TW201311269A - Pharmaceutical combination for use in inducing weight loss in diabetes type 2 patients or/and for preventing weight gain in diabetes type 2 patients - Google Patents

Abstract

The present invention refers to a pharmaceutical combination for use in inducing weight loss in diabetes type 2 patients or/and for preventing weight gain in diabetes type 2 patients.

Description

Medicinal composition for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes

The subject of the invention is a pharmaceutical composition for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes, the composition comprising (a) desPro ³⁶ Exendin-4 (1-39)- Lys ₆ -NH ₂ [AVE0010, lixisenatide] and/or its pharmaceutically acceptable salt, and (b) metformin and/or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is a method for inducing weight loss in Type 2 diabetes and/or preventing weight gain in Type 2 diabetes patients, the method comprising administering a composition of the present invention to a subject in need thereof.

In healthy humans, insulin released from the pancreas is closely linked to blood glucose levels. The increase in blood glucose that occurs after a meal is quickly offset by a separate increase in insulin secretion. In the fasting state, the amount of plasma insulin is reduced to a level sufficient to ensure continuous supply of glucose to insulin-sensitive organs and tissues, and to maintain low production of hepatic glucose at night.

In contrast to type 1 diabetes, type 2 diabetes is usually not insulin-deficient, but in many cases, especially in progressive cases, if oral anti-diabetic drugs are used in combination, insulin therapy is considered to be the most appropriate. Therapy.

During several years, the amount of glucose in the blood increases without initial symptoms, indicating a significant health risk. Large-scale by the United States The DCCT study [The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986] clearly shows that long-term chronic increase in blood glucose is a major cause of diabetic complications. Examples of diabetic complications are microtubule and macrovascular damage, which may be manifested in retinopathy, nephropathy or neuropathy and leading to blindness, renal failure, and extremity wear, with an increased risk of cardiovascular disease. Therefore, it can be inferred that the improved therapy of diabetes must mainly strive to maintain blood sugar within the physiological range as much as possible.

Overweight patients with type 2 diabetes, such as body mass index (BMI) There are specific risks in 30 patients. In these patients, the risk of diabetes overlaps with the risk of overweight, resulting in, for example, an increase in cardiovascular disease compared with a normal type 2 type 2 diabetes. Therefore, it is especially necessary to reduce weight while treating diabetes in these patients.

A saccharide tablet is a diterpene hypoglycemic agent for the treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) that does not respond to dietary correction. Glucose ingots improve glycemic control by improving insulin sensitivity and reducing intestinal absorption of glucose. The sugar ingots are usually administered orally. However, the use of a sugar ingot to control Type 2 diabetes in obese patients may not be sufficient. Therefore, in these patients, controlling type 2 diabetes may require additional measures.

The compound desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ (AVE0010, lixisenatide) is a derivative of Exendin-4, and in WO 01/04156, AVE0010 is disclosed as SEQ ID NO:93:

SEQ ID NO: 1: AVE0010 (44 AS)

HGEGTFTSDLSKQMEEEAVRL-FIEWLKNGGPSSGAPPSKKKK-KK-NH ₂

SEQ ID NO: 2: Exendin-4 (39 AS)

HGEGTFTSDLSKQMEEEAVRL-FIEWLKNGGPSSGAPPPS-NH ₂

Exendins are a group of peptides that can lower blood glucose concentration. The characteristic of ESS0010 is the C-terminal truncation of the original Exendin-4 sequence. AVE0010 contains the absence of 6 C-terminal amide residues in Exendin-4.

In the present specification, AVE0010 includes a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of AVE0010 are known to those skilled in the art. A preferred pharmaceutically acceptable salt of AVE0010 for use in the present invention is acetate.

In Example 1 of the present invention, AVE0010 (lixilax) has been shown to significantly improve glycemic control and reduce body weight in additional treatments of sucrose tablets:

̇HbA1c is significantly reduced in both groups

- 2-step titration: LS mean difference of HbA1c vs placebo was -0.41% (p<0.0001)

- 1 step titration: LS mean difference of HbA1c vs placebo was -0.49% (p<0.0001)

̇ significantly more patients with Lisilaa reach the HbA1c target ( 6.5% &<7.0%) ̇ Using lixisenatide, fasting blood glucose (FPG) is significantly improved; ̇ induces significant weight loss;

- 2 steps: The difference in LS mean relative to placebo is -1.05 kg (p=0.0025)

- 1 step: The difference in LS mean relative to placebo is -1.00 kg (p = 0.0042)

A sustained effect was observed throughout the treatment period.

In Example 2 of the present invention, in obese type 2 diabetes patients under the age of 50, in which the sugar ingot is not properly controlled, ̇ proves that lixisenatide (AVE0010) significantly reduces young obesity type 2 diabetes during 24 weeks. HbA1c and body weight; ̇ In terms of weight loss and similar magnitude of HbA1c reduction, it proves that lixisenatide (AVE0010) has a significant advantage over sitagliptin; ̇利西拉来 (AVE0010) exhibits transcenditacin Good safety and tolerability, especially the incidence of hypoglycemia, no difference; the efficacy of Philippine (AVE0010) is confirmed by its dual efficacy in reducing PPG and FPG; It is administered in addition to the treatment of the sugar ingot.

A first aspect of the present invention is a pharmaceutical composition for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes, the composition comprising (a) desPro ³⁶ Exendin-4 (1-39) And Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof, (b) a sugar ingot and/or a pharmaceutically acceptable salt thereof.

The saccharide tablet is an international non-proprietary name for 1,1-metformin (CAS No. 657-24-9); in the present invention, the term "sucrose tablet" includes any pharmaceutically acceptable salt thereof.

In the present invention, the saccharide tablet can be administered orally; it is known to those skilled in the art that the sucrose tablet formulation is suitable for the treatment of type 2 diabetes via oral administration. The sugar ingot can be sufficient to induce a therapeutic effect and to be administered to a subject in need thereof. The saccharide tablet can be administered at a dose of at least 1.0 gram per day or at least 1.5 grams per day. For oral administration, the sucrose can be formulated as a solid dosage form such as a lozenge or pill. The sucrose can be formulated with a suitable pharmaceutically acceptable carrier, adjuvant, and/or auxiliary.

In the present invention, desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt can be administered in an additional treatment for administration of a sugar ingot.

In the present invention, the terms "additional", "additional therapy" and "additional therapy" relate to the treatment of type 2 diabetes with a sugar ingot and AVE0010. The sugar ingot and AVE0010 can be administered at intervals of 24 hours; each can be administered once a day; and can be administered via different routes of administration; the sugar can be administered orally, AVE0010 can be administered parenterally .

The subject to be treated with the agent of the present invention suffering from type 2 diabetes may be a subject suffering from type 2 diabetes. Example 1 demonstrates such patients In the case, AVE0010, which combines the combination of the sugar ingots, provides advantageous treatment.

The subject to be treated with the agent of the present invention suffering from type 2 diabetes may be a mesosaccharide tablet alone, for example, a dose of 15 to 80 units/day of insulin for 3 months and, if necessary, at least 1.0 g/day of the sugar ingot or A dose of at least 1.5 g/day of sucrose is treated for 3 months, and patients with type 2 diabetes who are suffering from type 2 diabetes cannot be properly controlled. In the present invention, the subject of type 2 diabetes cannot be appropriately controlled, and may have an HbA1c value in the range of 7% to 10%.

The subject to be treated with the agent of the present invention suffering from type 2 diabetes may be an obese patient. In the present invention, an obese patient may have a body mass index of at least 30 kg/m 2 .

As described herein, a subject treated with the agent of the present invention suffering from type 2 diabetes may be an obese patient who is not properly controlled by a sugar ingot and may be under 50 years of age, for example, at least 18 years old and under 50 years old. Example 2 demonstrates that AVE0010, which is administered in combination with a saccharide tablet, provides advantageous treatment in such patients.

A subject treated with the agent of the present invention suffering from type 2 diabetes may have a normal body weight. In the present invention, a subject having a normal body weight may have a body mass index ranging from 17 kg/m 2 to 25 kg/m 2 or from 17 kg/m 2 to < 30 kg/m 2 .

The subject treated with the agent of the present invention may be an adult subject; the subject may be at least 18 years old or may be 18 to 80 years old, 18 to 50 years old, or 40 to 80 years old, or 50 to 60 years old; the subject Can be under 50 years old.

The subject to be treated with the agent of the present invention preferably does not receive anti-diabetic treatment, for example, using insulin and/or related compounds.

A subject treated with the agent of the present invention may develop type 2 diabetes for at least 1 year or at least 2 years. In particular, the subject to be treated has been diagnosed with Type 2 diabetes at least 1 year or at least 2 years prior to initiation of treatment with the agent of the invention.

The subject of treatment can have a HbA _1c value of at least about 8% or at least about 7.5%. The subject may also have a HbA _1c value of from about 7 to about 10%. The practice of the present invention demonstrates that treatment with AVE0010 results in a decrease in HbA _1c value in type 2 diabetes.

In yet another aspect of the invention, a composition as described herein can be used to improve glycemic control. In the present invention, improving blood sugar control specifically means improving postprandial blood glucose concentration, improving fasting blood glucose concentration, and/or improving HbA _1c value.

In yet another aspect of the invention, a composition as described herein can be used to improve HbA _1c values in patients with type 2 diabetes. Improving the HbA _1c value means, for example, that the HbA _1c value is reduced to 6.5% or less after treatment for at least one month, at least two months, or at least three months.

In yet another aspect of the invention, a composition as described herein can be used to improve glucose tolerance in a Type 2 diabetic patient. Improving glucose tolerance means reducing the postprandial blood glucose concentration with the active agent of the present invention; specifically, the decrease means that the blood glucose concentration reaches or is at least close to the normal blood glucose level.

