Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin
- Conditions
- Type 2 Diabetes Mellitus
- Interventions
- Registration Number
- NCT01596504
- Lead Sponsor
- Sanofi
- Brief Summary
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
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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 142
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Lixisenatide 20 μg Lixisenatide (AVE0010) 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. Lixisenatide 20 μg Metformin 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. Liraglutide 1.2 mg Liraglutide 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. Lixisenatide 20 μg Insulin Glargine 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. Liraglutide 1.2 mg Insulin Glargine 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. Liraglutide 1.2 mg Metformin 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. Liraglutide 1.8 mg Liraglutide 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. Liraglutide 1.8 mg Insulin Glargine 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. Liraglutide 1.8 mg Metformin 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.
- Primary Outcome Measures
Name Time Method 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 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 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).
- Secondary Outcome Measures
Name Time Method Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 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 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).
Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56 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.
Change From Baseline to Day 56 in PPG Excursion 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 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.
Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG) 0.5 hour (prior to standardized breakfast) on Day -3; 0.5 hour (prior to standardized breakfast) on 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 value of FPG on Day -3 was the baseline.
Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG) 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 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.
Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 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 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.
Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2) 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 Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry.
Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 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 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.
Change From Baseline to Day 56 in HbA1c Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56 HbA1C was assessed using the high performance liquid chromatography method.
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 Coefficient 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 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.
Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate 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 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.
Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure 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 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.
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 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 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.
Trial Locations
- Locations (8)
Investigational Site Number 276008
🇩🇪Berlin, Germany
Investigational Site Number 276006
🇩🇪Berlin, Germany
Investigational Site Number 276005
🇩🇪Mönchengladbach, Germany
Investigational Site Number 276003
🇩🇪Neu-Ulm, Germany
Investigational Site Number 276004
🇩🇪Kiel, Germany
Investigational Site Number 276007
🇩🇪München, Germany
Investigational Site Number 276002
🇩🇪Mainz, Germany
Investigational Site Number 276001
🇩🇪Neuss, Germany