µg: disposable pen-injector device containing 3 ml of a sterile aqueous solution with 150 µg of the active ingredient (50 µg/ml), * 2D µg maintenance dose: disposable pen-injector device containing 3 ml of sterile aqueous solution with 300 µg active ingredient (100 µg/ml)

Route(s) of administration: Subcutaneous injection of all IMPs. The fixed ratio combination was self-administered using a pre-filled disposable SoloSlar® wide-handle injector. Insulin glargine was self-administered using a pre-filled disposable Lantus® SoloStar® pen-type injector. Lixisenatide was self-administered using a pre-filled disposable pen (lixisenatide pen).

Dosing regimen:

Constant Ratio Combination

The fixed ratio combination was self-administered once a day in the morning, within an hour (0 minutes to 60 minutes) before breakfast. Treatment was initiated with pen A with a daily dose of 10 units of insulin glargine·' 5 µg of lixissnatide.

insulin glargine

Insulin glargine was self-administered once a day at any time of the day, but at approximately the same time each day. The initial daily dose of insulin glargip during the first week of treatment was 10 IU.

Dose adjustment (fixed ratio combinations and insulin glargine)

The same dose adjustment algorithm was recommended for the fixed ratio combination with insulin glargine and was based on the patient's need for insulin. After the first week, the dose was titrated once a week to achieve and maintain a target fasting plasma glucose self-monitoring (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L). ), while avoiding hypoglycemia.

In the combination group, pen A was used with total daily doses of 10 units/day to 40 units/day and pen B was used with total daily doses of 41 units/dip to 60 units/dep.

Lixisenatide

Lixisenatide was self-administered once daily in the morning within an hour (0 minutes to 60 minutes) before breakfast or dinner.

Lixisenatide was started with injections of 10 mcg once daily for 2 weeks, and then continued at a maintenance dose of 20 mcg once a day from week 2 until the end of the treatment period.

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NIMP: Background treatment: Metformin

Ingredients: metformin tablets

Way(s) of introduction; Administered orally as directed on the label. approved at the regional level.

Metformin was the mandatory background therapy. If used, previous oral preti in diabetic agents other than metformin was discontinued at visit 2. Patients on all 3 ips of treatment continued to receive metformin during the study. The daily dose of mst(]yurmin was increased weekly during the run-in phase by increasing to 500 mg to a final daily dose of at least 2000 mg to the maximum tolerated dose, which should be >1500 mg/day to ensure randomization. treatment).

This dose was maintained until the end of the study unless there was a particular safety concern associated with these treatments.

Regular measurements and alerts from the central laboratory were selected to ensure that glycemic parameters remained within the predetermined thresholds set for emergency treatment. If the values were above these thresholds, no cause was found, or if appropriate measures did not help.

or a dose of >60 U was needed to bring glycemic parameters below cut-offs, then rescue therapy should have been given with IMP and metformin (if available). Newly initiated anti-diabetic drugs or an increase from the value at the initial time of the dose of metformin phonon was considered as emergency therapy

Duration of treatment: Up to 30 weeks

Duration of follow-up: Up to 37 weeks (up to 6 weeks screening period - 30-week randomized treatment period - 3-day follow-up period to evaluate safety after treatment)

Criteria for evaluation

Efficiency

Primary endpoint of potency: Change in HbAlc levels from liver at baseline to week 30.

Key secondary endpoints of effectiveness; percentage of patients with HbAlc <7% or £5.5% by week 30, change from baseline value to week 30 for 2-hour glucose deviation and 2-hour postprandial plasma glucose deviation (PPG ) measured during a standardized meal, fasting plasma glucose (FPG), body weight. as well as the average value of the concentration of SMPG in the profile at Ί points in time of the percentage of patients.

reaching HbAlc < 1% without gaining body weight by week 30; percentage of patients achieving HbAlc ≤7% without weight gain by week 30 and without documented symptomatic hypoglycemia during the treatment period; daily dose of insulin glargine by week 30.

Safety:

* Symptomatic gschll lyxmia

Documented: Typical symptoms of hypoglycemia with plasma glucose <70 mg/dL (3.9 mmol/L).

- Probable: symptoms of hypoglycemia without measurement of plasma glucose concentration, which was presumably due to the concentration of blood plasma glucose <70 mg / dl (3.9 mmol / l)

- Severe: an episode in which another person's assistance is required to actively administer carbohydrates, glucagon, or perform other resuscitative actions • Adverse events during the liver (TELE): serious TELE, TELE, leading to death. TELE, leading to discontinuation of treatment, undesirable events of particular interest (ie, elevated alanine aminotransferase [AMT], pregnancy, symptomatic 1MP/N1MP overdose), major cardiovascular events, potential events. associated with allergic reactions, events related to the pancreas (confirmed elevated levels of amylase/lipase > 2 x ULN, pancreatitis, pancreatic neoplasms), events related to confirmed elevated levels of calcitonin > 20 ng / ml (5.9 pmol / l ), pen-related events • Safety related laboratory data (general blood test, clinical chemistry, lipase/yampesh and calcitocin levels)

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statistical methods;

Achalic ef(|k;k1ivnis] was based on a modified treatment-dependent population (ιπΠΤ), using efficacy estimates collected during the study, including those obtained after discontinuation of b1P or administration of A population of hGHT total of all randomized patients who underwent both an assessment at baseline and at least one assessment after baseline of any of the primary or secondary efficacy variables.

The primary efficacy endpoint was analyzed for the applied repeated measures mixed effects model (MMRMM model included treatment groups, randomization strata, visits, interaction with treatment factor effect versus visit dependent and country as fixed affect factors and Factor HhAl c at baseline in oxidization from carina t to cocaria r. The shortened mean of change in ITA1 levels from οι levels at baseline to week 30 for each treatment group will be assessed within this model, as well as difference between groups and 95% CI for adjusted value.

A similar method, based on MMRM or ANCOVA, was applied with subsequent secondary efficacy endpoints, and the Cochran-Muntsl-Hsusl method, stratified by randomization strata, was applied with categorical efficiency skewed points. Procedure hierarchically! o ice ι grading was used for the purpose of conjpu.m error 1 tyne. As soon as they were beaten under 1nsrzhdsny, both joint ι u1sz: about ciathcjhhcckh a significant superiority of the combination with a constant ratio of insulin glargine inAxxissshiid over lixissiahid separately, and also about the non-inferiority of the combination with a constant ratio of insulin glargine'lyusnsenyatkd to insulin glorpshu separately for the primary efficacy endpoint , testing was carried out according to the following order: deviations in glucose levels at 2 hours and body weight in ORAEESpni with insulin glargine, FPG and mid-day SMPG profile changes at 7 time points in comparison with lixisspatide, toast on percentage superiority compared with insulin glorgine the share of panisEEGs. Achieving llbAlc <7% without adding body weight, UbAlc, average daily SAWG values in rofnlo at 7 time points, percentage of patients. achieved HbAlc’ <7% of body weight gain n without documented symptomatic gynor. subsequent tests were not performed.

Short description:

Population Characteristics: A total of 1170 patients were randomized to one of three treatment groups (469 in the insulin glargine lycoiseEshtnd combination with continuous dose, 467 in the insulin glargine n group, 234 in the lycom se nagida group).

One patient was not exposed to study treatments (patient request) and 3 jtg raided patients were included in the mITT population due to lack of efficacy data after baseline. Demographics and characteristics at baseline were broadly similar among the three treatment groups. Average voz]>ast was 59.0 lay down. the mean duration of diabetes was 9 years and the mean BMI was 32 κι/ ^mg . The study population was predominantly Caucasian (90.1%) and 49.4% of the echopsy patients were women (GNB 3).

Efficacy ratio results:

Primary efficacy endpoint:

The primary objectives of the dashuto study were met as non-inferiority and superiority of fixed ratio combinations compared with insulin j shp1 in in changing HbAlc or cream eh and by week of ON were demonstrated. l also statistical and pt output then combinations with a constant carrier over lixisenate.

Change in the average value determined by the method of least squares (LS). from time base to week 30 in HbALc levels were -1.63% for the constant-match combination group, -1.34% for the insulin glargine n group and -0.85% for the lxnsepatada group, reaching mean HbAlc levels of 6.5% 6.836 and 7. 3% to pedal 30, respectively.

Statistical superiority of the constant ratio combination over lxnssnatidog was demonstrated for the combined primary endpoint (difference in mean values determined by the LS method, but compared with jmktshnashd - * 058% 95% CI - [from -0.898% to -0.665%]). p<0.0001).

The mean LS mean difference between the combination group and the insulin glargine group was -0.29% 95% CI=Tor-0.384% to -0.194%]. Based on the primary analysis with pre-set parameters, there was less efficacy in the combination group than in the insulin glargine group, because the upper limit of the 2-sided 95% CI for the mean difference determined by the LS method. was below the pre-established threshold of non-inferiority of 0.3%. C1<trnsp:cheik.k prvosheadstas of the combination over insupin v largine was also demonstrated for this combined primary endpoint (sacristy of mean values determined by the LS method compared with chrushui insu. uipa yarhnnd - -0.29%;, difference *-0.0001), based on the hierarchical testing procedure.

Secondary efficiency points:

Significantly more patients treated with the constant ratio optene combination achieved Illi AI with <796 compared with patients receiving insulin ι batches or lixisenakhide: 73.7%, 59.4% and 33%, respectively. The proportional difference (95% CI) compared with mhcv;ihhom khahyarchin was 14.31% (8.37% to 20.25%) and 40.61% (33.63% to 47.59%) compared with lixisenyahmdom.

In addition, the proportion of patients achieving an HbAlo <6.5% was significantly higher in the combination group (55.8%) than in the ineulipa glargEEa group (39.5%) and the lixnseiatide group (19.3%). (95% CI) and compared with insulin glargpa was 16.35% (from 10 _; 13% to 22.58%) and 36.38% (from 29-81% to 422) 5%) compared with lixisenagide.

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Treatment with the combination significantly improved postprandial glycemic control with a standardized liquid breakfast compared with insulin glargine, as shown by the results for glucose deviations at 2 hours (LS mean change was -2.31 and -0.18 mmol/L, respectively). LS mean difference (95% CF vs & insulin glargine = -2.13 mmol [-2.498 mmol/L to -1.770 mmol/L] p<0.0001) For PPG assessment at 2 hour, the mean change in LS method was -5.68 and -3.31 mmol/L, respectively, and the difference in mean values determined by LS method [95%CI] compared to insulin glargine was -2.3 mmol /l, [from -2.794 mmol/l to -1.963 mmol/l]). The corresponding results for the .ticineenatide group were -3.23 mmol/L in terms of mean change in LS method for glucose deviations at 2 hours and -4.58 mmol/L in terms of mean change in 1.S method. , for PPG after 2 hours; difference in mean values determined by the LS method [95% CI|] between the combination and lxnsenatide = 0.91 mmol/l [from 0.448 mmol/t to 1.377 mmol/l] n -1.11) mmol/l [from -1.627 mmol 'l lo -0.573 mmol/l]), respectively.

Wee body weight decreased in the constant ratio and lnxisepatkda combination groups and increased in the insulin glargine group with a change in mean body weight determined by the LS method from baseline to week 30 -0.29 kg, -2.30 kt and -1. 10 kg for each group, respectively. A statistically significant difference in body weight change from baseline to week 30 was found in the fixed ratio combination group and the insulin glargine group (LS method mean difference -1.40 kg; 95% CI: [-1.891 to -0.910 ]: p<0.0001).

The reductions in mean LS values from baseline to week 30 in FPG were similar in the ipynne constant ratio combination (-3.46 mmol/l) to the ipsulip glargine group (-3.27 mmol/l) and it was lower (-1.50 mmot/L) in the lixisenatide group. The difference in mean values determined by the LS method for ipvruitj constant ratio and compared with ιργιιπυϋ insulin glargine was -0.19 mmol/l. 95% CI: [-0.420 to 0.038]. p ^_ 0.1017). and compared with the yanconsepatide group, it was significantly higher (LS mean difference *1.96 mmex/.g, 95% CI; [-2.246 to -1.682]; p<0.0001).

The 11 patients treated with the constant ratio combination had a statistically significant greater decrease in the mean SMPG profile at 7 time points compared to patients treated with insulin glargine and patients treated with lixnsnatnd, respectively (difference in mean values determined by the LS method compared with glarish insulin group -0.69 mmol^c, 95% CI: [-0.892 to -0.495], p <0.0001; difference in mean values determined by LS method compared with ^{lixnssnatndom} -1.40 mmol/l, 95 % CI: [-1.645 to -1.15BJ; p<0.0001). The graphical representation of the SXUO profiles at 7 points shows a significant decrease in plasma glucose concentration at all time points by week 30 compared to the initial time point in all treatment groups. After 30 weeks of treatment, the SMPG profiles at 7 time points showed that the mean values at all time points were lower in the constant ratio combination group compared to the insulin glargine group (except for a similar value before breakfast) and the .ticoioendtide group, respectively (Figure 4 ).

A higher proportion of patients achieved the combined endpoint IlbAlc <7.0% without gaining body weight in the fixed ratio combination group (43.2%) compared to the insulin glargine group (25.1%) and lixisenatide group (27.9%), respectively (proportional difference vs. insulin glargine - 18.08% 95% CI - [12.15% to 24.01%]. p<0.0001: proportional difference vs. ^{lycoisspatide _} 15.22% 95% CI - [8.05% to 22.39%]), and the difference between the combination group and the insulin glargine group was moderately significant. More patients achieved a triple combined end-race HbAlc <7.0% without weight gain by week 30 and without documented (plasma glucose concentration <70 mg^L [3.9 mml/L]) symptomatic spoglycemia during the ipymie combination study ( 31.8%) versus insulin margine ipyuiioii (18.9%) and lixisenatide ipymioft (26.2%), respectively (proportional difference versus insulin ^glargine 12.98% 95% CI ^_ [from 7.50 % to 18.45%], p<0.0001; the proportional difference compared to lixiseiatide was 5.61%, 95% CI was [from -1.33% to 12.55%], and the difference between the combination groups and the insulin glargine group was statistically significant.

At week 30, the mean dose of insulin glargine was similar between the fixed ratio combination group and the insulin glargine group (fixed ratio combination: 39.77 1; Insulin glargium: 40.46 KD: LS method mean difference of -0.69 U ;95% 01 - [-2.632 to 1.252); p-0.4857) (Figure 8).

Seventeen (3.6%) patients in the fixed ratio combination group, 16 (3.4%) patients in the insus/glargine group and 29 (12.4%) pacisitop in the lixisenatide group received rescue therapy.

Safety Results

The fixed dose combination was well tolerated during the 3-week period of treatment; the security profile of the combination group reflected the profile of the EC components.

A total of 267 (56.9%) patients in the fixed ratio combination group, 227 (48.6%) patients in the insulin glargine group, and 157 (67.4%) patients in the lixisenatide group reported post-treatment adverse events. .

The most commonly reported adverse events (AEs) (RT>5%) in the constant n-ratio combination groups of insulin glargine and lixisenatide were nausea (9.6%, 3.6%, and 24%). diarrhea (9.0% 4.3% and 9.0%) and upper respiratory infection (7.0% 4.9% and 5.2%).

The overall incidence of gastrointestinal adverse events was 21.7%, 12.6%, and 36.9% in the combination, insulin glargine, and lixisenatide groups. respectively. Overall, 45 (9.6%) patients in the combination group experienced topgnot, compared with 17 (3.6%) in the insulin glargine group and 56 (24%) in the lixisene shda group.

In total, 6 patients experienced at least 1 TEAE resulting in death: 2 from the fixed ratio combination group (IG: metastatic lung cancer; congestive heart failure), 3 from the insulin glargine group (RT: acute myocardial infarction and acute

- 81 039114 pulmonary edema; oral squamous cell carcinoma) and 1 from the lixisenatide group (RT: death) (Table 21).

Serious ΤΈΑΕ was reported by a similar proportional number of patients in each treatment group: 18 (3.8%) patients in the combination group, 19 (4.1%) in the insulin glargine group, and 9 (3.9%) in the lixisenatide group (Table 22). ).

More patients discontinued treatment due to TEAE in the lixisenatide group (9.0%) than in the combination group (2.6%) or insulin glargine group (1.9%). Most of these withdrawals were due to gastrointestinal adverse events in the lixisenatide group (5.2%) compared to the combination (0.9%) and insulin glargine (0.2%) groups (Table 23).

Injection site reactions during the treatment period were reported by a similar low percentage of patients across all treatment groups (fixed ratio combination: (2.6%), insulin glargine: (1.7%), and lixisenatide: (3, 0%)) (Table 24). None of them were considered serious. One patient in the lixisenatide group had injection site redness that led to discontinuation of treatment.

Adverse events recognized by the Allergy Assessment Committee (ARAC) as allergic reactions possibly related to IMPs were reported in 3 patients (0.6%) (RT: urticaria) in the fixed ratio combination group, in 2 patients (0.9 %) (RT: anaphylactic reaction and urticaria) in the lixisenatide group and in one of the insulin glargine group. Three patients (0.6%) reported angioedema, all in the fixed ratio combination group, which was recognized by the ARAC as IMP related allergic reactions (Table 25).

There were no cases of pancreatitis explicitly recognized by the Pancreas Safety Assessment Committee (PSAC) (Table 26).

Two patients (0.4%) in the fixed ratio combination group, 7 patients (1.5%) in the insulin glargine group, and 2 patients (0.9%) in the lixisenatide group experienced TEAE, recognized by CAS as major cardiovascular events, during the period of receiving treatment (table 27).

One case of pancreatic cancer was reported in the insulin glargine group. No thyroid carcinomas were reported in any treatment group. One patient in the insulin glargine group reported a TEAE of elevated calcitonin (>20 pg/mL) compared to both the fixed ratio combination group and the lixisenatide group (Table 28).

No symptomatic overdose of IMP was reported in any of the treatment groups during the treatment period.

One patient in the fixed insulin glargine/lixisenatide combination group, 2 patients in the insulin glargine group, and 1 patient in the lixisenatide group experienced ALT elevation AE during the treatment period (Table 29). None of the phenomena fit the definition of Hay's law.

A total of 44 patients (fixed ratio combination: 25 (5.3%), insulin glargine: 10 (2.1%), and lixisenatide: 9 (3.9%)) reported 54 pen-related events , in the pen-related event questionnaire during the treatment period.None of these were associated with a clinical event (i.e., symptomatic hypoglycemia event, hyperglycemic adverse event, other adverse event) (Table 30).

27.3% of patients treated with the fixed ratio combination, 25.5% of patients treated with insulin glargine, and 6.4% of patients treated with lixisenatide reported 409, 338, and 46 symptomatic hypoglycemic events according to the determination protocol. on the page dealing specifically with hypoglycemia (Table 31). The number of symptomatic events per patient-year was 1.55 in the fixed ratio combination group, 1.29 in the insulin glargine group, and 0.37 in the lixisenatide group. When documented (<70 mg/dL) symptomatic hypoglycaemia was found, the event rate was 25.6% in the combination group, 23.6% in the insulin glargine group, and 6.4% in the lixisenatide group, with corresponding event rates by patient-year 1 .44, 1.22 and 0.34, respectively.

Only 1 event of severe symptomatic hypoglycemia was reported during the study and it occurred in the insulin glargine group.