In the present invention, the normal blood sugar level is specifically 60 to 140. A blood glucose concentration of milligrams per deciliter (equivalent to 3.3 to 7.8 mM per liter); this range specifically refers to the blood glucose concentration in the fasting state and the postprandial state.

The subject to be treated may have a blood glucose concentration of at least 10 millimoles per liter, at least 12 millimoles per liter, or at least 14 millimoles per liter after a meal; such blood glucose concentrations exceed normal blood glucose concentrations.

The subject to be treated may have a glucose fluctuation of at least 2 millimoles per liter, at least 3 millimoles per liter, at least 4 millimoles per liter, or at least 5 millimoles per liter. In the present invention, the glucose fluctuation specifically refers to the difference between the blood glucose concentration 2 hours after the meal and the blood glucose concentration 30 minutes before the meal test.

"Post-meal" is a term familiar to those familiar with diabetes. Specifically, the term "post-meal" is used to describe the stage of eating and/or exposure to glucose under experimental conditions. In healthy humans, this stage is characterized by an increase in blood glucose concentration followed by a decrease. The words "post-meal" or "post-meal" usually end after eating and/or exposure to glucose for 2 hours.

The subject disclosed herein may have a fasting blood glucose concentration of at least 8 millimoles per liter, at least 8.5 millimoles per liter, or at least 9 millimoles per liter; such blood glucose concentrations exceed normal blood glucose concentrations.

In another aspect of the invention, a composition as described herein can be used to ameliorate (i.e., reduce) fasting blood glucose in a type 2 diabetic patient. In particular, a decrease means that the blood glucose concentration reaches or is at least close to the normal blood glucose level.

The compositions of the present invention are useful for treating one or more of the medical signs described herein, such as treating a type 2 diabetes or a condition associated with type 2 diabetes, such as improving glycemic control, reducing fasting blood glucose levels, improving glucose fluctuations, and reducing Postprandial blood glucose concentration, improved glucose tolerance, improved HbA _1c value, weight loss and/or prevention of weight gain.

In the present invention, desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may be administered in an amount sufficient to induce a therapeutic effect, and administered to a subject in need thereof.

In the present invention, desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may be combined with a suitable pharmaceutically acceptable carrier, adjuvant, and/or auxiliary The substances are blended together.

The compound desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof can be administered parenterally, for example by injection (e.g., via intramuscular or subcutaneous injection). Suitable injection devices, for example, so-called "pens" and injection needles containing syringes containing active ingredients are known. An appropriate amount of the compound desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may be administered, for example, in the range of 10 to 15 μg per dose or 15 to 20 μg per dose The amount.

In the present invention, desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may vary from 10 to 20 μg, from 10 to 15 μg, or from 15 to 20 The daily dose of micrograms is not equal. DesPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or its pharmaceutically acceptable salt can be administered once daily by injection.

In the present invention, desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may be provided as a liquid composition. Those skilled in the art are familiar with liquid compositions suitable for parenteral administration of AVE0010. The liquid composition of the present invention may have an acidic or physiological pH, and the acidic pH is preferably in the range of pH 1 to 6.8, pH 3.5 to 6.8, or pH 3.5 to 5; physiological pH is preferably pH 2.5 to 8.5, pH 4.0. To 8.5, or pH 6.0 to 8.5. The pH can be adjusted using a pharmaceutically acceptable dilute acid (usually HCl) or a pharmaceutically acceptable dilute base (usually NaOH).

A liquid composition comprising desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may contain a suitable preservative; suitable preservatives may be selected from the group consisting of phenol, m-cresol, benzyl alcohol And parabens; preferred preservatives are m-cresol.

The liquid composition comprising desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may contain a tonicity agent; the appropriate tonicity agent may be selected from the group consisting of glycerin, lactose, sorbitol, and mannose A sugar alcohol, glucose, NaCl, a compound containing calcium or magnesium such as CaCl ₂ . The concentration of glycerol, lactose, sorbitol, mannitol and glucose may range from 100 to 250 mM, and the concentration of NaCl may be as high as 150 mM; preferably the tonicity agent is glycerol.

The liquid composition comprising desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof may contain from 0.5 μg/ml to 20 μg/ml, preferably 1 μg/ml to 5 μg/ml of methionine; preferably, the liquid composition comprises L-methionine.

A further aspect of the present invention is a method for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes patients, the method comprising administering desPro ³⁶ Exendin in combination with a sugar ingot having a need thereof -4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof; in particular, a composition as described herein may be administered. In the method of the invention, the object can be the subject matter defined herein.

A further aspect of the invention is the use of a composition as described herein for the manufacture of a medicament for the treatment of a medical indication as described herein. For example, the compositions of the present invention can be used to manufacture a medicament for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes. The compositions of the present invention may also be used in the manufacture of medicaments for the treatment of type 2 diabetic patients, or in the treatment of conditions associated with type 2 diabetes, such as improved glycemic control, reduced fasting blood glucose concentrations, improved glucose fluctuations, reduced postprandial blood glucose concentrations, Improve HbA _1c value, and / or improve glucose tolerance. The agent may be formulated as described herein; for example, the agent may comprise a parenteral formulation of AVE0010 and/or a pharmaceutically acceptable salt thereof, and an oral formulation of a sugar ingot and/or a pharmaceutically acceptable salt thereof .

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

Example 1

For type 2 diabetes patients, the evaluation of the randomization of efficacy and safety of lixisenatide as an additional treatment for sucrose ingots compared to placebo, Double-blind, placebo-controlled, parallel-group, multicenter, multinational studies.

Overview

This example is a standard for patients with type 2 diabetes. Compared with placebo, lixisenatide is a randomized, double-blind, placebo-controlled, parallel-group, multi-center, multi-centered National studies. The minimum study duration for each patient was approximately 79 weeks (up to 3 weeks screening + 24 weeks primary treatment + variable extension + 3 days follow-up). The study was conducted at 75 centers in 15 countries. The primary objective of the study was to use a two-step dose-titration therapy to assess the efficacy of lixisenatide as an additional treatment for glycemic control in terms of HbA _1c reduction (absolute change) over 24 weeks compared to placebo.

A total of 484 patients were randomly assigned to four treatment groups (161 lixhilla to two-step titration group, 161 lixisenatide one-step titration group, 80 placebo two-step titration group, and 82 placebo One of the steps of the titration group). Of the 484 randomly assigned patients, 482 were exposed to study treatment; two patients (one in each of the placebo groups) were randomly assigned to receive no errors in any study treatment; the two patients were treated with efficacy And excluded from the safety analysis. In their analysis, placebo one-step and two-step titrations were combined. The demographics of the treatment groups were generally similar to those of the baseline, but placebo-treated patients were slightly older than patients treated with Bilisila. Of the 482 randomly assigned and treated patients, 5 patients (1 lixisenatide two-step titration group, 3 lixisenatide one-step titration group, and 1 placebo-step titration group) Patients) due to the lack of post-baseline efficacy data, Excluded from the efficacy analysis of the mITT population. During the entire study period, 103 (21.3%) patients discontinued the study treatment earlier than expected. The percentage of patients discontinued in the study treatment was higher in the Lixila two-step titration group (24.8%) than in the one-step titration group (18.6%) and the combined placebo group (20.4%). For the lixisenatide treatment group, the main reason for the treatment interruption was “bad condition” (Lisila two-step titration 11.8% and lixisenatide titration 8.7%, compared to 6.2% combined placebo). Followed by "other reasons" (9.9% and 7.5%, compared to 9.9% of combined placebo).

The mean square root (LS) change from baseline to week 24 for HbA _{1c was} -0.82% compared to the placebo group, and the lixisenatide two-step titration group was -0.83% (Vs. LS with placebo) The mean difference = -0.41%; p value <.0001), the lixisenatide one-step titration group was -0.92% (Vs. combined with placebo LS mean difference = -0.49%; p value <.0001). Reached HbA _{1c at} week 24 6.5 or <7% of patients, two lixisenatide-treated groups were significantly higher than the placebo-treated group (for HbA _1c For 6.5%, Lixila titrated 20.4% in two steps and Lisila to titrate 25.6% in one step, 7.6% in comparison with placebo; in the case of HbA _1c <7%, Lisila came in two steps to titrate 42.1 % and lixisenatine titrated 47.4% in one step, compared to 24.1% in placebo. Compared with the placebo group, the two lixisenatide treatment groups showed a statistically significant reduction in fasting blood glucose (the difference in LS mean of the two-step titration group in the Lixila two-step titration = -0.67 millimoles per liter and p-value) =0.0004; LS mean difference in a one-step titration group of lixisenatide = -0.65 millimoles/liter and p-value = 0.0007). Compared with the placebo group, the two lixisenatide treatment groups also showed a statistically significant reduction in body weight from baseline to week 24 (the difference in LS mean of the two-step titration of Lisila was = -1.05 kg, The p value is 0.0025; the difference in LS average value of the first step titration of Syrah is -1.00 kg, p value is 0.0042). The percentage of patients requiring rescue therapy during the main 24-week double-blind treatment was slightly lower in the two lixisenatide-treated groups compared with the placebo group (4.4%) (two-step titration 3.1) % and one step titration 1.3%). Because of the low incidence of rescue patients, there is no evidence of significant differences between the lixisenatide group and the placebo group.

Lisila is well tolerated. The incidence of adverse events (TEAE) after treatment was comparable between the treatment groups (87.6% in the two-step titration group, 85.7% in the lixisenatide one-step titration group, and 86.3 in the combined placebo group). %). Five patients (1 lixisenatide two-step titration group, 2 lixisenatide one-step titration group, and 2 placebo patients) died of TEAE during treatment. During the entire study period, 59 patients developed at least one severe TEAE, and the incidence was similar between the lixisenatide two-step titration group (13.0%) and the combined placebo group (13.8%), but Lixila was titrated in one step. The incidence of the group (9.9%) was slightly lower. The most frequently reported TEAE for patients treated with lixisenatide was nausea [62-digit (38.5%) patients in two-step titration and 47 (29.2%) in one-step titration, compared with 13 (8.1%) in placebo) , followed by vomiting [two-step titration of 29 (18.0%) patients and Twenty-one (13.0%) was titrated in one step, relative to placebo (0.6%). During the entire study period, compared with 12 (7.5%) placebo-treated patients with symptomatic hypoglycemia as defined by the protocol, the lixisenatide two-step titration group was 12 (7.5%). Patients and lixisenatide one-step titration group of 6 (3.7%) patients with symptomatic hypoglycemia during the same period; no symptomatic hypoglycemia was extremely severe. A total of 15 patients [Lisila two-step titration 6 (3.7%), lixisenatide titration 3 (1.9%) and combined placebo 6 (3.8%)] were declared allergic, after The Allergic Response Assessment Committee (ARAC) determined that it was an allergic reaction, but only two allergic conditions (one for each Lixila group) were determined to be related to the study drug. No cases of acute pancreatitis were observed in the study. There were no differences in safety and tolerability between the two lixisenatide titrations (one step and two steps).

1. Purpose

1.1 main purpose

The primary objective of this study was to use a two-step dose-titration therapy for type 2 diabetic patients. During the 24 weeks period, lixisenatide was used as an additional treatment for the reduction of HbA1c (absolute change) compared to placebo. The effectiveness of blood sugar control.

1.2 secondary objectives

The secondary objectives of this study were: ̇Evaluate the effect of AVE0010 on the following variables: - For one-step dose titration therapy, in terms of HbA _1c reduction, blood glucose control compared to placebo; - up to HbA _1c <7 % or HbA _1c 6.5% of patients; - weight; - postprandial blood glucose; ̇ assessment of AVE0010 safety and tolerability; ̇ evaluation of AVE0010 PK and anti-AVE0010 antibody development.

2 test design

This was a randomized, double-blind, placebo-controlled, 4-arm (4-arm), unbalanced design, parallel group, multicenter, multinational study: two-step titration (150 lixisenatide treatment versus 75 Placebo treatment of patients) and one-step titration (150 lixisenatide treatment and 75 placebo treatment patients). In this study, both active and placebo treatments were double-blind, and the amount of study drug (ie, active drug or matched placebo dose) and titration therapy (ie, one step and two steps) were not concealed.

Use HbA1c (<8%, 8%) and body mass index (BMI < 30 kg / square meter, Screening values were graded by screening values such as 30 kg/m2. After the screening period, patients were randomly assigned to four branches at a ratio of 2:1:2:1 via the Interactive Voice Response System (IVRS) (Lisila two-step titration, placebo two-step titration, Lisila Take one-step titration, and placebo one-step titration).

According to protocol revision 4 (date January 19, 2010), the minimum study duration for each patient is approximately 79 weeks (up to 3 weeks screening + 24 weeks primary double-blind treatment + variable double-blind treatment extension + 3 days chase trace). Patients who completed the main double-blind period of 24 weeks underwent a variable double-blind extension, which for all patients was approximately at the end of the 76th week of the last randomly assigned patient (V24).

According to the revised version of the program 3 (date July 3, 2009), patients who discontinued IP earlier than expected continued their study until the expected date of completion of the study; the study steps detailed according to the revised version of the protocol (3 days safety) Follow-up after treatment, pharmacokinetic assessment, and meal challenge trials were followed.

3 major and key secondary assessment points (ENDPOINT)

3.1 Main evaluation points

The primary efficacy variable was the absolute HbA _1c change from baseline to Week 24, the system is defined as: 24 weeks HbA _1c - HbA _1c baseline of.

Use the last baseline post-HbA during the main 24-week double-blind treatment if the patient discontinues treatment earlier than expected, or receives rescue therapy during the main 24-week double-blind treatment, or if there is no HbA _1c at the 24th week of the visit. _{The 1c} measurement is taken as the HbA _1c value at week 24 [Last Observation Carried Forward (LOCF) program].

3.2 secondary assessment points

3.2.1 Evaluation point of efficacy

With regard to secondary efficacy variables, the same procedure as for the absence/early interruption was evaluated using the treatment used for the primary variables.

Continuous variable

FPFPG (milli/er) change from baseline to week 24

变化Change in body weight (kg) from baseline to week 24

Category variable

Percentage of patients with HbA _1c <7% at week 24

̇24th week HbA _1c 6.5% of patients with a percentage

Percentage of patients requiring rescue therapy during the main 24-week double-blind treatment

减 Weight loss (kg) from baseline to week 24 5% of patients

3.2.2 Security assessment point

Safety analysis is based on declared TEAE and other safety information, including symptomatic hypoglycemia and severe symptomatic hypoglycemia, local tolerance at the injection site, allergy (determined by ARAC), suspected pancreatitis, blood loss Increased calcium, vital signs, 12-lead ECG, and laboratory tests. Major cardiovascular conditions were also collected and determined by the Cardiovascular Judging Committee (CAC). The CAC judgments and confirmations obtained from the study and other Lisila's Phase 2 to 3 clinical studies were analyzed for analysis and summarized in another statistical analysis plan based on Lisila's overall cardiovascular assessment. Report. KRM/CSR will not present an overview of the CV conditions determined and confirmed from this study.

4 sample number estimation hypothesis

Estimation of the number of samples/power was performed based on the primary efficacy variable, absolute change in HbA1c from baseline to week 24.

A bilateral standard of 5% significant, assuming a common standard deviation of 1.3%, a 150% patient in a lixisera branch and 2x75 patients in the combined placebo group provided 91% (or 75%) of the test power to Detection of libila and placebo from baseline to week 24 HbA1c The difference is 0.5% (or 0.4%). The sample size calculation was based on a two-sample t-test using nQuery® Advisor 5.0. The standard deviation, which is considered for early withdrawal, is estimated in a conservative manner from previously conducted diabetes studies (based on published information from similar design studies and unpublished internal data).

5 statistical methods

5.1 Analysis of ethnic groups

The modified intent-to-treat (mITT) population consists of all randomized patients who received at least one dose of double-blind study drug (IP) and underwent a baseline assessment of efficacy variables and at least one post-baseline assessment.

The safety population is defined as all randomly assigned patients who use at least one dose of double-blind IP.

5.2 main efficacy analysis

Screening for HbA _1c (<8.0, using treatment groups (Lisila two-step titration and placebo spurs, lixisenatide one-step titration and placebo spurs) 8.0%) random class, screening BMI (<30, The random stratum and country of 30 kg/m 2 are the fixed effect covariance analysis (ANCOVA) model, and the baseline HbA _1c value is used as a covariate to analyze the main assessment points (HbA _1c change from baseline to week 24) . Differences between the individual lixisenatide and placebo combined groups, bilateral 95% confidence intervals, and p-values were estimated within the ANCOVA framework. In the ANCOVA model, two titration placebo spurs were included in separate treatment stratifications, but when used with appropriate comparisons, they were combined into one group [eg, to compare lithila two-step titration with pooled placebo, Then, according to the placebo one-step titration, placebo two-step titration, lixisenatide one-step titration and lixisenatide two-step titration (-0.5, -0.5, 0, +1) order].

A step-by-step test procedure is applied to ensure that Type I errors are controlled. First, a comparison of the two-step titration of the lixisenatide and the placebo combination (primary target) was performed. If the test is statistically significant, then a three-step titration of the branch and placebo combination (secondary goal) is performed.

A primary analysis of the primary efficacy variables was performed based on the mITT population and the efficacy variable measurements obtained during the main 24-week double-blind treatment period. The primary 24-week double-blind treatment period for which the efficacy variable is to be obtained is defined as the last dose from the first dose of double-blind IP to V12/week 24 or before (or D169 if V12/week 24 is absent) Double-blind IP injections for 3 days (except for FPG in the Central Laboratory, which is 1 day), or until the introduction of rescue therapy, depending on which is earlier. The HbA _1c value was measured as the 24th week using the LOCF program with the last available baseline post-treatment HbA _1c assay (in the case of rescue treatment, before starting new drug treatment).

5.3 secondary efficacy analysis

Once the primary variables of the two comparisons are statistically significant at a = 0.05, the test procedure is followed in the following order of preference to test the following secondary efficacy variables: 1. FPG from baseline to week 24 (mole/liter) Change, 2. change in body weight (kg) from baseline to week 24, 3. Percentage of patients requiring rescue therapy during the main 24-week double-blind treatment.

A diagram providing a detailed description of all of the step-by-step test procedures is shown in Figure 2 .

Analyze all consecutive secondary efficacy variables at week 24 as described in Section 3.2.1 using a similar approach to the primary analysis of primary efficacy assessment points and the ANCOVA model as described in Section 5.2; provide each lithilla Adjusted estimates of differences in treatment mean between the sputum and placebo groups and a bilateral 95% confidence interval.

Use in a random hierarchy [screen HbA _1c (<8.0, 8.0%) and screening BMI (<30 kg/m2, The equivalent of 30 kg/m2] is divided into different levels of the Cochrane-Mantel-Hensel (CMH) method, and the following secondary efficacy variables are analyzed in the 24th week: ̇ Week 24 HbA _1c <7% of patients, ̇24th week HbA _1c Percentage of patients with 6.5% of patients, and the percentage of patients requiring rescue therapy during the main 24-week double-blind treatment period.

Treatment groups presented at week 24 compared to baseline weight loss The number and percentage of patients with 5%.

All secondary assessment points at the end of treatment were evaluated only with narrative statistics (average, standard deviation, median, and range provided in CSR).

5.4 Security Analysis

Security analysis is mainly based on the entire treatment period of the study; treatment of the entire system as defined in the study of the entire study period regardless of the status of the rescue, from first dose to last dose of double-blind IP IP investment of time and date of 3 days; The 3-day interval is selected based on the half-life of IP (about 5 times the half-life).

In addition, safety analysis during the 24-week double-blind treatment will be summarized in the CSR.

A summary of safety outcomes (narrative statistics or timetables) is presented for each treatment group.

6 results

6.1 Research patients

6.1.1 Patient Responsibilities

The study was conducted in 75 centers in 15 countries (Brazil, Chile, Colombia, Estonia, Germany, Italy, Lithuania, Malaysia, Mexico, Philippines, Poland, Romania, Slovakia, Ukraine, and the United States). A total of 884 patients were screened and 484 were randomly assigned to one of the four treatment spurs (161 in the Lisila two-step titration group, 161 in the Lisilaa one-step titration group, and 80 in the placebo two-step titration). Groups, and 82 are in the placebo one-step titration group). The main reason for the screening failure was that the HbA _1c value at the screening visit was outside the scope defined by the protocol [257 of the 884 screening patients (29.1%)].

Of the 484 randomly assigned patients, 482 were exposed to study treatment and included in the analysis. Two patients (1 in each placebo group) were not exposed to any study treatment due to random assignment errors; the two patients were excluded from efficacy and safety analysis. Of the 482 randomly assigned and treated patients, 5 patients (1 lixisenatide two-step titration group, 3 lixisenatide one-step titration group, and 1 placebo one-step titration Group of patients) were excluded from the mITT population of efficacy analysis due to lack of post-baseline efficacy data. Table 1 provides the number of patients included in each analysis group.

6.1.2 Research deployment

Table 2 provides a summary of the deployment of patients in each treatment group. During the entire treatment period, 103 patients discontinued the study treatment earlier than expected. The percentage of patients discontinued in the study treatment was higher in the two-step titration group (24.8%) than in the lixisenatide one-step titration group (18.6%) and the combined placebo group (20.4%). For the lixisenatide treatment group, the main reason for discontinuation of treatment was “bad conditions” (Lisila's two-step titration of 11.8% and lixisenatide titration of 8.7% in one step, compared to 6.2% of combined placebo) , followed by "other causes" (9.9% and 7.5%, compared to 9.9% of the combined placebo). Similar results were observed during the main 24 weeks of treatment, with a total of 40 (8.3%) patients discontinuing the study treatment earlier than expected, in the case of the lixisenatide treatment group (6.8% in two steps and 5.0% in one step, The main reason was also a bad situation compared to 1.9% of the combined placebo. The onset of treatment discontinuation for any reason during the entire treatment period is depicted in Figure 3 ; during the first 6 months, a similar discontinuation trend between the two lixisenatide groups was observed compared to the slightly lower interruption rate in the combined placebo group. After 6 months, the Lixila one-step titration group showed a similar trend to the combined placebo group, while the lixisenatide two-step titration maintained a high interruption rate.

Among the 4 placebo-treated two-step titration patients who discontinued treatment due to AE ( Table 2 ), the last dosing date at the “end of treatment” CRF was absent and classified as post-treatment AE according to SAP data processing practices. Treatment was discontinued and 3 patients had TEAE leading to treatment discontinuation ( Table 16 ).

6.1.3 Demographics and baseline characteristics

In terms of the safety population, the demographics between the treatment groups were generally similar to those of the patients ( Table 3 ), but the placebo-treated patients were slightly older than the patients treated with the patient. The median age of the study population was 57.0 years. Most patients were Caucasian (90.2%).

The disease characteristics including the history of diabetes were generally comparable across treatment groups, but the mean age of onset of type 2 diabetes was slightly higher in patients treated with placebo than in patients treated with lixisenatide ( Table 4 ).

For the safety population, the treatment groups were comparable at baseline for HbA _1c , FPG, and body mass ( Table 5 ).

6.1.4 Dose and duration

The mean treatment exposure time was similar between the treatment groups [combined placebo 552.8 days (79.0 weeks), lixisenatide two-step titration 518.6 days (74.1 weeks), and lixisenatide one step titration 538.1 days (76.9 weeks)] ( Table 6 ). Of the 482 patients with safety, 439 (93.8% in the placebo group, 88.2% in the two-step titration group, and 91.3% in the lixiliary one-step titration group) were treated for at least 169 days (24 weeks). 298 (compared with placebo group 63.8%, lixisenatide 2 step titration group 59.0%, and lixisenatide one-step titration group 62.7%) were treated for at least 547 days (18 months). Two patients (one in each placebo group) were absent from the final dose date at the "end of treatment" CRF, so the duration of treatment was set to be absent according to SAP data processing practices.

In the two-step titration group of Lisila, 141 (87.6%) patients had a target total daily dose of 20 μg at the end of the double-blind treatment, the end of the titration, and the end of the 24-week double-blind treatment period ( Tables 7 and 8). Table 9 ). In the one-step titration group of Lisila, 147 (91.3%) patients, 150 (93.2%) patients, and 150 (93.2%) patients were treated at the end of double-blind treatment, end of titration, and 24 weeks. At the end of the blind treatment period, the target total daily dose was 20 micrograms ( Table 7 , Table 8 and Table 9 ). In the placebo group, 156 (97.5%) patients, 155 (96.9%) patients, and 156 (97.5%) patients ended at the end of double-blind treatment, end of titration, and 24-week double-blind treatment. At the time, the target daily dose was 20 micrograms ( Table 7 , Table 8 and Table 9 ).

6.2 efficacy

6.2.1 main efficacy assessment points

Main analysis

Table 10 summarizes the results of changes in HbA _1c from baseline to Week 24 (LOCF) using the primary efficacy parameters of ANCOVA analysis.

The basic analysis detailed previously showed that the two lixisenatide treatment groups showed a statistically significant reduction in HbA _1c from baseline to week 24 compared to the pooled placebo group (for the lixisenatide two-step titration group) , LS mean difference = -0.41%; p value <0.0001; for lixisenatide one-step titration group, LS mean difference = -0.49%; p value <0.0001).

Figure 4 illustrates the mean (±SE) change in HbA ₁ c compared to baseline during the main 24-week double-blind treatment. Figure 7 in the Appendix illustrates the HbA ₁ c mean (±SE) change from baseline over time to week 76; the decrease in HbA _{1c is} relatively maintained for more than 24 weeks.

Secondary analysis

Table 11 is summarized in the 24th week with HbA _1c 6.5% or <7% of patients with treatment response. The treatment response was similar between the lixisenatide treatment groups. HbA _1c responder analysis using the CMH method showed significant differences in treatment compared to placebo in each lixisenatide group (on week 24 of HbA _1c) 6.5%, Lisila comes to the second step titration p value = 0.0009 and Lisila to a step titration of the p value <0.0001; in the 24th week of HbA _1c <7%, Lisila two The p-value of the step titration = 0.0005 and the p-value of the Lixila one-step titration <0.0001).

6.2.2 Secondary efficacy assessment points

Tables 12 and 13 summarize the ANCOVA analysis of FPG and body weight, respectively. Figures 5 and 6 illustrate the change in mean time (± SE) of FPG and body weight compared to baseline during the main 24-week double-blind treatment, respectively. Figures 8 and 9 in the Appendix depict the mean (±SE) change in FPG and body weight over the baseline, respectively, over time to week 76.

In the case of FPG, the two lixisenatide treatment groups showed a statistically significant reduction from baseline to week 24 compared with the placebo group (the difference in the LS mean of the two-step titration group in the Lixila two-step titration =- 0.67 millimoles/liter and p-value = 0.0004; lixisenatide one-step titration group LS mean difference = -0.65 millimoles / liter and p value = 0.0007).

At the 24th week, compared with the baseline LS mean body weight change, the lixisenatide two-step titration group was -2.668 kg, the lixisenatide one-step titration group was -2.63 kg, and the combined placebo group was -1.63 kg; A statistically significant difference was observed between the two lixisenatide-treated groups compared with the placebo group (the LS mean of the two-step titration of the lixisenatide) The difference was -1.05 kg and the p value was 0.0025; the LS mean difference of one step titration of Lixila was -1.00 kg and the p value was 0.0042).

From baseline to week 24, 25.8% lixisenatide for two-step titration patients, 19.6% lixisenatide for one-step titration patients, and 15.2% placebo for patients with weight loss 5% ( Table 14 ); two lixisenatide treatment groups continued to lose weight after the 24 week primary treatment period ( Figure 9 ).

The percentage of patients requiring rescue treatment during the main 24-week double-blind treatment compared with the placebo group (4.4%) showed that the two lixisenatide treatment groups were slightly lower (two-step titration 3.1% and one step) Titration 1.3%) ( Table 15 ). There was no significant difference between the lixisenatide group and the placebo group due to the low incidence of rescue patients during the main 24-week double-blind treatment.

6.3 Security

Table 16 provides an overview of the adverse events observed during the entire study treatment period. The proportion of patients suffering from TEAE was comparable between the treatment groups (87.6% in the Lisila two-step titration group, 85.7% in the lixisenatide one-step titration group, and 86.3% in the combined placebo group). Five patients (1 lixisenatide two-step titration group, 2 lixisenatide one-step titration group, and 2 placebo patients) died of TEAE during treatment. During the entire study period, 59 patients had at least one severe TEAE, and the incidence of the lixisenatide two-step titration group (13.0%) was similar to that of the placebo group (13.8%). The incidence of the step titration group (9.9%) was slightly lower. The percentage of patients with TEAE leading to discontinuation of treatment was slightly higher in the biscildula treatment group (11.8% for two-step titration; 8.7% for one-step titration) than for the placebo group (5.6%). The TEAE ratio leading to treatment discontinuation was observed between the two lixisenatide groups, and the one-step titration was slightly lower than the two-step titration. Table 17 , Table 18 , and Table 19 respectively summarize death TEAE, severe TEAE, and TEAE caused by treatment based on basic SOC, HLGT, HLT, and PT. Two lixisenatide-treated groups (6 (3.7%) patients in each lixiseradine group) most commonly resulted in discontinuation of treatment for TEAE as nausea; in the placebo group, none of the patients discontinued treatment due to nausea.

