JP2019517459A - Use of LIK 066 in heart failure patients - Google Patents

Abstract

The present invention relates to the use of LIK 066 in heart failure patients and patients with heart failure in combination with type II diabetes.

Description

  The present invention relates to the pharmaceutical use of LIK 066, its pharmaceutically acceptable salts and prodrugs, in particular for the treatment of heart failure.

  Type 2 diabetes (T2D) is a serious condition associated with high-risk cardiovascular disease (CVD) and its complications such as heart failure (HF). In patients with T2DM, both the incidence of HF and admission / mortality are higher than those without diabetes (Nichols et al, 2004; Kazsnicki et al, 2014). The poor prognosis of patients with T2DM and HF has previously been thought to be due to myocardial hypertrophy, myocardial fibrosis and increased abnormal cardiac metabolism (Kazsnicki et al, 2014), and these symptoms are the occurrence of myocardial ischemia, It can aggravate ventricular dysfunction and contribute to arrhythmias (Taegtmeyer et al, 2002). HF is associated with repeated hospitalization and increased mortality (Chun et al, 2012). Hospitalization and mortality risks associated with heart failure are standard treatments such as mineralocorticoid receptor antagonists (MRAs), beta-blockers, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), and recently It is significantly reduced by the Squibitril / Valsartan treatment being studied (Yancy et al, 2013; Solomon et al, 2016).

Sodium-glucose cotransporter (SGLT) 2 inhibitors are approved for the treatment of type 2 diabetes. Furthermore, long-term treatment with the SGLT2 inhibitor empagliflozin in the EMPA REG Outcome study resulted in a relative reduction (RR) of 14% of major adverse cardiovascular events (MACE) versus placebo. , This had a statistically significant 38% RR of cardiovascular (CV) death. The risk of hospitalization for HF also decreased (Zinman et al, 2015). In this study, patients with eGFR dropped to 30 ml / min / 1.73 m ² were included. In subgroup analysis by renal function category, the risk of CV death or HF admission was significantly reduced in groups with mild and moderate renal dysfunction. This composite endpoint is significantly reduced even in patients who have not been previously diagnosed with HF, and patients with HF at baseline have a lower figure, and these patients are approximately equivalent to the trial population It constituted 10% (Fitchett et al, 2016). The benefits observed may have been derived from the specific effects of SGLT2 inhibition on renal sodium and glucose handling, with free fatty acid oxidation switching to more efficient beta hydroxybutyrate oxidation in the heart, and blood Enhanced oxygenation due to enrichment (Ferrannini et al, 2016) results in both diuresis and improvement of diabetes-related maladaptive renal arteriolar response (Sattar et al. al, 2016), is assumed.

  Thus, in a subject in need of treatment capable of addressing different aspects of this complex condition, in any patient in need of such treatment while demonstrating acceptable safety and / or tolerability profiles. There is a need to provide treatment for heart failure. Inhibition of both SGLT1 and SGLT2 may provide additional benefits that improve the efficacy and response rate of treatment.

LIK066 is an inhibitor of SGLT1 and SGLT2. Through the inhibition of both SGLT1 and SGLT2 in the renal proximal tubule, this drug can further enhance its effect on renal sodium and glucose handling compared to selective SGLT2 inhibitors. Furthermore, SGLT1 is expressed in the small intestine where it is required for glucose and galactose absorption. Inhibition of intestinal SGLT1 results in malabsorption of glucose and galactose (Turk et al, 1991), thus leading to calorie waste and other potential endocrine-based weight loss mechanisms. In view of its dual mechanism of action on glucose reabsorption / absorption (kidney and intestine), LIK 066 is planned to be studied in obese and overweight patients as a thinning drug (calorie loss enhancer). In a phase 1 study in normal and dysglycemic adults with body mass index (BMI) 35 35 kg / m ² , treatment with LIK066 150 mg qd deducted an average 5.7% placebo effect at 12 weeks Weight loss was obtained.

  The SGLT1 receptor is expressed in the heart, and it is believed that administration of LIK066 may ameliorate, treat or ameliorate the symptoms associated with individuals exhibiting reduced cardiac function.

  According to a first aspect of the invention, a method for treating or preventing heart failure in a subject in need of such treatment comprising administering to said subject a therapeutically effective amount of SGLT1 and an inhibitor of SGLT2, such as for example Provided is a method comprising administering LIK066, or a pharmaceutically acceptable salt thereof.

  In another aspect, the invention is compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.

  In yet another embodiment, the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.

  In another embodiment, the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of heart failure.

  According to another aspect of the present invention, there is provided a method for the treatment or prevention of heart failure in a subject having type 2 diabetes, comprising administering to said subject a therapeutically effective amount of LIK 066, or a pharmaceutically acceptable salt thereof. A method is provided that includes:

  In another aspect, the invention is compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure in a patient having type 2 diabetes.

  In yet another embodiment, the invention is a pharmaceutical composition comprising LIK 066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure in a patient having type 2 diabetes. .

  In another embodiment, the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for use in the treatment or prevention of heart failure in a patient having type 2 diabetes. .

It is a figure which shows clinical trial design. It is a figure which shows an evaluation schedule. It is a figure which shows an evaluation schedule. It is a figure which shows an evaluation schedule. It is a figure which shows an evaluation schedule.

  In a first embodiment, the present invention is for the treatment or prevention of heart failure in a subject in need of such treatment, including heart failure with maintained ejection fraction and heart failure with reduced ejection fraction. A method according to claim 1, comprising administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.

  In a second embodiment, the invention is the method of the first embodiment, wherein about 2.5 mg of LIK066 is administered.

  In a third embodiment, the invention is the method of the first embodiment, wherein 10 mg of LIK066 is administered.

  In a fourth embodiment, the invention is the method of the first embodiment, wherein 50 mg of LIK066 is administered.

  In the fifth embodiment, the invention is the method of any one of the first to fourth embodiments, wherein LIK066 is administered once daily.

  In the sixth embodiment, the invention is a method according to any one of the first to fifth embodiments, wherein LIK066 is administered before bedtime.

  In the seventh embodiment, the invention is the method of any one of the first to sixth embodiments, wherein the subject is at least 18 years old.

In the eighth embodiment, the invention is the method of any one of the first to seventh embodiments, wherein the subject has a BMI of 2222 kg / m ² .

  In the ninth embodiment, the present invention is described in any of the first to eighth embodiments, wherein the subject has type 2 diabetes with HbA1c between 7.0% and 10.0%. Method.

  In a tenth embodiment, the present invention is a written document wherein the subject has at least one of the following symptoms selected from dyspnea, orthopnea, paroxysmal nocturnal dyspnea and peripheral edema: The method according to any of the first to ninth embodiments, having symptomatic chronic heart failure (NYHA II-IV).

  In the eleventh embodiment, the invention is the method according to any one of the first to the tenth embodiments, wherein the subject has NT-proBNP> 400 pg / ml in plasma.

  In a twelfth embodiment, the present invention provides that the subject is concurrently receiving a drug therapy selected from ACEi, ARB, MRA, ARNi and / or β-blockers, and receiving a stable dose of said drug therapy The method according to any one of the first to eleventh embodiments.

  In the thirteenth embodiment, the invention is the method of any one of the first to twelfth embodiments, wherein the subject is undergoing diuretic therapy.

  In the fourteenth embodiment, the invention is a method according to any one of the first to thirteenth embodiments, wherein the subject has a controlled systolic BP of less than 140 mm HG.

In the fifteenth embodiment, the invention is the method according to any one of the first to fourteenth embodiments, wherein the subject has an eGFR of 45 45 ml / min / 1.73 m ² .

  In the sixteenth embodiment, the invention is the method according to any one of the first to fifteenth embodiments, wherein the subject has ≦ 5.2 mM serum potassium.

  In the seventeenth embodiment, the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.

  In an eighteenth embodiment, the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.

  In the nineteenth embodiment, the invention is the pharmaceutical composition according to the eighteenth embodiment, wherein the composition comprises 2.5 mg, 10 mg or 50 mg of LIK066.

  In the twentieth embodiment, the invention is the pharmaceutical composition according to the eighteenth or nineteenth embodiment, which is administered once a day.

In the twenty first embodiment, the invention is the pharmaceutical composition according to any one of the nineteenth or twentieth embodiments, wherein the subject has a BMI of 2222 kg / m ² .

  In the twenty second embodiment, the invention is any of eighteenth through twenty first practices wherein the subject is any individual having type 2 diabetes, particularly wherein the HbA1c is between 7.0% and 10.0%. It is a pharmaceutical composition of any of the forms.

  In a twenty-third embodiment, the invention is directed to a subject having at least one of the following symptoms selected from dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea and peripheral edema. The pharmaceutical composition of any of the eighteenth to twenty second embodiments, having symptomatic chronic heart failure (NYHA II-IV).

  In a twenty-fourth embodiment, the present invention provides that the subject is concurrently receiving a drug therapy selected from ACEi, ARB, MRA, diuretics, ARNi and / or β-blockers, or a combination thereof, wherein said drug therapy is stable The pharmaceutical composition of any one of the eighteenth to twenty-third embodiments, wherein the pharmaceutical composition has received a given dose.

  In the twenty-fifth embodiment, the invention is the pharmaceutical composition of any one of the eighteenth to twenty-fourth embodiments, wherein the subject has a controlled systolic BP less than 140 mm Hg.

In the twenty sixth embodiment, the invention is the pharmaceutical composition of any one of the eighteenth to twenty fifth embodiments, wherein the subject has an eGFR of 45 45 ml / min / 1.73 m ² .

  In the twenty-seventh embodiment, the invention is the pharmaceutical composition of any one of the eighteenth to the twenty-sixth embodiments, wherein the subject has ≦ 5.2 mM serum potassium.

  In a twenty eighth embodiment, the present invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for use in the treatment or prevention of heart failure.

  In the twenty ninth embodiment, the invention is the medicament according to the twenty eighth embodiment, wherein the composition comprises 2.5 mg, 10 mg or 50 mg of LIK066.

  In a thirtieth embodiment, the invention is a medicament for use in the treatment of heart failure in a subject having type 2 diabetes, in particular any individual whose HbA1c is between 7.0% and 10.0%.

  In a thirty first embodiment, the present invention comprises LIK 066 for use in the treatment of heart failure.

  In a thirty-second embodiment, the invention includes LIK 066 for use in the treatment of heart failure (HF pEF) in which the ejection fraction is maintained.

  In a thirty-third embodiment, the invention includes LIK066 for use in the treatment of heart failure (HF rEF) with reduced ejection fraction.

  In a thirty-fourth embodiment, the present invention includes LIK 066 for use in the treatment of heart failure in a subject having T2D, particularly any individual whose HbA1c is between 7.0% and 10.0%.

  In a thirty-fifth embodiment, the present invention provides heart failure (HF pEF) in which the ejection fraction is maintained in a subject having T2D, in particular in any individual whose HbA1c is between 7.0% and 10.0%. Includes LIK 066 for use in therapy.

  In a thirty-sixth embodiment, the present invention relates to heart failure with reduced ejection fraction (HFrEF) in a subject having T2D, particularly any individual with HbA1c between 7.0% and 10.0%. Includes LIK 066 for use in therapy.

