24-week Study Comparing Lixisenatide to Sitagliptin as add-on to Metformin in Obese Type 2 Diabetic Patients Younger Than 50 Years

• ClinicalTrials.gov Identifier: NCT00976937
• Recruitment Status: Completed
• First Posted: September 15, 2009
• Results First Posted: October 11, 2016
• Last Update Posted: October 11, 2016
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Type 2 Diabetes Mellitus
• Interventions: Drug: Lixisenatide (AVE0010); Drug: Lixisenatide Placebo; Device: Pen auto-injector; Drug: Sitagliptin; Drug: Sitagliptin Placebo; Drug: Metformin
• Enrollment: 319

Participant Flow

Recruitment Details	The study was conducted at 92 centers in 13 countries between August 31, 2009 and March 19, 2011.
Pre-assignment Details	A total of 620 patients were screened of which 301 (48.5%) were screen failures; main reason for screen failure was glycosylated hemoglobin (HbA1c) values being out of the defined protocol range (greater than or equal to 7% and less than or equal to 10%). A total of 319 patients were randomized.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description	2-step initiation regimen of lixisenatide along with sitagliptin placebo: lixisenatide 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24 along with placebo matching to sitagliptin 100 milligram (mg) capsule orally QD up to Week 24.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo: sitagliptin 100 mg capsule orally QD up to Week 24 along with volume matching lixisenatide placebo 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24.
Period Title: Overall Study
Started	158 [1]	161
Treated/Safety Population	158 [2]	161
Modified Intent-to-Treat(mITT)Population	158 [3]	161
Completed	142	150
Not Completed	16	11
Reason Not Completed
Adverse Event	4	5
Lost to Follow-up	2	1
Withdrawal by Subject	5	3
Poor compliance to protocol	3	0
Personal and Familial Reason	2	2
[1] Randomized; [2] All patients who were exposed to at least 1 dose, regardless of amount of treatment administered.; [3] All randomized patients who received at least 1 dose of study drug.

