A Study to Assess the Safety and Efficacy of SAR425899 in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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Primary Objective: The primary objective of this study was to assess the dose-response relationship of SAR425899 versus placebo in terms of glycemic control as measured by the change in glycosylated hemoglobin (HbA1c). Secondary Objectives: To assess the effect of SAR425899 on body weight. To assess the safety and immunogenicity profile of SAR425899, including assessment of the heart rate (HR) change by electrocardiogram (ECG) and Holter monitor. To assess the proportion of participants achieving predefined HbA1c targets of <7% and <6.5% as well as the proportion of participants achieving >=5% and >=10% body weight loss. To assess the effect of once daily dosing of SAR425899 on additional parameters of glycemic control and lipid metabolism. To assess the effect of once daily dosing of SAR425899 on additional pharmacodynamic (PD) biomarkers. To assess the pharmacokinetic (PK) profile and parameters of SAR425899, inter-individual and inter-occasion variability in PK parameters using a population PK approach.

Detailed Description
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The total study duration will be approximately 30 weeks, consisting of 3 weeks screening period at the site, a 26 weeks treatment period, and 3 days post treatment follow up period.

Official Title
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A 26-Week Randomized, Double-blind, Placebo-controlled, Dose-ranging Phase 2 Study to Assess the Safety and Efficacy of SAR425899 in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: SAR425899
* Drug: Placebo
* Drug: Liraglutide
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with type-2 diabetes mellitus (T2DM) for at least 3 months before the screening visit. On diet/exercise and/or treatment with metformin (stable dose of ≥1500 mg/day or maximal tolerated dose) for at least 3 months prior to screening. Signed informed consent. Exclusion criteria: At screening, participant's age < legal age of adulthood and >80 years. Glycated hemoglobin at screening visit <7.0% or >10.0%. Body mass index (BMI) <25 kg/m^2 or >45.0 kg/m^2. Pregnant or lactating women. Women of childbearing potential (WOCBP) not protected by highly-effective method(s) of birth control and/or who are unwilling or unable to be tested for pregnancy. Diagnosis of type 1 diabetes mellitus. Fasting plasma glucose of >15 mmol/L (270 mg/dL) measured by the central laboratory at screening (Visit 1), and confirmed (>15 mmol/L [270 mg/dL]) by a repeat test before randomization. Treatment with glucose-lowering agents(s) other than metformin, currently or within the 3 months prior to screening. Previous insulin use, except for episode(s) of short-term treatment (≤15 consecutive days) for intercurrent illness or pregnancy, or use of insulin within the last 6 months. Contraindication(s) to metformin use. Contraindication(s) to liraglutide use. Significant change in body weight in the 3 months before screening. Poorly controlled hypertension (a resting systolic blood pressure (SBP) >160 mm Hg and/or diastolic blood pressure (DBP) >95 mm Hg at screening). History of long QT syndrome and/or QTc more than 450 ms at screening visit. History of pancreatitis or pancreatectomy. History of weight loss surgery. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC. Any prior exposure to drugs belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists/GLP-1 analogs. Contraindications or known hypersensitivity reaction to glucagon. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg. | Drug: Placebo<br>* Self-administered by SC injection using a solution for injection in cartridge.<br>Drug: Metformin<br>* Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.<br>|
| Experimental: SAR425899 0.12 mg<br>SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1). | Drug: SAR425899<br>* Self-administered by SC injection using a solution for injection in cartridge.<br>Drug: Metformin<br>* Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.<br>|
| Experimental: SAR425899 0.16 mg<br>SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2). | Drug: SAR425899<br>* Self-administered by SC injection using a solution for injection in cartridge.<br>Drug: Metformin<br>* Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.<br>|
| Experimental: SAR425899 0.20 mg<br>SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3). | Drug: SAR425899<br>* Self-administered by SC injection using a solution for injection in cartridge.<br>Drug: Metformin<br>* Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.<br>|
| Active Comparator: Liraglutide<br>Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2). | Drug: Liraglutide<br>* Self-administered by SC injection using a pre-filled pen.<br>* Other names: Victoza;Drug: Metformin<br>* Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c to Week 26 | Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based multiple imputation (MI) method under the missing not at random framework. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Body Weight to Week 26 | Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing post- baseline values were imputed by placebo control-based MI method under the missing not at random framework. | Baseline, Week 26 | 
| Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Participants with no measurement at Week 26 were treated as non-responders. | Week 26 | 
| Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Participants with no measurement at Week 26 were treated as non-responders. | Week 26 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based MI method under the missing not at random framework. | Baseline, Week 26 | 
| Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | Change in 7-point SMPG profile from baseline to Week 26 was assessed by summary statistics. 7-point SMPG profiles were measured at the following 7 points at each visit (Baseline, and Week 26): pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) is defined as 2 hours after the start of the meal. | Baseline, Week 26 | 
| Percentage of Participants Requiring Rescue Therapy | Rescue medication was introduced in case FPG or HbA1c values were above pre-defined thresholds, and if no reasons were found for insufficient glucose control, and appropriate action failed to decrease FPG / HbA1c under the threshold values (from baseline to Week 8: FPG >270 mg/dL 15.0 mmol/L, from Week 8 to Week 14: FPG >13.3 mmol/L, and from Week 14 to Week 26: FPG >11.1 mmol/L or HbA1c>8%). The choice of rescue therapy was at the Investigator's discretion with the exception of using glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase 4 (DPP4) inhibitors. | Baseline up to 26 weeks | 
| Change From Baseline in Beta-Cell Function to Week 26 | Beta-cell function was assessed by homeostatic model assessment (HOMA)-beta, derived from FPG and fasting plasma insulin (FPI). HOMA-beta was derived from FPG and FPI as (20*FPI [micro units/milliliter]) divided by (FPG [mmol/L] minus 3.5). Change was calculated for HOMA-beta by subtracting the Baseline value from Week 26 value*100. | Baseline, Week 26 | 
| Change From Baseline in Insulin Resistance to Week 26 | Insulin Resistance was assessed by homeostasis model assessment for insulin resistance (HOMA-IR), derived from FPG and FPI. HOMA-IR was derived from FPG and FPI as (FPI [micro units per milliliter] * FPG [mmol/L]) divided by 22.5. Change was calculated for HOMA-beta by subtracting the Baseline value from Week 26 value. | Baseline, Week 26 | 
| Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist circumference was measured at the midpoint between the lower margin of the least palpable rib and the top of the iliac crest, using a stretch-resistant tape providing a constant 100 gm tension. Hip circumference was measured around the widest portion of the buttocks, with the tape parallel to the floor. Each measurement was repeated twice; if the measurements were within 1 cm of one another, the average was calculated, and if the difference exceeded 1 cm, the measurements were repeated. | Baseline,Week 26 |