  In the thirty seventh embodiment, the invention is the use according to any of the thirty first to thirty sixth embodiments, wherein the composition comprises 2.5 mg, 10 mg, or 50 mg of LIK066.

  In another embodiment, the invention is a pharmaceutical unit dose comprising 2.5 mg, 10 mg or 50 mg of LIK066.

  "Pharmaceutically acceptable salt" refers to the release of a compound of formula (I) which is nontoxic, not biologically unacceptable, and which is not otherwise biologically undesirable. It is intended to mean the salt of the base / free acid. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective without excessive toxicity, irritation or allergic response and that are suitable for contact with a patient's tissue. Such salts are known in the art (e.g. SM Berge, et al, "Pharmaceutical Salts", J. Pharm. Sd., 1977, 66: 1-19; and "Handbook of Pharmaceutical Salts, Properties, Selection. , and Use ", Stahl, RH., Wermuth, CG, Eds .; Wiley-VCH and VHCA: Zurich, 2002).

  LIK 066 is an inhibitor of sodium-glucose cotransporter-1 (SGLT1) and sodium-glucose cotransporter-2 (SGLT2). LIK 066 has the following chemical structure:

LIK 066 has the following IUPAC name: (2S, 3R, 4R, 5S, 6R) -2- (3-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -4-Ethylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

  LIK 066 for use in the present invention is obtained in free form, as a salt thereof or as a prodrug derivative thereof.

  In addition, LIK 066, including its salts, can also be obtained in its hydrate form, or include other solvents used for its crystallization. LIK 066 can form essentially or intentionally a solvate with a pharmaceutically acceptable solvent (including water); therefore, the present invention provides both solvated and unsolvated forms. It is intended to be included. The term "solvate" refers to a molecular complex of one or more solvent molecules and a compound of the invention (including pharmaceutically acceptable salts thereof). Such solvent molecules are commonly used in the pharmaceutical field and are molecules known to be harmless to the recipient, such as water, ethanol and the like.

  The term "hydrate" refers to a complex where the solvent molecule is water. LIK066, including its salts, hydrates and solvates, can form polymorphs essentially or intentionally.

  The higher oral bioavailability of LIK 066 may result in the following beneficial effects with less bioavailable compounds: (i) enhanced biological effects after oral administration May be achieved; (ii) an initial onset of action may be observed following oral administration; (iii) a smaller dose may be required to achieve the same effect; (iv) the same Higher doses may be achieved with the dose or (v) long-term effects may be observed with the same dose.

  As used herein, the term "subject" typically refers to humans, particularly human patients diagnosed with heart failure or human patients suffering from heart failure associated with type 2 diabetes.

  The term "treatment" as used herein also refers to any type of treatment that benefits a subject afflicted with heart failure.

Heart failure (HF), often referred to as congestive heart failure (CHF), occurs when the heart can not pump enough to maintain blood flow to meet the body's needs. Signs and symptoms generally include shortness of breath, extreme fatigue, and leg swelling. Breathlessness is usually exacerbated by lying-down exercises and may wake up at night. It is also a common feature that motor skills are limited. Chest pain, including angina, typically does not occur because of heart failure.
Common causes of heart failure include coronary artery disease, including a history of myocardial infarction (heart attack), hypertension, atrial fibrillation, valvular heart disease, excessive drinking, infection, and unexplained cardiomyopathy. These cause heart failure by altering the structure or function of the heart.

  Heart failure has two major types of heart failure due to left ventricular dysfunction and heart failure with normal ejection fraction, depending on whether the ability of the left ventricle to contract is affected or depending on the ability of the heart to relax. There is heart failure. The severity of the disease is usually graded according to the degree of exercise problems. Heart failure is not the same as myocardial infarction (a portion of the heart muscle dies) or cardiac arrest (blood flow ceases completely). Other diseases that may have symptoms similar to heart failure include obesity, renal failure, liver injury, anemia, and thyroid disease. Conditions are diagnosed based on previous symptoms, and echocardiography, blood tests, electrocardiography, and physical examinations confirmed by chest x-ray may be useful to determine the underlying cause.

  For the above mentioned indications (conditions and disorders), the appropriate dosage will vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at a daily dosage of about 0.01 to about 100 mg / kg body weight, preferably about 1 to about 30 mg / kg body weight, eg 10 mg / kg ing. The daily dose indicated is, for example, about 0.1 to about 1000 mg, preferably about 1 to about 100 mg, most preferably about 1 to about 75 mg, conveniently administered in a single dose once daily. Range of LIK066. In one embodiment, about 2.5 mg of LIK066 is administered once daily. In another embodiment, about 10 mg of LIK066 is administered once daily. In yet another embodiment, about 50 mg of LIK066 is administered once daily.

  For use according to the invention, LIK 066 is in any conventional manner, for example orally, for example in the form of tablets, capsules or beverage solutions; in the rectum, for example in the form of suppositories; Or in the form of a suspension; or transdermally, for example in the form of a patch.

  In one embodiment, the mode of administration is, for example, oral administration in the form of a tablet, capsule or beverage solution. In one embodiment, the mode of administration is, for example, rectal administration in the form of a suppository. In one embodiment, the mode of administration is transdermal administration, for example in the form of a patch. In one preferred embodiment, the mode of administration is oral administration.

  Preferred pharmaceutical compositions comprise LIK 066 with at least one pharmaceutical carrier or diluent. Such compositions can be manufactured in a conventional manner. The unit dosage form can contain LIK066 in an amount such as more than or equal to 2.5 mg, such as more than or equal to 10 mg, such as more than or equal to 50 mg. The unit dosage form can also contain LIK066 in an amount greater than or equal to 2.5 mg, 10 mg, 40 mg, 50 mg, 75 mg or 100 mg, or greater than or equal to 150 mg or 200 mg.

  The unit dosage form is less than or equal to 100 mg, such as less than or equal to 100 mg, such as less than or equal to 50 mg, such as less than or equal to 10 mg, such as less than or equal to 2.5 mg, such as LIK 066 can be contained in equal amounts and the like. The unit dosage form can also contain LIK066 in an amount ranging from 1 to 60 mg, such as 1 to 100 mg, such as 1 to 75 mg or 2 to 55 mg.

  The pharmaceutical composition according to the present invention is for enteral administration such as oral or rectal administration to warm-blooded animals (human and animals); or for parenteral administration such as intramuscular, intravenous and intranasal or transdermal administration. A composition comprising an effective amount of a pharmacologically active ingredient alone or together with a substantial amount of a pharmaceutically acceptable carrier. The dose of active ingredient depends on the species of warm-blooded animal, body weight, age and condition of the individual, pharmacokinetic data of the individual, the disease to be treated and the mode of administration.

The pharmaceutical composition comprises approximately 1% to approximately 95%, preferably approximately 20% to approximately 90%, of the active ingredient. The pharmaceutical composition according to the invention may be in unit dose form such as, for example, in the form of ampoules, vials, suppositories, Dragees, tablets or capsules. Compositions for transdermal administration ^{Remington's Pharmaceutical Sciences 16 th Edition Mack} ; Sucker, Fuchs and Spieser, Pharmazeutische Technologie, 1 st Edition, are described in Springer.

List of abbreviations ACE (i) Angiotensin converting enzyme (inhibitor)
AE Adverse events ALT Alanine transaminase ARB Angiotensin II receptor blocker AST Aspartate aminotransferase AV AV Atrioventricular BL Baseline BMI Body mass index BMD Bone density BP Blood pressure CFR US Federal Regulations CHF CHF Chronic Heart Failure CRF Case Report Book / Recording format (paper or electronic)
CPO Country Pharma Organization CRO Drug Development Contractor CV Cardiovascular CVD Cardiovascular disease DBP Diastolic blood pressure DXA Dual energy X-ray absorptiometry ECG Electrocardiogram EDC Electronic data collection EOS End of trial EQ-5D-5L EuroQoL 5 Dimension 5 version FAS Largest Analysis Target Population FDA Food and Drug Administration FPG Fasting Blood Glucose GCP Superior Clinical Test Criteria (e) GFR (Estimated) Glomerular Filtration Rate GI Gastrointestinal HbA1c Glycated Hemoglobin HDL High Density Lipoprotein HF Heart Failure HFpEF Ejection fraction maintained Heart failure IB with reduced heart failure HFrEF Ejection fraction decreased Investigate drug summary document ICD Implantable defibrillator ICF Consent instruction document ICH International Conference on Regulations of Pharmaceutical Regulations IEC Independent Ethics Committee IN Investigator notification (Investigator notification)
IRB Investigative Review Committee IRT Two-way automatic response technology ITT Trial Intention KCCQ Kansas City Cardiomyopathy Questionnaire (V) LDL (super) low density lipoprotein LFT Liver function test LVEF Left ventricular ejection fraction MACE Major cardiovascular event MAR Random Missing MI Myocardial Infarction MMRM Repeatedly Measured Model MRA Mineralocorticoid Receptor Blocker NOAEL Nontoxic Amount NYHA New York Heart Association OAD Antidiabetic Drug OC / RDC Oracle Clinical / Remote Data Collection PCI Percutaneous Coronary Angioplasty PGIS Patient Impression Patient Global Impression of Severity
PK pharmacokinetic PPD Early patient discontinuation (Premature patient discontinuation)
PPS Per Protocol Set (e) PRO (Electronic) Patient Reported Outcomes PROMIS Patient Reported Outcomes Measurement Information System RAN Randomized Set RBC Red Blood Cells (Number)
RR Relatively Low SAE Serious Adverse Event SAF Safety Set (Safety Set)
SBP systolic blood pressure SCR screening set (Screened set)
SD standard deviation SGLT (i) Sodium-glucose cotransporter (inhibitor)
SU sulfonylurea T2DM type 2 diabetes TG triglyceride triglyceride discontinuation treatment TSH thyroid stimulating hormone UACR urinary albumin to creatinine ratio UGE urinary glucose excretion ULN normal upper limit UTI urinary tract infection WBC white blood cells (number)
WHO World Health Organization

The term control drug: as a comparator to reduce evaluation bias, maintain blinding of the study drug, assess internal trial validity, and / or evaluate the comparative efficacy of the study drug. Drug (s) used
Dose: The investigational treatment dose given to the patient on an hourly basis (eg, 100 mg once daily, 75 mg twice daily)
Enrollment: At the time of clinical trial registration of a patient who must have informed consent (eg, prior to the commencement of any of the procedures described in the protocol)
Epoch: The part of a clinical trial that serves a specific purpose. Typical epochs are screening / mobilization, lavage, treatment and follow-up.
Study drug: A drug whose properties are being tested in a clinical trial; this definition is in accordance with 21 USC セ ク シ ョ ン 312.3, and is synonymous with "test drug" or "test drug."
Drug therapy pack number: Unique identifier on the label of each study drug package Patient ID: Unique number assigned to each patient when signed informed consent Randomized number: Each corresponding to a specific treatment group assignment Unique identifier study drug / treatment assigned to randomized patients in: any single drug or combination of drugs administered to the patient as part of the required study procedure, the study drug (s), placebo / Including comparator active drug introduction or background therapy.
Study treatment discontinuation (TD): Permanent discontinuation of the patient to study treatment prior to the prescribed study treatment completion date Variable: Determined in a specific assessment to evaluate the drug being tested in the trial Regression of measured values used in data analysis or evaluated response consent: Withdrawal of consent from the trial is that the patient no longer wants to participate in the trial, no more visits or assessments, no more It is defined as not allowing analysis of previously obtained biological material that does not require trial related contact.

