Type 2 Diabetes Mellitus
Conditions
Brief summary
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
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.
Interventions
DRUGSAR425899
Self-administered by SC injection using a solution for injection in cartridge.
DRUGPlacebo
Self-administered by SC injection using a solution for injection in cartridge.
DRUGLiraglutide
Self-administered by SC injection using a pre-filled pen.
DRUGMetformin
Orally administered at a stable dose , \>=1500 mg daily stable dose or maximal tolerated dose.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c to Week 26 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | 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. |
| Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | 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. |
| Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | Baseline, 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. |
| Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | Baseline, 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. |
| Mean Change From Baseline in Body Weight to Week 26 | Baseline, 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. |
| Change From Baseline in Beta-Cell Function to Week 26 | Baseline, 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. |
| Change From Baseline in Insulin Resistance to Week 26 | Baseline, 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. |
| Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Baseline,Week 26 | 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. |
| Percentage of Participants Requiring Rescue Therapy | Baseline up to 26 weeks | 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. |
Countries
Canada, Czechia, Germany, Hungary, Mexico, Russia, Spain, United States
Participant flow
Recruitment details
The study was conducted at 59 centers in 8 countries. A total of 539 participants were screened between 2 December 2016 and 2 June 2017, of whom, 245 participants were screen failures. Screen failures were mainly due to exclusion criteria met. The study was double-blind for SAR425899 vs placebo and open-label for active comparator liraglutide.
Pre-assignment details
Total of 294 participants were randomized using interactive response technology, however 2 participants were screened failures and were randomized by error in liraglutide and SAR425899 0.20 mg groups, therefore a total of 296 participants were randomized and treated in study. Randomization was stratified by glycosylated hemoglobin(HbA1c) at screening visit(\<8% vs \>=8%) and body mass index (BMI)(\<35.0 kg/m\^2 vs \>=35.0kg/m\^2) at Day 1(start of investigational medicinal product\[IMP\]administration).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for SAR425899) SC injection QD from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg. | 33 |
| SAR425899 0.12 mg 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). | 66 |
| SAR425899 0.16 mg 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). | 66 |
| SAR425899 0.20 mg 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). | 64 |
| Liraglutide 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). | 67 |
| Total | 296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 10 | 11 | 13 | 3 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other than specified | 0 | 5 | 3 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | SAR425899 0.12 mg | SAR425899 0.16 mg | SAR425899 0.20 mg | Liraglutide | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 9.3 | 56.8 years STANDARD_DEVIATION 9 | 54.5 years STANDARD_DEVIATION 10.1 | 55.0 years STANDARD_DEVIATION 10.4 | 56.1 years STANDARD_DEVIATION 11.4 | 55.6 years STANDARD_DEVIATION 10.2 |
| Baseline HbA1c | 8.04 Percentage of HbA1c STANDARD_DEVIATION 0.86 | 7.97 Percentage of HbA1c STANDARD_DEVIATION 0.88 | 7.99 Percentage of HbA1c STANDARD_DEVIATION 0.85 | 8.14 Percentage of HbA1c STANDARD_DEVIATION 0.94 | 8.11 Percentage of HbA1c STANDARD_DEVIATION 0.86 | 8.05 Percentage of HbA1c STANDARD_DEVIATION 0.88 |
| BMI | 32.07 kg/m^2 STANDARD_DEVIATION 4.41 | 33.67 kg/m^2 STANDARD_DEVIATION 5.37 | 34.23 kg/m^2 STANDARD_DEVIATION 4.68 | 33.63 kg/m^2 STANDARD_DEVIATION 4.35 | 34.23 kg/m^2 STANDARD_DEVIATION 5.51 | 33.74 kg/m^2 STANDARD_DEVIATION 4.96 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian/Oriental | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 6 Participants | 6 Participants | 2 Participants | 4 Participants | 20 Participants |
| Race/Ethnicity, Customized Hispanic | 15 Participants | 19 Participants | 25 Participants | 28 Participants | 13 Participants | 100 Participants |
| Race/Ethnicity, Customized Non Hispanic | 18 Participants | 47 Participants | 41 Participants | 36 Participants | 54 Participants | 196 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 59 Participants | 59 Participants | 59 Participants | 61 Participants | 269 Participants |
| Sex: Female, Male Female | 15 Participants | 29 Participants | 35 Participants | 28 Participants | 36 Participants | 143 Participants |
