Type 2 Diabetes Mellitus
Conditions
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
Interventions
DRUGLixisenatide (AVE0010)
Pharmaceutical form: solution for injection self-administered with a pen-like injector (OptiClik®). Route of administration: subcutaneous
DRUGLiraglutide
Pharmaceutical form:solution for injection Route of administration: subcutaneous
DRUGInsulin Glargine
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)
DRUGMetformin
If previously taken metformin to be continued at stable dose throughout the study
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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). |
| 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 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. |
| Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose | Day -7 (Baseline), Day 56 | — |
Countries
Germany
Participant flow
Recruitment details
The study was conducted at 8 centers in Germany between 22 May 2012 to 25 July 2013.
Pre-assignment details
A total of 236 participants were screened and 142 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Lixisenatide 20 μg Subcutaneous injection of lixisenatide10 μg QD for 2 weeks followed by 20 μg QD for 6 weeks, on top of insulin glargine with or without metformin. | 48 |
| Liraglutide 1.2 mg Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 7 weeks, on top of insulin glargine with or without metformin. | 47 |
| Liraglutide 1.8 mg 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, on top of insulin glargine with or without metformin. | 47 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 |
| Overall Study | Participant's Private Reason | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Liraglutide 1.2 mg | Lixisenatide 20 μg | Liraglutide 1.8 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 7.9 | 61.6 years STANDARD_DEVIATION 7.4 | 62.6 years STANDARD_DEVIATION 9.4 | 61.9 years STANDARD_DEVIATION 8.3 |
| Body Mass Index (BMI) | 30.52 (kg/m²) STANDARD_DEVIATION 4.01 | 30.68 (kg/m²) STANDARD_DEVIATION 4.34 | 31.17 (kg/m²) STANDARD_DEVIATION 4.34 | 30.79 (kg/m²) STANDARD_DEVIATION 4.22 |
| HbA1c at Screening (Day -7) | 7.19 percentage of haemoglobin STANDARD_DEVIATION 0.53 | 7.22 percentage of haemoglobin STANDARD_DEVIATION 0.48 | 7.33 percentage of haemoglobin STANDARD_DEVIATION 0.5 | 7.25 percentage of haemoglobin STANDARD_DEVIATION 0.5 |
| Metformin Use at Screening No | 6 participants | 5 participants | 6 participants | 17 participants |
| Metformin Use at Screening Yes | 41 participants | 43 participants | 41 participants | 125 participants |
| Race Caucasian/White | 46 participants | 48 participants | 47 participants | 141 participants |
| Race Other | 1 participants | 0 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 8 Participants | 15 Participants | 14 Participants | 37 Participants |
| Sex: Female, Male Male | 39 Participants | 33 Participants | 33 Participants | 105 Participants |
| Weight | 91.62 kg STANDARD_DEVIATION 13.92 | 90.56 kg STANDARD_DEVIATION 13.09 | 92.92 kg STANDARD_DEVIATION 15.33 | 91.69 kg STANDARD_DEVIATION 14.07 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 48 | 27 / 47 | 27 / 47 |
| serious Total, serious adverse events | 1 / 48 | 1 / 47 | 0 / 47 |
Outcome results
Primary
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).