Study Objectives and Endpoints Main Objective LIK066 2.5 mg, 10 mg, and 50 mg qd as measured by change from baseline (BL) of NT-proBNP versus placebo after 12 weeks of treatment in T2DM patients with HF Determine the dose response signal of and assess the dose response relationship

Secondary purpose 1. Assess the change from BL up to 36 weeks with all LIK066 doses versus placebo for NT-proBNP. Assess the safety (adverse event (AE) and laboratory parameters) and tolerability of LIK066 for 12 weeks and 36 weeks for all patients

Study Design This is a multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy, safety and tolerability of three doses of LIK 066 versus placebo and versus empagliflozin It is.

Epoch 1 (screening)
Patients are screened at Visit 1 (see Figure 1). The screening period (Epoch 1) takes up to 2 weeks. Patients who meet all eligibility criteria will enter Introductory Epoch 2 at Visit 101. If the patient does not meet one or more inclusion / exclusion criteria, it is rescreened once.

Epoch 2 (placebo introduced)
Patients who meet the eligibility criteria enter placebo (epoch 2). Patients receive single-blind, placebo-guided drug therapy for two weeks of the Epoch 2 period. At Visit 101, the patient's volume status is assessed based on physical and laboratory values and, in the case of blood loss, corrected during induction.

Epoch 3 (treatment)
After placebo-introduced epoch 2, eligible patients have the following regimen on Visit 201 (randomized): LIK066 2.5 mg qd before bedtime; LIK066 10 mg qd before bedtime; LIK066 50 mg qd before bedtime; Two weeks after qd titrated up to 25 mg qd (up-titrated); and before bedtime on one of the placebo LIK 066 / morning placebo empagliflozin at a ratio of 1: 1: 2: 2: 2 Be randomized.

  In randomization, patients are stratified based on left ventricular ejection fraction (LVEF) measurement at geographic area and visit 101: <45% vs. 4545%. Following randomization, patients will go to the study visit at Epoch 3 (12 weeks) for assessment of short-term efficacy (NT-proBNP changes). During Epoch 3, patients receive study drug.

Treatment of T2DM Patients continue their regular T2DM treatment. Patients receiving sulfonylurea (SU) or insulin may increase the risk of hypoglycemia with the addition of LIK066 or empagliflozin, therefore, dose reduction of SU or insulin should be considered. In patients using such medications (alone or in combination with other oral antidiabetic agents (OADs)), 50% of the dose of SU based on locally available dose options, or You should consider weight loss as close to 50% as possible. If glycemic control continues to deteriorate, combined background OAD should first be increased to the maximum approved dose, followed by additional rescue medication, if necessary. There is an FPG randomization criterion to limit the number of patients meeting the FPG rescue criteria early after randomization, with early deterioration of glycemic control (To limit the number of patients with early determination of glycemic control who would meet the FRG rescue criteria early after randomization an FPG randomization criterion.

  For patients receiving insulin, an initial dose reduction of 10% or more of the total daily insulin dose should be considered at the Investigator's discretion based on the patient's total daily dose and glycemic control. Due to the potential risk of ketoacidosis with SGLT2i, dose reduction in patients with HbA1c ≧ 8% may not be appropriate. In the case of worsening glycemic control, insulin can be titrated up.

Epoch 4 (treatment)
After completing the necessary procedures at the last clinical trial visit of Epoch 3 (Visit 301), the patient continues the treatment assigned at Epoch 3 for 24 weeks at Epoch 4. Long-term efficacy (as assessed by HbA1c, echocardiography and NT-proBNP), tolerability and safety parameters are assessed.

Clinical trial design rationale The clinical trial is designed as a standard randomized, controlled, parallel group study. A single-blind, placebo-introduced epoch (Epoch 2) is included to acclimate the patient to the study drug intake schedule and correct for hypovolemia (if diagnosed at Visit 101). The effect on NT-proBNP is evaluated after 12 weeks of epoch 3 treatment and after a 36 week trial (epoch 4) to provide information on the long-term effects on NT-proBNP and on clinical and echocardiographic parameters. Glycemic control is assessed after 12 and 36 weeks of treatment.

Dose / Dimension, Grounds of Administration and Duration of Treatment LIK066 is administered in healthy subjects, patients with T2DM and patients with obesity using a single dose or multiple daily doses for up to 12 weeks and varying doses It has been studied in several clinical trials using a regimen. The pharmacokinetic half-life of LIK 066 (approximately 16 hours) allows once-daily oral administration of LIK 066 and significant pharmacodynamic effects such as 24-hour urinary glucose excretion (UGE 24) and body weight are observed in these populations It was done. Based on pharmacodynamic data from a phase 1 trial in patients with T2DM, a minimal test dose of 2.5 mg qd results in approximately 37 g of 24-hour urinary glucose excretion (diabetes), the lowest effective dose in this trial It is considered appropriate. Urinary glucose excretion over 24 hours reached steady state at about 90 g with a dose ≧ 30 mg qd. After 14 days of once-daily dosing at 15 mg in patients with T2DM, the 24-hour UGE reached steady state at about 100 g. The aim is to find doses that have suboptimal to optimal effects on SGLT1 and SGLT2 inhibition in the kidney, but because there is no or minimal intestinal effect to minimize the risk of diarrhea, LIK066 50 mg qd is for this trial It is chosen as the highest dose. The 50 mg dose represents the dose at the very end of the potentially UGE dose response curve in patients with T2DM, and it would be appropriate to test in this vulnerable population. Gastrointestinal (GI) tolerance was better with LIK066 30 mg qd than with 150 mg qd. In order to minimize the risk of GI adverse effects of SGLT1 inhibition in the intestines such as diarrhea, LIK066 dose should not be taken before and after meal times, therefore, dose administration is recommended before bedtime. The 10 mg dose is selected to allow investigation of the shape of the dose response curve, between low and maximum doses in clinical trials.

  Based on the results of a previous phase II trial in HF comparing Sacvitril / Vallartan and Valsartan (eg LCZ 696 B 2214; Solomon et al, 2012), treatment with NTK-proBNP with LIK066 for a 12-week period It is expected to be sufficient to reveal significant changes. Twelve weeks after the introduction of anti-diabetic treatment, it is an acceptable time point for an initial assessment of the effect of the drug on glycemic control (HbA1c). A full 36 week exposure will provide data as well as safety data for parameters requiring longer follow-up (echocardiography) to assess.

Rationale for Comparator Selection The efficacy, tolerability and safety data will be obtained in an unbiased manner and included in the placebo group to determine the dose response characteristics of the study drug. The active comparator, empagliflozin, has been approved for the treatment of T2DM to improve glycemic control and is included as a reference (Zinman et al, 2015). Empagliflozin also showed CV benefits in T2DM patients in the EMPA-REG Outcome trial. Given that the mechanism leading to CV benefit with empagliflozin is still unclear at present, the higher of the two doses approved in patients with T2DM, empagliflozin 25 mg qd, is the maximal effect on NT-proBNP Was selected as a potential comparator. Choosing the higher of the two doses should not be a safety concern. The reason is that there is no difference between the safety profiles of empagliflozin 10 mg and 25 mg, in the EMPA-REG Outcome test, eGFR 30 30 ml / min / with a cutoff value lower than 45 ml / min / 1.73 m ^{2 with} CLIK066 B2204. From 1.73 m ² of patients reported (Fitchett et al, 2016). In order to minimize the potential adverse effects, empagliflozin will be titrated up from 10 mg qd to 25 mg qd after 2 weeks of treatment.

  The benefits of participation in the trial may include blood sugar reduction, weight loss and potentially improvement in HF signs and symptoms and some cardiovascular metabolic markers such as NT-proBNP, blood pressure or lipids.

Population The study population was from male and female patients (≧ 18 years old) with type 2 diabetes and heart failure (heart failure with maintained ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF)) Become. The goal is to randomize approximately 496 patients in total at approximately 100 centers worldwide. Since a 25% screening failure rate and a 33% induction failure rate are expected, approximately 1000 patients will be screened.

Inclusion criteria Patients who are eligible for inclusion in the trial have the following criteria: A written informed consent must be obtained before any assessments are conducted; Male or female outpatients, visit 1 ≧ 18 years old; BMI ≧ 22 kg / m ² at Visit 1; Type 2 diabetes with HbA1c between 7.0% and 10.0% at Visit 1; Documented symptomatic chronic heart failure (NYHA II-IV) with at least one of the following symptoms (respiratory distress at work; orthopnea; paroxysmal nocturnal dyspnea; and peripheral edema) at Visit 1 6; Plasma NT-proBNP> 400 pg / ml at Visit 1; Patients receiving ACEi, ARB, MRA, ARNi and / or beta blockers must have received stable doses of these medications for one month prior to Visit 1; Patients must have received diuretic therapy prior to Visit 1 (flexible dosing allowed); The controlled systolic BP defined as BP at target systole is less than 140 mm Hg; if the patient has received three or more medications to control BP at randomization (visit 201) When contracted, BP is less than 160 mmHg; 11. Visit 1 at eGFR / 45 ml / min / 1.73 m ² (calculated by the Dietary Improvement Formula for Renal Disease (MDRD)); and At Visit 1, all of the serum potassium ≦ 5.2 mM must be satisfied.

Exclusion Criteria Patients who meet any of the following criteria are not eligible for inclusion in this study. There is no additional exclusion applied by the investigator to ensure that the study population represents all eligible patients.
1. Use of the other test drug within the 5 half-life of Visit 1 or within 30 days, whichever is longer. History of hypersensitivity to either the investigational drug or its excipients or to similar chemical classes. Critical safety for patients participating in clinical trials such as concomitant clinically significant arrhythmias such as persistent ventricular tachycardia and clinically significant second or third degree AV block without pacemakers History or present diagnosis of electrocardiogram (ECG) abnormalities that show significant risk; history of familial QT prolongation syndrome or known family history of torsade de pointes: and resting heart rate> 100 beats per minute (bpm) Atrial fibrillation4. Patients taking medications prohibited by the protocol 5. Malignant neoplasia of any organ system (local basal cell carcinoma of the skin or in situ child within the last 5 years, with or without evidence of local recurrence or metastasis) Medical history of non-cervical cancer Women who are pregnant or nursing (nursing) 7. A deliverable woman, defined as any woman who can be physiologically pregnant if they do not use basic contraception during administration of the study drug. Basic contraception: All abstinence (if this is consistent with the patient's preferred normal lifestyle), periodic abstinence (eg calendar, ovulation, temperature, post-ovulation) and withdrawal are not acceptable contraceptions; female infertility Includes surgery (which may have undergone surgical bilateral ovariectomy with or without hysterectomy), total hysterectomy or fallopian tube ligation at least 6 weeks before taking study medication. In the case of ovariectomy only, female reproductive status is only ascertained by follow-up hormone level assessment; male infertility (at least 6 months before screening). For female patients in the trial, a vasculectomy male partner should be the only partner of that patient; barrier-based contraception: condom or sealed cap (Pessary or cervical / arched cap). In the UK, with spermicidal effervescent agent / gel / film / cream / vaginal suppositories; and oral of contraception (female hormone and luteinizing hormone), injection or transplantation hormone method or comparable efficacy (failure rate <1% 2.) Other forms of hormonal infertility, for example the use of hormonal vaginal rings or placement of percutaneous hormonal contraception or intrauterine devices (IUD) or intrauterine systems (IUS).

