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

• ClinicalTrials.gov Identifier: NCT01596504
• Recruitment Status: Completed
• First Posted: May 11, 2012
• Results First Posted: October 14, 2016
• Last Update Posted: October 14, 2016
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Type 2 Diabetes Mellitus
• Interventions: Drug: Lixisenatide (AVE0010); Drug: Liraglutide; Drug: Insulin Glargine; Drug: Metformin
• Enrollment: 142

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.

Arm/Group Title	Lixisenatide 20 μg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description	Subcutaneous injection of lixisenatide10 μg once daily (QD) for 2 weeks followed by 20 μg QD for 6 weeks, on top of insulin glargine with or without metformin.	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.	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.
Period Title: Overall Study
Started	48	47	47
Completed	46	44	46
Not Completed	2	3	1
Reason Not Completed
Participant's Private Reason	0	1	0
Adverse Event	1	2	1
Withdrawal by Subject	1	0	0

Baseline Characteristics

Arm/Group Title		Lixisenatide 20 μg	Liraglutide 1.2 mg	Liraglutide 1.8 mg	Total
Arm/Group Description		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.	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.	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.	Total of all reporting groups
Overall Number of Baseline Participants		48	47	47	142
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	48 participants	47 participants	47 participants	142 participants
		61.6 (7.4)	61.4 (7.9)	62.6 (9.4)	61.9 (8.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants	47 participants	47 participants	142 participants
	Female	15 31.3%	8 17.0%	14 29.8%	37 26.1%
	Male	33 68.8%	39 83.0%	33 70.2%	105 73.9%
Race; Measure Type: Number; Unit of measure: Participants	Number Analyzed	48 participants	47 participants	47 participants	142 participants
Caucasian/White		48	46	47	141
Other		0	1	0	1
Metformin Use at Screening; Measure Type: Number; Unit of measure: Participants	Number Analyzed	48 participants	47 participants	47 participants	142 participants
Yes		43	41	41	125
No		5	6	6	17
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	48 participants	47 participants	47 participants	142 participants
		90.56 (13.09)	91.62 (13.92)	92.92 (15.33)	91.69 (14.07)
Body Mass Index (BMI); Mean (Standard Deviation); Unit of measure: (kg/m²)
	Number Analyzed	48 participants	47 participants	47 participants	142 participants
		30.68 (4.34)	30.52 (4.01)	31.17 (4.34)	30.79 (4.22)
HbA1c at Screening (Day -7); Mean (Standard Deviation); Unit of measure: Percentage of haemoglobin
	Number Analyzed	48 participants	47 participants	47 participants	142 participants
		7.22 (0.48)	7.19 (0.53)	7.33 (0.5)	7.25 (0.50)

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lixisenatide 20 μg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	45
Least Squares Mean (Standard Error); Unit of Measure: h*mmol/L
	-13.33 (1.11)	-7.32 (1.12)	-8.72 (1.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lixisenatide 20 μg, Liraglutide 1.2 mg
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	p-values ordered(p1≤p2) as per rules:if p2≤0.05: lixisenatide superior to liraglutide (both doses);if p2>0.05 & p1≤0.025:lixisenatide superior to dose of liraglutide associated with p1;if p2>0.05 & p1>0.025:no comparison as statistically significant.
	Method	Linear fixed effects model
	Comments	The threshold for significance at 0.05 level.
Method of Estimation	Estimation Parameter	Least squares (LS) mean difference
	Estimated Value	-6.01
	Confidence Interval	(1-Sided) 95%; -7.77
	Parameter Dispersion	Type: Standard Error of the mean; Value: 1.06
	Estimation Comments	Lixisenatide vs Liraglutide 1.2 mg

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lixisenatide 20 μg, Liraglutide 1.8 mg
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	p-values ordered(p1≤p2) as per rules:if p2≤0.05:lixisenatide superior to liraglutide (both doses);if p2>0.05 & p1≤0.025:lixisenatide superior to dose of liraglutide associated with p1;if p2>0.05 & p1>0.025: no comparison as statistically significant.
	Method	Linear fixed effects model
	Comments	The threshold for significance at 0.05 level.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.61
	Confidence Interval	(1-Sided) 95%; -6.34
	Parameter Dispersion	Type: Standard Error of the mean; Value: 1.04
	Estimation Comments	Lixisenatide vs Liraglutide 1. 8 mg

