Trial Outcomes & Findings for GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Basal Insulin (NCT NCT00715624)

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

496 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2016-11-28

Participant Flow

The study was conducted at 111 centers in 15 countries between July 29, 2008 and February 8, 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 879 patients were screened of which 383 (43.6%) 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 496 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	167	329
Overall Study Treated/Safety Population	167	328
Overall Study Modified Intent-to-Treat(mITT)Population	166	327
Overall Study COMPLETED	115	213
Overall Study NOT COMPLETED	52	116

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	12	37
Overall Study Lack of Efficacy	11	11
Overall Study Lost to Follow-up	1	2
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	11	25
Overall Study Familial and personal reasons	10	22
Overall Study Poor compliance	6	13
Overall Study Sponsor decision	0	4
Overall Study Incorrect randomization (not treated)	0	1
Overall Study Other	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=167 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=328 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=495 Participants Total of all reporting groups
Age, Continuous	56.9 years STANDARD_DEVIATION 9.8 • n=5 Participants	57.4 years STANDARD_DEVIATION 9.5 • n=7 Participants	57.2 years STANDARD_DEVIATION 9.6 • n=5 Participants
Sex: Female, Male Female	85 Participants n=5 Participants	182 Participants n=7 Participants	267 Participants n=5 Participants
Sex: Female, Male Male	82 Participants n=5 Participants	146 Participants n=7 Participants	228 Participants n=5 Participants
Race/Ethnicity, Customized Race: Caucasian/White	130 participants n=5 Participants	254 participants n=7 Participants	384 participants n=5 Participants
Race/Ethnicity, Customized Race: Black	6 participants n=5 Participants	14 participants n=7 Participants	20 participants n=5 Participants
Race/Ethnicity, Customized Race: Asian/Oriental	30 participants n=5 Participants	53 participants n=7 Participants	83 participants n=5 Participants
Race/Ethnicity, Customized Race: Other	1 participants n=5 Participants	7 participants n=7 Participants	8 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic	40 participants n=5 Participants	94 participants n=7 Participants	134 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Non Hispanic	127 participants n=5 Participants	234 participants n=7 Participants	361 participants n=5 Participants
Glycosylated Hemoglobin (HbA1c)	8.37 percentage of hemoglobin STANDARD_DEVIATION 0.84 • n=5 Participants	8.42 percentage of hemoglobin STANDARD_DEVIATION 0.88 • n=7 Participants	8.40 percentage of hemoglobin STANDARD_DEVIATION 0.87 • n=5 Participants
2-Hour Postprandial Plasma Glucose (PPG)	16.11 mmol/L STANDARD_DEVIATION 3.86 • n=5 Participants	16.47 mmol/L STANDARD_DEVIATION 4.30 • n=7 Participants	16.35 mmol/L STANDARD_DEVIATION 4.15 • n=5 Participants
Average 7-Point Self Monitored Plasma Glucose (SMPG)	10.58 mmol/L STANDARD_DEVIATION 2.69 • n=5 Participants	10.76 mmol/L STANDARD_DEVIATION 2.61 • n=7 Participants	10.70 mmol/L STANDARD_DEVIATION 2.64 • n=5 Participants
Fasting Plasma Glucose (FPG)	8.05 millimole per liter (mmol/L) STANDARD_DEVIATION 2.65 • n=5 Participants	8.13 millimole per liter (mmol/L) STANDARD_DEVIATION 2.83 • n=7 Participants	8.10 millimole per liter (mmol/L) STANDARD_DEVIATION 2.76 • n=5 Participants
Body Weight	88.94 kilogram (kg) STANDARD_DEVIATION 20.84 • n=5 Participants	87.10 kilogram (kg) STANDARD_DEVIATION 20.01 • n=7 Participants	87.72 kilogram (kg) STANDARD_DEVIATION 20.29 • n=5 Participants
Total Insulin Dose	57.73 units per day STANDARD_DEVIATION 34.54 • n=5 Participants	53.43 units per day STANDARD_DEVIATION 33.89 • n=7 Participants	54.88 units per day STANDARD_DEVIATION 34.14 • n=5 Participants
Glucose Excursion	7.32 mmol/L STANDARD_DEVIATION 3.43 • n=5 Participants	7.59 mmol/L STANDARD_DEVIATION 3.60 • n=7 Participants	7.50 mmol/L STANDARD_DEVIATION 3.54 • n=5 Participants
Duration of Diabetes	12.43 years STANDARD_DEVIATION 6.33 • n=5 Participants	12.48 years STANDARD_DEVIATION 7.04 • n=7 Participants	12.46 years STANDARD_DEVIATION 6.80 • n=5 Participants
Body Mass Index (BMI)	32.56 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.32 • n=5 Participants	31.91 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.17 • n=7 Participants	32.13 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.22 • n=5 Participants
Basal Insulin Treatment Duration	3.20 years STANDARD_DEVIATION 3.96 • n=5 Participants	3.06 years STANDARD_DEVIATION 3.37 • n=7 Participants	3.11 years STANDARD_DEVIATION 3.57 • n=5 Participants
Number of Patients With Insulin Therapy at Baseline Glargine	83 participants n=5 Participants	165 participants n=7 Participants	248 participants n=5 Participants
Number of Patients With Insulin Therapy at Baseline Detemir	19 participants n=5 Participants	24 participants n=7 Participants	43 participants n=5 Participants
Number of Patients With Insulin Therapy at Baseline Neutral protamine hagedorn (NPH)	64 participants n=5 Participants	134 participants n=7 Participants	198 participants n=5 Participants
Number of Patients With Insulin Therapy at Baseline Premix (Mixed Insulin)	3 participants n=5 Participants	5 participants n=7 Participants	8 participants n=5 Participants
Number of Patients With Metformin use at Baseline Yes	131 participants n=5 Participants	261 participants n=7 Participants	392 participants n=5 Participants
Number of Patients With Metformin use at Baseline No	36 participants n=5 Participants	67 participants n=7 Participants	103 participants n=5 Participants
Metformin Daily Dose	2008.02 milligram (mg) per day STANDARD_DEVIATION 441.88 • n=5 Participants	1961.02 milligram (mg) per day STANDARD_DEVIATION 459.07 • n=7 Participants	1976.72 milligram (mg) per day STANDARD_DEVIATION 453.38 • 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. LOCF was 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=158 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=304 Participants 2-step initiation regimen of lixisenatide.
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	-0.38 percentage of hemoglobin Standard Error 0.107	-0.74 percentage of hemoglobin Standard Error 0.090