  When using oral contraceptives, women should have been stable with the same pill for at least three months before taking study medication.

Women had 12 months of natural (natural) amenorrhea with an appropriate clinical profile (eg, a history of commensurate, vasomotor symptoms) or surgical bilateral ovariectomy (uterine) at least 6 weeks ago It is considered to be postmenopausal and not childbearing if it has been under hysterectomy or tubal ligation with or without removal). In the case of ovariectomy only, it is considered not deliverable only if the female's reproductive status is confirmed by follow-up hormone level assessment. If the above statement does not conform to a particular local regulation, the exclusion criteria for women capable of giving birth are treated locally to be consistent with that regulation.
Type 8.1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary diabetes (eg, Cushing's syndrome or acromegaly-related diabetes)
9. Use of SGLT2 inhibitor within 2 months of visit 1 or between visit 1 and visit 201 (randomized) 10. Self-measured FPG> 12.2 mM (220 mg / dL) twice weekly prior to randomization (visit 201)
11. Ketoacidosis, lactic acidosis, or hypertonic coma within 12 months of visit 1 or between visit 1 and visit 201 (randomized). Symptomatic reproductive infection or UTI at 4 weeks prior to Visit 1 or between Visit 1 and Visit 201 (randomized)
13. GI disorders associated with chronic diarrhea 14. Myocardial infarction (MI), stroke, heart surgery, percutaneous coronary angioplasty (PCI) in 3 months prior to visit 201 (randomized)
15. Unstable angina within 3 months of Visit 1 or between Visit 1 and Visit 201 (randomized) 16. Isolated right HF due to lung disease
17. Dyspnea and / or edema from non-cardiac causes such as lung disease, anemia, or severe obesity. Hemodynamically significant mitral valve and / or aortic valve disease 19. Hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic valve stenosis. Hypertrophic obstructive cardiomyopathy 21. Secondary forms of cardiomyopathy such as restrictive cardiomyopathy or invasive cardiomyopathy (eg, amyloid disease)
22. Patients who have any history of organ transplants or were on the transplant list (average life <6 months at study entry)
23. 24. Patients with mean sitting systolic blood pressure ≦ 100 mmHg at randomization (visit 201). 25. A patient with an implantable medical device (e.g., a defibrillator (ICD) discharging in the month preceding Visit 1). Malignant ventricular tachycardia or any other type of severe arrhythmia episode (s) deemed to have serious hemodynamic consequences or life-threatening within 3 months of visit 1
26. Acute or chronic liver disease (except fatty liver) such as hepatitis, cirrhosis or portal hypertension at visit 1 or visit 201 (randomized)
27. 28. A history of hepatitis B or hepatitis C, or a hepatitis A or hepatitis B vaccine, for the last 3 months prior to visit 1 or between visit 1 and visit 201 (randomized). Active substance abuse, alcohol abuse (defined by intake above 24 alcohol units per week) and alcohol related medical history within the last two years. Chronic treatment with potentially hepatotoxic drug therapy 30. Continuous use of antiretroviral therapy 31. Continuous use of potent CYP3A4 inhibitors (eg clarithromycin, telithromycin, itraconazole, ketoconazole, voriconazole or posaconazole) or potent uridine-5'-diphosphoglucuronosyltransferase (UTG) inhibitors (eg probenecid, Continuous use of valproic acid or mefenamic acid) 32. Concurrent medical conditions that may interfere with the interpretation of efficacy and safety data. Clinically significant thyroid stimulating hormone (TSH) levels beyond the normal range at Visit 1 34. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) (> 3 × ULN), or total bilirubin / direct bilirubin> 1.5 × ULN, which is three times above the upper limit of normal at Visit 1 respectively Confirmed by repeated measurement within 5 working days of visit 35. Hemoglobin <11 g / L male, <10 g / L female at Visit 1 (screening) 36. Platelet count <100,000 / μl and / or white blood cell (WBC) count <4000 / μl at Visit 1 (screening)
37. Hematuria determined by dipstick measurement at Visit 1 (screening). Fasting triglycerides (TG)> 5.6 mM (500 mg / dl) elevated at Visit 1 (screening), verified by repeated measurements within 3 working days of each visit 39. In the investigator's opinion, clinically significant laboratory abnormalities that cause patients to be considered inappropriate for inclusion in a clinical trial

Treatment group All patients who enter Epoch 2 (introduction) receive a single-blind placebo. At Visit 201 (randomized), patients eligible for randomization included the following 5 treatment groups with epoch 3 (treatment): 2.5 mg qd LIK 066; 10 mg qd LIK 066; 50 mg qd LIK 066; 10 mg qd empaglyph Two weeks after rosin titrated up to 25 mg qd; and assigned to one of the placebo qds in the ratio 1: 1: 2: 2: 2.

  In epoch 4 (epoch 4 (treatment)), the patient continues to receive the epoch 3 assigned treatment.

Treatment Allocation and Randomization At Visit 201 (randomization), all eligible patients are randomized into one of the treatment groups via interactive automatic response technology (IRT). The investigator or his / her representative contacts the IRT after confirming that the patient meets the inclusion / exclusion criteria. IRT assigns a randomized version number to the patient, which is used to link the patient to the treatment group and to identify a unique medication number for the first package of study drug to be distributed to the patient become. The randomization number is not communicated to the user of the IRT system.

  Randomized numbers are generated using the following procedure to ensure that treatment assignments are not biased and hidden from the patient and investigator staff. Patient randomization lists are generated by the IRT provider using a validated method that automates the random assignment of patient numbers to randomization numbers. These randomized numbers are linked to different treatment groups, which in turn are linked to drug therapy numbers. A separate medication list is created by or under the responsibility of Novartis Drug Supply Management using a validated method that automates the random assignment of medication numbers to packs containing study drug (s). Ru. A randomized design for patients has been reviewed and approved by members of the Novartis Randomized Group. Randomization is stratified according to geographic area and LVEF (<45% vs. ≧ 45% at Visit 101).

Treatment-blinding Patients, investigator staff, Novartis trial teams, people performing the assessments, and data analysts will know about the identity of the treatment from the time of randomization to the database lock using the following method It is not done: 1. Randomized data is strictly kept secret until blinding, and randomization codes related to patients taking PK samples are disclosed to PK analysts who keep PK results secret until database lock Are not available to anyone else involved in the trial, and The use of investigational drugs with the same packaging, labeling, dosing schedule, appearance, taste and smell all will mask the identity of the treatment. A dual dummy design is used because the identity of the investigational drug can not be disguised because of its different form.

  Unmasking occurs only at Week 12 analysis and at the end of the trial in case of a patient emergency.

  The analysis group (statist / programmer) is unmasked to perform 12 analyzes per week, but after its unmasking it is not involved in any clinical trial activity involving 12 weeks to 36 weeks (Epoch 4) . A separate analysis group does not have access to analysis results and treatment identity at week 12 analysis, but performs a preplanned final analysis at the end of the trial.

  The core clinical trial team (including clinical trial leader (s), clinical trial physicians and data administrators) is directly involved in clinical trial activities during 12 weeks to 36 weeks (Epoch 4), but at the time of weekly 12 analysis Unable to obtain patient level data with treatment identity, such as patient inventory.

  Week 12 analysis results and treatment identities are not shared with trial site personnel until after the final database lock at the end of the trial.

Patient Numbering Each patient is uniquely identified in the trial by the combination of its institution number and patient number. The site number is assigned to the study site by Novartis. Upon signing the informed consent form, the patient is assigned a patient number by the investigator. At each site, the first patient is assigned patient number 1 and subsequent patients / subjects are assigned consecutive numbers (eg, the second patient is assigned patient number 2; the third patient is patient) Assigned the number 3). The investigator or his staff contacts the IRT and provides the identifying information required of the patient to enroll the patient in the IRT. In trials using eCRF, only the assigned patient number must be entered into the field labeled "Patient ID" on the EDC data entry screen (eg, the inputs "1", "2", etc.). After being assigned to a patient, the patient number is not reused. If the patient is not randomized for any reason, IRT should be notified that the patient was not randomized within 2 days. The reasons for not being randomized are entered on the Screening Log and the demographic eCRF is completed.

Distribute the investigational product Each investigational site will be supplied with the investigational drug in the same package. The investigational drug package has a 2 part label. A unique randomization number is printed on each part of this label corresponding to one of the treatment groups. The investigator staff identifies the investigational drug package (s) to be distributed to the patient by contacting the IRT and obtaining the medication number (s). Just before distributing the package to the patient, the investigator's staff pulls the outer part of the label from the package and applies that part to the original document (Drug Label Form) for the patient's unique patient number .

Handling of investigational treatment If investigational treatment is received, handled, safely and properly stored at the investigational site by designated persons, and stored at a safety-safe location available only to designated investigators. It does not. Once received, all study treatments must be stored according to the instructions specified on the label. Clinical supplies are only distributed according to the protocol. Dissatisfaction with the technology is reported to the respective Novartis CPO Quality Assurance. Drug treatment labels are in the local language and follow the legal requirements of each country. Drug therapy labels include storage conditions for study treatment but do not include information about the patient except for drug therapy numbers. The investigator maintains an accurate record of the investigational product transport and distribution in the investigational drug management record. Drug management monitoring is performed by the monitor during facility visits or remotely and at the end of the study. Patients are told to return all unused study treatment and packaging at their respective study visits, if applicable, upon discontinuation of study treatment.

  At the end of the trial, and as needed while the trial is in progress, the Investigator is responsible for all copies of unused trial treatment, packaging, drug labels, and completed study drug records on Novartis Monitor or at the respective site. Return to the Novartis address provided in the responsible doctor folder.

Instructions for Prescribing and Taking Study Treatment Patients should take study drug one capsule in the morning with or without food, and one tablet before bedtime. All prescribed doses and dose changes under study are recorded in the appropriate study drug dose dose record eCRF. All IRT assigned trial treatment kits are recorded / databaseized in IRT. During each trial visit, the investigator will instruct the patient to take the study drug exactly as prescribed to maintain the efficacy of the study and optimize any potential effects of the study drug regimen. Should encourage compliance with investigational drugs. Patients are instructed to contact the investigator if the study drug regimen can not be taken as prescribed for any reason.

Acceptable dose adjustment and discontinuation of trial treatment Trial dose adjustment and / or discontinuation is not acceptable unless done for safety reasons.

Rescue Drug Therapy During Epoch 3 and Epoch 4, rescue medication may be used in addition to ongoing investigational drugs for patients with impaired glycemic control. If the self-measured FPG exceeds the limits of Table 5-1 three times in a row, and the FPG results of the blood samples analyzed in the central laboratory exceed the limits described in Table 1, the patient is admitted to the central laboratory Have to go to an unscheduled visit to have samples taken for FPG and HbA1c measurements performed by.

  If the results confirm that the limit has been exceeded, background OAD should first be raised to the maximum approved dose, followed by additional rescue medication. The rescue medication is preferably insulin and should be used according to the local label and must be provided locally. Patients who receive rescue will continue to participate in the trial to be able to assess the exposure and safety of LIK066. The use of rescue medications should be recorded in the rescue medication eCRF.

Combination Medication The investigator should instruct the patient to notify the trial site about any new medications he or she will take after the patient is enrolled in the trial. All medications, procedures and critical non-drug therapies (including physical therapy and transfusion) to be given after the patient is enrolled in the trial should be recorded in the combination medication / surgery and medical procedure eCRF. Investigators should make every effort to keep the dose level of each patient's accepted background heart failure medication stable throughout the entire study period. However, if the patient's clinical condition justifies any change in these medications, this change is acceptable at the investigator's discretion. Each concomitant drug should be evaluated individually in the light of any exclusion criteria / banned medications. If in doubt, the investigator should contact the Novartis medical monitor before randomizing the patient or initiating a new medication.

Prohibited Medications The use of the treatments listed in Table 2 is not permitted after the patient is eligible to participate in the trial. At the latest, patients should stop using the medications listed in Table 2 at the start of epoch 2.

  Some medications or products must be used with caution. The use of grapefruit juice (a potent inhibitor of CYP3A4) should be discouraged and you should not drink grapefruit juice within 2 hours of study drug intake. The use of antibiotics or antifungals that are potent inhibitors of CYP3A4 should be limited to 10 days during the trial and should not be used at randomization. Examples of such medications are clarithromycin, telithromycin, itraconazole, ketoconazole, voriconazole or posaconazole; use of UGT inhibitors such as probenecid, valproic acid or mefenamic acid is limited to 10 days during the trial It should be used and not during randomisation.

Emergency Decoding of the Assigned Treatment Code Emergency code decoding is performed only when needed to safely treat the patient. In many cases, findings of study treatment discontinuation and possible treatment assignments are sufficient to treat study patients presenting with an emergency. Emergency treatment code decoding is performed using IRT. When contacting the system to decipher the patient's treatment code, the investigator must provide the requested patient identification and confirm the need to decipher the treatment code for the patient. The investigator will then receive the identified patient treatment details of the patient and information exchange to confirm this information. The system automatically informs the field Novartis Monitor and the clinical trial team that the code has been deciphered.

  It is the investigator's responsibility to ensure that there is a credible procedure in place to grant access to the IRT system at any time in an emergency situation. The investigator will provide the protocol number, study drug name (if available) and patient number.

  In addition, in the event of an emergency or when the investigator can not be found, the patient is provided verbal or written information about how to contact the investigator's support, and blinding can be done anytime Guarantee that. Patients whose treatment is unmasked should be discontinued from study treatment.

Trial Completion and Post Trial Treatment Patients are considered to have completed the trial once the last scheduled visit has been completed (see FIGS. 2-5). The entire trial is considered complete when all randomized subjects have completed the last visit scheduled in the protocol or discontinued the trial early. The investigator must provide follow-up care to all subjects who have discontinued early from the trial, or must direct appropriate on-going care to them.

Visit Schedule and Evaluation Figures 2-5 contain all of the clinical study visits and evaluations, and indicate when the evaluation is performed with an "X". The patient must be consulted for all visits on the designated day or as close as possible. An absent or rescheduled visit should not be automatically terminated. Patients who discontinue the trial at any time, for whatever reason, should be scheduled for a visit as soon as possible, at which time all assessments included in the final visit will be conducted. At this final visit, every dispensed test product should be adjusted, adverse events and concomitant medications are adjusted on eCRF. Patients will be contacted for safety assessment during the 30 days following the last dose of study treatment.

Patient Demographics / Other BL Features Demographic data and BL feature data collected for all randomized patients include: Date of birth, age, gender, race, ethnicity, smoking and alcohol history included Includes relevant medical history / current medical condition that existed prior to signing the formed consent. If possible, diagnoses and significant symptoms are recorded. Investigators have the discretion to record abnormal laboratory findings on the medical history eCRF whenever an abnormal laboratory test occurs prior to an informed consent document (ICF) signature at their discretion.

Treatment Exposure and Compliance Compliance is assessed at each visit by investigators and / or investigators using pill counts and information provided by the patient. This information is stored in the source material at each visit. All investigational treatments distributed and returned must be recorded in the investigational drug management record. Institutions are also required to complete an appropriate dose management record eCRF that records any investigational drug regimen changes or withdrawals.

Efficacy Weight and Height Weight is measured at the calibration scale to the nearest 0.1 kg at the visits shown in FIGS. The measurement is performed on a trial patient who took off the shoes and put on the underwear. Urination is required before weight measurement. Height is measured at Visit 1 and used to calculate BMI automatically.

NT-proBNP
NT-proBNP is measured from blood samples obtained after an overnight fast (at least 8 hours after last dinner) at the visits shown in FIGS. 2-5 and analyzed in the central laboratory. NT-proBNP measured at Visit 1 is used to evaluate inclusion criteria and is not masked. The results of all other NT-proBNP measurements remain masked until the final database lock, except that the results are drawn to the restricted area for the statistics / programming team to perform the analysis at 12 database locks per week.

Body Composition Body composition is all used using bioimpedance at the visits shown in Figure 2, except for patients who are contraindicated, for example, those using an implantable defibrillator. Measured in patients. In approximately 25% of the patients at participating institutions, DXA scans are performed at the visits shown in FIGS. Whole body DXA scans are obtained to assess body composition (fat free mass, body fat mass, visceral fat mass, body water (by calculation)); additionally, bone density (BMD) is assessed. The test takes approximately 10-15 minutes and is not invasive. In order to guarantee quality throughout the trial, DXA equipment manufacturers and models are consistent at the facility and their calibration should be monitored. The use of standardized scan acquisition protocols and appropriate and unaltered scan acquisition and analysis software is essential to achieve consistent results. Centralized scan analysis is performed by experienced staff to reduce variability in scan interpretation. DXA is performed according to the procedure described in the image processing manual. Prior to testing, patients are checked for the absence of removable metallic objects on the body such as clasps, belts, underwire bras, jewelry, etc. Next, the patient is positioned so that the body is straight on the mat, and facility personnel must ensure that positioning is consistent from scan to scan. Next, a whole body array scan is initiated on the patient. Immediately after a full body scan, a DXA scan is acquired to measure lumbar spine, hip and / or distal forearm bone density. DXA data is transferred to a central reading vendor for independent review and analysis.

HF Signs and Symptoms HF signs and symptoms are reviewed at the visits shown in FIGS. Signs and symptom evaluations include paroxysmal nocturnal dyspnea, fatigue, edema, dyspnea at rest, dyspnea on exertion, orthopnea, rales, jugular venous distention, and the presence of a third heart sound. May be included. The NYHA classification will be assessed and scored at each visit, and the results will be entered into the appropriate eCRF.

Echocardiography Echocardiography is performed at the visits shown in FIGS. A subset of standard echocardiography 2D and Doppler studies is performed. Images are sent to a central reading vendor for independent review and analysis. Echocardiographic manuals with detailed instructions and data transfer procedures are provided to the study site. Echocardiographic evaluations as follows: ventricular ejection fraction (LVEF); left ventricular end-systolic volume (LESV); left ventricular end-diastolic volume (LEDV); left atrial size and volume; tricuspid regurgitation (TR) rate; left ventricular volume Mitral valve inflow pulse wave Doppler (E wave, A wave); and isovolumetric relaxation time (IVRT) are performed.

HbA1c
HbA1c is measured from blood samples obtained at the visits shown in FIGS. 2-5 and analyzed in the central laboratory using the National Glycohemoglobin Standardization Program (NGSP) certification method.

FPG
FPG is measured from blood samples obtained after an overnight fast (at least 8 hours after the last dinner) at the visits shown in Figures 2 to 5 and analyzed in the central laboratory.

Blood pressure (BP)
Arterial BP, pulse rate readings and signs and symptoms of rising effects are assessed using an automated electronic BP device available at the study site. Three sitting BP measurements and one standing BP measurement are performed at the visits shown in FIGS. At each visit, every effort should be made to have the same staff member obtain BP measurements for a given patient using the same equipment at the same time of day. Sitting BP and standing measurements should be performed prior to any procedure (eg, blood collection) or taking medication. At Visit 1 (screening), BP must be measured on both arms. The arm showing the higher SBP reading should be used for BP measurement at Visit 1, and the same arm should be used at all subsequent visits. The arms used at each visit must be recorded in the source material. Patients should be in a relaxed atmosphere and measurements should not be taken immediately after moving the body or drinking coffee. At each trial visit, SBP and DBP are measured three times using an automatic BP monitor and an appropriately sized cuff after the patient is on his back and both feet are on the floor and sitting for 5 minutes. The cuff bladder should be sized to surround 80% of the arms. The cuff should be placed so that its bottom is 1 to 2 cm above the elbow, and the arms should be supported so that the bottom of the cuff is at the level of the heart. The tube should go down the center of the arm and be roughly along the middle finger. The patient is told to lift the arm and turn the palm up. Patients should not talk or move their arms while deflating the cuff for measurement. Three separate seatings BP are taken between the full two minute interval measurements and the cuff is obtained with the air completely removed between measurements. Next, the patient stands up, stands for 2 minutes, and then performs one BP measurement. All three sitting BP measurements and one standing measurement are recorded and recorded in the eCRF and in the patient's source material. All three Seated BO readings are used to assess sitting BP.

Fasting Lipid Profiles The fasting lipid profiles and TGs described in Table 3 are measured in blood samples obtained after an overnight fast at the visit shown in FIGS. 2-5 and analyzed in the central laboratory.

Twenty-four hour urine collection UGE, albumin, creatinine and sodium excretion are measured from a twenty-four hour urine collection from approximately 25% of patients randomized at the visit shown in FIGS. 2-5 and analyzed in the central laboratory. UGE results after baseline assessment are kept blinded until final analysis, but the results are drawn to a restricted area for the statistics / programming team to perform analysis at 12 database locks per week. Bone biomarkers (urine and calcium excretion) and kidney biomarkers (cystatin C / creatinine ratio) are measured from the same urine collection. Detailed instructions for urine collection are provided to the patient, and handling of urine samples is described in the laboratory manual. Twenty-four hour urine collection is performed by the patient at home, so no overnight stay at the facility is required.

Validity of efficacy evaluation N-terminal pro-brain natriuretic peptide (NT-proBNP) is a stable, biologically inactive fragment that is cleaved from proBNP along with BNP. NT-proBNP is a marker of left ventricular wall stress. In patients with HF, elevated NT-proBNP levels were associated with adverse events, and decreased NT-proBNP levels were associated with better outcomes (Masson et al. 2006; Komajda et al 2011).

  Echocardiography, body weight and body composition, BP and fasting lipids are standard measures to evaluate the efficacy of drugs used in HF patients. HbA1c and FPG give information about the glucose lowering effect of the drug. UGE measurements allow an assessment of the contribution of LIK066's primary mechanism of action to glycemic control and potential improvement of HF parameters.

Data collection Trials are conducted with a well-validated data collection system in accordance with Federal Regulations Chapter 21 Article 11. Study site staff can not access this system until after training. The designated clinical trial staff inputs the data required by the protocol into the data collection system. An automated verification program within the system examines data discrepancies in the eCRE and allows the trial staff to confirm or correct the data by generating appropriate error messages. The trial staff must ensure that the data entered is complete and accurate. After the database lock, the investigator receives a copy of the patient data for recording at the study site.

  The designated clinical trial staff inputs the data required by the protocol into the OC / RDC system. Designated laboratory staff can not access this system until after training. An autoverification program within the system checks for data discrepancies during and after data entry, and allows designated clinical site staff to review or correct data online by creating appropriate error messages. The investigator should ensure that the data entered into the eCRF is complete and accurate. After the database lock, the investigator receives a copy of the patient data for recording at the study site.

Database management and quality control Novartis staff (or CRO acting on behalf of Novartis) review data entered into eCRF by clinical trial staff for completeness and accuracy and add any necessary corrections or additions to facility personnel To teach. Queries are sent to the trial site using electronic data queries. Designated study center staff will respond to inquiries to verify or correct data. If electronic data queries are not used, a paper data query form is faxed to the facility. Facility personnel fill out and sign the copy sent by fax, and send it back to Novartis staff via fax, and the staff corrects the database. A signed copy of the data inquiry form will be stored at the study site.

  Combination medications entered into the database are encoded using the World Health Organization (WHO) Essential Medicines List, which uses the Anatomical Therapeutic Chemistry (ATC) classification. Combination procedures, non-drug therapies and adverse events are encoded using Pharmaceutical Regulatory Glossary (MedDRA) terminology.

  Laboratory samples are centrally processed and the results are electronically sent to Novartis (or designated CRO). ECG, echocardiography and DXA assessments are processed centrally and the results are sent electronically to Novartis (or designated CRO).

  Patients using e-PRO enter their PRO data on a facility-based tablet. The system is supplied by the manufacturer and maintains a database. The database is electronically sent to Novartis personnel (or designated CROs). If the electronic PRO is not available, the patient writes on a paper PRO.

  Randomization codes and data for all study drug (s) and all dose changes distributed to patients are tracked using interactive automatic response technology (IRT). The system is supplied by the manufacturer and maintains a database. The database is electronically sent to Novartis (or a designated CRO).

  Every occurrence of code disclosure via IRT is reported to the clinical team and monitor. The code disclosure feature is still available until the trial is closed or at the request of Novartis. The occurrence of associated protocol deviations is determined. After these actions are complete and the database is declared complete and accurate, the database is locked and the treatment code is unblinded and available for data analysis. No later changes to the database can only be made after the written consent of Novartis Development Management.

Data analysis Primary analysis is performed at the end of Epoch 3 when all patients complete their treatment and evaluation with Epoch 3, data collected up to and including Week 12 (visit 301) is deleted (Called “Week 12 Analysis” in the lower section). The trial remains blinded. The data collected during the epoch 4 is analyzed based on secondary objectives that require data collection past week 12 to capture the results of the week 12 analysis. The analysis performed after the end of the trial is referred to as "termination of trial analysis" in the lower section. At both Week 12 and at the end of the clinical analysis, treatment groups refer to LIK066 2.5 mg qd, LIK066 10 mg qd, LIK 066 50 mg qd, empagliflozin 25 mg qd and placebo qd, unless otherwise specified.

Analysis Set The following analysis groups are defined for statistical analysis. These analysis sets are a subset of the patients who signed informed consent at Visit 1.

Screening Set (SCR)-All patients who have signed informed consent. The SCRs include only unique screened patients, ie, for rescreened subjects, only the last screening data is counted over time.

Randomized Set (RAN)-All patients who received a randomized number, regardless of whether they received study medication.

Safety set (SAF) (double-blind phase)-All patients who received at least one dose of double-blind investigational drug. Patients are analyzed according to the treatment received. The treatment received is considered identical to the randomized treatment if the patient has received at least one dose of randomized treatment.

Complete Analysis Set (FAS)-All patients in RAN incorrectly randomized. Patients are analyzed according to the treatment assigned at randomization according to the Intention to Care (ITT) principle. Incorrectly randomized patients are those who did not qualify for randomization and who were inadvertently randomized to the trial but did not receive double-blind investigational drugs. Patients who were incorrectly randomized were given IRT contact prematurely or improperly by the center before ascertaining their final randomization eligibility and double-blind drug therapy was not administered to patients It is defined as a case. These patients were subsequently discontinued from the trial.

Per Protocol Set (PPS)-All patients in FAS who received at least one dose of study drug and did not have significant protocol deviations.

  Critical protocol deviations are deviations that affect the primary endpoint analysis and are pre-defined prior to the blinded treatment code for analysis. A list is provided for the Clinical Study Report Statistical Analysis Plan.

Patient Demographics and Other Baseline Features For demographic and baseline features, gender, age, race, weight, height, obesity (BMI), systolic blood pressure, relaxation blood pressure, eGFR, LVEF, Summary statistics are provided by the treatment group including the LVEF group (<45% vs. 4545%), geographic area, NYHA classification and medical history. These summaries are implemented for the FAS. Continuous variables are summarized using n, mean, standard deviation (SD), median, Q1 (25th percentile), Q3 (75th percentile), minimum value, and maximum value. Categorical variables are summarized using frequencies and percentages.

Week 12 analysis The duration of double-blind treatment exposure of Epoch 3 is summarized descriptively by treatment group for SAF (n, mean, standard deviation, median, Q1, Q3, minimum and maximum values are used ). In addition, the number and percentage of patients are summarized by treatment group for time category. Combination drug therapy and previous serious non-drug therapies are summarized in separate tables by treatment groups for drug class, preferred term and safety group. The number and percentage of patients who met rescue criteria during Epoch 3 and took rescue medications and the duration of exposure to rescue medications are summarized by treatment group for SAF. The use of prohibited medications, if any, is also summarized.

End of Trial Analysis The analysis for the end of trial analysis is similar to the analysis performed for the Week 12 analysis above. However, a summary of treatment is provided during the entire study treatment period: Epoch 3 + Epoch 4.

Analysis of Major Variable (s) In general, NT-proBNP data follow a lognormal distribution. Thus, log conversion on NT-proBNP data is performed before all statistical analysis is performed. The analysis results are then inverse transformed and displayed as a percentage to facilitate data interpretation.

Variable (s)
The primary efficacy variable is the log conversion ratio of NT-proBNP (pg / mL) to BL collected at week 12 (ie, the change from BL of log converted NT-proBNP at week 12). Missing Week 12 values are complemented using a multiple completion approach.

Statistical Models, Hypotheses, and Analysis Methods The purpose of determining the dose response signal and dose response relationship at LIK 066 dose compared to placebo is described by the multiple comparison procedure modeling described in Pinheiro et al, 2006 & Pinheiro et al, 2014 (MCP -Evaluated using the MOD) method.

Testing of Dose Response Signals The null hypothesis of a flat dose response relationship for the reduction of NT-proBNP compared to placebo was tested at one-sided significance level of 2.5% against the alternative hypothesis of dose response relationship, 12 weeks Results in a significant reduction of NT-proBNP after treatment of

  Thus, the following null and alternative hypotheses are tested. H01: There is no dose-response or response in the wrong direction for LIK 066 after 12 weeks of treatment (ie the dose-response relationship is flat or as the dose increases, the decrease of NT-proBNP from baseline is H11: There is a dose response in the right direction for LIK 066 after 12 weeks of treatment (ie, the dose increases, the decrease in NT-proBNP from baseline increases).

  There are six candidate models that capture the shape of the dose response relationship for LIK 066 at Week 12 endpoint. The candidate model creates a set of six contrasts evaluated using data to test the dose response hypothesis above: Model 1: ED50 Emax at 3 mg: Model 2: ED50 Emax at 10 mg Model 3: ED50 Emax at 25 mg; Model 4: Linear: ED50 S-shaped Emax at model 5, 15 mg and Hill parameter h = 2; and S: ED50 at model 6: 25 mg and Hill parameter h = 3 Shape Emax.

  Analysis to derive test statistics: NT-proBNP (pg / mL) versus baseline as response variable, treatment as factor (brasevo and all LIK 066 doses), stratification variables, geographical area and LVEF (weeks 12) Based on analysis of the covariance (ANCOVA) model using <45% vs. 4545% at visit 101, as well as a baseline log conversion ratio in log-transformed NT-proBNP as covariate. Where necessary, facilities are pooled according to country and region for analysis purposes.

  Response variables for the baseline log-transformed ratio used in NTOC-ProBNP (pg / mL) vs. ANCOVA at Week 12 are derived from the complementation data set and missing for Week 12 NT- proBNP is complemented using multiple complementation schemes. To account for the complementation uncertainty, this ANCOVA model is repeated for each complementation data set, which yields a set of least squares (LS) mean estimates and associated covariance matrices for all dose groups. Covariance matrix associated with multiple sets of LS mean estimates using rubin rule, single week of log conversion ratio of NT-proBNP (pg / mL) versus baseline for all dose groups at 12 Combine to the set of LS mean estimates and the associated covariance matrix.

  The optimal contrast from the candidate model set is applied to the combined estimated dose average and covariance matrix to obtain t statistics and common critical value C 0.025 for each candidate model. C 0.025 is the common critical value derived from the reference multivariate t distribution, and a 6 × 6 correlation matrix is derived by testing the candidate dose response model for comparing all LIK doses with the placebo group. H01 will be rejected and statistical significance of dose response with NT-proBNP reduction will be established if maximal (t1, t2, t3 ... t6) C C0.025.

Model Averaging to Obtain Dose Response Response data in each complementary data set, including associated covariates, are used for model fitting in the candidate set. The estimated dose response is derived by using the model averaging method on a subset of candidate models for which the accompanying contrast test is statistically significant. If there are more than three candidate models that are statistically significant, then the top three models with the largest t statistic calculated above are selected as the basis for model averaging.

  Model averaging is performed for each complementary data set, and the resulting mean efficacy estimates and confidence intervals are derived using combinatorial variance, which describes the uncertainty of the complementary data using a combination rule of Rubin. The comparison between LIK 066 dose and placebo is simultaneously derived for the model averaged estimates together with a confidence interval that reflects the applied extrapolation process. A model-averaged-based estimate of the mean change of log-transformed NT-proBNP within each dose group implies the difference between LIK 066 and placebo, then its confidence interval is inversely transformed to NT at week 12 -Expressed as the ratio of the geometric mean of proBNP to the baseline within the dose group and the relative ratio of these ratios between LIK066 and placebo. Targeted dose selection is based on model averaged dose response estimates of the mean NT-proBNP reducing efficacy of LIK066 across the dose range studied in this study.