Baseline Characteristics

Arm/Group Title		Lixisenatide	Sitagliptin	Total
Arm/Group Description		2-step initiation regimen of lixisenatide along with sitagliptin placebo: lixisenatide 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24 along with placebo matching to sitagliptin 100 mg capsule orally QD up to Week 24.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo: sitagliptin 100 mg capsule orally QD up to Week 24 along with volume matching lixisenatide placebo 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24.	Total of all reporting groups
Overall Number of Baseline Participants		158	161	319
Baseline Analysis Population Description		Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	158 participants	161 participants	319 participants
		42.7 (5.2)	43.4 (4.7)	43.1 (4.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	158 participants	161 participants	319 participants
	Female	103 65.2%	88 54.7%	191 59.9%
	Male	55 34.8%	73 45.3%	128 40.1%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	158 participants	161 participants	319 participants
Race: Caucasian/White		132	127	259
Race: Black		8	11	19
Race: Asian/Oriental		1	1	2
Race: Other		17	22	39
Ethnicity: Hispanic		73	72	145
Ethnicity: Non Hispanic		85	89	174
Glycosylated Hemoglobin (HbA1c); Mean (Standard Deviation); Unit of measure: Percentage of hemoglobin
	Number Analyzed	158 participants	161 participants	319 participants
		8.16 (0.89)	8.09 (0.96)	8.12 (0.93)
Body Mass Index (BMI) [1]; Mean (Standard Deviation); Unit of measure: Kilogram per square meter (kg/m^2)
	Number Analyzed	158 participants	161 participants	319 participants
		36.76 (7.25)	36.76 (6.34)	36.76 (6.80)
		[1] Measure Description: BMI was calculated by dividing body weight by the height squared.
Duration of Diabetes; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	158 participants	161 participants	319 participants
		4.40 (3.86)	4.43 (3.56)	4.42 (3.70)
Body Weight; Mean (Standard Deviation); Unit of measure: Kilogram
	Number Analyzed	158 participants	161 participants	319 participants
		98.51 (23.48)	100.56 (23.77)	99.55 (23.61)
2-hour Postprandial Plasma Glucose (PPG) [1]; Mean (Standard Deviation); Unit of measure: Millimole per liter (mmol/L)
	Number Analyzed	158 participants	161 participants	319 participants
		13.77 (3.78)	13.92 (3.99)	13.84 (3.88)
		[1] Measure Description: The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Number of patients analyzed = 158 and 157 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting Plasma Glucose (FPG); Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		9.09 (2.60)	8.96 (2.59)	9.03 (2.59)
Glucose Excursion [1]; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		4.37 (2.64)	4.48 (2.59)	4.42 (2.61)
		[1] Measure Description: Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the meal test, before study drug administration. Number of patients analyzed = 157 and 157 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting Plasma Insulin (FPI) [1]; Mean (Standard Deviation); Unit of measure: Picomole/liter (pmol/L)
	Number Analyzed	158 participants	161 participants	319 participants
		108.56 (82.03)	106.99 (82.69)	107.76 (82.23)
		[1] Measure Description: Here, number of patients analyzed = 149 and 154 for lixisenatide and sitagliptin treatment arm, respectively.
2-hour Postprandial Plasma Insulin [1]; Mean (Standard Deviation); Unit of measure: pmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		424.67 (350.96)	420.45 (302.17)	422.56 (327.02)
		[1] Measure Description: Here, number of patients analyzed = 152 and 151 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting C-Peptide [1]; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		1.19 (0.51)	1.20 (0.52)	1.20 (0.52)
		[1] Measure Description: Here, number of patients analyzed = 154 and 156 for lixisenatide and sitagliptin treatment arm, respectively.
2-hour Postprandial C-peptide [1]; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		2.79 (1.28)	2.92 (1.35)	2.86 (1.32)
		[1] Measure Description: Here, number of patients analyzed = 154 and 156 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting Glucagon [1]; Mean (Standard Deviation); Unit of measure: Nanogram/liter (ng/L)
	Number Analyzed	158 participants	161 participants	319 participants
		59.12 (15.81)	59.43 (20.53)	59.28 (18.32)
		[1] Measure Description: Here, number of patients analyzed = 154 and 157 for lixisenatide and sitagliptin treatment arm, respectively.
2-hour Postprandial Glucagon [1]; Mean (Standard Deviation); Unit of measure: ng/L
	Number Analyzed	158 participants	161 participants	319 participants
		66.36 (17.58)	67.72 (25.77)	67.04 (22.05)
		[1] Measure Description: Here, number of patients analyzed = 154 and 155 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting Proinsulin [1]; Mean (Standard Deviation); Unit of measure: pmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		45.06 (39.50)	44.62 (36.42)	44.83 (37.91)
		[1] Measure Description: Here, number of patients analyzed = 154 and 157 for lixisenatide and sitagliptin treatment arm, respectively.
2-hour Postprandial Proinsulin [1]; Mean (Standard Deviation); Unit of measure: pmol/L
	Number Analyzed	158 participants	161 participants	319 participants
		105.50 (75.38)	105.51 (74.00)	105.51 (74.57)
		[1] Measure Description: Here, number of patients analyzed = 154 and 156 for lixisenatide and sitagliptin treatment arm, respectively.
Fasting Proinsulin-to-Insulin Ratio [1]; Mean (Standard Deviation); Unit of measure: Ratio
	Number Analyzed	158 participants	161 participants	319 participants
		0.53 (0.70)	0.59 (0.73)	0.56 (0.71)
		[1] Measure Description: Here, number of patients analyzed = 149 and 154 for lixisenatide and sitagliptin treatment arm, respectively.
2-hour Postprandial Proinsulin-to-Insulin Ratio [1]; Mean (Standard Deviation); Unit of measure: Ratio
	Number Analyzed	158 participants	161 participants	319 participants
		0.36 (0.53)	0.32 (0.24)	0.34 (0.41)
		[1] Measure Description: Here, number of patients analyzed = 152 and 151 for lixisenatide and sitagliptin treatment arm, respectively.
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [1]; Mean (Standard Deviation); Unit of measure: Milliunit * mmol /liter^2(mU * mmol/L^2)
	Number Analyzed	158 participants	161 participants	319 participants
		6.30 (5.08)	6.26 (5.32)	6.28 (5.20)
		[1] Measure Description: HOMA-IR was derived from FPG and FPI as: (FPI [micro units per milliliter] * FPG [mmol/L]) divided by 22.5. Here, number of patients analyzed = 148 and 154 for lixisenatide and sitagliptin treatment arm, respectively.
Homeostatic Model Assessment of Beta-cell Function (HOMA-beta) [1]; Mean (Standard Deviation); Unit of measure: Percentage of normal beta cells function
	Number Analyzed	158 participants	161 participants	319 participants
		62.01 (59.78)	60.74 (50.80)	61.36 (55.29)
		[1] Measure Description: HOMA-beta was derived from FPG and FPI as: (20 * FPI [micro units/milliliter]) divided by (FPG [mmol/L] minus 3.5). Here, number of patients analyzed = 148 and 154 for lixisenatide and sitagliptin treatment arm, respectively.