Preliminary conclusions:

In conclusion, the primary objectives of this study were met as non-inferiority and superiority of fixed ratio combination versus insulin glargine in HbAlc change from baseline to week 30 was demonstrated, as well as statistical superiority of fixed ratio combination over lixisenatide. Fixed-ratio combination added to metformin for patients who were not well controlled with metformip, with or without a second OAD, significantly improved HbA1c levels and reduced 2-hour glucose and 2-hour PPG deviations, mean SMPG profile at 7 time points and body weight compared with insulin glargine. The combination also significantly improved HbAlc, FPG, mean SMPG concentration profile over 7 time points compared to lixisenatide.

In summary, fixed ratio combinations were well tolerated. Nausea was the most commonly reported adverse event in the combination group, but was reported less frequently than in the lixisenatide group. The incidence of symptomatic hypoglycaemia was similar in the combination treatment groups and lower in the lixisenatide treatment group with insulin glargine, as expected. The security profile for a combination group reflected the profile of its components.

The benefits of initiating treatment with the fixed ratio combination versus initiating treatment with either component alone in patients in whom OAD is not adequately controlled is therefore supported based on the benefits demonstrated for HbAlc and body weight versus insulin glargine. and for HbAlc, FPG, and gastrointestinal tolerance (descriptive analysis) versus lixisenatide.

3. Results.

3.1. Patients participating in the study.

3.1.1. Patient records.

Of 2457 screened patients, 1170 were randomized to one of three treatment arms (469 to the combination arm, 467 to the insulin glargine arm and 234 to the lixisenatide arm) at 240 centers distributed in 23 countries (Australia, Belgium, Canada, Chile, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Mexico, Poland, Romania, Russian Federation, South Africa, Spain, Sweden, Ukraine, United Kingdom and United States of America). The main reason for screening dropout was the HbA1c value at the time of

- 82,039,114 screening visits that were outside the protocol-defined range (653 [26.6%] of 2457 screened patients).

A total of 1169 randomized patients were treated openly and 1167 patients were included in the mITT population for efficacy analyzes (Table 1). One patient was randomized but not treated at the request of the patient. Three randomized patients (1 in each treatment group) were not included in the mITT population because they had no efficacy data after baseline.

Table 1

Analyzed populations

Constant Ratio Combination insulin glargine Lixisenatide Total randomized population 469 (100%) 467 (100%) 234 (100%) 1170 (100%) Efficiency Evaluation Population 468 (99.8%) 466 (99.8%) 233 (99.6%) 1167 (99.7%) Modified intent-to-treat population (mITT) Population for safety assessment 469 467 233 1169

Note: Patient data from the safety population are tabulated according to actual treatment received (as treated). For the efficacy population, patient data were tabulated according to their randomized treatment. There are no patients randomized in the group and treated in another study.

The study plan is described in Fig. eight.

3.1.2. Distribution of study participants.

table 2

Patient Distribution - Randomized Population

Fixed Ratio Combination (N=469) insulin glargine (\=467) Lixisenatide (N=234) Randomized and treated 469 (100%) 467 (100%) 233 (99.6%) Passed the open treatment period 440 (93.8%) 440 (94.2%) 205 (87.6%) Have not passed the period in open mode 29 (6.2%) 27 (5.8%) 28 (12.0%) Subject's decision to discontinue treatment 25 (5.3%) 17 (3.6%) 18 (7.7%) Reason for stopping investigational treatment Adverse event 12 (2.6%) 9 (1.9%) 21 (9.0%) Insufficient efficiency 1 (0.2¾) 0 3 (1.3%) Lack of adherence to protocol 8 (1.7%) 9 (1.9%) 4(1.7%) Lost to follow up 0 0 0 Other reasons 8 (1.7%) 9 (1.9%) 0 Status at the time of last contact during research live 467 (99.6%) 462 (98.9%) 233 (99.6%) Dead 2 (0.4%) 4 (0.9%) 1 (0.4%) Lost to follow up 0 1 (0.2%) 0

Note: Percentages are calculated using the number of randomized patients as the denominator.

3.1.3. Demographic data and baseline parameters.

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Table 3

Patient demographics and parameters at screening _____ or at study entry - randomized population _____

Combination with constant too [wearing (N=469) Insulin glargine (A = 467) Lixisenstide (N=234) Total (Ν=117β) Age (years) Number 469 467 234 1170 Mean value (SD) 58.2(9.5) 58.3 (9.4) 58.7(8.7) 58.4 (9.3) Median value 59.0 59.0 59.0 59.0 Minimum : maximum 18:79 25; 82 31:80 eighteen; 82 Age group (lay down) |n (%)| Number 469 467 234 1170 <50 86 (18.3%) 82(17.6%) 28 (12.0%) 196(16.8%) >50 to <65 250 (53.3%) 271 (58.0%) 147 (62.8%) 668 (57.1%) >65 to <75 121 (25.8%) 97 (20.8%) 53 (22.6%) 271 (23.2%) >75 12(2.6%) 17 (3.6%) 6 (2.6%) 35 (3.0%)

Gender [n (%)J Number Male Female 469 222 (47.3%) 247 (52.7%) 467 237 (50.7%) 230 (49.3%) 234 133 (56.8%) 101 (43.2%) 1170 592 (50.6%) 578 (49.4%) Race [a (%)] Number Caucasoids scoops Mongol oids/represents ate and eastern races Other 469 417 (88.9%) 33 (7.0%) 8(1.7%) 11 (2.3%) 467 421 (90.1%) 33 (7.1%) 7 (1.5%) b (1.3%) 234 216 (92.3%) 12(5.1%) 3 (1.3%) 3(1.3%) 1170 1054 (90.1%) 78 (6.7%) 18(1.5%) 20(1.7%) Ethnicity [n (%)' Number Hispanics Non-Hispanics one 469 85 (18.] "8) 384 (81.9%) 467 87 (18.6%) 380 (81.4%) 234 51 (21.8%) 183 (78.2%) 1170 223 (19.1%) 947 (80.9%) HbA1u (%) at the time of visit 1 (week -b) Number Mean value (SD) Median value Minimum : maximum 469 8.17 (0.70) 8.10 6.8; 10.4 467 8.20 (0.68) 8.10 7.0 10.0 233 8.28 (0.70) 8.20 7.0 10.0 1169 8.20 (0.69) 8.10 6.8 : 10.4 HNA 1c (%) at visit 4 (week-1). Number Mean value (SD) Median value Minimum : maximum 469 8.11 (0.67) 8.10 7.0 : 9.8 467 8.13(0.65) 8.00 7.0 : 10.0 234 8.16(0.69) 8.10 7.0 : 10.0 1170 8.13 (0.67) 8.10 7.0 : 10.0 Randomization strata but HbAlc ( %) at visit 4 (week 1) [n (%)], Number 469 <8 207 (44.1%) >8,262 (55.9%) 467 207 (44.3%) 26(1 (55.7%) 234 103 (44.0%) 131 (56.0'14) 1170 5L7 (44.2%) 653 (55.8%) Randomization strata for second OAD at screening [and (%)] Number Yes Not 469 291 (62.0%) L78 (38.0%) 467 288 (61.7%) 179 (38.3%") 234 146 (62.4%) 88 (37.6%) 1170 725 (62.0%) 445 (38.0%) Initial BMI (kgm') Number Mean value (SD) Median value Minimum : maximum 469 31.64 (4.40) 31.40 18.9:40.1 467 31.66 (4.51) 31.45 21.0:41.5 234 31.99 (4.39) 32.09 20.2:40.3 1170 31.72 (4.44) 31.53 18.9:41.5 Categories by initial BMI (kg/m ² ) [p (%)] Number <30 >30 469 174 (37.1%) 295 (62.9%) 467 179 (38.3%) 288 (61.7%) 234 75 (32.1%) 159 (67.9%) 1170 428 (36.6%) 742 (63.4%)

BMI - body mass index;

OAD is an oral antidiabetic drug.

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Table 4

Disease data and patient parameters at screening or baseline - randomized population

Fixed Ratio Combination (N=469) Insulin glargine (N=467) Lixisenatide (N=234) Total (N=1170) Duration of diabetes (years) Number 469 467 234 1170 Mean value (SD) 8.89 (5.51) 8.66 (5.59) 8.89 (6.26) 8.80 (5.69) Median value 8.14 7.60 7.65 7.69 Minimum : maximum 1.0 : 34.2 1.0:39.7 1.0 : 44.5 1.0: 44.5 Age of onset of type 2 diabetes (years) Number 469 467 234 1170 Mean value (SD) 49.3 (9.8) 49.6 (8.8) 49.7 (9.1) 49.5 (9.3) Median value 50.0 50.0 50.0 50.0 Minimum : maximum 14:75 17:76 22:74 14:76 History of gestational diabetes [n (%)] Number (women) 247 230 101 578 Yes (women) 20 (8.1%) 12 (5.2%) 6 (5.9%) 38 (6.6%) No (women) 227 (91.9%) 218 (94.8%) 95 (94.1%) 540 (93.4%) Duration of metformin treatment (years) Number 466 466 232 1164 Mean value (SD) 6.42 (4.85) 6.46 (4.70) 6.12 (4.45) 6.38 (4.71) Median value 5.25 5.45 5.45 5.37 Minimum : maximum 0.3 : 34.2 0.3 : 26.4 0.2 : 24.7 0.2 : 34.2

Daily dose of Metformin at baseline (mg)

Number 469 467 234 1170 Mean value (SD) 2246.1 (456.8) 2244.7 (444.7) 2267.3 (427.4) 2249.8 (445.9) Median value 2000.0 2000.0 2000.0 2000.0 Minimum : maximum 1000 : .3000 1000 : 3000 1000 : 3000 1000 : 3000 Categories for daily dose metformin at the start time (mg) [n (%)] Number 469 467 234 1170 < 1500 3 (0.6%) 4 (0.9%) 1 (0.4%) 8 (0.7%) >1500-<2500 283 (60.3°/.) 285 (61.0%) 139 (59.4%) 707 (60.4%) >2500-<3000 98 (20.9%) 98(21.0%) 55 (23.5%) 251 (21.5%) >3000 85 (18.1%) 80 (L7.l%) 39 (16.7%) 204 (17.4%) Application of the second OAD on moment of screening by class [n (%)] Number (yes) 274 (58.4%) 270 (57.8%) 133 (56.8%) 677 (57.9%) Sulfonylurea 259 (55.2%) 249 (53.3%) 123 (52.6%) 631 (53.9%) G.tincd 3 (0.6%) 10(2.1%) 5 (2.1%) 18(1.5%) SGLT-2 inhibitor 2 (0.4%) 2 (0.4%) 0 4 (0.3%) DPP-4 inhibitor 12 (2.6%) 11 (2.4%) 5(2.1%) 28 (2.4%) The duration of the second treatment OAD (years) Number 274 269 133 676 Mean value (SD) 3.98 (4.07) 4.61(4.67) 3.94 (3.54) 4.22 (4.23) Median value 2.59 3.26 2.49 2.82 Minimum : maximum 0.3 : 21.3 0.3 : 25.4 0.3 : 16.0 0.3 : 25.4 Previous application GLP-1 receptor agonist [in (%)] Number 469 467 234 1170 Yes 15 (3.2%) 21 (4.5%) 10(4.3%) 46 (3.9%) Not 454 (96.8%) 446 (95.5%) 224 (95.7%) 1124 (96.1%) Previous application insulin [p (%)] Number 469 467 234 1170 Yes 11 (2.3%) 14 (3.0%) 4(1.7%) 29 (2.5%) Not 458(97.7%) 453 (97.0%) 230 (98.3%) 1141 (97.5%)

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Diabetic retinopathy [n (%)] Number 469 467 234 1170 Yes 44 (9.4%) 27 (5.8%) 26 (11.1%) 97 (8.3%) Photocoagulation performed: Yes 4 (0.9%) 2 (0.4%) 0 6 (0.5%) Photocoagulation performed: No 39 (8.3%) 25 (5.4%) 23 (9.8%) 87 (7.4%) Photocoagulation performed: Unknown 1 (0.2%) 0 3 (1.3%) 4 (0.3%) Deleted 0 0 0 0 vitreous body due to diabetic retinopathy: yes Deleted 42 (9.0%) 27 (5.8%) 22 (9.4%) 91 (7.8%) vitreous body due to diabetic retinopathy: no Deleted 2 (0.4%) 0 4 (1.7%) 6 (0.5%) vitreous body due to diabetic retinopathy: unknown Not 416 (88.7%) 429 (91.9%) 199 (85.0%) 1044 (89.2%) unknown 9(1.9%) AND (2.4%) 9 (3.8%) 29 (2.5%) Diabetic sensory or motor neuropathy [n (%)] Number 469 467 234 1170 Yes 111 (23.7%) 98(21.0%) 51 (21.8%) 260 (22.2%) Not 347 (74.0%) 360 (77.1%) 180 (76.9%) 887 (75.8%) unknown 11 (2.3%) 9 (1.9%) 3 (1.3%) 23 (2.0%) Diabetic autonomic neuropathy [n (%)] Number 469 467 234 1170 Yes 5(1.1%) 5(1.1%) 3 (1.3%) 13 (1.1%) Not 450 (95.9%) 453 (97.0%) 224 (95.7%) 1127 (96.3%) unknown 14 (3.0%) 9 (1.9%) 7 (3.0%) 30 (2.6%)

Diabetic nephropathy [n (%)] Number 469 467 234 1170 Yes 33 (7.0%) 13 (2.8%) 8 (3.4%) 54 (4.6%) Renal failure (estimated MDRD GFR below 60 ml/min) 2 (0.4%) 0 1 (0.4%) 3 (0.3%) Microalbuminuria (30 mcg/mg to 299 mcg/mg creatinine) 23 (4.9%) 8 (1.7%) 7 (3.0%) 38 (3.2%) Overt proteinuria (equal to or greater than 300 micrograms per mg creatinine) 7 (1.5%) 5 (1.1%) 0 12 (1.0%) Not 424 (90.4%) 445 (95.3%) 218 (93.2%) 1087 (92.9%) unknown 12 (2.6%) 9 (1.9%) 8 (3.4%) 29 (2.5%) Albumin/creatinine ratio at baseline (mcg/mg) [p (%)] Number 466 466 234 1166 <30 (norm) 365 (78.3%) 380 (81.5%) 187 (79.9%) 932 (79.9%) >30-<300 (microalbuminuria) 89 (19.1%) 74 (15.9%) 41 (17.5%) 204 (17.5%) >300 (microalbuminuria) 12 (2.6%) 12 (2.6%) 6 (2.6%) 30 (2.6%) Creatinine clearance at screening (mL/min) Number 465 464 232 1161 Mean value (SD) 116.02 (34.99) 115.10 (36.25) 116.50 (33.12) 115.75 (35.12) Median value 109.93 107.86 114.02 110.42 Minimum : maximum 51.8:263.9 49.3:255.0 46.6:239.0 46.6:263.9 Categories of creatinine clearance (ml/min.) at the time of screening [n (%)] Number 465 464 232 1161 <15 (end-stage kidney disease) 0 0 0 0 >15 -<30 (great decrease in GFR) 0 0 0 0 >30 -<60 (moderate decrease in GFR) 4 (0.9%) 3 (0.6%) 3 (1.3%) 10 (0.9%) >60 -<90 (slight decrease in GFR) 117 (25.2%) 128 (27.6%) 44 (19.0%) 289 (24.9%) >90 (norm) 344 (74.0%) 333 (71.8%) 185 (79.7%) 862 (74.2%)

OAD - oral antidiabetic drug;

SGLT-2 - sodium-glucose cotransporter type 2;

DPP-4 - dipeptidyl peptidase 4;

GLP-1 - glucagon-like peptide-1;

GFR - glomerular filtration rate.

The creatinine clearance value is obtained using the Cockcroft-Gault equation.

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3.1.4. Dosage and duration of study drug administration. Table 5

IMP Exposure - Safety Assessment Population

Fixed Ratio Combination (N-469) Insulin glargine (N=467) Lixisenatide (N=233) Cumulative duration of treatment exposure (patient-years) 261.5 261.2 124.6 Duration of investigational treatment (days) Number 468 467 232 Mean value (SD) 204.1 (33.9) 204.3 (32.5) 196.1 (48.2) Median value 211.0 211.0 211.0 Minimum : maximum 2:252 1:249 6:224 Duration of investigational treatment by category [n (%)] Duration not specified 1 (0.2%) 0 1 (0.4%) 1-14 days 3 (0.6%) 4 (0.9%) 4 (1.7%) 15-28 days 3 (0.6%) 5(1.1%) 3 (1.3%) 29-56 days 6 (1.3%) 2 (0.4%) 7 (3.0%) 57-84 days 3 (0.6%) 2 (0.4%) 3 (1.3%) 85-126 days 6 (1.3%) 5 (1.1%) 4 (1.7%) 127-168 days 6 (1.3%) 4 (0.9%) 2 (0.9%) 169-210 days 113 (24.1%) 200 (42.8%) 66 (28.3%) >210 days 328 (69.9%) 245 (52.5%) 143 (61.4%) Albumin/creatinine ratio presented in µg/mg, which is equivalent to mg/g, and the coefficient

conversion to the standard international unit, mg/mmol, is 0.1130.

Combinations with „ ..

Insulin glargine Lixisenatide constant (N=467) (\=233) ratio (X=469)

Cumulative duration of investigational treatment by category [n (%)]

Duration not specified 1 (0.2%) 0 1 (0.4%) >1 dep 468 (99.8%) 467 (100%) 232 (99.6%) >15 days 465 (99.1%) 463 (99.1%) 228 (97.9%) >29 days 462 (98.5%) 458 (98.1%) 225 (96.6%) >57 days 456 (97.2%) 456 (97.674) 218 (93.6%) >85 days 453 (96.6%) 454 (97.2%) 215 (92.3%) >127 days 447 (95.3%) 449 (96.1%) 211 (90.6%) >169 days 441 (94.0%) 445 (95,374) 209(89.77-4) >211 days 328 (69.9%) 245 (52.574) 143 (61.4%)

IMP is an investigational drug.

Duration of exposure=(date of last open-label IMP injection - date of first open-label IMP injection)+1.

Note: Patients were considered to be in the treatment group they were actually assigned to at randomization.

Table 6

Number (%) of patients by final insulin dose at the end of open-label treatment - safety population

final dose of insulin Fixed Ratio Combination (N=469) Insulin glargine (N=467) <20 units 59 (12.6%) 43 (9.2%) >20 U to <30 U 76 (16,270) 96(20.67-4) >30 U to <40 U 126 (26.9%) 1 17 ( 25.174) >40 U to <60 U 208 (44.3%) 209 (44.8%) >60 units 0 2 (0.4%) 60 units 73 (15.6%) 94 (20.1%)

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Table 7

Number (%) of patients treated with a fixed ratio combination at the final dose of lixisenatide at the end of open-label treatment - safety population

Final dose of lixisenatide mcg >10 mcg to <15 mcg >15 mcg to <20 mcg >20 mcg

Combination with permanent (#469) (12.6%)

131 (27.9%)

275 (58.6%) (0.4%)

Pen A' < 10 µg >10 µg to <15 µg >15 µg to <20 µg >20 µg

Pen Syringe ^Bb >10 µg to <15 µg (12.6%) (16.0%)

104 (22.2%) (0.4%)

Final dose of psulpp

Youth Ratio Combination (#469)

Insulin glargine ”(λ=467)

<20u 59 (12.6%) 43 (9.2%) Pen syringe A ¹¹ <20 units 59 (12.6%) Or >20 U to <30 U 75 (16.0%) <30 U to <40 U 104 (22.2%) >40 U to <60 U 2 (0.4%) >60 units 0 ^Syringe pen B <20 units 0 Or <20 U to <30 U 0 >30 U to <40 U 21 (4.5%) >40 U to <60 U 206 (4.3.9%) '60 units 0

^a - 2 units/1 µg fixed ratio of insulin glargine/lixisenatide, intended for administration with daily doses of 10 to 40 units (10 units/5 µg to 40 units/20 µg);

^b - 3 U/1 µg fixed ratio of insulin glargine/lixisenatide, intended for administration with daily doses of 41 to 60 U (41 U/14 µg to 60 U/20 µg).