Handling Missing Values / Cut-offs / Abortions Missing values at the primary endpoint are complemented using a multiple-complement approach that assumes that missing mechanisms are recovered from observed data (randomly missing (MAR)) . Complement models include baseline, longitudinal alignment of NT-proBNP data collected at Week 4 and Week 12 visits, stratification factor geographic area at Visit 101, and LVEF (<45% vs. 4545%), As well as other baseline covariates (eg, NYHA classification, age, gender, race).

Assisted Analysis As sensitivity analysis, dose response modeling is performed on PPS. Results based on single best dose response model fit are also reported. Summary statistics of NT-proBNP are represented by visits (up to and including Week 12 visits) and treatment for observed and complemented values. Summary statistics (n, mean, standard deviation (SD), and median, Q1, Q3, minimum and maximum) are represented by visits and treatments for NT-proBNP and changes from NT-proBNP's BL . Figures are generated to visually show raw and complemented mean changes by 12 weeks of epoch 3 visits by treatment group and by LVEF group (<45% vs. 4545% at V101) for all patients Be done.

  In addition, summary statistics for NT-proBNP can be obtained from visits (up to and including 12 visits per week) and treatments for observed and complemented values, with the following subgroups: LVEF at visit 101 <45 % Vs. 45 45%; NYHA classification at baseline: II vs. III and IV; HbA1c at baseline: <8% vs. 8 8%; and NT-proBNP at baseline: <median vs. 中央 median expressed.

Efficacy variables Comparison of LIK 066 dose versus placebo and LIK 066 dose versus empagliflozin (EMPA) at week 12 and week 36: change from BL of HbA1c; change from BL of FPG; change from BL of SBP and DBP Changes in body weight from BL; changes in body composition from BL (evaluated by bioimpedance); changes in body composition from BL (evaluated by DXA in a subset of patients); fasting lipid profile (TG, Total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, percentage change from BL of lipoproteins (apolipoprotein A-1, apolipoprotein B)); change of log transformed hs-CRP from BL; 24 Hourly sugar and Changes from thorium excretion BL (subset of patients). Comparison of LIK 066 dose vs placebo at week 12 and week 36; change from BL of left atrial size and volume as assessed by echocardiography; and change from BL of NYHA classification. Comparison of LIK 066 dose vs placebo at week 36; change from BL of log transformed NT-proBNP.

Analysis of the change from BL of log transformed NT-proBNP at week 36 Using the same dose response modeling approach using MCP-Mod at the primary endpoint of the change from BL of NT-proBNP at week 12 Dose response is assessed in NT-proBNP changes at BL up to week 36 for LIK066 dose compared to placebo. Summary statistics of NT-proBNP are represented by visits and treatments for observed and complemented values throughout the study period. Summary statistics (n, mean, standard deviation (SD), median, Q1, Q3, minimum and maximum) are BL values in NT-proBNP, visits and treatments for changes from post-BL values and BL values expressed. The figures are generated to visually show the raw and complemented mean changes by treatment group visits and by LVEF groups (<45% vs. 4545% at V101) for all patients.

Analysis of Other Continuous Outcome Variables The following continuous variables are analyzed using the methods described in this section: Changes from BL of HbA1c at Weeks 12 and 36; FPG at Weeks 12 and 36 Change from BL; change from SBP and DBP from BL at week 12 and week 36; change from body weight at week 12 and week 36 from BL; change from body composition at BL 12 and week 36 (from BL As assessed by bioelectrical impedance; fasting lipid profile at 12 and 36 weeks (TG, total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, lipoprotein (apolipoprotein A-1, apolipoprotein B) Percentage change from BL); Logarithmic conversion at week 12 and week 36 Changes from BL of hs-CRP from BL; Changes from BL of 24 h glucose intake and sodium excretion (subset of patients); Changes from BL of left atrial size and volume assessed by echocardiography at week 12 and week 36 .

  The change from baseline in continuous outcomes at week 12 (or week 36) is analyzed using the repeated measures mixed effects model (MMRM), where the stratification variables (geographical region and LVEF at V101 < 45% vs. 4545%), treatment groups, visits, and treatment interactions with visits are included as fixed effect factors, and baseline outcome variables have a common amorphous covariance matrix common to all treatment groups It will be included as a co-variable. Analysis is based on changes from baseline in outcome variables at all post-baseline planned visits to week 12 (or week 36) and to likelihood methods using MAR's assumption for missing data It will be implemented on the basis of Based on the MMRM model, estimates and 95% confidence intervals are to the adjusted mean of change from baseline for outcome variables at week 12 (or 36) per treatment group and at week 12 (or 36) It is given to the adjusted average difference.

  In outcome variables, the treatment effect (average difference) of LIK066 dose vs placebo or LIK066 dose vs empagliflozin for all treatment groups: LIK066 2.5 mg qd, LIK 066 10 mg qd, LIK 066 50 mg qd, empagliflozin 25 mg qd and placebo Analyzed using the above MMRM model including qd. LIK 066 dose vs placebo comparisons show the therapeutic effect of LIK 066 2.5 mg qd vs placebo qd, LIK 066 10 mg qd vs placebo qd and LIK 066 50 mg qd vs placebo qd; in comparison of LIK 066 dose vs EMPA, LIK 066 2.5 mg qd Anti-Epagliflozin 25 mg qd, LIK 066 10 mg qd versus Empagliflozin 25 mg qd and LIK 066 50 mg qd to Empagliflozin 25 mg qd The therapeutic effect is presented. In addition, summary statistics (n, mean, SD, median, Q1, Q3, minimum and maximum, and geometric mean of log transformed variables) for these variables are presented by visit and treatment.

Analysis of Ordered Outcome Variables The change from NYHA classification BL at a given visit is defined as follows: Improved if NYHA classification is reduced by at least one level from BL; If the NYHA classification has not changed from BL, no change; Three categorical order variables (improved / no change / exacerbated) with the NYHA classification being at least one level increased from BL, worse. NYHA classification changes from BL at week 12 (or week 36) are analyzed using the repeated measures proportional odds cumulative logit model, in which stratification factors (LVEF <45% vs geographic area and V101 vs. V 101 ≧ 45%), treatment groups, visits, and interactions between treatment groups and visits are included as fixed effect factors, baseline NYHA classification is included as a covariate, and patients are included as random effects. Analysis based on changes from NYHA classification baseline at all post-baseline planned visits to week 12 (or week 36) and to likelihood methods using MAR's assumption for missing data It will be implemented on the basis of Based on the longitudinal proportional odds cumulative logit model, estimates and 95% confidence intervals are given for adjusted odds ratios at week 12 (or week 36).

  The treatment effect (odds ratio) of LIK 066 dose versus placebo was calculated for all treatment groups: LIK066 2.5 mg qd, LIK 066 10 mg qd, LIK 066 50 mg qd, empagliflozin 25 mg qd and placebo qd above for repeated measures proportional odds cumulative logit It is analyzed using a model. The LIK 066 dose vs. placebo comparison presents the therapeutic effect of LIK 066 2.5 mg qd vs. placebo qd, LIK 066 10 mg qd vs. placebo qd and LIK 066 50 mg qd vs. placebo qd. In addition, the NYHA classification will be summarized by visit and treatment group using frequencies and percentages. A shift table is provided to summarize NYHA classifications that move from BL to week 12 (or week 36) for weekly 12 analysis (or at the end of clinical analysis).

Pharmacokinetics A list of PK concentrations is provided. Summary statistics of PK concentrations are provided where possible. Concentrations below the lower limit of the quantification range (LLOQ) are treated as zero in summary statistics of concentration data.

PK / PD
Investigate the feasibility of PK / PD analysis separately from clinical trials.

Analysis of exploratory variables Exploratory variables are analyzed in FAS. Hypothetical statistical tests for exploratory endpoints are performed at the two-sided 0.05 significance level without multiplicity adjustment.

Variables Comparison of LIK 066 dose versus placebo and LIK 066 dose versus EMPA at week 12 and week 36: change from BL of echocardiographic parameters other than left atrial size and volume; change from BL of quality of life (clinical from KCCQ Summary score, total symptom score and general summary score; Descriptive system from EQ-5D-5L and VAS; SF-36 total score; and assessed by PROMIS and PGIS status for physical function). Comparison of LIK 066 dose versus EMPA at week 12 and week 36: change from BL of log transformed NT-proBNP; change from BL of left atrial size and volume assessed by echocardiography; and from BL of NYHA classification change.

Analysis Methods Exploratory variables are analyzed according to the methods described in Analysis Methods. The MMRM model is used for continuous outcome variables, and the repeated measures proportional odds cumulative logit model is used for ordered outcomes.

Analysis of the change from BL of log transformed NT-proBNP at week 12 and week 36 The change from BL of log transformed NT-proBNP at week 12 and week 36 is analyzed using the MMRM method. The MMRM model uses stratification variables (LVEF <45% vs. 45 45% at geographic area and V101), treatment groups, visits, and interactions with treatment groups as fixed effect factors, and baseline log The transformed NY-proBNP will be included as covariates with a common amorphous covariance matrix for all treatment groups. The analysis is performed based on the change from baseline of log transformed NY-proBNP at all post-baseline planned visits up to week 12 (or week 26). Based on the MMRM model, estimates and 95% confidence intervals correspond to the adjusted mean of change from baseline in log-transformed NY-proBNP at week 12 (or week 36) by treatment group and week 12 (or week 36). It is given to the adjusted average difference in).

  The treatment effect (average difference) of LIK066 dose versus EMPA using the above MMRM model, including all treatment groups: LIK066 2.5mg qd, LIK066 10mg qd, LIK066 50mg qd, empagliflozin 25mg qd and placebo qd It is analyzed. A comparison of LIK 066 dose versus EMPA presents the therapeutic effect of LIK 066 2.5 mg qd versus empagliflozin 25 mg qd, LIK 066 10 mg qd versus empagliflozin 25 mg qd and LIK 066 50 mg qd versus empagliflozin 25 mg qd. Analysis results are inversely transformed and displayed as a percentage representing ease of data interpretation.

Analysis of changes from BL of echocardiography parameters at week 12 and week 36 Changes from echocardiographic parameters BL at week 12 and week 36 are analyzed using the MMRM method. The treatment effect (average difference) of LIK 066 dose vs. EMPA or LIK 066 vs placebo for all treatment groups: The above MMRM model including LIK 066 2.5 mg qd, LIK 066 10 mg qd, LIK 066 50 mg qd, empagliflozin 25 mg qd and placebo qd Parsed using. The LIK 066 dose vs. placebo comparison presents the therapeutic effect of LIK 066 2.5 mg qd vs. placebo qd, LIK 066 10 mg qd vs. placebo qd and LIK 066 50 mg qd vs. placebo qd. A comparison of LIK 066 dose versus EMPA presents the therapeutic effect of LIK 066 2.5 mg qd versus empagliflozin 25 mg qd, LIK 066 10 mg qd versus empagliflozin 25 mg qd and LIK 066 50 mg qd versus empagliflozin 25 mg qd.

