Trial Outcomes & Findings for GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Pioglitazone (NCT NCT00763815)

Last Updated: 2016-11-28

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 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

484 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2016-11-28

Participant Flow

The study was conducted at 150 centers in 13 countries between September 29, 2008 and June 29, 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 906 patients were screened of which 422 (46.6%) 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 484 patients 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	161	323
Overall Study Treated/Safety Population	161	323
Overall Study Modified Intent-to-Treat(mITT)Population	159	320
Overall Study COMPLETED	109	239
Overall Study NOT COMPLETED	52	84

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	14	29
Overall Study Lack of Efficacy	10	11
Overall Study Poor Compliance to Protocol	6	6
Overall Study Lost to Follow-up	2	4
Overall Study Early Termination	1	0
Overall Study Familial and Personal Reasons	9	16
Overall Study Physician Decision	1	0
Overall Study Withdrawal by Subject	7	12
Overall Study Protocol Violation	2	5
Overall Study Sponsor's Decision	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=161 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=323 Participants 2-step initiation regimen of lixisenatide: 10 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.	Total n=484 Participants Total of all reporting groups
Age, Continuous	55.3 years STANDARD_DEVIATION 9.5 • n=93 Participants	56.0 years STANDARD_DEVIATION 9.5 • n=4 Participants	55.8 years STANDARD_DEVIATION 9.5 • n=27 Participants
Sex: Female, Male Female	79 Participants n=93 Participants	151 Participants n=4 Participants	230 Participants n=27 Participants
Sex: Female, Male Male	82 Participants n=93 Participants	172 Participants n=4 Participants	254 Participants n=27 Participants
Race/Ethnicity, Customized Race: Caucasian/White	132 participants n=93 Participants	273 participants n=4 Participants	405 participants n=27 Participants
Race/Ethnicity, Customized Race: Black	9 participants n=93 Participants	14 participants n=4 Participants	23 participants n=27 Participants
Race/Ethnicity, Customized Race: Asian/Oriental	8 participants n=93 Participants	14 participants n=4 Participants	22 participants n=27 Participants
Race/Ethnicity, Customized Race: Other	12 participants n=93 Participants	22 participants n=4 Participants	34 participants n=27 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic	41 participants n=93 Participants	87 participants n=4 Participants	128 participants n=27 Participants
Race/Ethnicity, Customized Ethnicity: Non Hispanic	120 participants n=93 Participants	236 participants n=4 Participants	356 participants n=27 Participants
Glycosylated Hemoglobin (HbA1c)	8.06 percentage of hemoglobin STANDARD_DEVIATION 0.79 • n=93 Participants	8.08 percentage of hemoglobin STANDARD_DEVIATION 0.90 • n=4 Participants	8.07 percentage of hemoglobin STANDARD_DEVIATION 0.86 • n=27 Participants
Fasting Plasma Glucose (FPG)	9.13 millimole per liter (mmol/L) STANDARD_DEVIATION 2.20 • n=93 Participants	9.11 millimole per liter (mmol/L) STANDARD_DEVIATION 2.15 • n=4 Participants	9.12 millimole per liter (mmol/L) STANDARD_DEVIATION 2.16 • n=27 Participants
Body Weight	96.74 kilogram STANDARD_DEVIATION 25.58 • n=93 Participants	92.93 kilogram STANDARD_DEVIATION 22.90 • n=4 Participants	94.20 kilogram STANDARD_DEVIATION 23.87 • n=27 Participants
Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta)	36.23 percentage of normal beta cells function STANDARD_DEVIATION 26.50 • n=93 Participants	34.69 percentage of normal beta cells function STANDARD_DEVIATION 30.30 • n=4 Participants	35.18 percentage of normal beta cells function STANDARD_DEVIATION 29.12 • n=27 Participants
Fasting Plasma Insulin (FPI)	66.07 picomole per liter (pmol/L) STANDARD_DEVIATION 48.12 • n=93 Participants	63.32 picomole per liter (pmol/L) STANDARD_DEVIATION 57.69 • n=4 Participants	64.21 picomole per liter (pmol/L) STANDARD_DEVIATION 54.76 • n=27 Participants
Duration of Diabetes	8.09 years STANDARD_DEVIATION 5.58 • n=93 Participants	8.11 years STANDARD_DEVIATION 5.44 • n=4 Participants	8.10 years STANDARD_DEVIATION 5.48 • n=27 Participants
Duration of Pioglitazone Treatment	1.79 years STANDARD_DEVIATION 2.51 • n=93 Participants	1.69 years STANDARD_DEVIATION 2.00 • n=4 Participants	1.72 years STANDARD_DEVIATION 2.18 • n=27 Participants
Pioglitazone Daily Dose >=30 milligram (mg) to Less Than (<) 45 mg	126 participants n=93 Participants	242 participants n=4 Participants	368 participants n=27 Participants
Pioglitazone Daily Dose >= 45 mg	35 participants n=93 Participants	81 participants n=4 Participants	116 participants n=27 Participants
Metformin Use at Screening	131 participants n=93 Participants	261 participants n=4 Participants	392 participants n=27 Participants
Body Mass Index (BMI)	34.44 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.04 • n=93 Participants	33.66 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.71 • n=4 Participants	33.92 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.82 • n=27 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=148 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=308 Participants 2-step initiation regimen of lixisenatide.
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	-0.34 percentage of hemoglobin Standard Error 0.100	-0.90 percentage of hemoglobin Standard Error 0.089