Note: Percentages are calculated using the number of patients in the denominator safety population.

3.2.1. Primary efficacy endpoint.

Table 9

Change in mean HbA1c (%) from time base to week 30 using the MMRM procedure - mITT population (Figures 1 and 2)

HbAlc(%) Fixed Ratio Combination (N=468) Insulin glargine (#466) Lixisenatide (#233) Start time Number Mean value (SD) Median value Minimum : maximum 467 8.08 (0.71) 8.00 4.5 : 10.2 464 8.08 (0.69) 8.00 5.9 : 10.4 233 8.13 (0.72) 8.00 6.7 : 10.3 Week 30 Number Mean value (SD) Median value Minimum : maximum 443 6.50 (0.75) 6.30 4.9 : 9.6 446 6.81 (0.76) 6.70 4.6 : 10.7 221 7.31 (0.87) 7.20 5.2:11.0 Change from start time to week 30 Number Average value obtained by the method LS (SE)“ ’ 467 -1.63 (0.038) 464 -1.34 (0.039) 233 -0.85 (0.052) Final dose of lixisenatide Fixed Ratio Combination (#469) <10 mcg 59 (12.6%) >15 µg to <20 µg 171 (36.5%)

^a - 2 units/1 µg fixed ratio of insulin glargine/lixisenatide, intended for administration with daily doses of 10 to 40 units (10 units/5 µg to 40 units/20 µg);

^b - 3 U/1 µg constant ratio of insulin glargine/lixisenatide, intended for administration with daily doses of 41 to 60 KD (41 U/14 µg to 60 U/20 µg). Note: Percentages calculated using the number of patients in the denominator safety population.

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Table 8

Number (%) of patients by final dose of lixisenatide at the end of open-label treatment - safety population

Final dose of lixisenatide Lixisspatide (N=233) mcg 26 (11.2%) mcg 207 (88.8%)

Note: Percentages are calculated using the number of patients in the denominator safety population.

3.2. Efficiency.

Table 10

Number (%) of patients with HbA1c value <6.5% or <7.0% at week 30 - mITT population

HbAlc (%) Combination with iosomnia ratio (>=468) Insulin Glargip (Ν=46ί) Dixisenatic (6=233) Number 468 466 233 <6.5% 261 (55.R%) 184 (39.5%) 45 (19.3%) Proportional difference (95% CI) vs. 16.35% (from 10.13% to insulin glargine 22.58%) - - 1 [proportional difference (95% CI) vs. 36.38% (from 29.81% lo lixisenatide 42.95%) - - <7% 345 (73.7%) 277 (59.4%) 77 (33.0%) I [proportional difference (95% CI) compared to 14.31% (from 8.37% lo insulin glargine ¹¹ 20.25%) - Proportional difference (95% CI) vs. 40.61% (or 33.63% before li xisen a t il om 47.59%) -

⁽ a) Weighted mean of proportional difference between treatment groups (constant ratio combination, insulin glargine, lixisenatide) from each stratum (HbA1c randomization strata [<8.0, >8.0%] at Visit 4 (week-1), randomization strata regarding the use of the second OAD at the time of screening [yes, no]) using Cochran-Mantel-Haenszel (CMH) values.

Proportional difference=difference in the proportion of patients achieving an HbA1c value of <6.5%, or <7%. All measurements at week 30 were used, including those taken after stopping MP or initiating rescue therapy. If no analysis was available at week 30 at all, then patients were treated as non-responders.

HbAlc (%) Fixed Ratio Combinations (N=46S) Insulin glargine (N=466) Zixisenatite (A=233) Difference in mean values determined by the LS (SE) method compared with insulin glargine* -0.29 (0.048) - - 95%CI (from -0.384 to -0.194) - - p-values <0.0001 - - Difference of mean values determined by I.S (SE) method in comparison with pixie senate id -0.78 (0.059) - - 95%CI (from -0.898 to -0.665) - - p-ZNE1CHSNIS <0.0001 - -

( ^a ) Repeated measures mixed effects model (MMRM) with treatment groups (constant ratio combinations of insulin glargine alone, lixisenatide alone), HbA1c randomization strata (<8.0, >8.0%) at visit 4 (week -one). randomization strata by using a second OAD at screening (yes, no), visit (weeks 8, 12, 24 and 30), treatment-visit and country interactions as fixed effects, and HbA1c value interactions at baseline-visit as a covariate. Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy. All patients for whom there are measurements at the initial time and after the initial time are excluded.

3.2.2. Other Key Performance Endpoints.

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Table 11

Mean Change in Plasma Glucose Variations at 2 Hours (mmol/L) During a Standardized Meal Trial from Time Base to Week 30 Using ANCOVA - mITT Population

Deviations in plasma glucose levels after 2 Combination with insulin glargine Lixisenatide hours (mmol/l) permanent (N-466) (N-233) ratio (N=468) Start time Number 428 425 192 Mean value (SD) 5.31 (2.86) 5.02 (2.96) 5.07 (2.54) Median value 5.20 4.90 5.00 Minimum : maximum -4.3 : 14.2 -4.7 : 14.5 -3.2: 12.2 Week 30 (14X11) Number 428 425 192 Mean value (SD) 2.81 (2.84) 4.80 (2.90) 1.70(3.23) Median value 2.80 4.70 1.05 Minimum : maximum -4.3: 12.3 -5.5 : 14.4 -5.0 : 10.2 Change from start time to week 30 (LOCF) Number 428 425 192 Mean value (SD) -2.49 (3.37) -0.22 (2.86) -3.37 (3.41) Median value -2.40 -0.10 -3.45 Minimum : maximum -12.2 : 10.1 -13.1 : 7.9 -12.4 : 4.8 Average value obtained by the LS (SE) method ^a -2.31 (0.154) -0.18 (0.157) -3.23 (0.216) Difference of mean values determined by LS method -2.13 (0.185) - - (SE), compared with insulin ι batch ¹ 95% st (from -2.498 to -1.770) - p-value <0.0001 - - Difference of mean values determined by LS method 0.91 (0.237) - - (SE) versus lixisenatide 95%CI (from 0.448 to 1.377) - -

LOCF - last observation data transfer;

^a - Analysis of covariance (ANCOVA) model with treatment groups (constant ratio combinations, insulin lixisenatide). HbA1c randomization strata (<8.0%. >8.0%) at visit 4 (week -1). by randomization strata for use of the second OAD at screening (yes, no), and by country as fixed effects factors and baseline value for 2-h plasma glucose abnormalities as covariates. Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more. The analysis included measurements collected during the course of the study, including those obtained after the final cessation of rescue therapy. Patients treated with IMP in the morning in the lixisenatide group and all patients in the fixed ratio combination or insulin glargine groups with both baseline and week 30 (LOCF) measurements were included.

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Table 12

Change in mean course of plasma glucose 2 hours postprandial (mmol/l) during a standardized meal trial from baseline to week 30 using ANCOVA - mITT population

Level 1.1 of yukota and blood plasma 2 hours after a meal (mmol/l) Fixed Ratio Combination (NM6S) Insulin ί largn (N=466) Lixisenatide (N=W) Start time Number 430 430 196 Average value (SU) 15.10 (3,&3) 14.61 (3.64) 14.72 (3.32) Median value 15.20 14.50 14.70 Minimum : maximum 3.1: 24.6 4.4: 26.6 4.9 : 24.1 Week 30 (LOCF) Number 430 430 196 Average value (SU) 9.15 (3.20) 11.35 (3.12) 9.99 (3.91) Median value 8.90 11.20 9.45 Minimum : maximum 2.8:24.0 3.3 : 19.9 4.0: 25.8 Change from early point in time to week 30 (LOCF) Number 430 430 196 Mean value (SD) -0.0*1 (4.27) -3.26 (3.54) -4.73 (4.11) Median value -6.00 -3 35 -5.05 minimum maximum -18.1 : 6.7 -17.2 : 6.3 -13.8:8.4 Average value obtained by the LS (SE) method“ -5.68 (0.176) -3.31 (0.178) -4.58 (0.245) The difference between the average values determined by the metol -2.38 (0.212) - LS (SE) versus insulin glargine ¹ 95%CI (from -2.794 to 1.963) Difference of average values determined by mvgo;um -1.10 (0.269) - LS (SEX versus lixisspatide* 95?'" CI (from -1.627 to 0.573) -

LOCF - last observation data carry forward.

( ^a ) Model analysis of covariance (ANCOVA) with treatment groups (constant ratio insulin glargine/lixisenatide combinations), randomization strata for HbA1c (<8.0%, >80%) at Visit 4 (week -1), randomization strata for use second OAD at screening (yes, no), and country as fixed effect factors and base time value for plasma glucose at 2 h as covariate. Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more. The analysis included measurements collected during the course of the study, including those obtained after permanent cessation of IMP use or the introduction of rescue therapy. Patients treated with IMP in the morning in the lixisenatide group and all patients in the fixed ratio combination or insulin glargine groups with both baseline and week 30 (LOCF) measurements were included.

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Table 13

Change in mean body weight (kg) from baseline to week 30 with MMRM - mITT population (Fig. 3) Body weight (kg) Combination e constant ratio (^6H) Targpi ipsulia (^=466) Lixpsenatpt (14=233) Start time Number 467 465 233 Average value (SB) 89.44 (17.16) 89.75 (16.34) 90.79(16.25) Median value 88.90 88.50 91.00 Minimum : maximum. 46.7:147.0 47.4 : 137.3 54.3 : 144.0 Week 30 Number 448 446 222 Average value (S1D) 89.16 (17.34) 90.68(16.03) 88.57 (16.20) Median value 88.00 89.00 88.90 Minimum : maximum 45.2 : 145.5 51.2:143.6 53.5:152.3 Change og initial time to 30 weeks Number 467 465 233 Average value obtained by the LS (Sit) method ¹¹ -0.29 (0.182) 1.11 (0.183) -2.30 (0.256) Difference of average values determined by the method -1.40 (0.250) - LS (SE). compared to insulin glargine ¹ 95%CI (from -1.891 to 0.910) - - p-value <0.0001 - - Difference of average values determined by the method 2.0L (0.307) - LS fSE). compared to lixisspatide ⁰ 95% a (from 1.404 to 2.609)

( ^a ) Repeated measures mixed affect model (MMRM) with treatment groups (constant ratio combinations of insulin glargine alone, lixisenatide alone) (<8.0%, >80%) at visit 4 (week -1), randomization strata with respect to the use of the second OAD at screening (yes, no), scheduled visit, treatment-visit and country interactions as fixed effects, and base-time-visit body weight interactions as covariates. Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more. The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy. All patients for whom measurements are available at the start time and after the start time are included.

Table 14

Change in Mean Fasting Plasma Glucose (mmol/L) from Time Base to Week 30 Using the MMRM Procedure - mITT Population (Figures 4 and 5)

Fasting plasma glucose (mmol/l) Fixed Ratio Combination (N=468) Insulin glargip (N=466) Lixisspatid (N=233) Start time Number 465 465 232 Mean value (SD) 9.88 (2.34) 9.75 (2.33) 9.79 (2.16) Median value 9.70 9.30 9.70 Minimum : maximum 4.3 : 17.8 4.7: 21.5 5.5 : 19.4

Table 15

Mean versus mean SMPG concentration profile across 7 time points (mmol/L) from baseline to week 30 using the MMRM procedure - mITT population (Fig. 6)

Mean SMPG over 7 time points (mmol/l) Combination with permanent ratio (N=468) Insulin glargine (N=466) Lixisenatide (N=233) Start time Number 421 411 204 Mean value(SD) 10.47 (2.15) 10.31 (2.15) 10.41 (2.01) Median value 10.03 10.07 10.33 Minimum : maximum 5.2 : 16.8 5.8 : 18.3 6.0 : 17.2 Week 30 Number 382 368 184 Mean value(SD) 7.09 (1.25) 7.75 (1.49) 8.54 (1.79) Median value 6.90 7.49 8.42 Minimum : maximum 4.9 : 13.6 5.0 : 15.5 5.4:18.1

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11for 30

Number Mean value (SD) Median value Minimum : maximum 436 6.32(1.47) 6.00 3.1 : 14.3 438 6.53(1.76) 6.20 3.3 : 15.9 216 8.27 (2.24) 8.00 3.2 : 24.4 Change in si from the beginning of time until week 30 Number Average value obtained by the LS method (SF) ^H Difference of average values. LS(SE) versus insulin glargine ³ 95% CI p-value 465 -3.46G0.09S) -0.19 (0.117) (from -0.420 to 0.038) 0.1017 465 -3.27 (0.091) 232 -1.50 (0.124) Difference of the average values determined by the 1,S(SE) method. vs. lixisenatide ⁴¹ 95% CI p-value -1.96 (0.144) (from -2.246 to -1.682) <0.0001

ⁿ Repeated measures mixed-effects model (MMR.M) with treatment groups (fixed ratio combinations, insulin glargine alone, lixisenatide alone), NbA1c randomization strata (<&,()%, >8.0%) at time neeita 4 (week -1), strata of randomization regarding the use of the second OA1) at the time of screening (yes. no), scheduled visit, treatment-visit interaction and lowercase as fixed effects, and interaction value at the initial time point in in relation to the level of glucose in the blood plasma on an empty stomach-nitnt and - as a conariaga.

Countries with less than 5 nationalities were grouped with the country with the lowest total of nationalities that is 5 or more. The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of [MR] use or the introduction of rescue therapy.

All patients for whom measurements are available at the initial time point and after the beginning of the th time point are included.

Average SMPG value for 7 lumens per belt (mmolLt) Combinations with permanent Ratio (NM68) Insulin glargine (N-466) Lixisenatide (M-233) Change from baseline to week 30 Number 421 411 204 Average value obtained by LS method -3.35 (0.081) -2.66 (0.084) -1.95 (0.1 11) (SE) ^s Difference of mean values determined -0.69 (0.101) - - LS method (SE), compared with insulin glargine® 95%CI (from -0.892 to -0.495) - - p-value -'0.0001 - - Difference of mean values determined -1.40(0.124) - - LS method (SE), compared with lixisenatide ¹¹ 95% a (from -1.645 to -1.158) - - p-value - 0.0001 - -

SMPG is the concentration of glucose in blood plasma during self-monitoring.

⁴ Repeated Measures Mixed Effects Model (MMRM) with treatment groups (fixed ratio combinations, insulin glargine alone, lixisenatide alone), HLA 1c randomization strata (<8.0%, >8.0%) at visit 4 (week-1). randomization strata with respect to the use of the second OAD at screening (yes. no), scheduled sighting, treatment-visit and country interaction as fixed effects, and base-time mean SMPG-visit interaction as covariate

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy.

All patients for whom measurements are available at the initial time and after the initial time are included.

Table 16

Number (%) of patients achieving HbAlc <7.0% without gaining body weight at week 30 - mITT population

HL1c<7% without body weight gain Combination with constant ratio (b=468) Insulin Glargine (>=466) Lixisenatide (N=233) Number 468 466 233 Yes 202 (43.2%) 117 (25.1%) 65(27.97-d) Proportional difference (95% CI) over 18.08% (t 12.15% to glargine 24.01%) - - p-ziachspis <0.0001 - -

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Table 17

Number (%) of patients achieving HbAlc <7.0% without gaining body weight at week 30 and without documented symptomatic hypoglycemia (plasma glucose <70 mg/dL [3.9 mmol/L]) during ____________________ study - mITT population____________________

HbA1c <7% without body weight gain l 5 without confirmed symptomatic [neoiikemip Combination with full ratio m ^=468) Insulin Glargine (Ν=4Λ6) .1ixisenatnd (A = 233) Number Yes Proportional difference (95% CI) compared to insulin [largin ¹¹ p-value Proportional difference (95% CI) compared to j ι and ks ise and a 1 id ⁴ 468 149 (31.8%) 12.98% (from 7.50% to 18.45%) <0.0001 5.61% (from -1.33% to 12.55%) 466 88 (1 8.9%) 233 61 (26.2%) ' Weighted mean of the proportional difference between treatment groups (constant ratio combination, insulin glargine alone, lixisenagide alone) from each stratum (IlbAI randomization strata with [<8.0, >R.()%] at Visit 4 (week - 1), randomization strata with respect to the use of the second OAI) at the time of screening [yes. pet]) using values according to the Cockrap-Maptel-Hensel (CMH) method. Documented symptomatic hypoglycemia is a phenomenon in which the typical symptoms of hypoglycemia are accompanied by a measured blood glucose concentration of <70 mg/dL (3.9 mmol/L). The analysis included all measurements of HbAlc and body weight at week 30, including those obtained after permanent discontinuation of IMP use or rescue drug administration. Patients were treated as nonresponders if they had no HbAlc and/or body nasal measurements at week 30. All documented symptomatic hypoglycemia that occurred during the 30-week open-label treatment period was considered, including those developed after definitive cessation of IMP use or rescue drug administration. HbA1c<7% without body weight gain Fixed Ratio Combination (N-468) Ivsulii glargine (A-466) Lixisenatide (Ν=233) Proportional difference (95% CI) vs. lixisena1ad ^a 1522% (from 8.05% to 22.39%) - -

^a Weighted mean of the proportional difference between treatment groups (constant ratio combination, insulin glargine alone, liqueisscatide alone) from each stratum (strata randomized by Hb1c [<8.0, >8.0%] at visit 4 (week -1 strata of randomization with respect to the use of the second OAD at the time of screening [yes, no]) using Cochran-May tel-Hsnsl (CMN) values.

The analysis included measurements of IbA 1 s and body weight at week 30, including those obtained after the final cessation of IMP use or the introduction of a rescue drug

Patients were treated as nonresponders. if they had no HbAlc and/or body weight scores by week 30.

Table 18

Mean daily dose of insulin glargine (ED) at week 30 using the MMRM procedure - mITT population (Fig. 7) Average daily dosh of insulin glargine (ED) Combination with PERMANENT soybeans (N=468) insulin glargine (N=466) Week 30 Number Mean value (SD) Median value Minimum : maximum 438 39.75 (14.87) 40.00 10.0 : 60.0 440 40.34 (14.85) 40.00 4.0: 62.0 Week 30

Number Average value obtained by LS method (SE)* 467 39.77 (0.699) 463 40.46(0.701) Difference in mean values determined by the LS (SE) method in comparison with insulin glargine” -0.69 (0.990) - 95%CI (from -2.632 to 1.252) - p-values 0.4857

^a Repeated Measures Mixed Effects Model (MMRM) with treatment groups (constant ratio combinations, insulin glargine), randomization strata and HbAlc (<8.0%, ^8.0%) at visit 4 (week -1) , rhinestones randomized to second OAD at screening (yes. no), scheduled!x> visit, treatment-switched interaction, and country as fixed effects.

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included scheduled measurements taken up to the date of the last IMP injection. including those obtained after the introduction of emergency therapy.

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Table 19

Adverse Event Profile Review: Adverse Events Occurring During Treatment - Safety Population

η Combination with constant ratio CIV=469) Insulin Glargin (Ν=467) Lixiseiatide (N-233) Patients with any TELE 267 (56.9%) 227 (48.6%) 157 (67.4%) Patients with any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) PacisEgty with any TELE leading to 12 (2.6%) 9 (1.9%) 21 (9.0%) permanent cessation of treatment Patients with any TELE that resulted in death 2 (From .4%) 3 CO, b%) 1 (0.4%)

TEAE: Adverse event occurring during treatment.

η (%) = number and percentage of patients with at least one TEAE.

Table 20

Number (%) of patients who experienced (were observed) TEAE (RT> 3% in any of the treatment groups), presented by main SOC and TA - population for safety assessment

Main system-organization class Preferred term and (%) Fixed Ratio Combination (N=469) Insulin Glargine (N=467) like isena guide (N=233) Any TEAE 267 (56.9%) 227 (48.6%) 157 (67.4%)

3.3. Safety assessment.

Symptomatic hypoglycemic events were documented on the Hypoglycemic Events Form and not on the AE page of the CRF, and thus were not included in the TEAE summaries. They were summarized separately from TEAE.

Major system organ class Preferred term η (%) Fixed Ratio Combination (N-469) Insulin Glargin (Ν=467) lixisenatide (Ν=233) Any TEAE 267 (56.9%) 227 (48.6%) 157 (67.4%) Infections and infestations 130 (27.7%) 126 (27.0%) 60 (25.8%) Flu 15 (3.2%) 11 (2.4%) 4 (1.7%) Nasopharyngitis 26 (5.5%) 25 (5.4%) 15 (6.4%) Upper respiratory tract infection 33 (7.0%) 23 (4.9%) 12 (5.2%) Nervous System Disorders 50 (10.7%) 30 (6.4%) 31 (13.3%) Dizziness 16 (3.4%) 7 (1.5%) 7 (3.0%) Headache 24 (5.1%) 15 (3.2%) 18 (7.7%) Gastrointestinal disorders 102 (21.7%) 59 (12.6%) 86 (36.9%) Diarrhea 42 (9.0%) 20 (4.3%) 21 (9.0%) Nausea 45 (9.6%) 17 (3.6%) 56 (24.0%) Vomit 15 (3.2%) 7 (1.5%) 15 (6.4%) Disorders of the musculoskeletal and 51 (10.9%) 41 (8.8%) 29 (12.4%) connective tissue Backache 16 (3.4%) 10 (2.1%) 8 (3.4%)

TEAE - post-treatment adverse event, SOC - system organ class, PT - preferred term.

MedDRA 18.0.

n (%) - number and percentage of patients with at least one TEAE.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

Presented only SOC at least one RT>3% in at least one group.

.3.1. Deaths, serious adverse events that occurred during treatment.

Six patients experienced at least 1 TEAE resulting in death:

from the fixed ratio combination group, 3 from the insulin glargine group, and 1 from the lixisenatide group (Table 21).

None of the fatal events were considered related to IMP by the investigator.

Constant Ratio Combination Group:

A 64-year-old male patient died of metastatic lung cancer.

A 72-year-old male patient died of congestive circulatory failure.

Insulin glargine group:

A 55-year-old male patient died of acute myocardial infarction and acute pulmonary edema.

A 62-year-old male patient died of acute heart failure.

A 60-year-old male patient died approximately 3 months after the treatment period due to worsening of undifferentiated keratinized squamous cell carcinoma in the mouth

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Lixisenatide group.

a year-old female patient was reported to have been found dead in her bed of unknown causes 208 days after the first dose of study drug.

An autopsy was not performed.

No other information was provided.

This case was recognized by CAS as death due to CV pathology.

Table 21

Number (%) of patients who experienced (were observed) TEAE leading to death on the main SOC and RT - population for safety assessment

Major system organ class Preferred term [n (%)] Fixed Ratio Combination (N-469) Insulin Glargine (N=467) lixisenatide (N=233) Any TEAE resulting in death 2 (0.4%) 3 (0.6%) 1 (0.4%) Benign, malignant and unspecified 1 (0.2%) 1 (0.2%) 0 neoplasms (including cysts and polyps) metastatic lung cancer 1 (0.2%) 0 0 Squamous cell carcinoma of the oral cavity 0 1 (0.2%) 0 Heart disorders 1 (0.2%) 2 (0.4%) 0 Acute myocardial infarction 0 1 (0.2%) 0 Acute heart failure 0 1 (0.2%) 0 Congestive heart failure 1 (0.2%) 0 0 Respiratory, thoracic and 0 1 (0.2%) 0 mediastinum Acute pulmonary edema 0 1 (0.2%) 0 General disorders and complications at the injection site 0 0 1 (0.4%) Fatal outcome 0 0 1 (0.4%)

TEAE - post-treatment adverse event, SOC - system organ class, PT - preferred term.

MedDRA 18.0.

n (%) is the number and percentage of patients with at least one TEAE resulting in death.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

Table 22

Number (%) of patients who experienced serious TEAE, presented by the main SOC and RT - population for evaluation b security Major system organ class Preferred term [n (%)] Fixed Ratio Combination (N=469) Insulin Glargine (N=467) lixisenatide (N=233) Any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Infections and infestations 4 (0.9%) 2 (0.4%) 2 (0.9%) Bronchitis 0 1 (0.2%) 0 Erysipelas 1 (0.2%) 0 1 (0.4%) Infection with fever 1 (0.2%) 0 0

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Any serious TEAL 18(3.8%) 19 (4.1%) 9 (3.9%) Staphylococcal meningitis 0 0 1 (0.4%) ] 1nevmonia (one 1 (0.2%) 0 Acute pyelonephritis 0 1 (0.2%) 0 URINARY tract infection 2 (0.4%) 0 0 urospsis 0 1 (0.2%) 0 Benign, malignant and unspecified neoplasms (including cysts and polyps) 2 (0.4%) 4 (0.9%) 1 (0.4%) metastatic lung cancer 1 (0 2%) 0 0 Malignant neoplasms of the lungs 0 0 1 (0.4%) Metastases in the liver 0 0 1 (0.4%) pancreatic carcinoma 0 1 (0.2%) 0 Recurrent prostate cancer 0 1 (0.2%) 0 Squamous cell skin cancer 1 (0.2%) 0 0 Squamous cell carcinoma of the cavity 0 1 (0.2%) 0 Thyroid adenoma 0 1 (0.2%) 0 Disorders of the circulatory and lymphatic systems 0 1 (0.2%) 0 Pancytopenia 0 1 (0.2%) 0 Immune System Disorders 0 0 1 (0.4%) Anaphylactic reaction 0 0 1 (0.4%) Metabolic and nutrient absorption disorders 0 0 2 (0.9''h>) Diabetes mellitus without adequate control 0 0 1 (0.4%) metabolic acidosis 0 0 1 (0.4%) Nervous system disorders 1 (0.2%) 1 (0.2%) 2 (0.9%) Lacunar infarction 0 1 (0.2%) 0 radiculopathy 0 0 1 (0.4%) Transient ischemic attack 1 (0.2%) 0 1 (0.4%) Heart disorders 2 (0.4%) 6 (1.3%) 0 Acute myocardial infarction 0 1 (0.2%) 0 Acute heart failure 0 1 (0.2%) 0 Chronic heart failure 0 1 (0.2%) 0 Congestive heart failure ] (0.2%) 1 (0.2%) 0 coronary heart disease 0 1 (0.2%) 0 myocardial infarction 0 1 (0.2%) 0 Cardiopalmus 1 (0.2°- ”) 0 0

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Any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Vascular disorders 1 (0.2%) 1 (0.2%) 0 hypertension 1 (0.2%) 1 (0.2%) 0 Respiratory disorders, chest 0 3 (0.6%) 1 (0.4%) cells and mediastinum Acute pulmonary edema 0 1 (0.2%) 0 Chronic obstructive pulmonary disease 0 1 (0.2%) 0 Dyspnea 0 1 (0.2%) 0 Respiratory failure 0 0 1 (0.4%) Gastrointestinal disorders 1 (0.2%) 0 0 Esophagitis 1 (0.2%) 0 0 Liver and biliary disorders 1 (0.2%) 0 0 ways Chronic cholecystitis 1 (0.2%) 0 0 Skin and subcutaneous tissue disorders 2 (0.4%) 0 0 Angioedema 1 (0.2%) 0 0 Hives 1 (0.2%) 0 0 Disorders of the musculoskeletal and 0 1 (0.2%) 1 (0.4%) connective tissue Costal chondritis 0 1 (0.2%) 0 Spinal osteoarthritis 0 0 1 (0.4%) Renal and urinary tract disorders 1 (0.2%) 2 (0.4%) 1 (0.4%) Acute kidney injury 0 0 1 (0.4%) Bladder prolapse 0 1 (0.2%) 0 urinary stones 0 1 (0.2%) 0 hydronephrosis 0 1 (0.2%) 0 Renal colic 1 (0.2%) 0 0 Reproductive system and mammary disorders 3 (0.6%) 0 0 glands Acquired phimosis 1 (0.2%) 0 0 cervical dysplasia 1 (0.2%) 0 0 metrorrhagia 1 (0.2%) 0 0 General disorders and complications at the injection site 0 1 (0.2%) 1 (0.4%) doses Fatal outcome 0 0 1 (0.4%) non-cardiac chest pain 0 1 (0.2%) 0 Research 1 (0.2%) 1 (0.2%) 0 Pathology of the ST segment and T wave on 1 (0.2%) 0 0

3.3.2. Adverse events leading to discontinuation

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Table 23

Number (%) of patients who experienced (were observed) TEAE,

which resulted in permanent discontinuation of treatment, indicated depending on the main SOC and RT - population for safety assessment Major system organ class Preferred term [n (%)] Fixed ratio combination (N=4691 Insulin Glargine (N-467) Lixisenatide (N-233) Any TEAE leading to definitive discontinuation of treatment 12 (2.6%) 9 (1.9%) 21 (9.0%) Infections and infestations 1 (0.2%) 1 (0.2%) 1 (0.4%) bacteremia 0 0 1 (0.4%) Bronchitis 0 1 (0.2%) 0 Extradural abscess 0 0 1 (0.4%) Staphylococcal meningitis 0 0 1 (0.4%) urinary tract infection 1 (0.2%) 0 0 Benign, malignant and unspecified neoplasms (including cysts and polyps) 1 (0.2%) 1 (0.2%) 1 (0.4%) metastatic lung cancer 1 (0.2%) 0 0 Malignant neoplasms of the lungs 0 0 1 (0.4%) pancreatic carcinoma 0 1 (0.2%) 0 Immune System Disorders 0 1 (0.2%) 1 (0.4%) Anaphylactic reaction 0 0 1 (0.4%) Drug ι hypersensitivity 0 1 (0.2%) 0 Metabolic and absorption disorders 0 0 1 (0.4%) nutrients Decreased appetite 0 0 1 (0.4%)

Any serious TEAE 18 (3.8%) 19 (4.1%) 9 (3.9%) Elevated lipase 0 1 (0.2%) 0 Injury, poisoning and procedural complications 1 (0.2%) 1 (0.2%) 1 (0.4%) crushed fracture 0 1 (0.2%) 0 tendon rupture 1 (0.2%) 0 0 Intoxication by various means 0 0 1 (0.4%)

TEAE - post-treatment adverse event, SOC - system organ class, PT - preferred term;

MedDRA 18.0;

n (%) - the number and percentage of patients with at least one serious TEAE. Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

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Major System Organ Class Preferred Term [and (%)] Fixed Ratio Combination (N=469) Insulin Glargine (N=467) Lixisenatide (N-233) Any TEAE leading to a final 12 (2.6%) 9 (1.9%) 21 (9.0%) discontinuation of treatment Mental disorders 1 (0.2%) 1 (0.2%) 0 Depression 0 1 (0.2%) 0 Insomnia 1 (0.2%) 0 0 Nervous System Disorders 0 1 (0.2%) 1 (0.4%) Diabetic mononeuropathy 0 0 1 (0.4%) Headache 0 1 (0.2%) 1 (0.4%) Heart disorders 1 (0.2%) 3 (0.6%) 1 (0.4%) Acute myocardial infarction 0 1 (0.2%) 0 Atrial fibrillation 0 0 1 (0.4%) Acute heart failure 0 1 (0.2%) 0 Congestive heart failure 1 (0.2%) 0 0 myocardial infarction 0 1 (0.2%) 0 E1 disorders of the respiratory system, chest 0 2 (0.4%) 0 cells and mediastinum Acute pulmonary edema 0 1 (0.2%) 0 Cough 0 1 (0.2%) 0 E1 disorders of the gastrointestinal tract 4 (0.9%) 1 (0.2%) 12 (5.2%) Bloating 0 0 1 (0.4%) Pain in the abdomen 0 0 1 (0.4%) Colitis 0 0 1 (0.4%) Diarrhea 1 (0.2%) 0 2 (0.9%) Stomach upset 0 1 (0.2%) 0 Erosive gastritis 0 0 1 (0.4%) Nausea 2 (0.4%) 0 6 (2.6%) Vomit 2 (0.4%) 0 4 (1.7%) Skin and subcutaneous tissue disorders 4 (0.9%) 1 (0.2%) 1 (0.4%) Rash 0 1 (0.2%) 0 Skin burning sensation 1 (0.2%) 0 0 Hives 3 (0.6%) 0 1 (0.4%) E1 disorders of the musculoskeletal and 1 (0.2%) 0 0 connective tissue Backache 1 (0.2%) 0 0 General disorders and complications at the injection site 0 1 (0.2%) 2 (0.9%) doses Fatal outcome 0 0 1 (0.4%)

Any TEAE leading to a final 12 (2.6%) 5 (1.9%) 21 (9.0%) Fatigue 0 1 (0.2%) 0 Redness at the injection site 0 0 1 (0.4%) Research 0 1 (0.2%) 2 (0.9%) Elevated levels of alanine aminotransferase 0 0 1 (0.4%) Elevated blood creatinine 0 0 1 (0.4%) Elevated lipase 0 1 (0.2%) 0 Injury, poisoning and procedural complications 0 1 (0.2%) 0 crushed fracture 0 1 (0.2%) 0

TEAE - post-treatment adverse event, SOC - system organ class, PT - preferred term;

MedDRA 18.0;

n (%) - the number and percentage of patients with at least one TEAE, which led to the final discontinuation of treatment.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

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Table 24

Number (%) of patients who experienced reactions

at the injection site during the treatment period - safety population The source of the phenomenon Preferred Term Fixed Ratio Combination (N=469) Insulin Glargine (N=467) Lixisenatide (N=233) Any reactions at the injection site 12 (2.6%) 8 (1.7%) 7 (3.0%) RT coded based on reported 12 (2.6%) 8 (1.7%) 7 (3.0%) terms researcher Bruising at the injection site 4 (0.9%) 4 (0.9%) 0 Pain at the injection site 2 (0.4%) 2 (0.4%) 3 (1.3%) Local reaction to injection 2 (0.4%) 1 (0.2%) 2 (0.9%) Discomfort at the injection site 1 (0.2%) 0 0 Irritation at the injection site 1 (0.2%) 0 0 Plaque at the injection site 1 (0.2%) 0 0 Papule at injection site 1 (0.2%) 0 0 Rash at the injection site 1 (0.2%) 0 0 Redness at the injection site 0 0 2 (0.9%) Hemorrhage at the injection site 0 2 (0.4%) 0 Swelling at the injection site 0 1 (0.2%) 0 Hot flush at the injection site 0 1 (0.2%) 0 RT coded on the basis of diagnostic 2 (0.4%) 0 2 (0.9%) terms according to ARAC Local reaction to injection 2 (0.4%) 0 2 (0.9%)

ARAC - Allergy Assessment Committee, PT - preferred term.

One case of injection site erythema reported in the lixisenatide group resulted in treatment discontinuation. A 65-year-old female patient developed erythema at the injection site of lixisenatide (abdomen and anterior thighs), accompanied by local swelling and pruritus.

Mild erythema was diagnosed at the injection site and the patient subsequently permanently discontinued the IMP. No corrective treatment was given, and the patient's condition returned to normal without complications. The researcher considered the event to be related to the IMP.

Table 25

Number (%) of patients with events recognized by ARAC as allergic reactions during the period of receipt treatment- safety assessment population Addiction with Diagnosis category Encoded Combination with Insulin Lixisenatide treatment in pa micros by ARAC MedDRA term (NG) for diagnosis constant with rel. glargine (X=233) ARAC research ARAC (X=469) (N=467) Total Any category Any phenomenon ή (1.3%) 3 (0.6%) 2 (0.9%) Urticaria (croup) Hives 3 (0.6%) 1 (0.2%) 1 (0.4%) Angioneur! ic Angioedema 3 (0.6%) 0 0 rebound edema Amphipathic Anaphylactic 0 0 1 (0.4%) reaction reaction Other allergic allergic 0 1 (0.2%) 0 reaction CONJUNCTIVITIS Allergic 0 2 (0.4%) 0 rin I 1 Carry omni related with IMP Any category Any phenomenon 3 (0.6%) 0 2 (0.9%) Urticaria (croup) Stolen knit 3 (0.6%) 0 1 (0.4%) Anaphylactic Anaphylactic 0 0 1 (0.4%) reaction reaction Hs connected imp Any category Any phenomenon 3 (0.6%) 3 (0.6%) 0 Urticaria (croup) Hives 0 1 (0^%) 0 Angioedema Angioedema 3 (0.6%) about 0 edema snack Other allergic Allergic 0 1 (0.2%) 0 reaction CONJUNCTIVITIS allergic 0 2 (0.4%) 0 rhinitis

ARAC - Allergy Assessment Committee, IMP Investigational Medical Product.

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Table 26

Number (%) of Patients with Pancreatic Events Clearly Recognized by PSAC During Treatment Period - Safety Population

Combination with Insulin permanent glargine Lixisena teed ratio (X-469) (N=467) (N=233)

Any yes for PSAC pancreatitis 0 0 0 Acute pancreatitis 0 0 0 Exacerbation of chronic pancreatitis 0 0 0 Chronic pancreatitis 0 0 0 unknown pancreatitis 0 0 0

PSAC - pancreatic safety assessment committee.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

One allergic event recognized by the ARAC as an anaphylactic reaction was reported for the lixisenatide group and occurred in a 60-year-old female patient 1 hour after IMP administration. The patient developed generalized itching, skin rash, swelling of the hands and face, and wheezing. She was taken to the emergency room, and her condition returned to normal after intramuscular administration of dexamethasone.

One case of pancreatic cancer was reported in the insulin glargine group. A 75-year-old male patient was diagnosed with pancreatic carcinoma and permanently discontinued insulin glargine. The patient died 2 months later from gastrointestinal bleeding. The patient had a history of peptic ulcer. This lethal event was considered by the investigator as possibly unrelated to IMP. The PSAC ruled that this case was non-IMP-related pancreatic carcinoma.