2. Secondary Outcome

Title	Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	45
Least Squares Mean (Standard Error); Unit of Measure: h*mmol/L
	-13.82 (1.19)	-9.09 (1.21)	-10.33 (1.25)

3. Secondary Outcome

Title	Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Measure Type: Number; Unit of Measure: participants
	35	13	11

4. Secondary Outcome

Title	Change From Baseline to Day 56 in PPG Excursion
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	45
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-3.26 (0.4)	-1.79 (0.4)	-2.5 (0.42)

5. Secondary Outcome

Title	Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG)
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with plasma glucose assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	45	44	45
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	0.1 (0.22)	0.12 (0.22)	0.13 (0.23)

6. Secondary Outcome

Title	Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG)
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with 7 point SMPG assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Mean (Standard Deviation); Unit of Measure: mmol/L
	-0.69 (1.19)	-0.76 (1.23)	-1.2 (1.09)

7. Secondary Outcome

Title	Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with C-peptide assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	45
Least Squares Mean (Standard Error); Unit of Measure: h*nmol/L
	-1.16 (0.37)	1.23 (0.37)	0.88 (0.39)

8. Secondary Outcome

Title	Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with glucagon assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	45
Least Squares Mean (Standard Error); Unit of Measure: h*ng/L
	-16.56 (19.43)	11.58 (19.86)	5.6 (20.3)

9. Secondary Outcome

Title	Change From Baseline to Day 56 in HbA1c
Description	HbA1C was assessed using the high performance liquid chromatography method.
Time Frame	Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56

Outcome Measure Data

Analysis Population Description

Number of participants analyzed = participants with HbA1c assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Least Squares Mean (Standard Error); Unit of Measure: percentage of HbA1c
	-0.58 (0.06)	-0.66 (0.06)	-0.74 (0.06)

10. Secondary Outcome

Title	Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose
Description	[Not Specified]
Time Frame	Day -7 (Baseline), Day 56

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed=participants with insulin glargine dose assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Mean (Standard Deviation); Unit of Measure: units
	-4.7 (4.8)	-4.6 (6.8)	-4.0 (6.5)

11. Secondary Outcome

Title	Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2)
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed=participants with gastric emptying assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Least Squares Mean (Standard Error); Unit of Measure: minutes (min)
	453.56 (58.24)	175.31 (58.49)	130.49 (60.27)

12. Secondary Outcome

Title	Change From Baseline to Day 55 in Gastric Emptying Coefficient
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with gastric emptying at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Mean (Standard Deviation); Unit of Measure: coefficient (unit-less)
	-0.33 (1.09)	-0.34 (0.53)	-0.28 (0.52)

13. Secondary Outcome

Title	Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with heart rate assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	42	43	44
Least Squares Mean (Standard Error); Unit of Measure: beats per minute
	3.34 (1.33)	9.33 (1.24)	9.17 (1.31)

14. Secondary Outcome

Title	Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with blood pressure assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	42	43	44
Mean (Standard Deviation); Unit of Measure: mmHg
24-Hour Mean Systolic Blood Pressure	0.4 (6.4)	-0.5 (7.1)	-2.5 (7.7)
24-Hour Mean Diastolic Blood Pressure	0.8 (4.1)	2.4 (4.7)	1.6 (4.7)

15. Secondary Outcome

Title	Change From Baseline to Day 57 in Body Weight
Description	[Not Specified]
Time Frame	0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to study drug administration on Day 57

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with body weight assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Least Squares Mean (Standard Error); Unit of Measure: kg
	-1.61 (0.47)	-1.78 (0.48)	-2.42 (0.49)

16. Secondary Outcome

Title	Change From Baseline to Day 57 in Waist Circumference
Description	[Not Specified]
Time Frame	0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to IMP administration on Day 57

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed = participants with waist circumference assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	43	46
Mean (Standard Deviation); Unit of Measure: cm
	-1.40 (4.66)	-1.93 (3.59)	-2.12 (4.95)

17. Secondary Outcome

Title	Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast
Description	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

Outcome Measure Data

Analysis Population Description

PD population. Number of participants analyzed=participants with appetite perception assessment at specified time-points.

Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description:	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.	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.	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.
Overall Number of Participants Analyzed	46	44	46
Mean (Standard Deviation); Unit of Measure: mm
How hungry do you feel?	-3.7 (16.4)	-3.1 (16.8)	-1.0 (14.6)
How satisfied do you feel?	4.5 (15.8)	8.9 (13.2)	3.6 (11.0)
How full do you feel?	4.9 (17.0)	9.3 (15.6)	6.4 (13.8)
How much do you think you can eat?	-6.4 (16.1)	-4.5 (15.7)	-7.2 (12.0)

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study (10 weeks) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that developed/worsened during the ‘on treatment period’ (the time from the first drug injection [included] up to 3 days after the last injection of drug administration [included]).
Arm/Group Title	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
Arm/Group Description	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.	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.	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.
All-Cause Mortality
	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/48 (2.08%)	1/47 (2.13%)	0/47 (0.00%)
Cardiac disorders
Coronary artery disease † 1	1/48 (2.08%)	0/47 (0.00%)	0/47 (0.00%)
Myocardial infarction † 1	0/48 (0.00%)	1/47 (2.13%)	0/47 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lixisenatide 20 µg	Liraglutide 1.2 mg	Liraglutide 1.8 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	26/48 (54.17%)	27/47 (57.45%)	27/47 (57.45%)
Gastrointestinal disorders
Abdominal distension † 1	3/48 (6.25%)	7/47 (14.89%)	4/47 (8.51%)
Abdominal pain † 1	2/48 (4.17%)	3/47 (6.38%)	1/47 (2.13%)
Abdominal pain upper † 1	1/48 (2.08%)	0/47 (0.00%)	5/47 (10.64%)
Constipation † 1	0/48 (0.00%)	5/47 (10.64%)	3/47 (6.38%)
Diarrhoea † 1	3/48 (6.25%)	4/47 (8.51%)	5/47 (10.64%)
Dyspepsia † 1	3/48 (6.25%)	3/47 (6.38%)	4/47 (8.51%)
Flatulence † 1	2/48 (4.17%)	0/47 (0.00%)	4/47 (8.51%)
Nausea † 1	9/48 (18.75%)	8/47 (17.02%)	11/47 (23.40%)
Vomiting † 1	5/48 (10.42%)	2/47 (4.26%)	5/47 (10.64%)
General disorders
Fatigue † 1	3/48 (6.25%)	1/47 (2.13%)	4/47 (8.51%)
Malaise † 1	3/48 (6.25%)	0/47 (0.00%)	1/47 (2.13%)
Infections and infestations
Nasopharyngitis † 1	6/48 (12.50%)	10/47 (21.28%)	5/47 (10.64%)
Metabolism and nutrition disorders
Decreased appetite † 1	9/48 (18.75%)	9/47 (19.15%)	13/47 (27.66%)
Nervous system disorders
Dizziness postural † 1	3/48 (6.25%)	1/47 (2.13%)	0/47 (0.00%)
Headache † 1	4/48 (8.33%)	5/47 (10.64%)	8/47 (17.02%)
Psychiatric disorders
Insomnia † 1	0/48 (0.00%)	0/47 (0.00%)	3/47 (6.38%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If no publication has occurred within 12 months after trial completion, the Investigator can present or publish results. The investigator provides the sponsor with a copy of the presentation or publication for review and comment at least 30 days in advance of its submission.

The sponsor can delay the submission for a period not exceeding 90 days to allow for filing a patent application or such other measures as sponsor deems appropriate to establish and preserve its proprietary rights.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi
• EMail: Contact-US@sanofi.com

Publications of Results:

Meier JJ, Rosenstock J, Hincelin-Méry A, Roy-Duval C, Delfolie A, Coester HV, Menge BA, Forst T, Kapitza C. Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial. Diabetes Care. 2015 Jul;38(7):1263-73. doi: 10.2337/dc14-1984. Epub 2015 Apr 17.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01596504 History of Changes
• Other Study ID Numbers: PDY12625; 2012-000027-40 ( EudraCT Number ); U1111-1124-1364 ( Other Identifier: UTN )
• First Submitted: May 7, 2012
• First Posted: May 11, 2012
• Results First Submitted: August 22, 2016
• Results First Posted: October 14, 2016
• Last Update Posted: October 14, 2016