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24
Description	Percentage of patients who met both criteria (HbA1c <7% at Week 24 and at least 5% weight loss from baseline at Week 24) is reported. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

mITT population included randomized patients who received at least 1 dose of study drug. Missing data was imputed using Last observation carried forward (LOCF).

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	158	161
Measure Type: Number; Unit of Measure: percentage of participants
	12.0	7.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lixisenatide, Sitagliptin
	Comments	To demonstrate the superiority of lixisenatide over sitagliptin, 150 patients in each arm would provide a power of 90% with a 2-sided test at the 5% significance level, assuming the percentage of patients defined as responders on HbA1c (<7%) and weight (at least 5% loss) is 25% with lixisenatide and 10% with sitagliptin.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1696
	Comments	Cochran-Mantel-Haenszel (CMH) test stratified by randomization strata of screening HbA1c (<8.0 or >=8.0%) and randomization strata of screening BMI (<35 or >=35 kg/m^2) was used.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Response rate difference
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; -1.84 to 11.00
	Parameter Dispersion	Type: Standard Error of the mean; Value: 3.28
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Absolute Change From Baseline in HbA1c at Week 24
Description	Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	150	160
Least Squares Mean (Standard Error); Unit of Measure: percentage of hemoglobin
	-0.66 (0.094)	-0.72 (0.097)

3. Secondary Outcome

Title	Change From Baseline in Body Weight at Week 24
Description	Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	152	160
Least Squares Mean (Standard Error); Unit of Measure: kilogram
	-2.51 (0.294)	-1.17 (0.304)

4. Secondary Outcome

Title	Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24
Description	The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	129	139
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-3.35 (0.377)	-1.44 (0.384)

5. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Description	Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	153	161
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-0.45 (0.193)	-0.69 (0.198)

6. Secondary Outcome

Title	Change From Baseline in Glucose Excursion at Week 24
Description	Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucose excursion assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	127	139
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-2.55 (0.272)	-0.42 (0.275)

7. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24
Description	Change was calculated for fasting plasma insulin and 2-hour post prandial plasma insulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline plasma insulin assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	123	133
Least Squares Mean (Standard Error); Unit of Measure: pmol/L
FPI (n=119, 133)	-1.70 (6.789)	-0.88 (7.020)
2-hour PPI (n=123, 130)	-57.81 (22.788)	-2.85 (23.309)

8. Secondary Outcome

Title	Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24
Description	Change was calculated for fasting C-peptide and 2-hour postprandial C-peptide by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline C-peptide assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	125	139
Least Squares Mean (Standard Error); Unit of Measure: nmol/L
Fasting C-peptide (n= 123,139)	-0.02 (0.039)	-0.02 (0.038)
2-hour postprandial C-peptide (n=125, 139)	-0.15 (0.100)	0.08 (0.101)

9. Secondary Outcome

Title	Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24
Description	Change was calculated for fasting glucagon and 2-hour postprandial glucagon by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucagon assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	124	138
Least Squares Mean (Standard Error); Unit of Measure: ng/L
Fasting Glucagon (n=124, 138)	1.89 (1.667)	3.52 (1.661)
2-hour postprandial Glucagon (n=124, 134)	-8.16 (1.801)	-4.38 (1.824)

10. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24
Description	Change was calculated for fasting proinsulin and 2-hour postprandial proinsulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of the study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline proinsulin assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	125	140
Least Squares Mean (Standard Error); Unit of Measure: pmol/L
Fasting Proinsulin (n=125, 140)	-2.18 (3.172)	-4.84 (3.154)
2-hour postprandial Proinsulin (n=125, 139)	0.28 (6.502)	-3.95 (6.477)

11. Secondary Outcome

Title	Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24
Description	HOMA-IR was derived from FPG and FPI as: (FPI [micro units per milliliter]*FPG [mmol/L]) divided by 22.5. Change was calculated for HOMA-IR by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HOMA-IR assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	118	133
Least Squares Mean (Standard Error); Unit of Measure: mU * mmol/L^2
	-0.52 (0.366)	-0.57 (0.378)