Table 27

Number (%) of patients with events recognized by the CAS as major cardiovascular events during the period of treatment - population for safety assessment

η (%) Fixed Ratio Combination (N-469) Insulin Glargin (Ν=467) Lixisenatide (X-233) Any 2 (0.4%) 7 (1.5%) 2 (0.9%) Death due to cardiovascular disease 1 (0.2%) 2 (0.4%) 1 (0.4%) Non-fatal myocardial infarction 0 0 0 11fatal stroke 0 1 (0.2%) 1 (0.4%) Hospitalization due to unstable angina 1 (0.2%) 1 (0.2%) 0 Hospitalization due to heart failure 0 2 (0.4%) 0 Coronary revascularization procedure 0 1 (0.2%) 0

САС - expert committee on cardiovascular diseases;

η (%) - the number and percentage of patients with events recognized by the CAS as major cardiovascular events.

Table 29

Number (%) of patients with events reported on the AE form for elevated ALT during treatment period _________ - population for safety assessment _________

Preferred Term Combination with constant other ratio (Ν=469) Insulin Glargine (X-467) Lixisepyatide (M=233) Any 1¢0.2^0) 2 (0.4%) 1 (0.44¾) Elevated levels of alanine aminotransferase 1 (0.2%) 2 (0.4%) 1 (0.4%)

η (%) is the number and percentage of patients with any cases reported on the AE form for elevated levels of ALT along with an additional form.

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Table 30

Number (%) of patients with events reported in the pen-related event questionnaire during the treatment period - safety population

Fixed Ratio Combination (N—469) Ipsuli Glargine (N-467) Lixisenatide (N-233) Any phenomena associated with a syringe pen 25 (5.3%) 10(2.1%) 9 (3.9%) C-binding with a clinical event 0 0 O Not related to clinical event 25 (5.3%) 10 (2.1%) 9 (3.9%)

Clinical Event - An event of symptomatic hypoglycemia, an adverse event of hyperglycemia, or other adverse event collected in an event questionnaire associated with a pen.

Table 28

Number (%) of patients with events reported on the AE form for elevated calcitonin (>20 ng/l) during the treatment period - safety population

Combination with permanent ratio insulin glargine Lixisenatide Preferred Term (\-469) (\-467) (N=233)

Any 0 1 (0.2%) 0

Elevated blood pressure 0 1 (0.2%) 0 n (%) is the number and percentage of patients with any cases reported on the AE form for elevated calcitonin levels >20 pg/mL along with an additional form.

3.3.3. Other Safety Observations - Symptomatic Hypoglycemia

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Table 31

Overview of Symptomatic Hypoglycemia Cases Reported on the Designated eCRF Page and Satisfying the Protocol Definition During Treatment Period - Safety Population

Fixed ratio combination (Ν=469) Insulin Glargin (Ν=467) Lixisenatide (Ν=233) Total patient-years of exposure. 263.1 262.5 125.2 Symptomatic hypoglycemia Number of patients with events, η (%) 128 (27.3%) 119(25.5%) 15 (6.4%) Number of patients with events by patient-years ³ 0.49 0.45 0.12 Number of events 409 338 46 Number of events by patient- ^year 1.55 1.29 0.37 Documented symptomatic hypoglycemia (plasma glucose <70 mg/dL [3.9 mmol/L]) Number of patients with events, η (%) 120 (25.6%) Software (23.6%) 15 (6.4%) Number of patients with events by patient-years ³ 0.46 0.42 0.12 Number of events 378 321 43 Number of events by patient- ^year 1.44 1.22 0.34 Documented symptomatic hypoglycemia (plasma glucose <60 mg/dL [3.3 mmol/L]) Number of patients with events, η (%) 66 (14.1%) 50 (10.7%) 6 (2.6%) Number of patients with events by patient-years ³ 0.25 0.19 0.05 Number of events 128 75 13 Number of events by patient- ^year 0.49 0.29 0.10 Probable symptomatic hypoglycemia Number patients with events, η (%) 17 (3.6%) 12 (2.6%) 2 (0.9%) Number of patients with events by patient-years ³ 0.06 0.05 0.02 Number of events 31 16 3 Number of events by patient- ^year 0.12 0.06 0.02 Severe symptomatic hypoglycemia Number patients with events, η (%) 0 1 (0.2%) 0 Number of patients with events by patient-years ³ 0 <0.01 0 Number of events 0 one 0 Number of events by patient- ^year 0 <0.01 0

IMP - investigational medical product, eCRF - electronic individual registration card; Patient-years of exposure - calculated as the time from the first to the last injection of IMP plus 1 day; ^a - calculated as the number of patients with events divided by the total number of patient-years of exposure; ^b - calculated as the number of events divided by the total number of patient-years of exposure;

Symptomatic hypoglycemia - symptomatic hypoglycemia recorded on its intended eCRF and meeting the protocol definition for severe or documented or probable symptomatic hypoglycemia;

The treatment period is defined as the time from the first injection of IMP up to 1 day of onset of symptomatic hypoglycemia after the last injection of IMP, regardless of the introduction of rescue therapy.

Example 3

Randomized, 30-week, active-drug-controlled, open-label, 2-treatment, parallel-group, multicenter study comparing the efficacy and safety of a fixed-ratio combination of insulin glargine/lixisenatide with insulin glargine with or without metformin in patients with T2DM .

1. Abbreviations.

AE is an undesirable phenomenon,

ALT - alanine aminotransferase,

ARAC - Allergy Assessment Committee,

ANCOVA - analysis of covariance,

BMI - body mass index,

CAC - expert committee on cardiovascular diseases,

CI - confidence interval,

CMN - Cochran-Mantel-Genzel test,

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ECG - electrocardiogram,

FPG - fasting plasma glucose,

GFR - glomerular filtration rate,

GLP-1 - glucagon-like peptide-1,

HbA1c - glycosylated hemoglobin,

IMP is an investigational medical product,

LOCF - last observation data carry forward,

LS - least squares method, mITT - modified treatment population, OAD - oral antidiabetic drug,

PG - plasma glucose level,

PPG is the level of glucose in the blood plasma after a meal,

PSAC - Pancreas Safety Assessment Committee,

RT is the preferred term,

SAE is a serious adverse event,

SD - standard deviation,

SMPG is the concentration of glucose in the blood plasma during self-monitoring,

SOC - system organ class,

TEAE is an adverse event that occurred during treatment,

ULN - upper limit of normal.

2. Synopsis.

Study Title: Randomized 3D-study. controlled by active)' preparation. open. 2 ^- treatment, parallel-group, multi-center study comparing efficacy and safety of fixed-ratio combination insulin glargn Elixisenotide with insulin glargne with or without metformin in patients with T2DM

Ik*investigative centre(s): Multinational research facility (236 centers in 1S countries)

Phases" of development; phase 3

Goals:

Primary goal:

Demonstration of a combination with a constant ratio of insulin glarg/j xissnatide over insulin [Largin] and the change in HbAlc level from the level at the initial time point to the level at week 30.

Secondary chain, 1b(s)

Assessing the effects of a fixed ratio combination of insulin glargine/lixisenatide versus insulin glargine over 30 weeks by evaluating:

Percentage of patients. who have achieved target levels of HbAlc,

- Glycemic control in relation to meals, assessed by the level of plasma glucose levels 2 hours after ingestion of meals (PPG) and by the level of glucose in the blood plasma.

- body weight,

- 7-point self-monitoring plasma glucose profile (SMPG).

- Percentage of patients reaching target HbAlc levels without weight gain or documented symptomatic hypoglycemia,

Doses of ipsulip glargine

- Fasting plasma glucose (FPG).

To assess safety and tolerability in each treatment group,

Method-a: This study was an open-label, 1:1 randomized, active-drug-controlled, 2-arm, 30-week, parallel-group, international, and multicentre zirovaine study. Randomization was stratified by HbAlc value at visit 5 (week -1) (<8% >8%) and metformin use at screening (Y. K).

The study consisted of 3 periods:

* A screening period of up to 8 weeks including a screening phase of up to 2 weeks and a 6 week run-in phase with a transition (if necessary) and / or gmarovapismAtibilmzatsis dose of insulin [largin. continuation of metformin (if necessary) and discontinuation of sulfonylurea (SU), ishinda, ngibi yura sodium-) at V2 * 30-week period of randomized open-label treatment.

* 3-day period thereafter] about nb. lowering for safety post-treatment

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Number of patients: Planned: 700;

Randomized: 736;

Received treatment: 730:

Evaluated: Effectiveness: 731;

Security: 730:

Diagnosis for Inclusion Criteria: Inclusion Criteria: Patients with type 2 diabetes mellitus diagnosed at least 1 year ago and inadequately controlled by their current antidiabetic treatment. I [subjects to be treated with basal insulin and for at least 6 months with a stable daily dose, ate 15 to 40 units, sometimes in combination with 1 or 2 oral proto-diabetic drug cycles ((metformin, SU. glinide DPP-4 inhibitor or SGLT-2 inhibitor) at a stable dose for at least 3 months Key exclusion criteria for nph randomization C wt-tongue IIbAl level with <7% or >10% at visit 5 (week -1); mean fasting SMPG >140 mg/dL (7.8 mmol/L) in the 7 days prior to randomization visit (Visit 6); mean daily dose of insulin glargine <20 U or >50 U calculated during the last three days prior to visit 6.

Investigated Treatments

Investigational Medicinal Product(s) (IMP): Fixed Ratio Combination of Insulin Hiargin/Dnxssenatmd and Inmhishin ιbatch (Lantus)

Compound:

Study drug: Fixed-ratio insulin glargine/lixisenatide combination

The fixed ratio insulin glartine/lixisenatide combination (herein referred to as the constant saucitive combination) was supplied as a sterile aqueous solution in a pre-filled disposable injector and a SoloStar® syringe pen.

To ensure titration of insulin glargine from 10 U/day to 60 U/day, using a limiting dose of lixisenatide up to 20 µg/dep, two pens (A and B) were available with different fixed ratios:

• Pen A contained 100 U/mL of insulin glargine and 50 µg/mL of lixisenatide in a 2:1 ratio (2 units of insulin glartine per 1 µg of lixisenatide). Doses could include 10 to 40 units in 1 unit increments, allowing daily combination doses of 10 U 5 µg to 40 U x 20 µg to be administered.

• Pen B contained 100 U/ml insulin glargine and 33 µg/ml lixisenatide in a 3:1 ratio. Doses could include 30 to 60 units in 1 unit increments, allowing daily combination doses of 30 U/10 µg to 60 U-20 µg to be administered.

The maximum daily dose was 60 units (60 units of ipoulin glargine and 20 µg of lixisenatide).

Control drug: Insulin glargine (Lantus)

Insulin glargine was supplied as a sterile aqueous solution in a SoloStar pre-filled disposable pen-type injector (100 Uml glargine).

Doses could include from 1 unit! up to 80 units with a scale of 1 unit. However, in this study, the maximum allowable daily dose of insulin glargine was 60 units.

Way of introduction! self-administered subcutaneous injection

Dosing regimen:

During the cumulative phase

From departure 2., the only basal insulin approved was insulin glargine. Patients on any basal insulin other than pre-screening insulin glargine were switched to once daily insulin glargine at the start of Visit 2. Insulin glargine was administered at any time of the day and at approximately the same time each day. The timing of injection was at the discretion of the patient and investigator at Visit 2 and remained the same throughout the study (during the run-in phase for all patients and throughout the randomized treatment period for patients randomized to the insulin glargine arm).

During the period of open-label randomized treatment

The treatment combination was administered once a day within an hour before breakfast. The initial dose was 20 U 10 mcg administered in pen A, the dose of insulin glargine per day before randomization was <30 U, and 30 U ^; 10 mcg and was administered with stump in pen B, salt, the dose of ipsulin glargine per day before randomization was >30 units. The dose remained stable for 2 weeks, then it was titrated once a week based on the dose of insulin glargine to achieve and maintain a target SMPG glucose concentration of 80 to 100 mg/dL [4.4-5.6 mmol/L], while avoiding episodes of hypoglycemia.

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Patients randomized to the insulin glargine arm began the randomized treatment period at the same daily dose as received on the day before randomization, followed by titration of the insulin dose as needed.

The same dose adjustment algorithm was recommended for the fixed ratio combination with insulin glargine.

Non-investigational drug(s): Background treatment with metformin (if used) and rescue therapy were considered NIMPs

Metformin: tvblstkn, oral route of administration. The dosing regimen was in accordance with the regionally approved label. If previously used for a period of time, it is recommended that the patient be taken at a stable dose for the remainder of the study unless there is a major safety concern associated with this treatment.

Other pevoral protiodnabetic therapies: SU, glipids, SHL-2 inhibitors and DPP-4 inhibitors, if rapeseed was used, were discontinued from the start of the run-in period (Visit 2).

Urgent geryann:

Regular fasting SMPG readings and FPG readings (and HbAle after week 12) from the central laboratory were required to ensure that glycemic parameters remained within predetermined thresholds. If values were above these thresholds and no cause was found, or if appropriate measures failed, or >60 U was necessary to bring FPG or ^ or HbAle below the thresholds, then rescue therapy should have been given with IMP and metformin (if taken). Newly initiated anti-diabetic medications or an increase in initial time dose of background metformin were considered as rescue therapy.

Prtsdilzhntemy nitt .ucheniya: Up to 30 NSDSL

Duration of follow-up: Up to 39 weeks (screening period of up to K weeks l 3-week randomized treatment period - 3-day follow-up period to assess safety after treatment)

Criteria for evaluation:

Efficiency:

*Primary efficacy endpoint; Change in HbAle from baseline to week 30, ♦Secondary efficacy endpoints: Percentage of patients with HbAle <7% or dec.5% to week 30, change from baseline to week 30 in plasma glucose concentration 2 hours after a meal and plasma glucose levels, body weight, mean SMPG concentration in the profile for 7 time points; Percentage of Patients Achieving HbAle < 7% Without Gaining Body Weight by Week 30 and ILN Without Documented Symptomatic Hypoglycemia (PG <70 mg/dL [3.9 mmol]) During a 30-Week Randomized Treatment Period: Change in Daily Insulin Dose glargine; changes in plasma glucose levels on an empty stomach; percentage of patients requiring emergency care during a 30-week randomized treatment period.

Safety ♦ Symptomatic urticaria

- Documented: typical symptoms of hypoglycemia with plasma glucose <70 mg/l (3.9 mmol/l);

- Probable: symptoms of hypoglycemia without measurement of plasma glucose concentration, but which were presumably due to plasma glucose concentration <70 mg/dl (3.9 mmol/l);

• Severe: An episode in which the assistance of another person is required to actively administer carbohydrates, yukngong, or perform other resuscitation activities.

• Adverse events occurring during treatment (TEAE), serious TEAE. TEAE leading to death, TEAE leading to discontinuation of treatment. Adverse Events of Special Interest (AESI) (i.e., elevation of Alashamniotrapoferase (ALT), pregnancy, overdose of IMP/NIMP with clinical manifestations), major cardiovascular events, potential events associated with allergic reactions, events related to the pancreas (confirmed increase in amylase-lipase > 2 X upper limit of normal (ULN). pancreatitis, neoplasms of the pancreas), events related to confirmed elevated calcium levels >20 pg/ml (5.9 imol/l) , phenomena associated with sprlc-ruchkon ♦ Laboratory data. related to safety (community blood count, clinical chemistry, levels of lipid azides, n-katcytocytocytic enzymes)

Statistically* methods:

Efficacy analyzes were based on a modified treatment-dependent (mH G) population, using efficacy estimates collected during the study, including r. that were obtained after discontinuation of [MR] or the introduction of rescue therapy. The rnITT population consisted of all randomized patients who underwent both baseline, tata, and at least one postbaseline assessment of any of the primary or secondary efficacy variables.

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The primary efficacy endpoint was analyzed using a mixed-effects dyne repeated measures (MMRM) model. The MMRM model included treatment groups, randomization strata, visits, treatment factor effect versus screech, and country as fixed effect factors, and interaction with HbA1 c effect at baseline versus visit as covariates. The adjusted mean change in HbAlc at baseline to week 30 for each treatment group was assessed within this model, as well as the difference between groups and the 95% CI for the adjusted mean.

A similar MMRM-based method or ANCOVA analysis of covariance was applied with subsequent secondary efficacy endpoints, and the Cochran-Mantel-Haenszel method, stratified by randomization strata, was applied with categorical efficacy endpoints.

The hierarchical testing procedure was applied with a type 1 error control circuit. When the primary endpoint was statistically significant at the 2-tailed 5% level, testing was performed on the selected secondary endpoints of efficacy in the following order: plasma glucose deviation at 2 hours, body weight, mean SMPG concentration in the profile of 7 time points, percentage of patients achieving HbAlc <7% without gaining body weight by week 30, daily dose of insulin glargine, percentage of patients achieving HbAlc <7% without gaining body weight by week 30, and without documented symptomatic hypoglycemia. and FPG. When the end point was not statistically significant at the 5% level, no follow-up tests were performed.

Short description

Population Characteristics: A total of 736 patients were randomized to one of two treatment groups (367 in the fixed ratio combination group of insulin gl^ia'ish'likeient, 369 in the insulin glargine group).

A total of 731 randomized patients entered the TPT population for efficacy analyzes and 730 randomized patients were open-labeled and included in the safety population (Table 1. Demographics and characteristics at baseline were broadly similar between the two groups treatment.At screening, the mean age was 60 years, the mean duration of diabetes was 12 years, and the mean BMI was 31 kg/m ^5. The study population was predominantly Caucasian (91.7%) and 53.3% of patients from of this population were women (Table 3).

Efficiency results:

Primary efficacy endpoint:

The primary objective of this study was satisfied as a statistical advantage of the fixed ratio combination over insulin glargine was demonstrated in the change in HbAlc levels from baseline to week 3(1.

The change in the average value of the level of HbAlc, determined by the method of least squares (LS). from time base to week 30 was -1.13% for the fixed ratio combination group and -0.62% for the insulin glargine group, reaching mean HbA1 levels of 6.9% and 7.5% to nedrls 30, respectively .

The constant ratio combination was shown to be superior to insulin glargine (least squares mean difference = -0.52%,95%Cl -11.633% to A), 397% p<0.(1001) (Table eight).

Secondary efficacy endpoints:

By week 30, significantly more patients treated with the combined combination (549%) achieved an HbAlc level of <7.0% compared with patients treated with insulin glargine (29.6%) with a mean difference of 25.5%. and p<0,(x101. R addition, percentage) for patients with higher HbA1c levels <6.5% was significantly better in the combination group (33.9%) than in the insulin glargine group (14.2%) (difference mean values^ 19.76% p<0 ₃ 0001) (Table 9).

Treatment with the combination significantly improved postprandial glycemic control with a standardized liquid breakfast compared to insulin glargine, as shown by 2-hour glucose drift from baseline to week 30 (mean LS was -3.90 and %47 mmol respectively, the difference in mean values is 3.43 mmol/l, p<0.0001) (Table 10). For the PPG assessment after 2 hours, the change in the mean value determined by the LS method was -4.72 in the combination group and ≈1.39 mmol in the insulin gpargine group with a mean difference of *3.33 mmol/l and 95% C1: from * 3.889 mmol/L to *2.774 mmol/L (Table 11),

Body weight decreased in the combination group and increased in the insulin glargine group with a change in mean LS from time base to week 30 of -0.67 kg and +0.70 kg, respectively. The mean difference (-1.37 kg) between the two groups was statistically significant (p<0.0001) (Table 12).