Time frame: 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
Population: Pharmacodynamic (PD) population defined as all randomized participants, who received at least one dose of lixisenatide 20 μg, liraglutide 1.2 mg or liraglutide 1.8 mg, and had both a baseline assessment and at least one post-baseline assessment of any primary or secondary PD variables, irrespective of compliance with study protocol and procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | 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 | -13.33 h*mmol/L | Standard Error 1.11 |
| Liraglutide 1.2 mg | 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 | -7.32 h*mmol/L | Standard Error 1.12 |
| Liraglutide 1.8 mg | 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 | -8.72 h*mmol/L | Standard Error 1.16 |
Comparison: Analysis was performed using linear fixed effects model with treatment groups and stratification factors (HbA1c levels on Day -7 \[\<8% and \>=8%\], use of metformin at screening \[yes or no\]) and the study site) as fixed effects and baseline plasma glucose AUC from 0.5 to 4.5 hours as covariate. To address multiplicity issue and ensure overall 1-sided level of 5%, Hochberg method was used for testing procedure of comparison between lixisenatide vs liraglutide 1.2 mg or 1.8 mg.p-value: <0.0001Linear fixed effects model
Comparison: Analysis was performed using linear mixed effects model with treatment groups and stratification factors (HbA1c levels on Day -7 \[\<8% and \>=8%\], use of metformin at screening \[yes or no\]), and the study site) as fixed effects and baseline plasma glucose AUC from 0.5 to 4.5 hours as covariate. To address multiplicity issue and ensure overall 1-sided level of 5%, Hochberg method was used for testing procedure of comparison between lixisenatide vs liraglutide 1.2 mg or 1.8 mg.p-value: <0.0001Linear fixed effects model
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with gastric emptying at specified time-points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 55 in Gastric Emptying Coefficient | -0.33 coefficient (unit-less) | Standard Deviation 1.09 |
| Liraglutide 1.2 mg | Change From Baseline to Day 55 in Gastric Emptying Coefficient | -0.34 coefficient (unit-less) | Standard Deviation 0.53 |
| Liraglutide 1.8 mg | Change From Baseline to Day 55 in Gastric Emptying Coefficient | -0.28 coefficient (unit-less) | Standard Deviation 0.52 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed=participants with gastric emptying assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2) | 453.56 minutes (min) | Standard Error 58.24 |
| Liraglutide 1.2 mg | Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2) | 175.31 minutes (min) | Standard Error 58.49 |
| Liraglutide 1.8 mg | Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2) | 130.49 minutes (min) | Standard Error 60.27 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with 7 point SMPG assessment at specified time-points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG) | -0.69 mmol/L | Standard Deviation 1.19 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG) | -0.76 mmol/L | Standard Deviation 1.23 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG) | -1.2 mmol/L | Standard Deviation 1.09 |
Secondary
Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose
Time frame: Day -7 (Baseline), Day 56
Population: PD population. Number of participants analyzed=participants with insulin glargine dose assessment at specified time-points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose | -4.7 units | Standard Deviation 4.8 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose | -4.6 units | Standard Deviation 6.8 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose | -4.0 units | Standard Deviation 6.5 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with C-peptide assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours | -1.16 h*nmol/L | Standard Error 0.37 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours | 1.23 h*nmol/L | Standard Error 0.37 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours | 0.88 h*nmol/L | Standard Error 0.39 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with glucagon assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours | -16.56 h*ng/L | Standard Error 19.43 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours | 11.58 h*ng/L | Standard Error 19.86 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours | 5.6 h*ng/L | Standard Error 20.3 |
Secondary
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.
Time frame: 0.5 hour (prior to standardized breakfast) on Day -3; 0.5 hour (prior to standardized breakfast) on Day 56
Population: PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG) | 0.1 mmol/L | Standard Error 0.22 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG) | 0.12 mmol/L | Standard Error 0.22 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG) | 0.13 mmol/L | Standard Error 0.23 |
Secondary
Change From Baseline to Day 56 in HbA1c
HbA1C was assessed using the high performance liquid chromatography method.
Time frame: Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56
Population: Number of participants analyzed = participants with HbA1c assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in HbA1c | -0.58 percentage of HbA1c | Standard Error 0.06 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in HbA1c | -0.66 percentage of HbA1c | Standard Error 0.06 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in HbA1c | -0.74 percentage of HbA1c | Standard Error 0.06 |
Secondary
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).
