Trial Outcomes & Findings for Efficacy and Safety of Lixisenatide Versus Insulin Glulisine on Top of Insulin Glargine With or Without Metformin in Type 2 Diabetic Patients (NCT NCT01768559)

Last Updated: 2017-01-04

Results Overview

Change in HbA1C was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

894 participants

Primary outcome timeframe

Baseline, Week 26

Results posted on

2017-01-04

Participant Flow

The study was conducted at 199 centers in 18 countries. A total of 2159 participants were screened between January 08, 2013 and April 10, 2014.

Participants underwent a 12-week run-in period with switch from other basal insulins to insulin glargine. A total of 1265 participants were screen failures/run-in failures; the most frequent reason for run-in failure was that glycosylated hemoglobin (HbA1c) criteria were not met at the end of run-in phase. 894 participants were randomized.

Participant milestones

Participant milestones
Measure	Lixisenatide Lixisenatide 10 mcg once daily (QD) subcutaneously (SC) for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD Insulin glulisine QD SC up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine TID Insulin glulisine thrice daily (TID) SC up to Week 26 on top of insulin glargine with or without metformin.
Overall Study STARTED	298	298	298
Overall Study Treated	298	298	297
Overall Study COMPLETED	268	281	285
Overall Study NOT COMPLETED	30	17	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Lixisenatide Lixisenatide 10 mcg once daily (QD) subcutaneously (SC) for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD Insulin glulisine QD SC up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine TID Insulin glulisine thrice daily (TID) SC up to Week 26 on top of insulin glargine with or without metformin.
Overall Study Randomized but not treated	0	0	1
Overall Study Adverse Event	15	2	5
Overall Study Lack of Efficacy	6	4	0
Overall Study Poor compliance to protocol	0	3	2
Overall Study Other than specified	9	8	5

Baseline Characteristics

Efficacy and Safety of Lixisenatide Versus Insulin Glulisine on Top of Insulin Glargine With or Without Metformin in Type 2 Diabetic Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lixisenatide n=298 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=298 Participants Insulin glulisine QD SC up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine TID n=298 Participants Insulin glulisine TID SC up to Week 26 on top of insulin glargine with or without metformin.	Total n=894 Participants Total of all reporting groups
Age, Continuous	59.8 years STANDARD_DEVIATION 8.6 • n=5 Participants	60.2 years STANDARD_DEVIATION 8.6 • n=7 Participants	59.4 years STANDARD_DEVIATION 9.5 • n=5 Participants	59.8 years STANDARD_DEVIATION 8.9 • n=4 Participants
Gender Female	160 Participants n=5 Participants	163 Participants n=7 Participants	166 Participants n=5 Participants	489 Participants n=4 Participants
Gender Male	138 Participants n=5 Participants	135 Participants n=7 Participants	132 Participants n=5 Participants	405 Participants n=4 Participants
Race Caucasian/White	276 participants n=5 Participants	280 participants n=7 Participants	272 participants n=5 Participants	828 participants n=4 Participants
Race Black	13 participants n=5 Participants	11 participants n=7 Participants	12 participants n=5 Participants	36 participants n=4 Participants
Race Asian/Oriental	9 participants n=5 Participants	7 participants n=7 Participants	13 participants n=5 Participants	29 participants n=4 Participants
Race Other	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Ethnicity Hispanic	63 participants n=5 Participants	58 participants n=7 Participants	68 participants n=5 Participants	189 participants n=4 Participants
Ethnicity Non-Hispanic	235 participants n=5 Participants	240 participants n=7 Participants	230 participants n=5 Participants	705 participants n=4 Participants
Metformin Use at Screening Yes	262 participants n=5 Participants	260 participants n=7 Participants	259 participants n=5 Participants	781 participants n=4 Participants
Metformin Use at Screening No	36 participants n=5 Participants	38 participants n=7 Participants	39 participants n=5 Participants	113 participants n=4 Participants
Number of Participants with Categorical Body Mass Index (BMI) <30 kg/m^2	97 participants n=5 Participants	118 participants n=7 Participants	97 participants n=5 Participants	312 participants n=4 Participants
Number of Participants with Categorical Body Mass Index (BMI) ≥30 kg/m^2	201 participants n=5 Participants	180 participants n=7 Participants	200 participants n=5 Participants	581 participants n=4 Participants
Number of Participants with Categorical Body Mass Index (BMI) Participants not analyzed for BMI	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
BMI	32.27 kg/m^2 STANDARD_DEVIATION 4.57 • n=5 Participants	31.86 kg/m^2 STANDARD_DEVIATION 4.39 • n=7 Participants	32.50 kg/m^2 STANDARD_DEVIATION 4.60 • n=5 Participants	32.21 kg/m^2 STANDARD_DEVIATION 4.52 • n=4 Participants
Weight	90.06 kg STANDARD_DEVIATION 17.31 • n=5 Participants	88.45 kg STANDARD_DEVIATION 15.84 • n=7 Participants	90.08 kg STANDARD_DEVIATION 17.18 • n=5 Participants	89.53 kg STANDARD_DEVIATION 16.79 • n=4 Participants
HbA1c	7.77 percentage of hemoglobin STANDARD_DEVIATION 0.55 • n=5 Participants	7.73 percentage of hemoglobin STANDARD_DEVIATION 0.59 • n=7 Participants	7.79 percentage of hemoglobin STANDARD_DEVIATION 0.60 • n=5 Participants	7.76 percentage of hemoglobin STANDARD_DEVIATION 0.58 • n=4 Participants
Fasting Plasma Glucose (FPG)	6.58 mmol/L STANDARD_DEVIATION 1.82 • n=5 Participants	6.84 mmol/L STANDARD_DEVIATION 1.98 • n=7 Participants	6.65 mmol/L STANDARD_DEVIATION 1.89 • n=5 Participants	6.69 mmol/L STANDARD_DEVIATION 1.90 • n=4 Participants
2-Hour Postprandial Plasma Glucose (PPG)	14.26 mmol/L STANDARD_DEVIATION 3.55 • n=5 Participants	14.02 mmol/L STANDARD_DEVIATION 3.59 • n=7 Participants	14.25 mmol/L STANDARD_DEVIATION 3.35 • n=5 Participants	14.18 mmol/L STANDARD_DEVIATION 3.47 • n=4 Participants
2-Hour Glucose Excursion	7.31 mmol/L STANDARD_DEVIATION 3.19 • n=5 Participants	7.31 mmol/L STANDARD_DEVIATION 3.63 • n=7 Participants	7.35 mmol/L STANDARD_DEVIATION 3.34 • n=5 Participants	7.33 mmol/L STANDARD_DEVIATION 3.37 • n=4 Participants
Average 7-Point Self-monitored Plasma Glucose (SMPG)	9.02 mmol/L STANDARD_DEVIATION 1.75 • n=5 Participants	9.07 mmol/L STANDARD_DEVIATION 1.74 • n=7 Participants	8.99 mmol/L STANDARD_DEVIATION 1.57 • n=5 Participants	9.02 mmol/L STANDARD_DEVIATION 1.68 • n=4 Participants
Insulin Glargine Dose	67.25 Units (U) STANDARD_DEVIATION 31.95 • n=5 Participants	64.72 Units (U) STANDARD_DEVIATION 32.07 • n=7 Participants	64.97 Units (U) STANDARD_DEVIATION 26.90 • n=5 Participants	65.65 Units (U) STANDARD_DEVIATION 30.39 • n=4 Participants
Duration of Diabetes	11.89 years STANDARD_DEVIATION 6.43 • n=5 Participants	12.33 years STANDARD_DEVIATION 6.75 • n=7 Participants	12.41 years STANDARD_DEVIATION 6.80 • n=5 Participants	12.21 years STANDARD_DEVIATION 6.66 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Week 26

