Trial Outcomes & Findings for GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea (NCT NCT00713830)

Last Updated: 2016-12-14

Results Overview

Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in Modified Intent-to-Treat (mITT) population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

859 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2016-12-14

Participant Flow

The study was conducted at 136 centers in 16 countries between July 08, 2008 and January 14, 2011. The overall duration of treatment was at least 76 weeks (24 weeks main double-blind treatment; variable double-blind extension treatment).

A total of 1438 participants were screened of which 579 (40.3%) 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 859 participants were randomized.

Participant milestones

Participant milestones
Measure	Placebo 2-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Lixisenatide 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.
Overall Study STARTED	286	573
Overall Study Modified Intent-to-Treat(mITT)Population	286	570
Overall Study Safety Population	285	574
Overall Study Subgroup for Standardized Meal Test	155	313
Overall Study COMPLETED	204	396
Overall Study NOT COMPLETED	82	177

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 2-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Lixisenatide 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.
Overall Study Adverse Event	23	71
Overall Study Lack of Efficacy	24	16
Overall Study Lost to Follow-up	2	9
Overall Study Withdrawal by Subject	13	23
Overall Study Poor Compliance to Protocol	7	14
Overall Study Familial and Personal Reasons	9	34
Overall Study Sponsor Decision	4	10