Time frame: 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
Population: PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours | -13.82 h*mmol/L | Standard Error 1.19 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours | -9.09 h*mmol/L | Standard Error 1.21 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours | -10.33 h*mmol/L | Standard Error 1.25 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in PPG Excursion | -3.26 mmol/L | Standard Error 0.4 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in PPG Excursion | -1.79 mmol/L | Standard Error 0.4 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in PPG Excursion | -2.5 mmol/L | Standard Error 0.42 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed=participants with appetite perception assessment at specified time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How hungry do you feel? | -3.7 mm | Standard Deviation 16.4 |
| Lixisenatide 20 μg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How satisfied do you feel? | 4.5 mm | Standard Deviation 15.8 |
| Lixisenatide 20 μg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How full do you feel? | 4.9 mm | Standard Deviation 17 |
| Lixisenatide 20 μg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How much do you think you can eat? | -6.4 mm | Standard Deviation 16.1 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How much do you think you can eat? | -4.5 mm | Standard Deviation 15.7 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How hungry do you feel? | -3.1 mm | Standard Deviation 16.8 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How full do you feel? | 9.3 mm | Standard Deviation 15.6 |
| Liraglutide 1.2 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How satisfied do you feel? | 8.9 mm | Standard Deviation 13.2 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How much do you think you can eat? | -7.2 mm | Standard Deviation 12 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How satisfied do you feel? | 3.6 mm | Standard Deviation 11 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How full do you feel? | 6.4 mm | Standard Deviation 13.8 |
| Liraglutide 1.8 mg | Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast | How hungry do you feel? | -1.0 mm | Standard Deviation 14.6 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with heart rate assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate | 3.34 beats per minute | Standard Error 1.33 |
| Liraglutide 1.2 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate | 9.33 beats per minute | Standard Error 1.24 |
| Liraglutide 1.8 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate | 9.17 beats per minute | Standard Error 1.31 |
Secondary
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.
Time frame: 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
Population: PD population. Number of participants analyzed = participants with blood pressure assessment at specified time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Systolic Blood Pressure | 0.4 mmHg | Standard Deviation 6.4 |
| Lixisenatide 20 μg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Diastolic Blood Pressure | 0.8 mmHg | Standard Deviation 4.1 |
| Liraglutide 1.2 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Systolic Blood Pressure | -0.5 mmHg | Standard Deviation 7.1 |
| Liraglutide 1.2 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Diastolic Blood Pressure | 2.4 mmHg | Standard Deviation 4.7 |
| Liraglutide 1.8 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Systolic Blood Pressure | -2.5 mmHg | Standard Deviation 7.7 |
| Liraglutide 1.8 mg | Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure | 24-Hour Mean Diastolic Blood Pressure | 1.6 mmHg | Standard Deviation 4.7 |
Secondary
Change From Baseline to Day 57 in Body Weight
Time frame: 0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to study drug administration on Day 57
Population: PD population. Number of participants analyzed = participants with body weight assessment at specified time-points.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 57 in Body Weight | -1.61 kg | Standard Error 0.47 |
| Liraglutide 1.2 mg | Change From Baseline to Day 57 in Body Weight | -1.78 kg | Standard Error 0.48 |
| Liraglutide 1.8 mg | Change From Baseline to Day 57 in Body Weight | -2.42 kg | Standard Error 0.49 |
Secondary
Change From Baseline to Day 57 in Waist Circumference
Time frame: 0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to IMP administration on Day 57
Population: PD population. Number of participants analyzed = participants with waist circumference assessment at specified time-points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide 20 μg | Change From Baseline to Day 57 in Waist Circumference | -1.40 cm | Standard Deviation 4.66 |
| Liraglutide 1.2 mg | Change From Baseline to Day 57 in Waist Circumference | -1.93 cm | Standard Deviation 3.59 |
| Liraglutide 1.8 mg | Change From Baseline to Day 57 in Waist Circumference | -2.12 cm | Standard Deviation 4.95 |
Secondary
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.
Time frame: Day 56
Population: PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide 20 μg | Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56 | 35 participants |
| Liraglutide 1.2 mg | Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56 | 13 participants |
| Liraglutide 1.8 mg | Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56 | 11 participants |