Population: modified intent-to-treat (mITT) population: all randomized participants who received at least one dose of study drug; and had both baseline and at least one post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures.

Outcome measures

Outcome measures
Measure	Lixisenatide n=292 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=292 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in HbA1c From Baseline to Week 26	-0.63 percentage of hemoglobin Standard Error 0.054	-0.58 percentage of hemoglobin Standard Error 0.054	-0.84 percentage of hemoglobin Standard Error 0.053

PRIMARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.

Primary outcome was the comparison between Lixisenatide versus Insulin Glulisine TID. Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=295 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in Body Weight From Baseline to Week 26	-0.63 kg Standard Error 0.276	1.03 kg Standard Error 0.276	1.37 kg Standard Error 0.271

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.

The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Missing data was imputed using LOCF.

Outcome measures

Outcome measures
Measure	Lixisenatide n=292 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=292 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 HbA1c <7.0%	42.1 percentage of participants	38.4 percentage of participants	49.2 percentage of participants
Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 HbA1c ≤6.5%	20.5 percentage of participants	17.8 percentage of participants	30.8 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.

The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 3 days after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=295 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants With no Weight Gain at Week 26	64.7 percentage of participants	36.6 percentage of participants	30.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period.

Participants recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime three times in a week before baseline, before visit Week 12 and before visit week 26 and the average value across the profiles performed in the week a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=270 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=268 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=278 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in Average 7-point SMPG Profiles From Baseline to Week 26	-0.784 mmol/L Standard Error 0.1141	-0.782 mmol/L Standard Error 0.1133	-1.053 mmol/L Standard Error 0.1105

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment during on-treatment period.

Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=295 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=294 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in FPG From Baseline to Week 26	-0.23 mmol/L Standard Error 0.143	-0.21 mmol/L Standard Error 0.142	-0.06 mmol/L Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with IMP injection before breakfast and baseline and at least one post-baseline 2-hour PPG assessment during on-treatment period.

The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=69 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=55 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=68 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast)	-3.93 mmol/L Standard Deviation 4.29	-1.62 mmol/L Standard Deviation 4.01	-1.87 mmol/L Standard Deviation 3.18

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with IMP injection before breakfast and baseline and at least one post-baseline glucose excursion assessment during on-treatment period.

Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change in glucose excursions was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=64 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=53 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=66 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast)	-3.42 mmol/L Standard Deviation 4.13	-1.59 mmol/L Standard Deviation 3.42	-1.56 mmol/L Standard Deviation 2.52

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline insulin glargine dose assessment during on-treatment period.

Change in Insulin glargine dose was calculated by subtracting the baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=292 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=294 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=294 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Change in Insulin Glargine Dose From Baseline to Week 26	0.7 U Standard Error 1.002	-0.06 U Standard Error 0.999	-3.13 U Standard Error 0.982

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline insulin glulisine dose assessment during on-treatment period.

The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=293 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Insulin Glulisine Dose at Week 26	9.97 U Standard Deviation 7.8	20.24 U Standard Deviation 13.04	—

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline total insulin dose assessment during on-treatment period.

The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. The outcome is reporting results of total insulin (amounts of Insulin Glargine plus Insulin Glulisine ) only for the arms in which Insulin Glulisine was administered and is not applicable for the lixisenatide arm in which only Insulin Glargine is administered. Change in dose of the insulin used by patients in the Lixisenatide arm (i.e. Insulin Glargine) is reported in the secondary Outcome Measure 9.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=294 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Total Insulin Dose at Week 26	73.61 U Standard Deviation 39.13	81.05 U Standard Deviation 33.55	—

SECONDARY outcome

Timeframe: First dose of study drug up to 3 days after the last dose administration (maximum of 185 days)

Population: All randomized participants who were exposed to at least one dose of study drug, regardless of the amount of treatment administered. The 4 participants in the TID group who received Insulin Glulisine QD were analyzed according to the QD dose.The 1 participant in the QD group who received Insulin Glulisine TID was analyzed according to the TID dose

Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<60 mg/dL (3.3 mmol/L). Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the participant 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.

Outcome measures

Outcome measures
Measure	Lixisenatide n=298 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=301 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=294 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia Documented symptomatic hypoglycemia	31.5 percentage of participants	37.5 percentage of participants	44.6 percentage of participants
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia Severe symptomatic hypoglycemia	0 percentage of participants	0.7 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing.

The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug.

Outcome measures

Outcome measures
Measure	Lixisenatide n=296 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=293 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period	29.4 percentage of participants	24.2 percentage of participants	26.1 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: mITT population. Participants without post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response. Otherwise, they were counted as missing data.

Outcome measures

Outcome measures
Measure	Lixisenatide n=295 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=293 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26	31.2 percentage of participants	16.7 percentage of participants	17.6 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: mITT population.Participants without post-baseline on-treatment values(HbA1c;body weight),no more than 30 days apart counted as non-responders if at least one of components(HbA1c;body weight) was available,showed non-response or experienced at least one symptomatic hypoglycemia during on-treatment period.Otherwise,they were counted as missing data.

The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. Participants without post-baseline on-treatment values (HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response, or if they experienced at least one documented symptomatic hypoglycemia during the on-treatment period. Otherwise, they were counted as missing data.

Outcome measures

Outcome measures
Measure	Lixisenatide n=297 Participants Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.	Insulin Glulisine QD n=294 Participants Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin.	Insulin Glulisine TID n=295 Participants Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin.
Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period	22.2 percentage of participants	9.2 percentage of participants	10.8 percentage of participants

Adverse Events

Lixisenatide

Serious events: 11 serious events

Other events: 183 other events

Deaths: 0 deaths

Insulin Glulisine QD

Serious events: 11 serious events

Other events: 186 other events

Deaths: 0 deaths

Insulin Glulisine TID

Serious events: 14 serious events

Other events: 195 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Lixisenatide n=298 participants at risk Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin (Median exposure of 182 days).	Insulin Glulisine QD n=301 participants at risk Insulin glulisine QD SC up to Week 26 on top of Insulin glargine with or without metformin (Median exposure of 182 days).	Insulin Glulisine TID n=294 participants at risk Insulin glulisine TID SC up to Week 26 on top of Insulin glargine with or without metformin (Median exposure of 182 days).
Infections and infestations Nasopharyngitis	4.7% 14/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	7.0% 21/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	6.1% 18/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Metabolism and nutrition disorders Hypoglycaemia	35.9% 107/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	46.5% 140/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	52.4% 154/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Nervous system disorders Headache	6.7% 20/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	2.7% 8/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	4.1% 12/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Gastrointestinal disorders Nausea	25.2% 75/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	1.7% 5/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	1.0% 3/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Gastrointestinal disorders Vomiting	8.7% 26/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	1.7% 5/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	2.0% 6/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Gastrointestinal disorders Diarrhoea	6.7% 20/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	3.3% 10/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	1.4% 4/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Investigations Blood glucose decreased	20.1% 60/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	22.3% 67/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	27.9% 82/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/298 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	4.0% 12/301 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.	6.8% 20/294 • All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 185) regardless of seriousness or relationship to IMP. Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population. 4 participants randomized to TID group, but received insulin glulisine QD were analyzed according to the QD dose. 1 participant randomized to QD group, but received insulin glulisine TID was analyzed according to the TID dose.

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER