Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Study Overview
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Brief Summary
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Primary Objective: - To investigate the effects of repeated subcutaneous doses of lixisenatide 20 μg once daily (QD) as compared to liraglutide 1.2 mg QD or 1.8 mg QD in reducing post-prandial plasma glucose (PPG) assessed as area under the plasma glucose-concentration-time curve (AUC) after a standardized breakfast at the end of a 8-week treatment period in participants with type 2 diabetes mellitus (T2DM) not adequately controlled with insulin glargine (± metformin). Secondary Objectives: To assess the effects of lixisenatide 20 μg QD as compared to liraglutide 1.2 QD or 1.8 mg QD after an 8-week treatment period in participants with T2DM not adequately controlled with insulin glargine (± metformin) on: Post-prandial C-peptide, glucagon and appetite perceptions after a standardized breakfast, Appetite perceptions after standardized dinner, Gastric emptying after a standardized labelled test meal, Fasting plasma glucose, 24-hour plasma glucose profile, Glycosylated hemoglobin (HbA1c), Insulin glargine dose, 7-point self monitored plasma glucose (SMPG), Body weight and waist circumference, 24-hour heart rate and blood pressure, To assess lixisenatide and liraglutide safety and tolerability as add on treatment to insulin glargine (± metformin).

Detailed Description
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Up to 2-week screening period A run-in period of 12 weeks at maximum including a forced titration with insulin glargine up to 11 weeks and 1 baseline pharmacodynamic assessment week A 8-week treatment(s) period(s) up to Day 57 Follow-up: 7 ±2 days after the last treatment day Total study duration approximately 14 weeks up to 23 weeks

Official Title
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An Open-label, Randomized, Three-parallel-group Study on Pharmacodynamic Effects of 8-week QD Treatment With Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Lixisenatide (AVE0010)
* Drug: Liraglutide
* Drug: Insulin Glargine
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with T2DM diagnosed at least 1 year before the screening visit. Treatment with neutral protamine hagedorn (NPH) or insulin glargine for at least 3 months and at a stable dose (±20%) of at least 10 IU/day (for at least 2 months prior to screening) alone or combined with a stable dose of metformin with or without dipeptidyl peptidase 4 (DPP-4) inhibitor or sulfonylurea. Glycosylated hemoglobin (HbA1c) ≥6.5 and ≤9.5%. Body mass index (BMI) between 20 and 40 kg/m^2. Exclusion criteria: Pregnant women or breastfeeding women. Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to, gastroparesis and gastroesophageal reflux disease requiring medical treatment within 6 months prior to the time of screening. Any previous treatment with lixisenatide or participation in a previous study with lixisenatide (AVE0010), and any previous treatment with liraglutide stopped for safety concern or lack of efficacy. Allergic reaction to any glucagon-like peptide-1 (GLP-1) agonist in the past (eg, exenatide) or to metacresol. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease. Personal or family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTC. The above information was 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: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lixisenatide 20 μg<br>Subcutaneous injection of lixisenatide10 μg once daily (QD) for 2 weeks followed by 20 μg QD for 6 weeks under fasted conditions, on top of insulin glargine with or without metformin. | Drug: Lixisenatide (AVE0010)<br>* Pharmaceutical form: solution for injection self-administered with a pen-like injector (OptiClik®). Route of administration: subcutaneous<br>Drug: Insulin Glargine<br>* Doses to be adjusted to maintain a fasting self-measured plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL)<br>* Other names: Lantus® SoloSTAR®;Drug: Metformin<br>* If previously taken metformin to be continued at stable dose throughout the study<br>|
| Active Comparator: Liraglutide 1.2 mg<br>Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 7 weeks under fasted conditions, on top of insulin glargine with or without metformin. | Drug: Liraglutide<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>* Other names: Victoza®;Drug: Insulin Glargine<br>* Doses to be adjusted to maintain a fasting self-measured plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL)<br>* Other names: Lantus® SoloSTAR®;Drug: Metformin<br>* If previously taken metformin to be continued at stable dose throughout the study<br>|
| Active Comparator: Liraglutide 1.8 mg<br>Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for another 1 week and 1.8 mg QD for next 6 weeks under fasted conditions, on top of insulin glargine with or without metformin. | Drug: Liraglutide<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>* Other names: Victoza®;Drug: Insulin Glargine<br>* Doses to be adjusted to maintain a fasting self-measured plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL)<br>* Other names: Lantus® SoloSTAR®;Drug: Metformin<br>* If previously taken metformin to be continued at stable dose throughout the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 56 in Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve (AUC) From Time 0.5 Hours to 4.5 Hours | Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 milligram per decilitre (mg/dL) with 1 mg/dL as limit of detection (LOD). Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). | 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours | Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as limit of detection (LOD). Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 5 hours after breakfast start (time: 5.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). | 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56 | 
| Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56 | Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The 2-hour PPG test measured blood glucose 2 hours after start of a standardised breakfast. | Day 56 | 
| Change From Baseline to Day 56 in PPG Excursion | Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. PPG excursion was determined on Day -3 (Baseline) and Day 56 as the maximum change in PPG from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. | 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56 | 
| Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG) | Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The value of FPG on Day -3 was the baseline. | 0.5 hour (prior to standardized breakfast) on Day -3; 0.5 hour (prior to standardized breakfast) on Day 56 | 
| Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG) | Seven-point SMPG (before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime) was measured using Freestyle Precision glucometer and average of the 7 measurements was calculated. | Before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime on Day -3 (Baseline) and on Day 56 | 
| Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours | C-peptide was assessed using the Electro Chemiluminescence Immuno Assay.The range of the method was 0.2 to 25 nanogram per millilitre (ng/mL) and the LOD was 0.07 ng/mL. Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in C-peptide from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. | 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day-3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56 | 
| Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours | Glucagon was assessed using the radioimmunoassay. The range of the method was 4.7 to 150 picomole per litre (pmol/L). Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in glucagon from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. | 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56 | 
| Change From Baseline to Day 56 in HbA1c | HbA1C was assessed using the high performance liquid chromatography method. | Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56 | 
| Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose |  | Day -7 (Baseline), Day 56 | 
| Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2) | Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry. | 0 (prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55 | 
| Change From Baseline to Day 55 in Gastric Emptying Coefficient | Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry. Gastric emptying coefficient was derived from a mathematical formula that describes the gastric emptying rate and gives an overall index of gastric emptying. | 0 (7:30 clock time, prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55 | 
| Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate | The baseline value was the 24-hour mean on Day -2/-1 determined as overall, night and daytime mean. Measurements were made every 15 minutes from 07:00 to 23:00 (daytime) and every 30 minutes from 23:00 to 07:00 (night-time) at baseline and Day 57/58. Measurements were obtained after 10 minutes in the supine resting position. | Every 15 minutes from 07:00 clock time to 23:00 clock time (day-time) and every 30 minutes from 23:00 clock time to 07:00 clock time (night-time) on Day -2/-1 (Baseline) and Day 57/58 | 
| Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | The baseline value was the 24-hour means on Day -2/-1 determined as overall, night and day-time mean. Measurements were made every 15 minutes from 07:00 to 23:00 (day-time) and every 30 minutes from 23:00 to 07:00 (night-time) at baseline and at Day 57/58. Measurements were obtained after 10 minutes in the supine resting position. | Every 15 minutes from 07:00 clock time to 23:00 clock time (day-time) and every 30 minutes from 23:00 clock time to 07:00 clock time (night-time) on Day -2/ -1 (Baseline) and Day 57/58 | 
| Change From Baseline to Day 57 in Body Weight |  | 0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to study drug administration on Day 57 | 
| Change From Baseline to Day 57 in Waist Circumference |  | 0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to IMP administration on Day 57 | 
| Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | Visual Analogue Scale, 100 mm in length with words anchored at each end, expressing the most positive (100 mm) and the most negative rating (0 mm), was used to assess hunger, satiety, fullness and prospective food consumption. Responses were measured as distance from the left end of the line to the mark. Mean change from baseline was calculated for each parameter separately. | 0.5 (8:00 clock time, prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours on Day -3; 0 (prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56 |