Table 28 in the Appendix presents the incidence of TEAE in at least 1% of patients in any of the treatment groups throughout the study treatment period. Nausea for the two lixisela treatment groups [Lisila two-step titration 62 (38.5%) patients and lixisenatine titration 47 (29.2%) patients] the most commonly declared TEAE; ten Three placebo-treated patients (8.1%) reported nausea. The second most commonly reported TEAE was treated with lixisenatide for vomiting [Lisila two-step titration of 29 (18.0%) patients and lixisenatide to titrate 21 (13.0%) patients], Followed by headache [Lisila two-step titration 23 (14.3%) patients and lixisenatine titration 20 (12.4%) patients] with diarrhea [Lisila two steps titration 24 (14.9 %) Patients and lixisenatine titrated 16 patients (9.9%) in one step; the corresponding patients (%) in the placebo group were vomiting 1 (0.6%) and headache 20 (12.5%) And 21 (13.1%).

During the entire study period, 12 (7.5%) patients in the two-step titration group were given a benefit of 12 (7.5%) placebo-treated patients with symptomatic hypoglycemia as defined by the protocol. Syrah's one-step titration group of 6 (3.7%) patients had symptomatic hypoglycemia during the same period ( Table 20 ); none of their symptomatic hypoglycemia was extremely severe. Another patient (in the placebo two-step titration group) was reported for symptomatic hypoglycemia on a specific AE record for "symptomatic hypoglycemia", but this did not meet the definition of the protocol (ie, the relevant glucose value) 60 mg / dl).

Nine (5.6%) patients in the lixisenatide group and 3 (1.9%) in the placebo group received the injection site response AE ( Table 21 ). The injection site reaction AE is determined by the term "injection site" in the PT coded by the search investigator or by the PT of the ARAC certificate during the allergy response determination period. None of their reactions are critical or extremely serious.

During the entire study and treatment period, a total of 30 cases were reported as suspected allergic conditions and sent to ARAC for judgment. Among them, 15 patients (6 (3.7%) lixisenatide for two-step titration patients, 3 (1.9%) lixisenatide for one-step titration patients, and 6 (3.8%) The 16 cases of placebo-treated patients were judged to be allergic by ARAC, but only 2 cases of anaphylactic reaction (1 in each group) were judged to be IP-related ( Table 22 ). .

# 276303004 Patients (Lisilaa one-step titration), no personal or family history of allergies, after a random dose of 30 minutes after the first dose of treatment, gradually develop skin reactions. This condition was reported as "allergic rash" and was included in PT "allergic dermatitis"; IP was permanently interrupted. With the improved treatment of antihistamines and steroids, the situation was resolved that day. This condition was determined by ARAC to be an allergic reaction that may be related to IP.

# 642307010 (Lisila two-step titration) patients, no personal or family history of allergies, after IP5.5 months, after IP administration for a few seconds, nausea and dizziness, followed by skin reactions; Low blood pressure. This condition was reported as "allergic dermatitis" and was incorporated into PT "allergic dermatitis", and IP was permanently interrupted. The treatment with antihistamines and steroids was improved and the situation was resolved the next day. This condition was determined by ARAC to be an allergic reaction that may be related to IP.

Depending on the protocol, monitor any increase in the amylase and/or lipase that exceeds the upper limit of the normal range (ULN) and record it in the specific table: "Form of Adverse Reactions (AE) for Suspected Pancreatitis". During the entire study period, 4 (2.5%) patients in the lixisenatide group and 5 (3.1%) patients in the placebo group were enrolled ( Table 23 ). No cases of pancreatitis were observed in this study.

At least one value of lipase or amylase during treatment 3 ULN patients are summarized in Table 24 . A total of 17 patients were observed [8 in the two-step titration group (5.0%), lixisenatide one-step titration group 5 (3.1%), and placebo group 4 (2.5%) disease Suffering from elevated lipase ( 3ULN). A three-step (0.6%) increase in amylase in patients in the titration group 3ULN), the Lixila two-step titration group and the combined placebo group were absent.

According to the plan, the monitoring has been confirmed as Any calcitonin value of 20 picograms per milliliter and is reported as "increased calcitonin" A table of specific adverse reactions of 20 picograms per milliliter. During the entire study period, one (0.6%) patients in each lixisenatide group and one (0.6%) patient in the placebo group were enrolled ( Table 25 ). Of the 3 patients, 2 (one in each lixisela group) calcitonin value 20 Ng/L, but <50 Ng/L, the PT is "increased blood calcitonin"; the two patients recommended further diagnostic tests including thyroid ultrasound scans and specialist evaluations. normal. Third patient (placebo two-step titration group) calcitonin value 50 ng / liter, the PT is "thyroid cancer"; the patient was diagnosed with thyroid medullary cancer metastasized to the lymph, which was assessed by the investigator as not related to IP.

During the treatment period, Lisila came to the second step titration group 2 (1.4%), lixisenatide one-step titration group 2 (1.3%), and combined placebo group 4 (2.5%) patients at least one drop Calcitonin value 20 Ng / liter ( Table 26 ). Among the patients, in addition to the previous narrator, two other patients (Lisila came to the titration group 1 and the placebo group 1) in the "increased calcitonin" 20 pg/ml was declared on the specific adverse condition form, and there was a bad condition after the IP was interrupted. The lixisenatide treatment of patients was reported as "high-volume calciurin" after 5.5 months of IP discontinuation, and thyroid ultrasonography after 2.5 months showed thyroid nodules. The placebo-treated patients were reported to have an intermittent increase in calcitonin 7 months after discontinuation of IP; one month later, a thyroid ultrasound scan and a specialist assessment were performed, and the results were normal. It must be noted that the calcitonin measurement was performed in the revised version of the protocol after most of the patients had been randomly assigned to this study; therefore, the baseline calcitonin value was absent from most patients.

7 Appendix

Example 2

For patients with obese type 2 diabetes who are unable to properly control the sugar ingots and under 50 years of age, the efficacy and safety of lixisenatide as an additional treatment for sucrose ingots was evaluated compared to sitagliptin. Dispatch, double-blind, double-virtual, active-controlled, two-line parallel group, multi-country study.

This example is to evaluate the efficacy and safety of lixisenatide as an additional treatment for sucrose in patients with obesity type 2 diabetes who are not properly controlled by sucrose tablets and under 50 years of age. Random assignment, double-blind, double-virtual, active control, two-line parallel group, multi-country study. The duration of each patient study was approximately 27 weeks (up to 3 weeks screening + 24 weeks double-blind treatment + 3 days follow-up). The study was conducted in 92 centers in 13 countries. The primary objective of this study was to evaluate the efficacy of lixisenatide over 24 weeks on glycemic control [glycated heme A1c (HbA1c)] and composite composite endpoints compared to sitagliptin.

A total of 319 patients were randomly assigned to one of two treatment groups (158 lixisenatide group and 161 sitagliptin group), and all randomly assigned patients were exposed to study treatment and included modified intention-to-treat treatment. (mITT) ethnic group. The demographics of the treatment groups were generally similar to the baseline characteristics, with more female patients in the lixisenatide group. During the entire study period, 27 (8.5%) patients discontinued the study earlier than expected, compared with the sitagliptin group (6.8%) and the lixisenatide group (10.1%). The percentage is higher. Among the patients treated with lixisenatide, the main reason for discontinuation of treatment was "other causes" (7 patients: 4.4%, compared with 5 patients with sitagliptin: 3.1%), followed by "bad conditions" (4 Patient: 2.5%, compared with 5 patients with sitagliptin: 3.1%).

The percentage of patients with HbA1c < 7% at week 24 and at least 5% baseline weight at week 24 (primary efficacy assessment point) was higher in the lixisenatide group (12.0%) than in the sitagliptin group (7.5%). This treatment difference was statistically insignificant due to the lower expected response rate of the Belisha group [based on the use of the Cochran-Mantel-Haenszel (CMH) method. , vs. sitagliptin, the reaction rate difference weighted average = 4.6%; p value = 0.1696]. Supportive analysis using logistic regression mode showed consistent results (p value = 0.1160). Compared with 64 patients (40.0%) in the sitagliptin group, a total of 61 patients (40.7%) in the lixisenatide group had HbA1c <7% at week 24, and compared with 42 (16.3%) sitta Lenin treatment of patients, 36 (24.0%) lixisenatide to treat patients with HbA1c 6.5%. Bisitastatin in the treatment of patients [19 (11.9%)] more lixisenatide to treat patients [28 (18.4%)] weight loss from baseline to week 24 5%.

Patients treated with lixisenatide had a significantly greater reduction in body weight than those treated with sitagliptin [the difference in LS mean of -1.34 kg; 95% CI (-2.101; -0.575)]. The change in HbA1c from baseline to week 24 was similar to the sitagliptin group in the lixisenatide group: the LS mean values were -0.66% and -0.72%, respectively. For example, 2 hours postprandial blood glucose (PPG) [LS mean difference - 1.91 millimoles / liter; 95% CI (-2.876; -0.941)] And glucose fluctuations (LS mean difference - 2.13 millimoles / liter; 95% CI (-2.819; - 1.434)] assessment results show that lixisenatide treatment (compared to sitagliptin) significantly improved meal Post-glycemic control. In the case of HbA1c, fasting blood glucose (FPG), insulin resistance assessed by HOMA-IR, and beta-cell function assessed by HOMA-β at week 24 compared to baseline, in Lisila No significant differences were observed between the treatment and the sitagliptin treatment group. The percentage of patients requiring rescue treatment was 9.5% in the lixisenatide group and 6.8% in the sitagliptin group, and there was no significant difference between the two groups.