12. Secondary Outcome

Title	Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24
Description	HOMA-beta was derived from FPG and FPI as: (20*FPI [micro units/milliliter]) divided by (FPG [mmol/L] minus 3.5). Change was calculated for HOMA-beta by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HOMA-beta assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	118	133
Least Squares Mean (Standard Error); Unit of Measure: percentage of normal beta cells function
	17.66 (9.652)	17.79 (9.958)

13. Secondary Outcome

Title	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24
Description	The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	150	160
Measure Type: Number; Unit of Measure: percentage of participants
	24.0	26.3

14. Secondary Outcome

Title	Percentage of Patients Requiring Rescue Therapy During 24-Week Period
Description	Routine fasting self-measured plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%.
Time Frame	Baseline up to Week 24

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	158	161
Measure Type: Number; Unit of Measure: percentage of participants
	9.5	6.8

15. Other Pre-specified Outcome

Title	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24
Description	The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	150	160
Measure Type: Number; Unit of Measure: percentage of participants
	40.7	40.0

16. Other Pre-specified Outcome

Title	Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24
Description	The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	152	160
Measure Type: Number; Unit of Measure: percentage of participants
	18.4	11.9

17. Other Pre-specified Outcome

Title	Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24
Description	Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline proinsulin-to-insulin ratio assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	123	133
Least Squares Mean (Standard Error); Unit of Measure: ratio
Fasting Proinsulin-to-insulin ratio (n=119, 133)	-0.08 (0.035)	-0.17 (0.036)
2-hour PP Proinsulin-to-insulin ratio (n=123, 130)	-0.01 (0.025)	-0.05 (0.026)

18. Other Pre-specified Outcome

Title	Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia
Description	Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.
Time Frame	First dose of study drug up to 3 days after the last dose administration

Outcome Measure Data

Analysis Population Description

Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.

Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description:	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
Overall Number of Participants Analyzed	158	161
Measure Type: Number; Unit of Measure: participants
Symptomatic hypoglycemia	1	3
Severe symptomatic hypoglycemia	0	0

Adverse Events

Time Frame	First dose of study drug up to 3 days after the last dose administration
Adverse Event Reporting Description	Median exposure to study treatment was 169.0 days in both lixisenatide and sitagliptin treatment arm. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Arm/Group Title	Lixisenatide	Sitagliptin
Arm/Group Description	2-step initiation regimen of lixisenatide along with sitagliptin placebo.	Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo.
All-Cause Mortality
	Lixisenatide	Sitagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Lixisenatide	Sitagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	3/158 (1.90%)	3/161 (1.86%)
Hepatobiliary disorders
Bile duct stone * 1	0/158 (0.00%)	1/161 (0.62%)
Immune system disorders
Anaphylactic reaction * 1	1/158 (0.63%)	0/161 (0.00%)
Infections and infestations
Abscess limb * 1	0/158 (0.00%)	1/161 (0.62%)
Renal and urinary disorders
Nephrolithiasis * 1	1/158 (0.63%)	0/161 (0.00%)
Renal failure * 1	0/158 (0.00%)	1/161 (0.62%)
Vascular disorders
Arteriovenous fistula * 1	1/158 (0.63%)	0/161 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 13.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lixisenatide	Sitagliptin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	54/158 (34.18%)	45/161 (27.95%)
Gastrointestinal disorders
Diarrhoea * 1	14/158 (8.86%)	12/161 (7.45%)
Nausea * 1	28/158 (17.72%)	11/161 (6.83%)
Infections and infestations
Influenza * 1	8/158 (5.06%)	5/161 (3.11%)
Nasopharyngitis * 1	10/158 (6.33%)	12/161 (7.45%)
Nervous system disorders
Dizziness * 1	8/158 (5.06%)	5/161 (3.11%)
Headache * 1	20/158 (12.66%)	15/161 (9.32%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 13.1

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 of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.

Results Point of Contact

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

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00976937
• Other Study ID Numbers: EFC10780; EudraCT:2008-007 334-22
• First Submitted: September 14, 2009
• First Posted: September 15, 2009
• Results First Submitted: August 18, 2016
• Results First Posted: October 11, 2016
• Last Update Posted: October 11, 2016