Baseline Characteristics

GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=285 Participants 2-step initiation regimen of volume matching placebo: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Lixisenatide n=574 Participants 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Total n=859 Participants Total of all reporting groups
Age, Continuous	57.8 years STANDARD_DEVIATION 10.1 • n=5 Participants	57.0 years STANDARD_DEVIATION 9.8 • n=7 Participants	57.2 years STANDARD_DEVIATION 9.9 • n=5 Participants
Sex: Female, Male Female	135 Participants n=5 Participants	290 Participants n=7 Participants	425 Participants n=5 Participants
Sex: Female, Male Male	150 Participants n=5 Participants	284 Participants n=7 Participants	434 Participants n=5 Participants
Race/Ethnicity, Customized Race: Caucasian/White	151 participants n=5 Participants	297 participants n=7 Participants	448 participants n=5 Participants
Race/Ethnicity, Customized Race: Black	9 participants n=5 Participants	17 participants n=7 Participants	26 participants n=5 Participants
Race/Ethnicity, Customized Race: Asian/Oriental	125 participants n=5 Participants	260 participants n=7 Participants	385 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic	5 participants n=5 Participants	18 participants n=7 Participants	23 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Non Hispanic	280 participants n=5 Participants	556 participants n=7 Participants	836 participants n=5 Participants
Glycosylated Hemoglobin (HbA1c)	8.21 percentage of hemoglobin STANDARD_DEVIATION 0.84 • n=5 Participants	8.28 percentage of hemoglobin STANDARD_DEVIATION 0.86 • n=7 Participants	8.25 percentage of hemoglobin STANDARD_DEVIATION 0.85 • n=5 Participants
2-Hour Postprandial Plasma Glucose (PPG)	16.44 millimole per liter (mmol/L) STANDARD_DEVIATION 3.74 • n=5 Participants	16.69 millimole per liter (mmol/L) STANDARD_DEVIATION 4.02 • n=7 Participants	16.60 millimole per liter (mmol/L) STANDARD_DEVIATION 3.92 • n=5 Participants
Fasting Plasma Glucose (FPG)	9.29 mmol/L STANDARD_DEVIATION 2.37 • n=5 Participants	9.67 mmol/L STANDARD_DEVIATION 2.24 • n=7 Participants	9.55 mmol/L STANDARD_DEVIATION 2.29 • n=5 Participants
Body Weight	84.42 kilogram (kg) STANDARD_DEVIATION 22.83 • n=5 Participants	82.30 kilogram (kg) STANDARD_DEVIATION 21.76 • n=7 Participants	83.00 kilogram (kg) STANDARD_DEVIATION 22.13 • n=5 Participants
Homeostasis Model Assessment for Beta-cell Function (HOMA-beta)	36.43 percentage of normal beta cells function STANDARD_DEVIATION 39.43 • n=5 Participants	34.28 percentage of normal beta cells function STANDARD_DEVIATION 69.82 • n=7 Participants	34.99 percentage of normal beta cells function STANDARD_DEVIATION 61.39 • n=5 Participants
Fasting glucagon	0.89 nanogram per liter (ng/L) STANDARD_DEVIATION 0.55 • n=5 Participants	0.83 nanogram per liter (ng/L) STANDARD_DEVIATION 0.43 • n=7 Participants	0.85 nanogram per liter (ng/L) STANDARD_DEVIATION 0.47 • n=5 Participants
2-hour postprandial glucagon	102.27 ng/L STANDARD_DEVIATION 39.37 • n=5 Participants	97.83 ng/L STANDARD_DEVIATION 31.94 • n=7 Participants	99.31 ng/L STANDARD_DEVIATION 34.60 • n=5 Participants
Fasting plasma insulin (FPI)	66.89 picomole per liter (pmol/L) STANDARD_DEVIATION 63.92 • n=5 Participants	61.34 picomole per liter (pmol/L) STANDARD_DEVIATION 52.63 • n=7 Participants	63.18 picomole per liter (pmol/L) STANDARD_DEVIATION 56.61 • n=5 Participants
2-hour postprandial plasma insulin	281.26 pmol/L STANDARD_DEVIATION 243.56 • n=5 Participants	259.44 pmol/L STANDARD_DEVIATION 182.64 • n=7 Participants	266.76 pmol/L STANDARD_DEVIATION 205.09 • n=5 Participants
Fasting proinsulin	34.39 pmol/L STANDARD_DEVIATION 32.61 • n=5 Participants	33.35 pmol/L STANDARD_DEVIATION 27.43 • n=7 Participants	33.69 pmol/L STANDARD_DEVIATION 29.17 • n=5 Participants
2-hour postprandial proinsulin	61.73 pmol/L STANDARD_DEVIATION 46.48 • n=5 Participants	62.12 pmol/L STANDARD_DEVIATION 44.80 • n=7 Participants	61.99 pmol/L STANDARD_DEVIATION 45.31 • n=5 Participants
Fasting C-peptide	0.89 mmol/L STANDARD_DEVIATION 0.55 • n=5 Participants	0.83 mmol/L STANDARD_DEVIATION 0.43 • n=7 Participants	0.85 mmol/L STANDARD_DEVIATION 0.47 • n=5 Participants
2-hour postprandial C-peptide	2.12 mmol/L STANDARD_DEVIATION 1.05 • n=5 Participants	1.99 mmol/L STANDARD_DEVIATION 0.90 • n=7 Participants	2.03 mmol/L STANDARD_DEVIATION 0.95 • n=5 Participants
Glucose Excursion	6.84 mmol/L STANDARD_DEVIATION 3.78 • n=5 Participants	6.99 mmol/L STANDARD_DEVIATION 3.71 • n=7 Participants	6.94 mmol/L STANDARD_DEVIATION 3.73 • n=5 Participants
Fasting proinsulin-to-insulin ratio	0.62 ratio STANDARD_DEVIATION 0.36 • n=5 Participants	0.70 ratio STANDARD_DEVIATION 0.57 • n=7 Participants	0.67 ratio STANDARD_DEVIATION 0.51 • n=5 Participants
2-hour postprandial proinsulin-to-insulin ratio	0.30 ratio STANDARD_DEVIATION 0.22 • n=5 Participants	0.32 ratio STANDARD_DEVIATION 0.24 • n=7 Participants	0.31 ratio STANDARD_DEVIATION 0.23 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: mITT population:all randomized patients who received at least 1 dose;had baseline,at least 1 post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Last observation carried forward used. Number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=544 Participants 2-step initiation regimen of lixisenatide.
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	-0.10 percentage of hemoglobin Standard Error 0.071	-0.85 percentage of hemoglobin Standard Error 0.061

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in mITT population. Missing data was imputed using last observation carried forward (LOCF). Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period.

The 2-hour PPG blood sample was drawn 2 hours after start of a standardized meal (standardized meal challenge test performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=120 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=249 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24	-0.21 mmol/L Standard Error 0.489	-6.19 mmol/L Standard Error 0.408

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: 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.

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=283 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=564 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	-0.36 mmol/L Standard Error 0.161	-0.99 mmol/L Standard Error 0.139

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: 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.

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=554 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Body Weight at Week 24	-0.93 kilogram Standard Error 0.234	-1.76 kilogram Standard Error 0.202

SECONDARY outcome

Timeframe: Baseline, Week 24

Beta cell function was assessed by HOMA-beta. HOMA-beta blood samples were drawn during a standardized meal challenge test (performed in selected sites). HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin \[micro unit per milliliter\]) divided by (FPG \[mmol/L\] minus 3.5). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=116 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=241 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24	6.63 % of normal beta cells function Standard Error 5.663	4.83 % of normal beta cells function Standard Error 4.686

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in 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.

The fasting glucagon and the 2-hour postprandial glucagon blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=114 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=238 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 Fasting glucagon (n=111, 238)	2.03 ng/L Standard Error 2.566	-2.10 ng/L Standard Error 2.081
Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 2-hour postprandial glucagon (n=114, 234)	-1.19 ng/L Standard Error 2.999	-23.33 ng/L Standard Error 2.500

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in 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.

The fasting plasma insulin and the 2-hour postprandial plasma insulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=120 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=244 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 FPI (n=117, 242)	1.42 pmol/L Standard Error 6.587	-4.03 pmol/L Standard Error 5.445
Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 2-hour postprandial plasma insulin (n=120, 244)	-2.22 pmol/L Standard Error 18.754	-67.67 pmol/L Standard Error 15.944

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in 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.

The fasting Proinsulin and the 2-hour postprandial Proinsulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=97 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=205 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 Fasting proinsulin (n=97, 205)	-1.05 pmol/L Standard Error 1.983	-6.33 pmol/L Standard Error 1.671
Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 2-hour postprandial proinsulin (n=93, 193)	3.55 pmol/L Standard Error 4.200	-4.20 pmol/L Standard Error 3.550

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in 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.

The fasting C-peptide and the 2-hour postprandial C-peptide blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy.For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=119 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=248 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 Fasting C-peptide (n=117, 244)	-0.06 nmol/L Standard Error 0.038	-0.07 nmol/L Standard Error 0.031
Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 2-hour postprandial C-peptide (n=119, 248)	-0.14 nmol/L Standard Error 0.087	-0.37 nmol/L Standard Error 0.072

SECONDARY outcome

Timeframe: Week 24

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

The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=544 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24	13.5 percentage of participants	36.4 percentage of participants

SECONDARY outcome

Timeframe: Week 24

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

Outcome measures

Outcome measures
Measure	Placebo n=274 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=544 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24	4.7 percentage of participants	19.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: mITT population.

Routine fasting self-monitored 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%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=286 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=570 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period	12.6 percentage of participants	4.0 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test (performed in selected sites), before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=120 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=249 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Glucose Excursion at Week 24	0.35 mmol/L Standard Error 0.432	-5.22 mmol/L Standard Error 0.360

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

Population: Subgroup for standardized meal test in mITT population. Missing data imputed using LOCF. 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 specific category.

The fasting proinsulin-to-insulin ratio and 2-hour postprandial proinsulin-to-insulin ratio were measured during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Outcome measures

Outcome measures
Measure	Placebo n=95 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=199 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 Fasting proinsulin-to-insulin ratio (n=95, 199)	-0.04 ratio Standard Error 0.049	-0.13 ratio Standard Error 0.043
Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 2-hour postprandial ratio (n=92, 190)	0.01 ratio Standard Error 0.060	0.16 ratio Standard Error 0.053

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 24

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

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=554 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	7.2 percentage of participants	14.4 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks

Population: Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group

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.

Outcome measures

Outcome measures
Measure	Placebo n=285 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=574 Participants 2-step initiation regimen of lixisenatide.
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Symptomatic hypoglycemia	51 participants	127 participants
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Severe symptomatic hypoglycemia	1 participants	2 participants

Adverse Events

Placebo

Serious events: 35 serious events

Other events: 148 other events

Deaths: 0 deaths

Lixisenatide

Serious events: 58 serious events

Other events: 362 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=285 participants at risk 2-step initiation regimen of volume matching placebo.	Lixisenatide n=574 participants at risk 2-step initiation regimen of lixisenatide.
Infections and infestations Influenza	3.9% 11/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	5.2% 30/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Infections and infestations Nasopharyngitis	20.4% 58/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	15.9% 91/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Infections and infestations Upper respiratory tract infection	7.4% 21/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	7.5% 43/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Metabolism and nutrition disorders Hypoglycaemia	19.3% 55/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	24.4% 140/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Nervous system disorders Dizziness	6.3% 18/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	10.5% 60/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Nervous system disorders Headache	7.0% 20/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	7.7% 44/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Gastrointestinal disorders Constipation	3.9% 11/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	5.2% 30/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Gastrointestinal disorders Diarrhoea	9.5% 27/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	12.4% 71/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Gastrointestinal disorders Dyspepsia	1.4% 4/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	5.9% 34/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Gastrointestinal disorders Nausea	8.8% 25/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	28.0% 161/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Gastrointestinal disorders Vomiting	5.3% 15/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	10.6% 61/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Musculoskeletal and connective tissue disorders Back pain	4.2% 12/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	6.3% 36/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
Investigations Blood glucose decreased	3.9% 11/285 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group	5.2% 30/574 • First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks Median exposure to study treatment was 617 and 610 days in placebo and lixisenatide treatment arms, respectively. 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. The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group

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