Lisila is well tolerated. The incidence of adverse events (TEAE) occurred after treatment, and patients treated with lixisenatide were slightly higher than those treated with sitagliptin (63.9% for lixisenatide, 60.9% vs. sitagliptin). Six patients [3 (1.9%) in each group] had severe TEAE. In this study, there was no death declaration. The most common reported TEAE for patients treated with lixisenatide compared to sitagliptin was nausea (17.7% vs. 6.8%, respectively), followed by headache (12.7% vs. 9.3%, respectively). During treatment, compared with 3 (1.9%) patients with sitagliptin treated with 3 cases of symptomatic hypoglycemia as defined in the protocol, 1 (0.6) patient in the lixisenatide group had 2 Symptomatic hypoglycemia; their symptomatic hypoglycemia is not defined by the program. A total of 3 patients who reported 3 cases [2 (1.3%) lixisenatide group and 1 (0.6%) sitagliptin group] were allergic to the Allergic Response Assessment Committee (ARAC), but only benefit A condition of the Syrah group (allergic reaction) was judged to be possible with research medication Related to the product. No cases of pancreatitis were reported in this study.

1. Purpose

1.1 main purpose

The main purpose of this study was to evaluate the treatment of obese type 2 diabetes patients, which could not be properly controlled and the age of 50 years old, compared with sitagliptin and lixisenatide as an additional treatment for glycoside. The efficacy of blood glucose control (glycated heme A1c [HbA1c)] and body weight assessment points during the week.

1.2 key secondary objectives

The secondary objectives of this study are:

̇ Assess the impact of Lisila on the following variables:

-HbA1c value and absolute change in body weight

- fasting blood glucose (FPG)

- 2 hours of standardized blood meal, insulin, C-peptide, glycoside, and proinsulin during standardized meal trials

- Insulin resistance assessed using HOMA-IR

- Beta cell function assessed using HOMA-β

̇Assessing the safety and tolerability of lixisela

̇ Evaluate the development of antibodies against lixisenatide.

2 test design

This is a planned double-blind, double-virtual, randomized, active control, two-line parallel group, multi-center, multi-country study in 150 Syrahia-treated patients and 150 sitagliptin-treated patients; The study was double-blind for the treatment group; the amount of the study drug (ie active drug or The dose of matching comfort is not hidden.

Using glycated hemoglobin A1c (HbA1c) (<8%, 8%) and body mass index (BMI) (<35 kg/m2, Screening values were graded by screening values such as 35 kg/m2. After the screening period, patients were randomly assigned to either lixisenatide or sitagliptin at a ratio of 2:1 via the Interactive Voice Response System (IVRS).

The study consisted of three phases: 1) a screening period of up to 3 weeks, including a 2-week screening period and a 1-week single-blind placebo run-in period; 2) a 24-week double-blind, double-dummy, active controlled treatment period 3) All patients were followed up for 3 days after the interruption of permanent treatment (except for patients who discontinued the study treatment earlier than expected).

According to protocol revision 1 (date June 30, 2009), patients who discontinued IP earlier than expected continued their study until the final assessment at week 24; the study procedure detailed according to the protocol (meal challenge trial and 3 Follow-up after day safety treatment tracking).

3 major and key secondary assessment points

3.1 Main evaluation points

The primary efficacy variable was the percentage of patients with HbA1c < 7% at week 24 and at least 5% baseline weight loss at week 24.

If the patient discontinued treatment earlier than expected during the 24-week double-blind treatment or had no HbA1c or body weight at week 24, calculate the HbA1c at week 24 using the last baseline post-treatment HbA1c or body weight measurement for 24 weeks, respectively. Weight [last estimate of estimation (LOCF) program]. If the last baseline post-treatment HbA1c and body weight values were measured more than 30 days apart, the last post-baseline treatment value (HbA1c and body weight) that did not exceed 30 days was used as the composite assessment point for Week 24. Patients who did not have a 30-day baseline post-treatment value (HbA1c and body weight) within 24 weeks were counted as non-responders at the primary composite assessment point. For all patients who were rescued during the 24 weeks, HbA1c and body weight measurements were taken as the 24th week of HbA1c and body weight after the last baseline before the rescue.

3.2 key secondary assessment points

3.2.1 Evaluation point of efficacy

With regard to secondary efficacy variables, the same procedure as for the absence/early interruption was assessed using the treatment used for the primary efficacy variable. Using the LOCF program, the last available baseline post-treatment measurement (before rescue treatment in rescue treatment) was used as the value for Week 24.

Continuous variable

绝对Absolute change in HbA1c from baseline to week 24

绝对Absolute change in body weight (kg) from baseline to week 24

̇From baseline to week 24, after standardized meal, 2 hours postprandial change in blood glucose (mole/liter)

FPChange from baseline to week 24 FPG (mole/liter)

̇ From baseline to Week 24, during the standardized meal challenge trial, glucose fluctuations (2 hours postprandial blood glucose - blood glucose before study drug administration 30 minutes before the meal test) (milli/er)

̇From baseline to week 24, fasting collected during standardized meal trials Changes in the following variables (30 minutes before the study drug was administered) and 2 hours after the meal: insulin (picomol/liter), C-peptide (Nemo/L), sucrose (nike/liter), proinsulin (picomol/liter), and proinsulin to insulin ratio

Changes in insulin resistance assessed by HOMA-IR from baseline to week 24

βFrom baseline to week 24, beta cell function changes assessed using HOMA-β

Category variable

Percentage of patients with HbA1c <7% at week 24

̇24th week HbA1c 6.5% of patients with a percentage

百分比Percentage of patients requiring rescue treatment during the main 24-week double-blind treatment

减 Weight loss (kg) from baseline to week 24 5% of patients

3.2.2 Security assessment point

Safety analysis is based on declared TEAE and other safety information, including symptomatic hypoglycemia and severe symptomatic hypoglycemia, local tolerance at the injection site, allergy (determined by ARAC), suspected pancreatitis, blood loss Increased calcium, vital signs, 12-lead ECG, and laboratory tests.

Major cardiovascular conditions were also collected and sent to the Cardiovascular Decision Council (CAC) for decision. The CAC findings and confirmed cases of this study and other Lisila's Phase 3 clinical studies will be compiled for analysis and based on the statistical analysis plan of the overall cardiovascular assessment of Lisila. In another report. The Critical Results Record (KRM)/Clinical Research Report (CSR) will not present an overview of the cardiovascular status determined and confirmed from this study.

4 sample number estimation hypothesis

The number of samples was estimated based on the primary efficacy assessment point (HbA1c < 7% at week 24 and at least 5% of baseline weight loss at week 24). At a 5% significant level bilateral test, the percentage of patients defined as HbA1c (<7%) and body weight (at least 5% weight loss) was estimated to be 25% for lixisenatide and 10% for sitagliptin.

The sample size of 300 patients (150 patients per group) is considered to have a 90% test power, which is sufficient to demonstrate a patient who is defined as a HbA1c (<7%) and a body weight (weight loss of at least 5%) in the 24th week. Among the percentages, Lisila is superior to sitagliptin.

5 statistical methods

5.1 Analysis of ethnic groups

The modified intention-to-treat (mITT) population consisted of all randomly assigned patients who received at least one dose of double-blind study drug (IP). Patients were analyzed in their randomly assigned treatment group.

The safety population is defined as all randomly assigned patients who use at least one dose of double-blind IP.

5.2 main efficacy analysis

Used to screen HbA1c (<8%, 8%) random class and screening BMI (<35 kg/m2, 35 kg/m2) Cochrane-Mantel-Hensel (CMH) test for randomized grading, analysis of main efficacy variables (HbA1c < 7% at week 24 and at least 5% baseline weight loss at week 24) Percentage of patients); p-values are based on CMH assays from PROC FREQ; ratios of treatment differences (riskella compared to sitagliptin) are provided based on weighted averages of treatment differences from all classes using weighted variables Point estimates and associated 95% confidence intervals (CI).

In the absence of a unit of the class, the continuity correction of the class for mutation calculation is performed (ie, each unit of the 0.5 to 2x2 table is added); it should be noted that the weighted average of the estimated treatment differences is not applicable. Continuity adjustment; continuity correction is applied to estimate the variation that constitutes the overall 95% CI.

A primary analysis of the primary efficacy variables was performed based on the mITT population and the measured values of the therapeutic variables obtained during the treatment period. The treatment period for the benefit variable (except for the meal challenge trial) was defined as the first dose of double-blind IP (lixilax or sitagliptin) to the last dose of double-blind IP injection for 3 days (central laboratory) Except for FPG, which is 1 day), or until the introduction of rescue medication, whichever is earlier. The treatment period obtained from the two-hour post-meal blood glucose, insulin, C-peptide, glycoside, proinsulin, glucose fluctuation, HOMA index, and insulin-to-insulin ratio is defined as the first dose. Double-blind IP (lixilalid or sitagliptin) until the last dose of double-blind IP injection, or until the introduction of rescue medication, depending on which is earlier.

Use the LOCF program to get the most out of each other for less than 30 days The latter post-baseline treatment value (HbA1c and body weight before introduction of rescue treatment) was used as a composite assessment point at week 24. Patients who do not have this value are counted as non-responders at the primary assessment point.

5.3 key secondary efficacy analysis

No multiple adjustments were made to any secondary efficacy variables.

To have a treatment group (lixilaride and sitagliptin), screening HbA1c (<8.0, 8.0%) random class, screening BMI (<35 kg / square meter, A randomized class of 35 kg/m2, and a national model for the common effect analysis of fixed effects (ANCOVA), using the corresponding baseline values as covariates, and analyzing all consecutive secondary efficacy variables described in Section 3.2.1 Provide an adjusted estimate of the difference in mean treatment between lixisenatide and sitagliptin and a bilateral 95% confidence interval.

For the following categories of secondary efficacy variables, a statistical summary is presented according to the treatment group: 百分比24% of patients with HbA1c<7% at week 24, ̇24th week HbA1c Percentage of patients with 6.5% of patients, and the percentage of patients requiring rescue treatment during the 24-week treatment period, ̇ at week 24, compared to baseline weight loss (kg) Percentage of patients with 5%.

5.4 Security Analysis

The safety analysis is mainly based on the treatment period; the treatment period is defined as the time from the first dose of double-blind IP (lixilax and sitagliptin) to the last dose of IP, regardless of the rescue status; The time interval is selected based on the half-life of the IP (about 5 times the half-life).

A summary of safety outcomes (narrative statistics or timetables) is presented for each treatment group.

6 results

6.1 Research patients

6.1.1 Patient Responsibilities

The study was conducted at 92 centers in 13 countries (Australia, Brazil, Canada, Chile, Germany, Guatemala, Mexico, Peru, Poland, Romania, Russian Federation, Ukraine, and the United States). A total of 620 patients were screened, of which 319 were randomly assigned to one of the two treatment groups. The most common reason for not being randomly assigned was that the HbA1c value at screening visits was outside the scope of the protocol [203 of the 620 screening patients (32.7%)].

All 319 randomly assigned patients were exposed to study treatment and included in the mITT population. Table 1 provides the number of patients included in each analysis group.

6.1.2 Research deployment

Table 2 provides a summary of the deployment of patients in each treatment group. 319 random Of the assigned patients, 27 (8.5%) patients discontinued the study earlier than expected, compared with the sitagliptin group (11 patients: 6.8%), and the lixisenatide group (16 patients: 10.1) %) The percentage is higher. For the Lixi Lailai group, the main reason for treatment interruption was "other causes" (7 patients: 4.4%, compared with 5 patients with sitagliptin: 3.1%), followed by "bad conditions" (4) Patient: 2.5%, compared with 5 patients with sitagliptin: 3.1%). The onset of discontinuation of treatment for any reason is depicted in Figure 2; the overall rate of treatment discontinuation was observed in the lixisenatide group throughout the study.

6.1.3 Demographics and baseline characteristics

For the safety population, the demographics between the two treatment groups were broadly similar to the baseline characteristics of the patients (Table 3), however, compared to the sitagliptin group [88 (54.7%)], There were more female patients in the Lixila group [103 (65.2%)]; the median age was 44.0 years; the study population was mainly Caucasian (81.2%).

The disease characteristics including the history of diabetes are described in Table 4. In the study population, the median duration of diabetes was 3.31 years, the median age of onset of diabetes was 40 years, and the numbers in the two treatment groups were similar; the following figures were slightly different: the lixisenatide group was extinct at baseline The median daily dose of lozenges was higher (2000 mg vs. sitagliptin 1700 mg), more women had a history of gestational diabetes (12.6% vs. sitagliptin 6.8%) and more patients had randomized large amounts of proteinuria (4.6% relative Yuxilide (1.9%); however, fewer patients with diabetes in the Lixila group had diabetic sensory or motor neuropathy (12.2% vs. sitagliptin 17.5%) and fewer patients with randomized microalbuminuria (17.8%) 26.4% relative to sitagliptin).

For the safety population, HbA1c, 2-hour PPG, and FPG were comparable between the two treatment groups (Table 5). The average HbA1c at baseline was 8.12%. As shown in Table 3, the mean body weight at baseline was observed, compared with the sitagliptin group (100.56 kg), and the lixisenatide group (98.51 kg) was lower, but the baseline BMI of the two treatment groups was the average (36.76). Kg/m2) the same.

6.1.4 Dose and duration

The mean treatment exposure time was slightly shorter in the lixisenatide group than in the sitagliptin group: the lixisenatide group was exposed to lixisenatide for 160.2 days (22.9 weeks) (Table 6), and the sitagliptin group was exposed to Sitagliptin was 164.8 days (23.5 weeks) (Table 7). The vast majority of patients in the two treatment groups were treated for at least 85 days (90.5% and 96.3%, respectively, in the lixisenatide and sitagliptin groups). Five patients (4 in Lisila and 1 in sitagliptin) did not declare the final date of administration on the CRF page such as "end of treatment" and "drug for study drug". Therefore, according to SAP data processing practices, The exposure duration is set to be absent.

At the end of double-blind treatment, the proportion of patients with a target dose of 20 micrograms of Liscilla (active drug or volume matched placebo) was compared to the sitagliptin group (100%), the lixisenatide group (94.9) %) is lower (Table 8).

6.2 efficacy

6.2.1 main efficacy assessment points

Main analysis

Table 9 summarizes the main efficacy parameters of the CMH method, patients with HbA1c < 7% at week 24 and at least 5% baseline weight loss at week 24 The result of the percentage.

Previously, according to the basic analysis of the CMH method, there was no statistically significant difference in the percentage of patients with HbA1c < 7% at week 24 and at least 5% at baseline weight loss at week 24 (vs. sitar) The weighted mean difference of the response rate of statin = 4.6%; p value = 0.1696); the percentage of patients who met the criteria (reaction rate), the value of the lixisenatide group (12.0%) was higher than that of the sitagliptin group (7.5%). .

Supportive analysis

Supportive analysis using logistic regression models showed consistent results with findings from preliminary analysis of primary efficacy assessment points (p-value = 0.1160) (Table 10).

6.2.2 Other key efficacy assessment points

This section presents ANCOVA analysis of HbA1c, body weight, 2-hour PPG, FPG, glucose fluctuations, HOMA-IR and HOMA-β. Figures 4, 6 and 7 illustrate the change in mean (± SE) of HbA1c, body weight and FPG compared to baseline during the 24-week double-blind treatment. Figure 5 illustrates the HbA1c responders at the time of the selected visit (respectively 6.5% or <7%). The percentage of patients rescued during double-blind treatment is presented in Table 20.

For HbA1c, the mean LS change from baseline to week 24 was -0.66% in the lixisenatide group and -0.72% in the sitagliptin group. There was no significant difference between the treatment groups [vs sitar. Mean difference = 0.06%, 95% CI (-0.179; 0.308)] (Table 11). 1HbA1c in both treatment groups reached the flat line area after 12 weeks (Fig. 4). Compared with 64 patients (40.0%) in the sitagliptin group, a total of 61 patients in the lixisenatide group (40.7%) had HbA1c <7% at week 24, compared with 42 (26.3%). In the sitagliptin group, 36 (24.0%) lixisenatide was used to treat patients with HbA1c 6.5% (Table 12).

Treatment with lixisenatide resulted in a significant reduction in body weight [relative to LS mean difference of sitagliptin = -1.34 kg, 95% CI (-2.101; -0.575)] (Table 13). Sitalectin treatment patients reached the flat line after 16 weeks, while the weight of patients treated with lixisenatide continued to decrease (Figure 6). Compared with sitagliptin in patients [19 (11.9%)], more lixisenatide was used to treat patients [28 (18.4%)] weight loss from baseline to week 24 5% (Table 14).

The 2-hour PPG assessment showed a significant increase in the lixisenatide group compared to the sitagliptin group from baseline to week 24 [relative to the LS mean difference of sitagliptin = -1.91 millimoles per liter, 95 % CI (-2.876; -0.941)] (Table 15).

FPG LS mean change from baseline to week 24, lixisenatide-0.45 mmol/L and sitagliptin-0.69 mmol/L, no significant difference between treatment groups [vs. sitar The difference in LS mean of statin = 0.25 millimoles per liter, 95% CI (-0.254; 0.744)] (Table 16).

From the baseline to the 24th week of glucose fluctuations, lixisenatide treatment was significantly lower than the sitagliptin group [vs. statin LS mean difference = -2.13 millimoles / liter, 95% CI (-2.819) ;-1.434)] (Table 17).

In terms of insulin resistance assessed by HOMA-IR, from baseline The mean LS change at week 24 was -0.52 in the lixisenatide group and -0.57 in the sitagliptin group. There was no significant difference between the treatment groups [relative to the LS mean difference of sitagliptin = 0.05, 95% CI) (-0.823; 0.918)] (Table 18).

As for the β-cell function assessed by HOMA-β, the mean LS change from baseline to week 24 was 17.66 in the lixisenatide group and 17.79 in the sitagliptin group, and there was no significant difference between the treatment groups [relative to the sitar column] The difference in LS mean of Ting = -0.13, 95% CI (-23.108; 22.842)] (Table 19).

The percentage of patients requiring rescue treatment was 9.5% in the lixisenatide group and 6.8% in the sitagliptin group, and there was no significant difference between the two groups (Table 20).

6.3 Security

Table 21 provides a review of the adverse events observed during treatment; the proportion of patients suffering from TEAE was slightly higher in the lixisenatide group than in the sitagliptin group (63.9% for lixisenatide versus 60.9% for sitagliptin); The patient [3 (1.9%) in each group] had severe TEAE. In this study, no deaths were declared; the percentage of TEAE patients who experienced treatment discontinuation was similar in each group, with similar groups (2.5% for lixisenatide and 3.1% for sitagliptin). Tables 22 and 23 summarize severe TEAEs based on basic SOC, HLGT, HLT, and PT, respectively, and lead to treatment discontinuation TEAE.

Table 34 in the Appendix presents the incidence of TEAE occurring in at least 1% of patients in any of the treatment groups. The most commonly reported TEAE in the Lixila group [28 (17.7%) patients] was nausea, compared with 11 (6.8%) sitagliptin in patients. The second most commonly reported TEAE in the Lisila group was headache [20 (12.7%) patients with lixisenatide, compared with 15 (9.3%) patients with sitagliptin], followed by diarrhea [14 (8.9) %) Patients with lixisenatide, compared with 12 (7.5%) patients with sitagliptin].

During the treatment period, one (0.6%) lixisenatide was treated for the condition of two symptomatic hypoglycemia as defined in the protocol. During the same period, three (1.9%) sitagliptin treatment patients suffered from symptomatic hypoglycemia (Table 24). According to the definition of the program, none of their symptomatic hypoglycemia is serious. Three other patients (1 lixisenatide and 2 sitagliptin) reported hypoglycemia (related glucose values) that did not meet the protocol definition 60 mg/dl) (Table 34).