Patients treated with the combination had a statistically significant greater decrease in the mean SMPG concentration profile at 7 time points compared to patients treated with insulin glargine (mean difference = -0.90 mmol/d p<0, (Y01X table 13) Plotting the SMPG concentration profiles at 7 time points shows that values at all time points are reduced from baseline in both treatment groups by week 30. After 30 weeks of treatment, the SMPG concentration profiles at 7 time points show that values at all time points were lower in the combination group compared to the insulin glargine group (except for a similar value before breakfast) (Figure 12).

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A significantly higher percentage of patients achieved a lib Ale <7.0% without gaining body weight by week 30 in the combination group with a constant ratio (34.2%) compared to the collapsed insulin glargine (13.4%) with a mean difference of 20 .82% n p<0,<W11 (Table 14). The percentage of patients achieving an IlbAlc level of <7.0% by week 30 without documented symptomatic hypoglycaemia during the 30-ice period of treatment was higher in the first combination (31.7%) compared to the insulin glargna group <18-6%. (mean difference ^_ 13.22%, 95% CI; 7.12% to 19.32%) (Table 18). Furthermore, significantly more patients achieved an HbAlc level of <7.0% by week 30 and without documented symptomatic hiatus schismia during the 30-week treatment period in the combination group (19.9%) compared to the insulin glargna group (9.0%) (mean difference - 10.94% 95% CI from 5.93% to 15.96%) (Table 16)

A similar increase in insulin glargna daily dose from dose at baseline was observed in both treatment groups (10.64 U in the combination period and 10.89 U in insulin glargna xpvuue. Mean difference -0.26 U p-0.7362) with a similar mean the value of the daily dose at week 30 is approximately 47 units. (Table 15).

The reductions in the mean values determined by the LS method of the FIO level from the initial time point to week 30 were similar in rpyime combinations (-0.35 mmol? L) and cruchsche insu.hin hlargna (-0.46 mmol / L) (difference in the means - 0.11 mmol /L 95% CI: 0.207 to 0.428) (Table 17).

A total of 10 (2.7%) patients in the combination n group 22 (6.0%) patients in the insulin glargna group received rescue therapy (mean difference = -3.35% 95% CL from -6.33% to -0 .36%) (Table 19).

R "^ Ulmgy in relation to" sh "nin safety:

The combination with )K# of the chained whole in flails was well tolerated during the 3D-weekly! about the period of receiving treatment; the security profile of a combination group reflected the profile of its components.

A total of 195 (53.4%) patients in the H-combination group and 191 (52.3%) in the insulin glargna group reported adverse events after initiation of treatment (Table 20).

The most frequently reported TEAEs in the combination cohort were nausea (10.4% vs. 0.5% in the failed insulin glargna) and nasopharyngitis in the insulin glargine group (8.8% vs. 8.8% in the combination group). The incidence of adverse events in vice gastrointestinal disorders (systemic-ertain class) was 17.0% in the combination regimen and Ί^ί> in the insulin glargna regimen, the mean of which was nausea: 1 (1.4% d versus 0.5 %, vomiting: 3.6% versus 0.5%, and diarrhea: 4.4% in an age range of 2.74¾ were the most frequently reported in the respective ipvimax (Table 21).

Three patients experienced at least 1 TEAE resulting in death: 1 from the combination group (RT: pneumonia) and 2 from the insulin glargia group (WG: gallbladder cancer and cardiopulmonary failure).

Serious TELEs were reported by a similar proportional number of patients in each treatment group: 20 (5.5%) patients in the combination group and 18 (4.9%) in the insulin glargna troupe (Table 22). In both [ruins, there was no Suspected Suspected Serious Adverse Event (SUSAR).

More patients withdrew due to TEAE in the combination group (10 [2.7%]) than in the insulin glargna group (3 [0.8%]). This difference is mainly explained by the number of patients* who discontinued treatment due to nausea (4 |1.1%] in the combination group compared with no such patients in the insulin glargna group) (Table 23).

A total of 2 patients (none in the combination group and 2 patients in Shargin crashed insulin) experienced local injection reactions (Table 24). None of these reactions were serious or severe, or leading to discontinuation of treatment.

One allergic rhinitis event reported in the insulin glargna group was considered by the Allergy Assessment Committee (ARAC) to be an allergic reaction not related to IMP. None of the occurrences in the Gruil of the combination were recognized by the ARAC as an allergic reaction. (Table 25).

There were no cases of pancreatitis clearly recognized by the Pancreas Safety Assessment Committee (PSAC). In addition, no neoplasms in the pancreas were reported in this study.

Five patients (1.4%) in the combination group and 4 patients (1.1%) in the insulin glargna group reported events that were recognized as major cardiovascular events by the Expert Committee on Cardiovascular Diseases (ACD) (Table 26).

Two patients in the insulin glargna group reported TEDE with elevated calcitonin levels (>20 lg/mL) compared with no such patients in the combination group (Table 27).

One patient in the combination group and 2 patients in the insulin shargin group experienced an ΛΕ* increase in ALT during the treatment period” (Table 28). 1 [and one phenomenon did not meet the definition of Hay's law.

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No symptomatic overdose of IMP was reported in any of the treatment groups during the treatment period.

One pregnancy has been reported (in the insulin glargine group) during the treatment period, and the outcome of the pregnancy is not known.

A total of 26 patients (combination: 11 [3.0%] and insulin glargine: 15 [4.1%]) reported pen-related events on the pen-related event questionnaire during the receiving period. treatment. None of these were associated with a clinical event (i.e., symptomatic hypoglycemia event, hyperglycemia adverse event, or other adverse event) (Table 29).

Forty percent of patients in the combination group and 42.5% of patients in the insulin glargine group reported at least one event of documented (PG <70 mg/dL) symptomatic hypoglycemia. The corresponding event rates by patient-year were 3.03 and 4.22, respectively.

Four patients (1.1%) in the combination group and 1 patient (0.3%) in the insulin glargine group reported 5 and 1 severe symptomatic hypoglycemia, respectively (Table 30). All events of severe symptomatic hypoglycemia were reported as SAE.

Preliminary conclusions:

The primary objective of this study was met as a statistical advantage of the fixed ratio combination over insulin glargine on the change in HbAlc levels from baseline to week 30 was demonstrated. Fixed-ratio combination with or without metformin for patients in whom basal insulin with or without OAD is not adequately controlled significantly improved HbAlc levels, allowed more patients to reach HbAlc target on treatment, reduced glucose excursions through 2 hours and and PPG at 2 hours, mean SMPG concentration profile over 7 time points, and body weight versus insulin glargine.

The constant dose combination was well tolerated with a safety profile reflecting that of its components. Nausea was the most commonly reported adverse event in the combination group. In this study, the occurrence of TEAE in the form of gastrointestinal disorders (nausea and vomiting) was reported less frequently than reported for GLP-1 receptor antagonists, including lixisenatide. The incidence of symptomatic hypoglycaemia was similar between the combination group and the insulin glargine group.

3. Results.

3.1. Patients participating in the study.

3.1.1. Patient record.

Of 1930 screened patients, 1018 (52.7%) began a 6-week run-in period and 736 were randomized to one of two treatment arms (367 to the combination arm and 369 to the insulin glargine arm) at 187 centers from 18 countries ( Australia, Canada, Chile, Czech Republic, Denmark, Estonia, Hungary, Lithuania, Mexico, Netherlands, Poland, Romania, Russian Federation, Slovakia, Spain, Sweden, Ukraine, and United States of America). The main reason for screening dropout was an HbA1c value at the time of the screening visit that was outside the protocol-defined range (458 [23.7%]).

Table 1

Populations for Analysis - Randomized Population

Constant Ratio Combination Insulin Glargine Total randomized population 367 (100%) 369 (100%) 736 (100%) Efficiency Evaluation Population Modified Treatment Intended Population (mITT) 366 (99.7%) 365 (98.9%) 731 (99.3%) Population for safety assessment 365 365 730

Note: Patient data from the safety population are tabulated according to treatment actually received (as treated). For the efficacy population, patient data were tabulated according to their randomized treatment.

There are no patients randomized in the group and treated in another study.

There were no patients who changed their treatment during the study.

A total of 731 randomized patients were included in the mITT efficacy analyses, and 730 randomized patients were open-labeled and included in the safety population (Table 1). Five randomized patients (1 in the combination group and 4 in the insulin glargine group) were not included in the mITT population because they had no efficacy data after baseline. Six patients were randomized but not treated: 5 of 6 patients were randomized in error because the patients were not eligible for randomization, and one patient withdrew informed consent.

3.1.2. Distribution of study participants.

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Patient Distribution - Randomized Population

table 2

Combination with permanent ratio insulin glargine (X-367) (N=369)

Randomized and treated 365 (99.5%) 365 (98.9%) The period of treatment in the open mode 336 (91.6%) 355 (96.2%) Didn't pass the period open treatment 29 (7.9%) 10 (2.7%) Requests from Subjects to Discontinue Treatment 19 (5.2%) 7 (1.9%) Reason for stopping investigational treatment Adverse event 12 (3.3%) 3 (0.8%) Insufficient efficiency 0 0 Lack of adherence to protocol 4 (1.1%) 1 (0.3%) Lost to follow up 1 (0.3%) 0 Other reasons 12 (3.3%) 6 (1.6%) Status at the time of last contact during the study live 366 (99.7%) 367 (99.5%) Dead 1 (0.3%) 2 (0.5%) Lost to follow up 0 0

Note: Percentages are calculated using the number of randomized patients as the denominator.

3.1.3. Demographic data and parameters at the initial point in time

Table 3

Demographics and Patient Parameters at Screening or Baseline - Randomized Population

Fixed Ratio Combination (N=367) Insulin glargine (1X 369) Total (IX-736) Age (years) Number 367 369 736 Mean value (SD) 59.6 (9.4) 60.3 (8.7) 60.0 (9.1) Median value 60.0 61.0 60.0 Minimum : maximum 36:85 32:80 32:85

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Age group (years) [n (%)] Number 367 369 736 <50 50 (13.6%) 42 (11.4%) 92 (12.5%) > 50 to < 65 207 (56.4%) 207 (56.1%) 414 (56.3%) > 65 to < 75 89 (24.3%) 102 (27.6%) 191 (26.0%) >75 21 (5.7%) 18 (4.9%) 39 (5.3%) Gender [n (%)] Number 367 369 736 Male 165 (45.0%) 179 (48.5%) 344 (46.7%) Female 202 (55.0%) 190 (51.5%) 392 (53.3%) Race [n (%)] Number 367 369 736 Caucasian/White 337 (91.8%) 338 (91.6%) 675 (91.7%) black 17 (4.6%) 21 (5.7%) 38 (5.2%) Asians/Orientals 12 (3.3%) 8 (2.2%) 20 (2.7%) Other 1 (0.3%) 2 (0.5%) 3 (0.4%) Ethnicity [n (%)] Number 367 369 736 Hispanics 66 (18.0%) 66 (17.9%) 132 (17.9%) Non-Hispanics 301 (82.0%) 303 (82.1%) 604 (82.1%) HbAlc (%) at visit 1 (week -8) Number 367 369 736 Mean value (SD) 8.51 (0.65) 8.54 (0.67) 8.53 (0.66) Median value 8.40 8.50 8.40 Minimum : maximum 7.5:10.0 7.5:10.0 7.5:10.0 HbAlc (%) at visit 5 (week -1). Number 367 369 736 Mean value (SD) 8.19 (0.64) 8.24 (0.71) 8.21 (0.68) Median value 8.20 8.20 8.20 Minimum : maximum 7.0:10.0 7.0:10.0 7.0:10.0 Randomization strata for HbAlc (%) at time visit 5 (week -1) [n (%)] Number 367 369 736 <8 140 (38.1%) 142 (38.5%) 282 (38.3%) >8 227 (61.9%) 227 (61.5%) 454 (61.7%)

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Randomization strata for metformin use at screening [n (%)] Number Yes Not 367 332 (90.5%) 35 (9.5%) 369 331 (89.7%) 38 (10.3%) 736 663 (90.1%) 73 (9.9%) BMI at screening visit (kg/m ² ) Number 367 369 736 Mean value (SD) 31.46 (4.27) 31.08 (4.17) 31.27 (4.22) Median value 31.31 30.76 30.99 Minimum : maximum 20.4 : 40.0 20.3 : 40.0 20.3 : 40.0 BMI categories at screening visit (kg/m ² ) [p (%)] Number 367 369 736 <30 148 (40.3%) 157 (42.5%) 305 (41.4%) >30 219 (59.7%) 212 (57.5%) 431 (58.6%) Initial BMI (kg/m ² ) Number 367 369 736 Mean value (SD) 31.33 (4.25) 30.96 (4.15) 31.14 (4.20) Median value 31.18 30.62 30.86 Minimum : maximum 21.2 : 40.8 20.5 : 41.5 20.5 : 41.5 Categories by initial BMI (kg/m ² ) [p (%)] Number 367 369 736 <30 156 (42.5%) 158 (42.8%) 314 (42.7%) >30 211 (57.5%) 211 (57.2%) 422 (57.3%)

BMI - body mass index.

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Table 4

Disease data and patient parameters at screening or baseline - randomized population

Fixed Ratio Combination (N=367) Insulin Glargine (N=369) Total (N-736) Duration of diabetes (years) Number 367 368 735 Mean value (SD) 12.02 (6.64) 12.13 (6.85) 12.08 (6.74) Median value 10.49 11.32 10.75 Minimum : maximum 1.1:36.7 1.0:42.7 1.0:42.7 Age at onset of type 2 diabetes (years) Number 367 368 735 Mean value (SD) 47.5 (9.6) 48.1 (9.0) 47.8 (9.3) Median value 47.0 48.0 48.0 Minimum : maximum 22:79 20:72 20:79 Duration of previous treatment with basal insulin (years) Number 367 369 736 Mean value (SD) 3.12 (3.06) 3.31 (3.08) 3.22 (3.07) Median value 2.15 2.29 2.20 Minimum : maximum 0.4 : 20.6 0.2 : 24.8 0.2 : 24.8 Previous use of basal insulin by type, regimen introductions (visit 2) Number 367 369 736 insulin glargine 233 (63.5%) 241 (65.3%) 474 (64.4%) insulin detemir 48 (13.1%) 56 (15.2%) 104 (14.1%) NP1I 86 (23.4%) 72 (19.5%) 158 (21.5%) Daily dose of previous basal insulin treatment (AU) at the introductory visit (Visit 2) Number 367 369 736 Mean value (SD) 28.36 (8.22) 29.00 (8.14) 28.68 (8.18) Median value 30.00 28.00 28.00 Minimum : maximum 10.0 : 44.0 12.0 : 50.0 10.0 : 50.0 Average daily dose of insulin glargine (ED) at randomization (Visit 6)“ Number 366 369 735 Mean value (SD) 35.04 (9.22) 35.23 (8.63) 35.13 (8.92) Median value 35.00 36.00 36.00 Minimum : maximum 15.0 : 58.0 12.0 : 52.0 12.0 : 58.0

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Metformin use at screening reported for eCRF [η (%)]

Number 367 369 736 Yes 329 (89.6%) 329 (89.2%) 658 (89.4%) Not 38 (10.4%) 40 (10.8%) 78 (10.6%) Duration of treatment with metformin (years) ^b Number 329 329 658 Mean value (SD) 8.45 (5.48) 8.32 (5.62) 8.39 (5.55) Median value 7.76 7.54 7.69 Minimum : maximum 0.3 : 28.3 0.4 : 30.8 0.3 : 30.8 Metformin daily dose at baseline (mg) ^b Number 329 329 658 Mean value (SD) 2082.8 (499.2) 2042.0 (455.9) 2062.4 (478.1) Median value 2000.0 2000.0 2000.0 Minimum : maximum 850 : 3500 500 : 4000 500 : 4000 Categories for daily dose of metformin at baseline (mg) [n (%)] ^b Number 329 329 658 <1500 19 (5.8%) 10 (3.0%) 29 (4.4%) >1500-<2500 217 (66.0%) 244 (74.2%) 461 (70.1%) >2500-<3000 57 (17.3%) 48 (14.6%) 105 (16.0%) >3000 36 (10.9%) 27 (8.2%) 63 (9.6%) Number of OAD applications at the time of screening [n (%)] Number 367 369 736 No OAD 18 (4.9%) 19 (5.1%) 37 (5.0%) 1 OAD 189 (51.5%) 210 (56.9%) 399 (54.2%) 2 O.A.D. 160 (43.6%) 140 (37.9%) 300 (40.8%) OAD use by drug class at screening [n (%)] Number 349 350 699 1 OAD 189 (51.5%) 210 (56.9%) 399 (54.2%) Metformin only 170 (48.7%) 190 (54.3%) 360 (51.5%) Sulfonylurea only 16 (4.6%) 14 (4.0%) 30 (4.3%) DPP-4 inhibitor only 2 (0.6%) 4 (1.1%) 6 (0.9%) SGLT-2 inhibitor only 0 1 (0.3%) 1 (0.1%) Only glinide 1 (0.3%) 1 (0.3%) 2 (0.3%) Combination 2 OAD 160 (43.6%) 140 (37.9%) 300 (40.8%)

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Metformin plus sulfopilurea 137 (39.3%) 118 (33.7%) 255 (36.5%) Metformin plus DPP-4 inhibitor 20 (5.7%) 18(5.1%) 38 (5.4%) Metformin plus glinide 2 (0.6%) 3 (0.9%) 5 (0.7%) Supfoni.tmonegin plus DPP-4 inhibitor 1 (0.3%) 1 (0.3%) 2 (0.3%) Duration of treatment with first OA1) (years) ^s Number 349 350 699 Mean value (SD) 8.40 (5.51) 8.24 (5.64) 8.32(5.57) Median value 7.75 7.41 7.54 Minimum: maximum C.3:28.3 0.3 : 30.8 0.3 : 30.8 Duration of treatment with the second PDA (years/ Number 161 141 302 Mean value (SD) 4.35 (3.53) 4.75 (4.95) 4.53 (4.25) Median value 3.55 3.05 3.32 Minimum : maximum 0.3:23.6 0.2 : 29.7 0.2 : 29.7 History of gestational diabetes [n (%)] Number 202 190 392 Yes (women) 10 (5.0%) 10 (5.3%) 20 (5.1%) East (women) 192 (95.0%) 180 (94.7%) 372 (94.9%) Previous use of a GLP-I receptor agonist [P (%)] Number 367 369 736 Yes 29 (7.9%) 17 (4.6%) 46 (6.3%) Not 338 (92.1%) 352 (95.4%) 690 (93.8%) Creatinine clearance at the time of screening (yal^in.) Number 366 367 733 Mean value (SD) 106.75 (32.32) 106.06 (31.08) 106.40(31.69) Median value 103.85 101.31 102.24 Minimum : maximum 34.3:223.7 43.8:222.1 34.3 : 223.7

Categories of creatinine clearance at screening (md/min.) [P (%)] Number 366 367 733 -15 (end-stage kidney disease) 0 0 ΰ >15 -<30 (great decrease in GFR) 0 0 O >30 -<60 (moderate decrease in GFR) 18 (4.9%) 9 (2.5%>) 27 (3.7%) >60 -<90 (slight decrease in GFR) 104 (28.4%) 117(31.9%) 221 (30.2%) <90 (norm) 244 (66.7%) 241 (65.7%) 485 (66.2%)

^a - the average daily dose of insulin glargine recorded for eCRF 3 days before randomization, ^b - for patients who were taking metformin at the time of screening;

^c - for patients who were taking OAD at the time of screening;

^d - for patients who took the 2nd OAD at the time of screening.

