A Dose Finding Study to Assess the Effect of LIK066 Compared to Placebo or Empagliflozin in Patients With Type 2 Diabetes Mellitus and Heart Failure

Study Overview
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Brief Summary
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This was a dose-finding study to evaluate the efficacy, safety and tolerability of 3 different doses of LIK066 compared to placebo or empagliflozin in T2DM patients with heart failure

Detailed Description
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The study was prematurely discontinued on 04-May-2018 due to slow enrollment that would preclude obtaining study results in a timely manner.

Official Title
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A Multi-center, Randomized, Double-blind, Parallel-group Dose-finding Study to Assess the Effect of 3 Doses of LIK066 Compared to Placebo or Empagliflozin in Type 2 Diabetes Mellitus Patients With Heart Failure

Conditions
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Diabetes Mellitus and Heart Failure

Intervention / Treatment
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* Drug: LIK066
* Drug: Placebo
* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: BMI ≥ 22kg/m^2 Type 2 diabetes with HbA1c between 6.5% and 10.0% Documented symptomatic chronic heart failure (NYHA II-IV) Plasma NT-proBNP > 300pg/ml eGFR ≥ 45ml/min/1.73m^2 (calculated by MDRD) Key Exclusion Criteria: Pregnant or nursing (lactating) women Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes History of ketoacidosis, lactic acidosis, or hyperosmolar coma Symptomatic genital infection or UTI within 4 weeks of screening Myocardial infarction, stroke, surgery for heart disease, percutaneous coronary intervention within 3 months of randomization Unstable angina within 3 months of screening Isolated right HF due to pulmonary disease Patients with a mean sitting systolic blood pressure ≤ 100mmHg, at randomization History of lower limb amputation Diabetic foot ulcer at screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LIK066 2.5mg<br>Eligible participants randomized to this treatment arm received the LIK066 2.5mg dose regimen once daily for 36 weeks. | Drug: LIK066<br>* LIK066 was supplied in different doses as tablets taken orally.<br>|
| Experimental: LIK066 10mg<br>Eligible participants randomized to this treatment arm received the LIK066 10mg dose regimen once daily for 36 weeks. | Drug: LIK066<br>* LIK066 was supplied in different doses as tablets taken orally.<br>|
| Experimental: LIK066 50mg<br>Eligible participants randomized to this treatment arm received the LIK066 50mg dose regimen once daily for 36 weeks. | Drug: LIK066<br>* LIK066 was supplied in different doses as tablets taken orally.<br>|
| Active Comparator: Empagliflozin<br>Participants randomized to this treatment arm received empagliflozin once daily for 36 weeks. | Drug: Empagliflozin<br>* Empagliflozin was supplied as capsules taken orally.<br>|
| Placebo Comparator: Placebo<br>Participants randomized to this treatment arm received LIK066 matching placebo and empagliflozin matching placebo. | Drug: Placebo<br>* Placebo was supplied as tablets and capsules taken orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 12 | Evaluation of NT-proBNP was performed by a central laboratory. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this primary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Weeks 12 and 36 | HbA1c was measured from a blood sample and analyzed using a National Glycohemoglobin Standardization Program (NGSP) certified method at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 36 | FPG was measured from a blood sample after an overnight fast; patients were not allowed to eat or drink anything (except water) for at least 8 h before each study visit. Samples were analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Weight at Weeks 12 and 36 | Body weight was measured to the nearest 0.1 kg on a calibrated scale (weight and bio-impedance measurements), provided by the sponsor. Exceptionally (e.g. if the body weight exceeded the limits of the provided scale) sites were allowed to use another scale for weight measurement as available, but during the study the same scale was to be used for the same patient. The measurement was performed with the study patient in underwear and without shoes. Indoor clothing was also acceptable, but measurements were to be done consistently (either with underwear or with indoor clothing) throughout the study. Voiding before weight measurement was required. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by Bio-impedance (Total Body Fat Mass) at Weeks 12 and 36 | Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by Bio-impedance (Visceral Fat Level) at Weeks 12 and 36 | Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. Visceral fat levels were measured by Omron device. Levels ranged from 1 - 30 and are relative (not absolute) values. The Omron scale values are: 0 - 9 (normal), 10 - 14 (high) and 15 - 30 (very high). Visceral fat area ( 0 - approx. 300cm^2, 1 inch = 2.54 cm) distribution with 30 levels. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by Bio-impedance (Lean Body Mass) at Weeks 12 and 36 | Body composition was measured in all patients using bio-impedance, except in patients where it was contra-indicated, e.g. those using an implantable cardioverter-defibrillator. Body composition parameters were assessed as available for the different models of calibrated bio-impedance scales. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by DXA (Total Body Fat Mass) at Weeks 12 and 36 | A whole body DXA scan was performed to assess Total Body Fat Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by DXA (Visceral Fat Mass) at Weeks 12 and 36 | A whole body DXA scan was performed to assess Visceral Fat Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by DXA (Lean Body Mass) at Weeks 12 and 36 | A whole body DXA scan was performed to assess Lean Body Mass (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Body Composition Assessed by DXA (Total Body Water) at Weeks 12 and 36 | A whole body DXA scan was performed to assess Total Body Water (Whole Body Minus Head Hologic, Whole Body Minus Head Lunar). DXA data were transferred to a central reading vendor for independent review and analysis. Only descriptive statistics done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Sitting Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 12 and 36 | Three sitting BP measurements were performed. At each visit, sitting BP was derived as the mean of three readings of the sitting SBP/DBP at that visit. Pre-planned statistical analyses were not performed for these secondary endpoints due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Fasting Lipid Profile (Triglycerides (TG)) at Weeks 12 and 36 | TG was measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Fasting Lipid Profile (Lipoproteins) at Weeks 12 and 36 | Lipoproteins (High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol) were measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis were not performed for these secondary endpoints due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Fasting Lipid Profile (Total Cholesterol) at Weeks 12 and 36 | Total Cholesterol was measured on blood samples obtained after an overnight fast and analyzed at a central laboratory. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in High Sensitive C-reactive Protein (hsCRP) at Weeks 12 and 36 | hs-CRP is an inflammation biomarker. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in 24 Hour Urinary Glucose Excretion (UGE) at Weeks 12 and 36 | UGE was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive analysis done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in 24 Hour Sodium Excretion at Weeks 12 and 36 | Sodium excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive statistics were done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Left Atrial Size at Weeks 12 and 36 | A limited two-dimensional and Doppler ECHO examination was performed to assess ECHO parameters. The images were sent to a central reading vendor for independent review and analysis. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Left Atrial Volume at Weeks 12 and 36 | A limited two-dimensional and Doppler ECHO examination was performed to assess ECHO parameters. The images were sent to a central reading vendor for independent review and analysis.Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Number of Participants With New York Heart Association (NYHA) Class I, II, II or IV | The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 12, Week 36 | 
| Number of Participants With Change From Baseline in New York Heart Association (NYHA) Class at Week 12 and 36 | The change from BL in NYHA class at a given visit is a three-category ordinal variable (improved/unchanged/worsened) with the following definition: 1. Improved, if NYHA class decreases at least one level from BL; 2. Unchanged, if NYHA class is unchanged from BL; 3. Worsened, if NYHA class increases at least one level from BL. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Week 12, Week 36 | 
| Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 36 | Evaluation of NT-proBNP was performed by a central laboratory. For Change from baseline, Geometric mean is the geometric mean of the endpoint to baseline ratio. Pre-planned statistical analysis was not performed for this secondary endpoint due to early study termination. Only descriptive statistics are presented. | Baseline, Week 36 | 
| Change From Baseline in 24 Hour Urinary Calcium Excretion at Weeks 12 and 36 | Urinary calcium excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive analysis done. | Baseline, Week 12, Week 36 | 
| 24 Hour Urinary Phosphate Excretion at Weeks 12 and 36 | Urinary phosphate excretion was measured from a 24h urine collection from about 25% of randomized patients and analyzed at a central laboratory. Only descriptive statistics were done. | Baseline, Week 12, Week 36 | 
| Change From Baseline in Bone Mineral Density (BMD) at Weeks 12 and 36 | To evaluate bone mineral density as assessed by bone mineral content after 12 weeks and after 36 weeks of treatment. Only descriptive statistics were done. | Baseline, Week 12, Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes mellitus, LIK066, Obesity, Type 2 diabetes mellitus (T2DM), Heart Failure (HF), Hypertension, Renal dysfunction, Adult-onset diabetes, Noninsulin-dependent diabetes mellitus (NIDDM), High blood sugar