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 2-hour PPG assessment during on-treatment period.

The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is 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=123 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=235 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24	-1.72 mmol/L Standard Error 0.543	-5.54 mmol/L Standard Error 0.468

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 7-point SMPG assessment during on-treatment period.

Patients recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime once in a week and the average value for the 7-time points was calculated. 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=153 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=294 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profiles at Week 24	-0.61 mmol/L Standard Error 0.238	-1.49 mmol/L Standard Error 0.201

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=163 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	-0.55 mmol/L Standard Error 0.281	-0.63 mmol/L Standard Error 0.233

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=161 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=311 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Body Weight at Week 24	-0.52 kilogram Standard Error 0.293	-1.80 kilogram Standard Error 0.246

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 total insulin dose assessment during on-treatment period.

Change was calculated for total insulin dose by subtracting the 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=165 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=325 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Total Insulin Dose at Week 24	-1.93 units per day Standard Error 1.589	-5.62 units per day Standard Error 1.317

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=158 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=304 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24	12.0 percentage of participants	28.3 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=158 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=304 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	3.8 percentage of participants	14.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: mITT population.

Routine fasting 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=166 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=327 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period	7.2 percentage of participants	5.8 percentage of participants

OTHER_PRE_SPECIFIED 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 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 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=123 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=233 Participants 2-step initiation regimen of lixisenatide.
Change From Baseline in Glucose Excursion at Week 24	-0.34 mmol/L Standard Error 0.469	-4.14 mmol/L Standard Error 0.408

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=161 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=311 Participants 2-step initiation regimen of lixisenatide.
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	3.1 percentage of participants	13.2 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 125 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=167 Participants 2-step initiation regimen of volume matching placebo.	Lixisenatide n=328 Participants 2-step initiation regimen of lixisenatide.
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Symptomatic hypoglycemia	65 participants	138 participants
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia Severe symptomatic hypoglycemia	1 participants	7 participants

Adverse Events

Placebo

Serious events: 17 serious events

Other events: 104 other events

Deaths: 0 deaths

Lixisenatide

Serious events: 46 serious events

Other events: 245 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=167 participants at risk 2-step initiation regimen of volume matching placebo.	Lixisenatide n=328 participants at risk 2-step initiation regimen of lixisenatide.
Infections and infestations Bronchitis	7.8% 13/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	6.7% 22/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	5.4% 9/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	8.5% 28/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	12.6% 21/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	9.8% 32/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	3.6% 6/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	7.3% 24/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	3.6% 6/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	6.4% 21/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	40.7% 68/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	42.1% 138/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	6.6% 11/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	7.9% 26/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	10.2% 17/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	12.5% 41/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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 Tremor	3.6% 6/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	5.5% 18/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	5.4% 9/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	5.2% 17/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	6.0% 10/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	11.3% 37/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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 Dyspepsia	0.60% 1/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	5.2% 17/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	9.6% 16/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	29.3% 96/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	1.2% 2/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	9.8% 32/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	6.6% 11/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	4.9% 16/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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	6.6% 11/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	7.3% 24/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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 Asthenia	6.0% 10/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	5.5% 18/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.
Investigations Blood glucose decreased	4.2% 7/167 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.	5.8% 19/328 • First dose of study drug up to 3 days after the last dose administration for up to 125 weeks Median exposure to study treatment was 560 and 559 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.