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: 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 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=159 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=317 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	-0.32 mmol/L Standard Error 0.215	-1.16 mmol/L Standard Error 0.192

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=157 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=315 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Body Weight at Week 24	0.21 kilogram Standard Error 0.357	-0.21 kilogram Standard Error 0.324

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 FPI assessment during on-treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=125 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=281 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Fasting Plasma Insulin (FPI) at Week 24	-1.01 pmol/L Standard Error 4.080	-10.36 pmol/L Standard Error 3.397

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 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. 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=148 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=308 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24	26.4 percentage of participants	52.3 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=148 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=308 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With HbA1c Level Less Than or Equal to 6.5% at Week 24	10.1 percentage of participants	28.9 percentage of participants

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 HOMA-beta assessment during on-treatment period.

Beta cell function was assessed by HOMA-beta. HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin \[micro unit per milliliter\]) divided by (fasting plasma glucose \[mmol/L\] 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 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=124 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=281 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) at Week 24	6.98 % of normal beta cells function Standard Error 3.575	6.72 % of normal beta cells function Standard Error 2.963

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=159 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=320 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period	11.3 percentage of participants	3.8 percentage of participants

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.

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=157 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=315 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	5.1 percentage of participants	9.2 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 132 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.

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=161 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=323 Participants 2-step initiation regimen of lixisenatide.
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Symptomatic Hypoglycemia	7 participants	23 participants
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Severe Symptomatic Hypoglycemia	0 participants	0 participants

Adverse Events

Placebo

Serious events: 15 serious events

Other events: 105 other events

Deaths: 0 deaths

Lixisenatide

Serious events: 25 serious events

Other events: 219 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

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

Measure	Placebo n=161 participants at risk 2-step initiation regimen of volume matching placebo.	Lixisenatide n=323 participants at risk 2-step initiation regimen of lixisenatide.
Infections and infestations Bronchitis	9.9% 16/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	7.7% 25/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Infections and infestations Influenza	5.6% 9/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	7.4% 24/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Infections and infestations Nasopharyngitis	14.9% 24/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	16.4% 53/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Infections and infestations Upper respiratory tract infection	11.2% 18/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	12.7% 41/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Infections and infestations Urinary tract infection	6.8% 11/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	7.4% 24/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Metabolism and nutrition disorders Hypoglycaemia	5.0% 8/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	7.7% 25/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Nervous system disorders Dizziness	8.1% 13/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	10.2% 33/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Nervous system disorders Headache	11.8% 19/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	13.3% 43/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Vascular disorders Hypertension	5.6% 9/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	5.3% 17/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Respiratory, thoracic and mediastinal disorders Cough	6.8% 11/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	5.6% 18/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Gastrointestinal disorders Diarrhoea	14.3% 23/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	10.8% 35/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Gastrointestinal disorders Nausea	13.7% 22/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	26.0% 84/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Gastrointestinal disorders Vomiting	5.0% 8/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	8.0% 26/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Musculoskeletal and connective tissue disorders Arthralgia	6.8% 11/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	7.4% 24/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
Musculoskeletal and connective tissue disorders Back pain	8.7% 14/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	6.8% 22/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
General disorders Fatigue	1.9% 3/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	6.5% 21/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.
General disorders Oedema peripheral	5.6% 9/161 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.	5.3% 17/323 • First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks Median exposure to study treatment was 615.5 and 588.0 days in lixisenatide and placebo 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.