| Sex: Female, Male Male | 18 Participants | 37 Participants | 31 Participants | 36 Participants | 31 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 18 | 0 / 72 | 0 / 59 | 0 / 47 | 0 / 67 |
| other Total, other adverse events | 10 / 33 | 18 / 18 | 49 / 72 | 45 / 59 | 34 / 47 | 34 / 67 |
| serious Total, serious adverse events | 0 / 33 | 2 / 18 | 3 / 72 | 1 / 59 | 2 / 47 | 2 / 67 |
Outcome results
Primary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on Intent-to-treat (ITT) population which included all randomized participants, irrespective of compliance with the study protocol and procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c to Week 26 | -0.663 percentage of HbA1c | Standard Error 0.169 |
| SAR425899 0.12 mg | Change From Baseline in HbA1c to Week 26 | -1.517 percentage of HbA1c | Standard Error 0.137 |
| SAR425899 0.16 mg | Change From Baseline in HbA1c to Week 26 | -1.618 percentage of HbA1c | Standard Error 0.133 |
| SAR425899 0.20 mg | Change From Baseline in HbA1c to Week 26 | -1.562 percentage of HbA1c | Standard Error 0.131 |
| Liraglutide | Change From Baseline in HbA1c to Week 26 | -1.312 percentage of HbA1c | Standard Error 0.118 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Visit 4 (Day 1) BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline HbA1c as a covariate. Overall 1st trend test based on a contrast with coefficients of +3, +1, -1, -3 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide. Here it is test 1 of testing order.p-value: <0.0001ANCOVA
Comparison: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Visit 4 (Day 1) BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline HbA1c as a covariate. Second Trend test based on a contrast with coefficients of 0, +1, 0, -1 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide, respectively. Here, it is test no. 3 of hierarchical testing sequence.p-value: <0.000195% CI: [-1.359, -0.552]ANCOVA
Comparison: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Visit 4 (Day 1) BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline HbA1c as a covariate. Third Trend test based on a contrast with coefficients of 0, 0, +1, -1 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide, respectively. Here, it is test no. 5 of hierarchical testing sequence.p-value: <0.000195% CI: [-1.264, -0.444]ANCOVA
Secondary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population. Overall number of participants analyzed = participants with at least 1 baseline and 1 post-baseline SMPG assessment during 26 week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | -1.82 mmol/L | Standard Deviation 3.11 |
| SAR425899 0.12 mg | Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | -2.86 mmol/L | Standard Deviation 2.62 |
| SAR425899 0.16 mg | Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | -2.63 mmol/L | Standard Deviation 2.7 |
| SAR425899 0.20 mg | Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | -2.49 mmol/L | Standard Deviation 3.18 |
| Liraglutide | Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26 | -2.21 mmol/L | Standard Deviation 2.23 |
Secondary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Beta-Cell Function to Week 26 | 15.025 percentage of normal beta cells function | Standard Error 19.785 |
| SAR425899 0.12 mg | Change From Baseline in Beta-Cell Function to Week 26 | 26.768 percentage of normal beta cells function | Standard Error 15.833 |
| SAR425899 0.16 mg | Change From Baseline in Beta-Cell Function to Week 26 | 31.122 percentage of normal beta cells function | Standard Error 16.467 |
| SAR425899 0.20 mg | Change From Baseline in Beta-Cell Function to Week 26 | 17.932 percentage of normal beta cells function | Standard Error 14.397 |
| Liraglutide | Change From Baseline in Beta-Cell Function to Week 26 | 27.263 percentage of normal beta cells function | Standard Error 13.234 |
Secondary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | -0.931 mmol/L | Standard Error 0.394 |
| SAR425899 0.12 mg | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | -2.408 mmol/L | Standard Error 0.308 |
| SAR425899 0.16 mg | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | -2.548 mmol/L | Standard Error 0.301 |
| SAR425899 0.20 mg | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | -2.318 mmol/L | Standard Error 0.312 |
| Liraglutide | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26 | -2.124 mmol/L | Standard Error 0.28 |
Secondary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Insulin Resistance to Week 26 | -1.315 HOMA-IR Index | Standard Error 0.865 |
| SAR425899 0.12 mg | Change From Baseline in Insulin Resistance to Week 26 | -1.244 HOMA-IR Index | Standard Error 0.67 |
| SAR425899 0.16 mg | Change From Baseline in Insulin Resistance to Week 26 | -2.233 HOMA-IR Index | Standard Error 0.664 |
| SAR425899 0.20 mg | Change From Baseline in Insulin Resistance to Week 26 | -2.324 HOMA-IR Index | Standard Error 0.649 |
| Liraglutide | Change From Baseline in Insulin Resistance to Week 26 | -1.405 HOMA-IR Index | Standard Error 0.613 |
Secondary
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.
Time frame: Baseline,Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist Circumference | -2.0 cm | Standard Error 0.75 |
| Placebo | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Hip Circumference | -1.42 cm | Standard Error 0.781 |
| SAR425899 0.12 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist Circumference | -5.3 cm | Standard Error 1.34 |
| SAR425899 0.12 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Hip Circumference | -4.46 cm | Standard Error 1.378 |
| SAR425899 0.16 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist Circumference | -2.3 cm | Standard Error 1.61 |
| SAR425899 0.16 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Hip Circumference | -1.97 cm | Standard Error 1.572 |
| SAR425899 0.20 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Hip Circumference | -4.09 cm | Standard Error 0.945 |
| SAR425899 0.20 mg | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist Circumference | -3.2 cm | Standard Error 0.66 |
| Liraglutide | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Waist Circumference | -4.0 cm | Standard Error 2.03 |
| Liraglutide | Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences | Hip Circumference | -2.56 cm | Standard Error 1.513 |
Secondary
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.
Time frame: Baseline, Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Body Weight to Week 26 | -1.759 Kg | Standard Error 0.734 |
| SAR425899 0.12 mg | Mean Change From Baseline in Body Weight to Week 26 | -4.276 Kg | Standard Error 0.564 |
| SAR425899 0.16 mg | Mean Change From Baseline in Body Weight to Week 26 | -5.330 Kg | Standard Error 0.549 |
| SAR425899 0.20 mg | Mean Change From Baseline in Body Weight to Week 26 | -4.407 Kg | Standard Error 0.559 |
| Liraglutide | Mean Change From Baseline in Body Weight to Week 26 | -4.590 Kg | Standard Error 0.521 |
Comparison: Placebo, SAR425899 0.12,0.16,0.20 mg: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Day 1 BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 2 of hierarchical testing sequence.p-value: 0.0012ANCOVA
Comparison: SAR425899 0.16 mg vs Placebo: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Day 1 BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 4 of hierarchical testing sequence.p-value: <0.000195% CI: [-5.309, -1.832]ANCOVA
Comparison: 3rd Trend Test: SAR425899 0.12 mg vs Placebo: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (\<8, \>=8 %), randomization strata of Day 1 BMI (\<35.0 kg/m\^2, \>=35.0 kg/m\^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 6 of hierarchical testing sequence.p-value: 0.004795% CI: [-4.264, -0.77]ANCOVA
Secondary
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.
Time frame: Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=5% Body Weight Loss | 3.0 percentage of participants |
| Placebo | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=10% Body Weight Loss | 0.0 percentage of participants |
| SAR425899 0.12 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=5% Body Weight Loss | 33.3 percentage of participants |
| SAR425899 0.12 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=10% Body Weight Loss | 12.1 percentage of participants |
| SAR425899 0.16 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=5% Body Weight Loss | 45.5 percentage of participants |
| SAR425899 0.16 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=10% Body Weight Loss | 13.6 percentage of participants |
| SAR425899 0.20 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=10% Body Weight Loss | 15.6 percentage of participants |
| SAR425899 0.20 mg | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=5% Body Weight Loss | 35.9 percentage of participants |
| Liraglutide | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=5% Body Weight Loss | 40.3 percentage of participants |
| Liraglutide | Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26 | Participants Achieving >=10% Body Weight Loss | 9.0 percentage of participants |
Secondary
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.
Time frame: Week 26
Population: Analysis was performed on ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <6.5% | 12.1 percentage of participants |
| Placebo | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <7% | 36.4 percentage of participants |
| SAR425899 0.12 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <6.5% | 47.0 percentage of participants |
| SAR425899 0.12 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <7% | 66.7 percentage of participants |
| SAR425899 0.16 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <6.5% | 51.5 percentage of participants |
| SAR425899 0.16 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <7% | 68.2 percentage of participants |
| SAR425899 0.20 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <7% | 65.6 percentage of participants |
| SAR425899 0.20 mg | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <6.5% | 48.4 percentage of participants |
| Liraglutide | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <6.5% | 44.8 percentage of participants |
| Liraglutide | Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26 | Participants with HbA1c Target of <7% | 67.2 percentage of participants |
Secondary
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.
Time frame: Baseline up to 26 weeks
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Requiring Rescue Therapy | 18.2 percentage of participants |
| SAR425899 0.12 mg | Percentage of Participants Requiring Rescue Therapy | 0.0 percentage of participants |
| SAR425899 0.16 mg | Percentage of Participants Requiring Rescue Therapy | 1.5 percentage of participants |
| SAR425899 0.20 mg | Percentage of Participants Requiring Rescue Therapy | 3.1 percentage of participants |
| Liraglutide | Percentage of Participants Requiring Rescue Therapy | 6.0 percentage of participants |