Analysis of the change from BL of NYHA classification at week 12 and week 36 The treatment effect (odds ratio) of LIK066 dose vs. EMPA, all treatment groups: LIK066 2.5 mg qd, LIK066 10 mg qd, LIK 066 50 mg qd, empaglyph Analyzed using the same repeated measures proportional odds cumulative logit model, with 25 mg rosin and qd placebo. A comparison of LIK 066 dose versus EMPA presents the therapeutic effect of LIK 066 2.5 mg qd versus empagliflozin 25 mg qd, LIK 066 10 mg qd versus empagliflozin 25 mg qd and LIK 066 50 mg qd versus empagliflozin 25 mg qd.

Analysis of change from life quality BL at week 12 and week 36: Quality of life assessment from KCCQ: clinical summary score, total symptom score and general summary score, EQ VAS (from EQ-5D-5L), The PROMIS and SF-36 total scores for physical function are continuous variables. Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum) are the values at each visit for these continuous variables as well as changes from baseline values (week 12) Or for up to 36 weeks) by visit and treatment group. The following quality of life assessments: PGIS status and EQ-5D-5L description scheme are ordinal variables. These variables are summarized by visit and treatment group using frequencies and percentages. A shift table is also provided to summarize the endpoints moving from BL to week 12 (or week 36) for weekly 12 analysis (or the end of trial analysis).

Regulatory and ethical compliance This clinical study is based on the Harmonized Tripartite Guidelines for Good Clinical Practice of the ICH for conducting clinical trials of pharmaceuticals, applicable local regulations (European Directive 2001/20 / EC, US CFR21, And the Japanese Ministry of Health, Labor and Welfare, and the Helsinki Declaration, and is designed, implemented, implemented and reported in accordance with the ethical principles set forth in the Declaration of Helsinki.

References
Bailey CJ, Gross JL, Pieters A, et al (2010) Effect of dapagliflozin in patients with type 2 antibiotics who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet; 375: 2223-33 .

Chun S, Tu J, Wijeysundera H et al, (2012). Lifetime analysis of hospitalizations and survival of patients newly adopted with heart failure. Circ Heart Fail; 5: 414-421.

Ferrannini E, Mark M et Mayoux E (2016) CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care DOI: 10.2337 / dc16-0330; published ahead of print.

Eur Heart J; doi: 10.1093 / eurheartj / ehv728 Fitchett D, Zinman B, Wanner C et al, (2016) Heart failure outcomes with empagliflozin in patients with types 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. (published ahead of print).

Green CP, Porter CB, Bresnahan DR, Spertus JA (2000). Development and evaluation of the City of Cardiomyopathy questionnaire: a new health status measure for heart failure. Journal of the American College of Cardiology; 35 (5): 1245-55 .

Herdman M, et al (2011) Development and preliminary testing of the new five-level version of the EQ-5D (EQ-5D-5L). Qual Life Res; 20 (10): 1727-1736.

Kazsnick J, Drzewoski M (2014) Heart failure in the diabetic population-pathophysiology, diagnosis and management. Arch Med Sci; 10, 3: 546-556.

Circe Heart Fail; Koarjda M, Carson PE, Hetzel S, et al (2011) Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). 27-35.

Masson S, Latini R, Anand IS, et al. (2006). Direct Comparison of B-Type Natriuertic Peptide (BNP) and Amino-Terminal proBNP in a Large Population of Patients with Chronic and Symptomatic Heart Failure: The Valsartan Heart Failure ( Val-HeFT) Data. Clinical Chemistry; 52: 1528-1538.

Nauck MA, Del Prato S, Meier JJ, et al (2011) Dapagliflozin vs glipizide as add-on therapy with patients 2 types of diabetes who have inadequate glycemic control with metformin. Diabetes Care; 34 (9): 2015-22.

Nichols GA, Gullion CM, Koro CE et al, (2004). The incidence of congestive heart failure in
Type 2 Diabetes. Diabetes Care 27: 1879-1884.

Nyirjesy P, Zhao Y, Ways K, et al (2012) Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. ): 1173-8.
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies combining multiple comparisons and modeling procedures. Journal of Biopharmaceutical Statistics; 16: 639-56.

Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model uncertainty using general parametric models. Statistics in Medicine; 33: 1646-661
Rosenstock J and Ele Ferrannini (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabete Care; 38: 1638-1642.

Sattar N, McLaren J, Kristensen S et al, 2016 SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia; 59: 1333-1339.

Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor LCZ 696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet; 380: 1387-95.

Solomon SD, Claggett B, Desai AS, et al (2016) Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril / Valsartan (LCZ 696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality Circ. Heart Fail; 9: e002744. doi: 10.1161 (published ahead of print). and Morbidity in Heart Failure (PARADIGM-HF) Trial.

Stabin M (2016) RADAR medical procedure radiation dose calculator and consent language generator (Internet) Accessed 10 Oct 2016. Available from: http: //www.doseinfo- radar.com/RADARDoseRiskCalc.html.
Taegtmeyer H, McNulty P, Young M (2002) Adaptation and maladaptation of the heart in diabetes. Circulation; 105: 1727-1733

Turk E, Zabel B, Mundlos S, Dyer J, et al (1991) Glucose / galactose malabsorption caused by a defect in the Na / glucose cotransporter. Nature; 350: 354-356

van Reenen et Janssen, April 2015. EQ-5D-5L Userguide, Version 2.1 http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
5L_UserGuide_2015.pdf.

Ware J, Sherbourne C (1992). The MOS 36-Item Short-Form Health Survey (SF-36): Conceptual framework and item selection. Medical Care, 30 (6): 473-483.

Yancy CW, Jessup M, Bozkurt B et al, (2013) 2013 ACCF / AHA Guideline for the Management of Heart Failure: Executive Summary. Circulation; 128: 1810-1852.

Zinman B, Wanner C, Lachin JM, et al, (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM; 373: 2117-28.

References
Bailey CJ, Gross JL, Pieters A, et al (2010) Effect of dapagliflozin in patients with type 2 antibiotics who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet; 375: 2223-33 .

Chun S, Tu J, Wijeysundera H et al, (2012). Lifetime analysis of hospitalizations and survival of patients newly adopted with heart failure. Circ Heart Fail; 5: 414-421.

Ferrannini E, Mark M et Mayoux E (2016) CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care DOI: 10.2337 / dc16-0330; published ahead of print.

Eur Heart J; doi: 10.1093 / eurheartj / ehv728 Fitchett D, Zinman B, Wanner C et al, (2016) Heart failure outcomes with empagliflozin in patients with types 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. (published ahead of print).

Green CP, Porter CB, Bresnahan DR, Spertus JA (2000). Development and evaluation of the City of Cardiomyopathy questionnaire: a new health status measure for heart failure. Journal of the American College of Cardiology; 35 (5): 1245-55 .

Herdman M, et al (2011) Development and preliminary testing of the new five-level version of the EQ-5D (EQ-5D-5L). Qual Life Res; 20 (10): 1727-1736.

Kazsnick J, Drzewoski M (2014) Heart failure in the diabetic population-pathophysiology, diagnosis and management. Arch Med Sci; 10, 3: 546-556.

Circe Heart Fail; Koarjda M, Carson PE, Hetzel S, et al (2011) Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). 27-35.

Masson S, Latini R, Anand IS, et al. (2006). Direct Comparison of B-Type Natriuertic Peptide (BNP) and Amino-Terminal proBNP in a Large Population of Patients with Chronic and Symptomatic Heart Failure: The Valsartan Heart Failure ( Val-HeFT) Data. Clinical Chemistry; 52: 1528-1538.

Nauck MA, Del Prato S, Meier JJ, et al (2011) Dapagliflozin vs glipizide as add-on therapy with patients 2 types of diabetes who have inadequate glycemic control with metformin. Diabetes Care; 34 (9): 2015-22.

Nichols GA, Gullion CM, Koro CE et al, (2004). The incidence of congestive heart failure in
Type 2 Diabetes. Diabetes Care 27: 1879-1884.

Nyirjesy P, Zhao Y, Ways K, et al (2012) Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. ): 1173-8.
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies combining multiple comparisons and modeling procedures. Journal of Biopharmaceutical Statistics; 16: 639-56.

Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model uncertainty using general parametric models. Statistics in Medicine; 33: 1646-661
Rosenstock J and Ele Ferrannini (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabete Care; 38: 1638-1642.

Sattar N, McLaren J, Kristensen S et al, 2016 SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia; 59: 1333-1339.

Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor LCZ 696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet; 380: 1387-95.

Solomon SD, Claggett B, Desai AS, et al (2016) Influence of Ejection Fraction on Outcomes and Efficiency of Sacubitril / Valsartan (LCZ 696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality Circ. Heart Fail; 9: e002744. doi: 10.1161 (published ahead of print). and Morbidity in Heart Failure (PARADIGM-HF) Trial.

Stabin M (2016) RADAR medical procedure radiation dose calculator and consent language generator (Internet) Accessed 10 Oct 2016. Available from: http: //www.doseinfo- radar.com/RADARDoseRiskCalc.html.
Taegtmeyer H, McNulty P, Young M (2002) Adaptation and maladaptation of the heart in diabetes. Circulation; 105: 1727-1733

Turk E, Zabel B, Mundlos S, Dyer J, et al (1991) Glucose / galactose malabsorption caused by a defect in the Na / glucose cotransporter. Nature; 350: 354-356

van Reenen et Janssen, April 2015. EQ-5D-5L Userguide, Version 2.1 http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
5L_UserGuide_2015.pdf.

Ware J, Sherbourne C (1992). The MOS 36-Item Short-Form Health Survey (SF-36): Conceptual framework and item selection. Medical Care, 30 (6): 473-483.

Yancy CW, Jessup M, Bozkurt B et al, (2013) 2013 ACCF / AHA Guideline for the Management of Heart Failure: Executive Summary. Circulation; 128: 1810-1852.

Zinman B, Wanner C, Lachin JM, et al, (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM; 373: 2117-28.

The present invention includes the following embodiments.
[1] A method for treating or preventing heart failure in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of LIK 066, or a pharmaceutically acceptable salt thereof Method including.
[2] The method according to [1], wherein 2.5 mg of LIK066 is administered.
[3] The method according to [1], wherein 10 mg of LIK066 is administered.
[4] The method according to [1], wherein 50 mg of LIK066 is administered.
[5] The method according to any one of [1] to [4], wherein LIK066 is administered once a day.
[6] The method according to any one of [1] to [5], wherein LIK066 is administered before going to bed.
[7] Compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof for use in the treatment or prevention of heart failure.
[8] A pharmaceutical composition comprising LIK 066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.
[9] Use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the treatment or prevention of heart failure.
[10] Use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for use in the treatment or prevention of heart failure.

Claims (10)

  A method for treating or preventing heart failure in a subject in need of such treatment comprising administering to said subject a therapeutically effective amount of LIK 066, or a pharmaceutically acceptable salt thereof .   The method of claim 1, wherein 2.5 mg of LIK066 is administered.   The method of claim 1 wherein 10 mg of LIK066 is administered.   The method according to claim 1, wherein 50 mg of LIK066 is administered.   5. The method of any one of claims 1 to 4, wherein LIK066 is administered once daily.   6. The method of any one of claims 1 to 5, wherein LIK066 is administered before bedtime.   Compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.   Pharmaceutical composition comprising LIK 066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of heart failure.   Use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the treatment or prevention of heart failure. Use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for use in the treatment or prevention of heart failure.