11 [9 (5.7%) lixisenatide-treated patients and 2 (1.2%) sitagliptin-treated patients] suffered from injection site response AEs (Table 25). The injection site reaction AE is determined by the term "injection site" in the PT coded by the search investigator or by the PT of the ARAC certificate after the allergy response is determined. None of their reactions are critical or extremely serious.

During the treatment period, a total of 5 cases were reported as possible allergic conditions and sent to ARAC for judgment. Among them, 3 cases from 3 patients (2 (1.3%) lixisenatide treatment and 1 (0.6%) sitagliptin treatment] were identified as allergic reactions by ARAC, but only One of the conditions (allergic reaction) from a lixisenatide-treated patient (#320001015) was judged to be potentially related to IP (Table 26).

̇病#320001015, a 48-year-old postmenopausal woman with a history of hypertension and obesity. On the second day of treatment, after 10 minutes of IP administration, she suffered from moderate-intensity allergic reactions (general itching, eyes, face, hands and The feet are swollen and associated with chest tightness). At the time of the examination, he was noticed to have flushing, urticaria, and swelling at the injection site; dexamethasone and chlorphenamine were received; after 30 minutes, it was not improved and was taken to the emergency room for IV plugging. Rice pine, SC adrenaline, and nasal tube oxygen; 90 points after this treatment After the clock, the reaction was eliminated. After 1 hour, the patient was discharged from the hospital without complications. The IP was permanently interrupted from the date of the allergic reaction. According to the investigator, this AE is related to Lisila (or its placebo), and according to the sponsor, this association is not excluded. ARAC determined that this AE was "allergic reaction (allergic reaction)". After 5 days of follow-up, the patient no longer responded and felt good.

According to the protocol, monitoring any repeated measurements has confirmed that the amylase and / or lipase exceeds the upper limit of the normal range (ULN) twice, and remember Pre-designated AE form in "suspected pancreatitis". During the treatment period, 6 (3.8%) lixisenatide-treated patients and 2 (1.2%) sitagliptin-treated patients were enrolled in this form (Table 27). Among the 8 patients, statin in patients treated with sitagliptin increased blood amylase, 6 patients treated with lixisenatide and one patient treated with sitagliptin increased lipase. No cases of pancreatitis were reported during the study period.

At least one value of lipase or amylase during treatment 3 ULN patients are summarized in Table 28. A total of 5 patients [2 (1.3%) lixisenatide group and 3 (1.9%) placebo group patients] were observed to have elevated lipase ( 3ULN). Epilepsy is elevated during the treatment period (≧3ULN).

Monitor any confirmed by repeated measurements according to the protocol 20 picograms/ml of calcitonin value, and is recorded in "increased calcitonin" 20 picograms per milliliter of pre-specified AE form. During treatment, one (0.6%) sitagliptin-treated patients were enrolled in this form (Table 29); PT was an increase in blood calcitonin; the corresponding calcitonin value was 22 Ng/L.

The amount of calcitonin in four pre-defined categories based on baseline was summarized in Table 30 for patients who measured serum hemocalcin at least once during treatment. Baseline calcitonin value" 20 NEK/L to <50 Ng/Lg (0.7%) Patients in the Lixilale group and a baseline calcitonin value >>ULN to <20 Ng/Lg (0.6 %) Patients in the sitagliptin group have at least one calcitonin value during treatment" 20 NEK/L to <50 Ng/L; in these two patients, sitagliptin was treated with a pre-designated AE form (Table 29) to declare TEAE, while lixisenatide was used to treat the patient due to subsequent The calcitonin value was <20 Ng/L, and no increase in calcitonin was confirmed.

7 Appendix

Example 1 Figure 1 is the study design.

Example 1 Figure 2 shows the entire step-by-step test procedure.

Example 1 Figure 3 is a time-to-distribution Kaplan-Meier mapping for any reason.

Example 1 Figure 4 is a graph of the mean change in HbA1c (%) compared to baseline during the main 24-week treatment period - the mITT population. Where LOCF = the last observed value of the estimate. The mapping includes the last dose of double-blind study before the introduction of rescue medication and at the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available] The measured value obtained after 3 days of injection with the drug.

Example 1 Figure 5 is a graph showing the mean change in the mean value of fasting blood glucose (millim/liter) compared to baseline during the main 24 weeks of treatment - the mITT population. Where LOCF = the last observed value of the estimate. The drawing is included in Before the rescue medication and at the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available], the last dose of double-blind study was injected for 1 day. The measured value obtained afterwards.

Example 1 Figure 6 is a graph showing the mean change in body weight (kg) compared to baseline during the main 24 weeks of treatment - the mITT population. Where LOCF = the last observed value of the estimate. The mapping includes the last dose of double-blind study before the introduction of rescue medication and at the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available] The measured value obtained after 3 days of injection with the drug.

Example 1 Figure 7 is a graph of the mean change in HbA1c (%) at the point of assessment compared to baseline at the time of the visit-mITT population. Where LOCF = the last observed value of the estimate, EOT = the final treatment value. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days. For Week 24 (LOCF), the analysis included the last dose of the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available] Blind studies were obtained after 3 days of injection of the drug.

Example 1 Figure 8 is a graph of mean changes in fasting blood glucose (mole/L) compared to baseline at the point of assessment at the time of treatment - the mITT population. Where LOCF = the last observed value of the estimate, EOT = the final treatment value. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus one day. For Week 24 (LOCF), the analysis included the last dose of the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available] Blind studies were obtained after 1 day of injection of the drug.

Example 1 Figure 9 shows the body weight (kg) at the assessment point compared to the baseline at the time of the visit. Mean change graph - mITT population. Where LOCF = the last observed value of the estimate, EOT = the final treatment value. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days. For Week 24 (LOCF), the analysis included the last dose of the 12th visit (week 24) or before [or 169th, if the 12th visit (week 24) is not available] Blind studies were obtained after 3 days of injection of the drug.

Example 2 Figure 1 is the study design.

Example 2 Figure 2 is a plot of Kaplan-Mer plots for random interruption of treatment for any reason.

Example 2 Figure 3 shows the responders and responders at the assessment point (HbA1c<7% and weight loss) 5% baseline weight of patients) mapping - mITT ethnic group. Where LOCF = the last observed value of the estimate. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days. For Week 24 (LOCF), patients who did not have a distance of more than 30 days post-baseline treatment (HbA1c and body weight) were counted as non-responders.

Example 2 Figure 4 is a graph of the mean change in HbA1c (%) at the assessment point compared to the baseline at the time of the visit-mITT population. Where LOCF = the last observed value of the estimate. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days.

Example 2 Figure 5 shows the HbA1c responders at the selected visit and assessment points (respectively 6.5% or <7%) mapping - mITT population. Where LOCF = the last observed value of the estimate. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days.

Example 2 Figure 6 shows the body weight (kg) at the assessment point compared to the baseline at the time of the visit. Mean change graph - mITT population. Where LOCF = the last observed value of the estimate. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus 3 days.

Example 2 Figure 7 is a graph of the mean change in fasting blood glucose (millim/liter) at the point of assessment compared to baseline at the time of the visit-mITT population. Where LOCF = the last observed value of the estimate. The analysis does not include measurements obtained after the introduction of rescue medication and/or after treatment interruption plus one day.

<110> Sanofi Avantis Deutsche GmbH

<120> A pharmaceutical composition for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes

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<223> / Molecular Type = "Protein" /Note="desPro36Exendin-4(1-39)-Lys6-NH2" /bio="manual sequence"

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<213> Artificial sequence

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Claims (15)

A pharmaceutical composition for inducing weight loss in type 2 diabetes and/or preventing weight gain in type 2 diabetes, the composition comprising (a) desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ And/or a pharmaceutically acceptable salt thereof, and (b) metformin and/or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the subject is overweight. The pharmaceutical composition according to claim 1 or 2, wherein the subject has a body mass index of at least 30 kg/m 2 . A pharmaceutical composition according to any one of the preceding claims, wherein the subject is an adult patient. The pharmaceutical composition according to any one of claims 1 to 4, wherein the subject does not receive anti-diabetic treatment. A pharmaceutical composition according to any one of the preceding claims, wherein the subject has been diagnosed with type 2 diabetes at least 1 year or at least 2 years prior to initiation of treatment. A pharmaceutical composition according to any one of the preceding claims, wherein the subject has a HbA _1c value of from about 7 to about 10%. A pharmaceutical composition according to any one of the preceding claims, wherein the subject has a fasting blood glucose concentration of at least 8 millimoles per liter. A pharmaceutical composition according to any one of the preceding claims, wherein the subject has a 2-hour postprandial blood glucose concentration of at least 10 millimoles per liter, at least 12 millimoles per liter, or at least 14 millimoles per liter. A pharmaceutical composition according to any one of the preceding claims, wherein the subject has at least 2 millimoles per liter, at least 3 millimoles per liter, at least 4 millimoles per liter, or at least 5 millimoles per liter Glucose fluctuations, wherein the glucose fluctuation is the difference between the 2 hour postprandial blood glucose concentration and the blood glucose concentration 30 minutes before the meal test. The pharmaceutical composition according to any one of the preceding claims, wherein the desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof is prepared for parenteral administration use. The pharmaceutical composition according to any one of the preceding claims, wherein the desPro ³⁶ Exendin-4(1-39)-Lys ₆ -NH ₂ and/or a pharmaceutically acceptable salt thereof is prepared for selection from 10 μg to A daily dose of 20 micrograms is administered. A pharmaceutical composition according to any one of the preceding claims, wherein the saccharide tablet and/or its pharmaceutically acceptable salt is prepared for oral administration. A method for inducing weight loss in a type 2 diabetes patient and/or preventing weight gain in a type 2 diabetes patient, the method comprising administering to a subject in need thereof according to any one of claims 1 to 13 of the patent application scope combination. According to the method of claim 14, wherein the object is the object defined in any one of claims 2 to 10.