OAS - oral antidiabetic drug, SGLT-2 - sodium glucose cotransporter type 2, DPP-4 - dipeptidyl peptidase 4, GLP-1 - glucagon-like peptide-1, GFR - glomerular filtration rate.

The duration of the first OAD is calculated from the History of Diabetes page in the eCRF and is given as (date of informed consent - earliest date of initiation of OADs, including metformin, sulfonylurea, glinide, DPP-4, or SGLT-2+1)/365, 25. Similarly, the duration of the second OAD is based on the recorded earliest start date of the 2nd OAD. The creatinine clearance value is obtained using the Cockcroft-Gault equation.

3.1.4. Dosage and duration

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Investigational Medicinal Product Exposure - Safety Assessment Population

Table 5

Fixed Ratio Combination (N=365) insulin glargine (N=365) Total duration of treatment exposure (patient o-yo) 200.3 207.1 Duration of investigational treatment (days) Number 363 363 Mean value (SD) 201.5 (38.0) 208.4 (18.4) Median value 211.0 210.0 Minimum : maximum 1:242 12:224 Duration of investigational treatment categories [n (%)] Duration not specified 2 (0.5%) 2 (0.5%) 1-14 days 5 (1.4%) 1 (0.3%) 15-28 days 2 (0.5%) 1 (0.3%) 29-56 days 2 (0.5%) 0 57-84 days 6 (1.6%) 0 85-126 days 8 (2.2%) 3 (0.8%) 127-168 days 0 1 (0.3%) 169-210 days 153 (41.9%) 202 (55.3%) >210 days 187 (51.2%) 155 (42.5%) The total duration of the study categories [n (%)] Duration not specified 2 (0.5%) 2 (0.5%) > 1 day 363 (99.5%) 363 (99.5%) >15 days 358 (98.1%) 362 (99.2%) > 29 days 356 (97.5%) 361 (98.9%) >57 days 354 (97.0%) 361 (98.9%) >85 days 348 (95.3%) 361 (98.9%) >127 days 340 (93.2%) 358 (98.1%) >169 days 340 (93.2%) 357 (97.8%) >211 days 187 (51.2%) 155 (42.5%)

IMP is an investigational drug.

Duration of exposure - (date of last open IMP injection - date of first open IMP injection)+1.

Note: Patients were considered to be in the treatment group they were actually assigned to at randomization.

In the combination group, 1 patient (840539002) reported the final insulin dose (in the >40 U to <60 U category) without the kit number and pen used. Therefore, pen information (Pen A or Pen B) used at the end of the treatment period was treated as missing data (Table 6). For the same reason, the final dose of lixisenatide could not be determined for this patient (Table 7).

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Table 6

Number (%) of patients by final insulin dose at the end of open-label treatment period - safety population

final dose of insulin Fixed Ratio Combination (N=365) insulin glargine (14=365) <20 units 2 (0.5%) 3 (0.8%) οι >20 U to <30 U 44 (12.1%) 39 (10.7%) from >30 U to <40 U 97 (26.6%) 87 (23.8%) οι >40 U to <60 U 222 (60.8%) 236 (64.7%) >60 units 0 0 -60 ED 99 (27.1%) 112 (30.7%) Pen syringe A ^a <20 units 2 (0.5%) from >20 U to <30 U 43 (11.8%) >30 U to <40 U 53 (14.5%) >40 U to <60 U 2 (0.5%) >60 units 0 Pen B ^b Combination with insulin glargine final dose of insulin PERMANENT ratio (N=365) (N=365) <20 units 0 >20 U to <30 U 1 (0.3%) >30 U to <40 U 44 (12.1%) >40 U to <60 U 219 (60.0%) >60 units 0 ^a 2 U/1 mcg constant insulin glargine/lixisenatide ratio. ^ъ 3 U/1 µg constant insulin glargine/lixisenatide ratio. Note: Percentages calculated using the number of patients in the estimated population security in the denominator.

Table 7

Number (%) of patients by final dose at the end of open-label lixisenatide - safety population

Final dose of lixisenatide Fixed Ratio Combination (N=365) <10 mcg 3 (0.8%) >10 µg to <15 µg >15 µg to <20 µg >20 µg 108 (29.6%) 251 (68.8%) 2 (0.5%)

Pen syringe A ^a <10 mcg 2 (0.5%) >10 µg to <15 µg 43 (11.8%) >15 µg to <20 µg 53 (14.5%) >20 mcg 2 (0.5%) ^Syringe pen B <10 mcg 1 (0.3%) >10 µg to <15 µg 65 (17.8%) >15 µg to <20 µg 198 (54.2%) >20 mcg 0

^a 2 U/1 mcg constant insulin glargine/lixisenatide ratio.

^b 3 U/1 µg constant insulin glargine/lixisenatide ratio.

Note: Percentages are calculated using the number of patients in the safety population in the denominator.

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3.2. Efficiency

3.2.1. Primary efficacy endpoint.

Table 8

Change in Mean HbA1c (%) from Time Base to Week 30 Using the MMRM Procedure - mITT Population

HbAlc (%) Combination with odd ratio Insulin glargine (N=365) Baseline Number 364 364 Mean value (SD) 8.07 (0.68) 8.08 (0.73) Median value 8.00 8.00 Minimum : maximum 6.6:102 5.9 : 10.0 Week 30 Number 346 355 Mean value (SD) 6.94 (0.87) 7.48(0.91) Median value 6.80 7.40 Minimum : maximum 5.0:9.8 5.6 : 11.2

Change from start time to week 30

Number 364 364 Least Square Mean (SE) -1.13 (0.057) -0.62 (0.055) Difference in mean values determined by the LS (SE) method in comparison with insulin glargine’ -0.52 (0.060) - 95%CI (from -0.633 to -0.397) - p-values <0.0001 -

^a Repeated Measures Mixed Effects Model (MMRM) with treatment groups (constant ratio combinations, insulin glargine), HbAlc randomization strata (<Y.0°o, <_8.0%) at visit 5 (week -1 ), at visit 5 (week -1), randomization strata for metformin use at screening (yes, no), at visit (weeks 8,12,24 and 30), treatment-visit interaction and country as fixed effects, as well as the interaction value of 11BA 1c at the initial time-visit as a covariate.

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included the weight of the planned measurements obtained at the end of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy.

All patients for whom measurements are available at the start time and after the start time are included.

Mean HbA1c levels (%) at visit and change in mean HbA1c (%) from baseline at visit are shown in FIG. 9 and 10.

3.2.2. Other Key Performance Endpoints.

Table 9

Number (%) of patients with HbA1c value <6.5% or <7% at week 30 - mITT population PLA1s(%) Combination with permanent Insulpp glargpn ratio (N=366) (Y=365) Number 366 365 <6.5% 124 (33.9%) 52(14.254)

Proportional difference (95% CI) vs. 19>76% (13.90% to 25.62%) insulin glargine ³ <0 _3,0001 <7% 201 (54.9%) 108 (29.6%)

Proportional difference (95% CI) vs. 25.52% (range 18.94% to 32.10%) _ Insulin glargine p-value -<0.0g101 _ Average proportional difference between treatment groups (constant ratio combinations) insulin glargine) from each stratum (randomization strata for HbAlc [<8.0, >8.0%] at visit 5 (week-I), randomization strata for metformin use at screening [yes, no]) using the values of io to the Cochran-Mangsl-Hsnzel (SON) method.

Proportional difference = difference in the proportion of patients achieving an HbAlc value of <6.5% or <7%.

Weight measurements were used at nslsls 30, including mcs obtained after discontinuation of the IMP or the introduction of rescue therapy. No assay gels available at week 30 at all, then patients were treated as non-responders.

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Table 10

Mean Change in Plasma Glucose Variance at 2 Hours (mmol/L) During a Standardized Meal Trial from Time Base to Week 30 Using ANCOVA - mITT Population

Plasma glucose deviations after 2 hours (mmol/l) Fixed Number Combination (N=366) Insulin lar in (N=365) Baseline Number 329 336 Mean value (SD) 7.01 (3.47) 7.14 (3.11) Median value 7.10 7.05 Minimum : maximum -5.1:17.4 -1.1:17.7 Week 30 (LOCF) Number 329 336 Mean value (SD) 3.11 (3.55) 6.71 (3.34) Median value 2.90 6.40 Minimum : maximum -9.5:15.9 -5.7:16.7 Change from start time to week 30 (LOCF) Number 329 336 Mean value (SD) -3.90 (4.17) -0.44 (3.34) Median value -3.70 -0.30 Minimum : maximum -18.2:9.8 -13.1:11.2 Average value obtained by the LS (SE) method ^a -3.90 (0.285) -0.47 (0.274) Difference of mean values determined by the LS (SE) method. versus insulin glargine ^a 95% CI' p-value -3.43 (0.251) (from -3.925 to -2.939) <0.0001 -

LOCI' - carry the data of the last observation forward.

^a Model analysis of covariance (ANCOVA) with treatment groups (constant ratio combinations and inschlin glargine), randomization strata for HbAlc (<8.0%, >8.0%) at visit 5 (week >1), randomization strata for use metformin at screening (yes. no), and country b as fixed effect factors and base time value for plasma glucose deviations at 2 hours as covariates. Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included measurements collected during the course of the study, including those obtained after permanent cessation of IMP use or the introduction of rescue therapy.

Patients with both measurements at baseline and at week 30 (LOCF) are included.

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Table 11

Change in Mean Plasma Glucose 2 Hours Postprandial (mmol/L) During a Standardized Meal Trial from Time Base to Week 30 Using ANCOVA - mITT Population

Plasma glucose level 2 hours after a meal (mmol/l) Fixed Ratio Combination (N=366) Insulin glargine (N=365) Baseline Number 332 340 Mean value (SD) 14.85 (3.82) 14.97 (3.67) Median value 14.75 14.80 Minimum : maximum 3.5 : 25.9 4.9 : 27.5 Week 30 (LOCF) Number 332 340 Mean value (SD) 9.91 (3.90) 13.41 (3.83) Median value 9.20 13.10 Minimum : maximum 2.9:25.7 3.9:33.1 Change from start time to week 30 (LOCF) Number 332 340 Mean value (SD) -4.94 (4.49) -1.56 (4.20) Median value -5.10 -1.50 Minimum : maximum -17.7 : 11.5 -16.1 : 23.8 Average value obtained by the LS (SE) method ^a -4.72 (0.322) -1.39 (0.310) Difference in mean values determined by the LS (SE) method compared with insulin glargine ^a -3.33 (0.284) - 9574 CI (from -3.889 to -2.774) -

LOCF ^_ carry the data of the last observation forward.

^Η Model analysis of covariance (ANCOVA) and treatment groups (constant ratio combinations and insulin glargine), HbAlc randomization strata (<8.0%, >8.0%) at visit 5 (week -1). randomization strata for metformin use at screening (yes. no), and country as fixed effect factors and baseline value for plasma glucose 2 hours postprandial as a covariate.

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included measurements collected during the course of the study, including those obtained after permanent cessation of IMP use or the introduction of rescue therapy.

Patients with both measurements at baseline and at week 30 (LOCF) are included.

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Table 12

Change in Mean Body Weight (kg) from Time Base to Week 30 Using the MMRM Procedure - mITT Population

Body weight (kg) Combination with fixed ratio 0=366) Ipsulnp glargine 0=365) Baseline Number 365 365 Mean value (SD) 87.81 (14.42) 87.09(14.75) Median value 88.00 84.90 Minimum : maximum 44.3:127.5 44.8:135.6 Week 30 Number 348 357 Mean value (SD) 87.48 (14.35) 87.96(15.08) Median value 87.00 85.90 Minimum ; maximum 43.5; 127.9 45.7:137.0 Change from start time to week 30 Number 365 365 Average value obtained by LS method (Sfi) ^a -0.67 (0.181) 0.7(1 (0.178) Difference in mean values determined by the LS (SE) method compared with insulin glargine* -1.37 (0.224) - 95%CI (-1.808 to -0.930) - p-zachepie <0.0001 -

^a Repeated measures mixed effects model (MMRM) with treatment groups (fixed ratio combinations and insulin glargine), HbAlc randomization strata (<8.0%, >8.0%) at visit 5 (week -1) , randomization strata for metformin use at screening (yes, no), scheduled visit, treatment-visit and country interaction as fixed effects, and base-time value interaction for body weight-visit as covariate.

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy.

All patients for whom measurements are available at the start time and after the start time are included.

Changes in mean body weight from initial visit time are shown in FIG. eleven.

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Table 13

Change in mean versus mean SMPG concentration in 7-point profile (mmol/L) from baseline to week 30 using MMRM procedure - mITT population

Combination with

Mean SMPG over 7 time points (mmol/L) permanent ratio <N=366> Ineu.shn ι lar! in ^=365> Baseline Number 323 320 Mean value (SD) 9.22(1.56) 9.05(139) Median value 9.14 8.96 Minimum: maximum 53:13.8 4.9 : 15.7 Week 30 Number 301 305 Mean value (SD) 7.75(1.71) 8.62(1.74) Median value 7.40 836 Minimum: maximum 4.7:143 5.1 : 16.3 Change οι initial-o point in time up to week 30 Number 323 320 Average value obtained by the method ] ,S (SI )“ -1.50 (0.137) -0.60 (0.130) Difference of mean values determined by the LS (SE) method. compared to insulin ι Largin* -0.90 (0.131) - 95%CI (from -1.154 to 41.640) - p-value 0.0001 -

SMPG = self-monitoring plasma glucose concentration.

^a Repeated Measures Mixed Effects Model (MMRM) with treatment ιruin (constant ratio combination and insulin glargine), randomization strata for HbAlc ό, >8.0%) at visit 5 (week - L), at visit 5 (week -1), randomization strata for metformin use at screening (yes, no), scheduling screeching, treatment-visit and country interactions as fixed effects, and affinity SMPG value at baseline time-to-insit as covariates.

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included all planned measurements obtained during the course of the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy.

Included are the weights of patients for whom measurements are available at the start time and after the start time.

In FIG. 12 shows a graph of average SMPG concentrations in the profile for 7 time points at the initial time point and at 30 weeks.

Table 14

Number (%) of patients achieving HbA1c <7% without gaining body weight at week 30 - mITT population

Combination with permanent insulin glargine

HbAlc <7% 6ei iribacteriia of body weight (\=366) (Ν=3ό5)

number 366 365 Yes 125 (34.2%) 49(13.4%) Proportional difference (95% CI) vs insulin glargine* 20.829, (from 14.98% to 26.66%) - p-zachepie <0.0001 -

^a Weighted mean of the proportional difference between treatment groups (constant ratio combination and insulin glargine) from each stratum (randomization strata for HbAlc [<8D 2^8.0^¼] at visit 5 (week-1), randomization strata for metformin use at screening [yes, no]) using Cochran-Mash el-Hensel (CMN) no Mei values.

The analysis included measurements of 1 IbA 1 s and body weight at week 30, including those obtained after the final cessation of IMP use or the introduction of rescue medication.

Patients were treated as non-responders. if they had no IbA scores of 1c and/or body weight by week 30.

In FIG. 13 is a graph of the average daily dose of insulin glargine at the visit.

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Table 16

Number (%) of Patients Achieving HbAlc <7% (Plasma Glucose <70 mg/dL [3.9 mmol/L]) Without Weight Gain at Week 30 and Without Documented Symptomatic Hypoglycemia During Study - mITT Population

HbA1c<7% bet irbsh. weight and bel confirmation Combination with silptomatic hypoglycemia permanent matchspppem (^366) Insulin ι largine (1\=365) Number 366 Dee 73(19.9%) 365 33 (9.0%) Proportional difference (95%C1) versus insulin 10.94% (from 5.93% to glargine ¹ 15.96%) p-value <0.0001

^a Weighted mean of the proportional difference between treatment groups (combinations with constant dose of insulin glargine) from each stratum (Randomization strata for IlhAlc [<8D>8.0%J r at visit 5 (week -1). Randomization strata □ screening time [yes, no]) using the Xcrop-Mantel-Haenszel (CMN) value.

Documented |[Confirmed symptomatic spoglycemia is a phenomenon in which the typical symptoms of hypoglycemia are accompanied by a measured blood glucose concentration of <70 mg'dL (3.9 mmol/L)

The analysis included weight measurement 1 IbA 1 s and body weight at week 30, including those obtained after the final cessation of IMP use or the introduction of rescue medication. Patients were treated as non-responders if they did not have any Hb A]c and/or body weight scores by July 30,

All documented severe hypoglycemia ^that occurred during the 30-week open-label treatment period was considered ^, including those patched after the first cessation of IMP use or rescue drug administration.

As a testing strategy to adjust for the multiplicity of comparisons described in the protocol, exploratory inference testing was performed for the two subsequent variables (percentage of patients achieving HbA1c <7.0% without weight gain at week 30 and without documented symptomatic hypoglycemia , and FPG), since the analysis for the daily dose of insulin glargine did not reveal a statistically significant difference.

Table 17

Change in Mean Fasting Plasma Glucose (mmol/L) from Time Base to Week 30 Using the MMRM Procedure - mITT Population Combinations with

Fasting plasma glucose level (MM0u1b/.|) 1YUS [PYANNSH ratio (N=366) insulin glargip (N=365) Baseline Number 364 364 Mean value (SD) 7.33(1.94) 7.32 (2.07) Msdnaptos shachspis 7.10 7.00 Minimum: maximum 3.2:15.7 3.3:172 1 [week 30 Number 341 349 Mean value (SD) 6.78(226) 6.69(2.05) Median value 6.30 6.30 M1mimum:maximum 2.8:20.6 2.8:18.0 Change from start time to week 30 Number 364 364 The average value determined by Szeged of the smallest turnbuckles (Sl ^; ) ^a -0.35 (0.142) -0.46 (0.138) Difference of mean values determined by the method (SE). compared to insulin glargine 0.11(0462) - 95%CI (σι -0207 to 0.428) - p-value 0.4951

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Table 18

Number (%) of patients achieving HbAlc levels <7% at week 30 without documented (plasma glucose <70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia during the study - mITT population

HbAlc <7% without tadocumeptirovanpo and symptomatic Constant ratio combination (N=366) Ingush r.iapi in (IS-365) Number 366 365 Yes 116(31.7%) 68(18.6%) Proportional difference (95% CI) vs. 13.22% (from 7.12% to 19.32%) insulin glargine*

Weighted mean of the proportional difference between treatment groups (variable insulin glargine ratio combinations) from each stratum (randomization strata for HbAlc [-8.0, >8.HR] at visit 5 (week -1), randomization strata η octoptopia for metformin use at time screening [yes, no]) using Cockrap-Mantsl-Henssl (SMI) values.

Documented symptomatic hypoglycemia is a symptomatic hypoglycemia in which the typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration of >70 mg/dL (3.9 mmol/L).

The analysis included all measurements of HbAlc at week 30, including those obtained after permanent cessation of IMP use or rescue drug administration. Patients were treated as non-responders if they had no HbAlc scores to pedel 30.

All documented symptomatic hypoglycemia that occurred during the 30-week period of open-label treatment was considered, including those after permanent cessation of IMP use or rescue drug administration.

¹ Mixed-effects dig repeated measures (MMRM) model with treatment groups (combinations of fixed, ratio, and insulin glart), randomized by I HA 1s (<8.0%, >=8.0%) at visit 5 ( week -1), randomization strata for metformin use at screening (yes, peg), scheduled visit, treatment-visit interaction and country as fixed scores, and fasting plasma glucose interaction at baseline-visit as a covariate

Countries with fewer than 5 patients were grouped with the country with the lowest number of patients, which is 5 or more.

The analysis included the weight of the planned measurements obtained during the study, including those obtained after the final cessation of IMP use or the introduction of rescue therapy.

Includes all patients for whom measurements are available at the start time and after the start time

In FIG. 14 is a graph of mean fasting plasma glucose at visit.

Table 19

Number (%) of patients who required rescue therapy during the 30-month period of _______ investigational drug - mITT population _______

Necessary emergency treatment Combination with a constant sleep with a hundred ratio (N=366) Pisulip glargine (N=365) Number Yes I proportional difference (95% CI) compared to insulin glargine* 366 10 (2.7%) -3.35% (from -6.33% to -036%) 365 22 (6.09-6)

“Weighted mean difference in risk between treatment groups (constant ratio insulin glargine combinations) from each stratum (randomization strata for HbAlc [-8.0._23.0°ol at Visit 5 (week -1), randomization strata for metformin use at time of screening [yes, no]) using the Cochrye-Maptel-Hetzel11 (SON) scores.

'' Based on media method at 'ratification and randomization strata for HbAlc [-8.0, >8.0%] at sight 5 (week -1) and randomization strata for metformin use at screening [yes, no] .

Adverse Event Profile Review: Adverse Events Occurring During Treatment - Safety Population

Table 20

and (%) Fixed Ratio Combination (N=365) Insulin Glargip (N=365) Patients with any TEAE 195 (53.4%) 191 (52.3%) Patients with any serious TEAE 20 (5.5%) 18 (4.9%) Patients with any TEAE. leading to death 1 (0.3%) 2 (0.514) Patients with any TEAE. leading to the final 10 (2.7'/") 3 (0.8%)

discontinuation of treatment

TEAE - an undesirable phenomenon that arose during treatment;

η (%) - number and percentage of patients with at least one TEAE.

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3.3. Safety assessment.

Symptomatic hypoglycemic events were documented in the special hypoglycemic event form and not on the AE page of the CRF, and thus were not included in the TEAE summaries. They were summarized separately (see section 3.3.5).

3.3.1. Adverse events that occurred during treatment.

Table 21

Number (%) of patients who experienced (were observed) frequently described TEAE (RT> 3% in any of the treatment groups), presented by main SOC and RT - population for safety assessment

] Main spastem organ class Preferred term η (%) Combination with constant ratio (Ν=365) insulin glargine (N=365) Any TEAE 195 (53.4%) 191 (52.3%) Infections and infestations 98 (26.8%) 112(30.7%) grini 15 (4.1%) AND (3.0%) Pazopharyngitis 32 (8.8%) 32 (8.8%) Upper respiratory tract infection 13 (3,644) 1 1 (3.0%) Nervous System Disorders 39(10.7%) 19 (5.2%) head bolt. 21 (5.8%) 10(2.7%) Gastrointestinal disorders 02(17.0%) 29 (7.9%) Diarrhea 16 (4.4%) 10 (2.7%) Nausea 38(10.4%) 2 (0.5%)

Major system organ class Preferred term η (%) Fixed ratio combination (N=365) insulin glargine (N=365) Vomit 13 (3.6%) 2 (0.5%)

TEAE - an adverse event that occurred after the start of treatment, SOC - system organ class;

RT is the preferred term;

McdDRA version: 18.0;

n (%) - number and percentage of patients with at least one TEAE.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

Presented only SOC at least one RT>3% in at least one group.

3.3.2. Deaths, serious adverse events that occurred during treatment.

Three patients experienced at least 1 TEAE resulting in death: 1 from the combination group, 2 from the insulin glargine group.

Combination group:

A 74 year old male patient (ID 840519010) died of pneumonia. The researcher did not consider this phenomenon as possibly related to the intake of IMP.

Insulin glargine group:

A 63-year-old female patient (ID 840550018) died of gallbladder cancer.

A 54 year old male patient (ID 703504004) died of cardiopulmonary failure. The patient had a medical history of hypertension. 171 days after the first dose of IMP, the patient experienced cardiopulmonary failure (intensity - severe), and he died on the same day at 09:32 at home. An autopsy was performed and the cause of death reported was cardiopulmonary failure, cardiac hypertrophy, and grade III coronary atherosclerosis. No other AEs or hypoglycemia were reported during the study.

The investigator did not consider these 2 fatal events in 2 patients as possibly related to the IMP.

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Table 22

Number (%) of Patients with Serious TEAE Presented by Major SOC and RT - Safety Population

Major system organ class Preferred term [n (%)1 Combination with permanent Insulin glargine ratio ’ (#365) (#365) Any serious TELE 20(5.5%) 18(4.9%)

Infections and infestations 1 (0.3%) 3 (0.8%) Osteomyelitis 0 1 (0.3%) Pneumonia 1 (0.3%) 1 (0.3%) wound infection 0 1 (0.3%) Benign, malignant and unspecified neoplasms (including cysts and polyps) 4(1.1%) 2 (0.5%) Benign neoplasms of the breast 1 (0.3%) 0 Benign neoplasms of the gastrointestinal tract 1 (0.3%) 0 Mammary cancer 1 (0.3%) 0 gallbladder cancer 0 1 (0.3%) Kaposi's sarcoma 0 1 (0.3%) Squamous cell carcinoma of the tongue 1 (0.3%) 0 Metabolic and nutrient absorption disorders 2 (0.5%) 1 (0.3%) substances hypoglycemia 2 (0.5%) 1 (0.3%) Nervous System Disorders 3 (0.8%) 0 Hypoglycemic seizures 1 (0.3%) 0 Loss of consciousness due to hypoglycemia 2 (0.5%) 0 Violations of the organ of vision 0 1 (0.3%) Glaucoma 0 1 (0.3%) Heart disorders 7(1.9%) 2 (0.5%) Acute myocardial infarction 2 (0.5%) 0 Unstable angina 2 (0.5%) 0 Arteriosclerosis of the coronary artery 1 (0.3%) 0 Congestive heart failure 0 1 (0.3%) Cardiopulmonary failure 0 1 (0.3%) myocardial infarction 1 (0.3%) 0 Ventricular tachycardia 1 (0.3%) 0 Iarutpenia from the side of the vessels 0 1 (0.3%) hypertension 0 1 (0.3%) Liver and biliary tract disorders 1 (0.3%) 1 (0.3%) Acute cholecystitis 0 1 (0.3%) Chronic cholecystitis 1 (0.3%) 0 Musculoskeletal and connective tissue disorders 2 (0.5%) 1 (0.3%) Protrusion of the intervertebral disc 0 1 (0.3%) Osteoarthritis 1 (0.3%) 0 Tendinitis 1 (0.3%) 0 Iarutpenia from the kidneys and urinary tract 0 1 (0.3%) kidney failure 0 1 (0.3%)

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Reproductive system and breast disorders 0 1 (0.3%) benign hyperplasia 0 1 (0.3%) prostate General disorders and complications at the injection site 0 3 (0.8%) Discomfort in the chest area 0 1 (0.3%) non-cardiac chest pain 0 2 (0.5%) Injury, poisoning and procedural complications 2 (0.5%) 1 (0.3%) meniscus injury 0 1 (0.3%) Scar 1 (0.3%) 0 subdural hematoma 1 (0.3%) 0

TEAE - an undesirable event that occurred after the start of treatment, SOC - system organ class,

RT is the preferred term;

MedDRA version: 18.0;

n (%) - the number and percentage of patients with at least one serious TEAE.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

3.3.3 Adverse events leading to withdrawal.

Table 23

Number (%) of patients who experienced (were observed) TEAE, which led to the final discontinuation of treatment, specified depending on the main SOC and RT - population for safety assessment

Major system organ class Preferred term [n (%)] Constant Ratio Combination (N=365) insulin glargine (N=365) Any TELE leading to definitive discontinuation of treatment 10 (2.7%) 3 (0.8%) Infections and infestations 1 (0.3%) 0 Pneumonia 1 (0.3%) 0 Benign, malignant and unspecified neoplasms (including cysts and polyps) 1 (0.3%) 1 (0.3%) Benign neoplasms of the gastrointestinal tract 1 (0.3%) 0 gallbladder cancer 0 1 (0.3%) Nervous System Disorders 2 (0.5%) 0 1 tin wheel 1 (0.3%) 0 Loss of consciousness due to hypoglycemia 1 (0.3%) 0 Violations of the eo side of the heart 1 (0.3%) 1 (0.3%) Unstable angina 1 (0.3%) 0 Cardiopulmonary failure 0 1 (0.3%) Gastrointestinal disorders 4(1.1%) 0 Nausea 4(1.1%) 0 Pregnancy, postpartum and perinatal conditions 0 1 (0.3%) Pregnancy 0 1 (0.3%) Research 1 (0.3%) 0 Weight increase 1 (0.3%) 0

TEAE - post-treatment adverse event, SOC - system organ class, PT - preferred term.

MedDRA version: 18.0 n (%) - number and percentage of patients with at least one TEAE resulting in permanent treatment discontinuation.

Note: Events in the table are sorted by internationally agreed SOC order and RT alphabetical order.

3.3.4. Other significant adverse events.

local tolerance.

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Table 24

Number (%) of patients who experienced reactions at the injection site during the period of treatment - population for safety assessment

Combination with

The source of the phenomenon is a constant insulin glargine ratio gh-alst

Preferred Term 365)

Any reactions at the injection site 0 2 (0.5%) RT coded based on investigator-reported 0 2 (0.5%) terms Hot flush at the injection site 0 1 (0.3%) Local reaction to injection 0 1 (0.3%)

ARAC - Allergy Assessment Committee, RT is the preferred term.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

Allergic reactions.

Table 25

Number (%) of patients with events recognized by ARAC as allergic reactions during the period of treatment - population for safety assessment

Study Treatment Addiction (by ARAC) Categories of diagnosis by ARAC MedDRA (RT) coded term for ARAC diagnosis Fixed Ratio Combination (N=365) Insulin Glargine (N=365) Total Any category Any phenomenon 0 1 (0.3%) Other 0 1 (0.3%) allergic rhinitis 0 1 (0.3%) Not related to IMP 0 1 (0.3%) Other 0 1 (0.3%) allergic rhinitis 0 1 (0.3%)

ARAC - Allergy Assessment Committee, IMP - Investigational Medical Product.

Note: The 'treatment period' is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of whether rescue therapy is administered.

Phenomena related to the pancreas.

Major cardiovascular events.

Table 26

Number (%) of patients with events recognized by the CAS as major cardiovascular events during the period of treatment - population for safety assessment

and (%) Fixed Ratio Combination (N=365) insulin glargine (N=365) Any 5 (1.4%) 4 (1.1%) Death due to cardiovascular disease 0 1 (0.3%) Non-fatal myocardial infarction 2 (0.5%) 0 Nssmrtsl stroke 0 0 Hospitalization due to unstable angina 0 0 Hospitalization due to heart failure 0 1 (0.3%) Coronary revascularization procedure 5 (1.4%) 3 (0.8%)

САС - expert committee on cardiovascular diseases;

n (%) - the number and percentage of patients with events recognized by the CAS as major cardiovascular events.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

PSAC did not recognize any of the events as pancreatitis. In addition, no neoplasms in the pancreas were reported in this study.

Elevated levels of calcitonin.

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Table 27

Number (%) of patients with events reported on the AE form for elevated calcitonin (>20 ng/l) during the treatment period - safety population

Preferred Term Combination with cost-to-value ratio (N=365) Insulin 1 la pi pi (N=365) Any 0 2(0.5%) High blood pressure 0 2(0.5%)

n(%) is the number and percentage of patients with any cases reported on the AE form for elevated calcitonin levels >20 pg/ml along with an additional form.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

Increased ALT.

Table 28

Number (%) of Patients with Events Reported on AE Form for Elevated ALT During Treatment Period - Safety Population

Combination with constant insulin glargine ratio

Preferred term (N=365) (N=365)

Any 1 (0.3%) 2 (0.5%)

Elevated levels of alanine aminotransferase 0 2 (0.5%)

Elevated liver enzyme 1 (0.3%) 0 η (%) - number and percentage of patients with any cases reported on the AE form for elevated ALT levels together with the additional form.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

Phenomena associated with a syringe pen

Table 29

Number (%) of patients with events reported in the pen-related event questionnaire during the period

receiving treatment - safety assessment population Fixed Ratio Combination (N-365) insulin glargine (N=365) Any phenomena associated with a syringe pen 11 (3.0%) 15 (4.1%) Associated with clinical event 0 0 Hc is associated with a clinical event 11 (3.0%) 15 (4.1%)

Clinical Event - An event of symptomatic hypoglycemia, an adverse event of hyperglycemia, or another adverse event collected in the Pen Events Questionnaire.

Note: The treatment period is defined as the time from the first IMP injection up to 3 days after the last IMP injection, regardless of the introduction of rescue therapy.

3.3.5. Other safety observations are symptomatic hypoglycemia.

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Table 30

Overview of Symptomatic Hypoglycemia Cases Reported on the Designated eCRF Page and Satisfying the Protocol Definition During the Treatment Period - Safety Population

Fixed ratio combination (N=365) Insulin Glargine (N-365) Total patient-years of exposure. 201.9 208.6 Symptomatic hypoglycemia Number of patients with events, η (%) 132 (41.6%) 161 (44.1%) Number of patients with events by patient-years” 0.75 0.77 Number of events 639 910 Number of events by patient- ^year 3.17 4.36 Documented symptomatic hypoglycemia (plasma glucose <70 mg/dL [3.9 mmol/L]) Number of patients with events, η (%) 146 (40.0%) 1 55 (42.5%) Number of patients with events by patient-years ^a 0.72 0.74 Number of events 612 880 Number of events by patient- ^year 3.03 4.22 Documented symptomatic hypoglycemia (plasma glucose <60 mg/dL [3.3 mmol/L]) Number of patients with events, n (%) 89 (24.4%) 83 (22.7%) Number of patients with events by patient-years” 0.44 0.40 Number of events 229 235 Number of events by patient-years ¹ ' 1.13 1.13 Probable symptomatic hypoglycemia Number of patients with events, η (%) 13 (3.6%) 20 (5.5%) Number of patients with events by patient-years ³ 0.06 0.10 Number of events 22 29 Number of events by patient- ^year 0.11 0.14 Severe symptomatic hypoglycemia Number of patients with events, η (%) 4 (1.1%) 1 (0.3%) Number of patients with events by patient-years” 0.02 <0.01 Number of events 5 one Number of events by patient-year ¹¹ 0.02 <0.01

IMP - investigational medical product, eCRF - electronic individual registration card. Patient-years of exposure - calculated as the time from the first to the last IMP injection plus 1 day. ^a - calculated as the number of patients with events divided by the total number of patient-years of exposure. ^b - calculated as the number of events divided by the total number of patient-years of exposure.

Symptomatic hypoglycemia - Symptomatic hypoglycemia recorded on its designated eCRF and meeting the protocol definition for severe or documented or probable symptomatic hypoglycemia.

The treatment period is defined as the time from the first IMP injection up to 1 day of onset of symptomatic hypoglycemia after the last IMP injection, regardless of the introduction of rescue therapy.

Claims (17)

1. Use of a composition of (a) 33 μg/ml lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml insulin glargine and/or a pharmaceutically acceptable salt thereof to prepare a composition for the treatment of type 2 diabetes mellitus, wherein the composition is administered to a patient in need thereof in combination with metformin and/or a pharmaceutically acceptable salt thereof. 2. Use according to claim 1, wherein the age of the patient to be treated is at least 50 years old. 3. Use according to claim 1 or 2, wherein the patient to be treated is obese. - 131 039114 4. Use according to claim 3, where the patient to be treated has a body mass index of at least 30 kg/m ² , at least 31 kg/m ² , at least 32 kg/m ² , or at least 33 kg/ ^m2 . 5. Use according to any one of claims 1 to 4, wherein type 2 diabetes mellitus is not adequately controlled with metformin alone. 6. Use according to claim 5, wherein treatment with at least 1.5 g/day of metformin does not adequately control type 2 diabetes mellitus. 7. Use according to any one of claims 1 to 6, wherein the patient to be treated has an HbA1c value in the range of at least 7%, at least 8%, or at least 9% within one month prior to treatment with the composition. 8. Use according to any one of claims 1 to 7, wherein the patient to be treated has a fasting plasma glucose concentration of at least 7 mmol/l, at least 8 mmol/l, at least 9 mmol/l , at least 10 mmol/l or at least 11 mmol/l within one month prior to treatment with the composition. 9. Use according to any one of claims 1 to 8, wherein the patient to be treated has a self-monitoring plasma glucose concentration of at least 8 mmol/l, at least 9 mmol/l, at least 10 mmol/ l or at least 11 mmol/l within one month prior to treatment with the composition. 10. Use according to any one of claims 1 to 9, wherein the patient to be treated has a plasma glucose level 2 hours after a meal of at least 12 mmol/l, at least 13 mmol/l, at least at least 14 mmol/l, at least 15 mmol/l, at least 16 mmol/l or at least 17 mmol/l within one month prior to treatment with the composition. 11. The use according to any one of claims 1 to 10, where the patient to be treated has a difference between the concentration of glucose in blood plasma 2 hours after a meal and the concentration of glucose in blood plasma 30 minutes before a test meal of at least 5 mmol /l, at least 5.5 mmol/l, at least 6 mmol/l, at least 6.5 mmol/l or at least 7 mmol/l within one month prior to treatment with the composition. 12. Use according to any one of claims 1 to 11, wherein the patient to be treated is not receiving a GLP-1 receptor agonist and/or insulin. 13. A method of treating type 2 diabetes mellitus, comprising administering to a patient in need thereof a composition containing (a) 33 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof; an acceptable salt, wherein the composition is administered in combination with metformin and/or a pharmaceutically acceptable salt thereof. 14. The method of claim 13, wherein the dose of insulin glargine is 0.25 to 1.5 U/kg body weight. 15. The method of claim 13 wherein the dose of lixisenatide is 0.05 to 0.5 µg/kg body weight. 16. The method according to any one of claims 13, wherein the composition is administered parenterally. 17. The use of a combination containing (I) a pharmaceutical composition containing (a) 50 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical composition comprising (a) 33 μg/ml of lixisenatide and/or a pharmaceutically acceptable salt thereof and (b) 100 U/ml of insulin glargine and/or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of diabetes mellitus 2 of the type administered in combination with metformin and/or a pharmaceutically acceptable salt thereof.