Trial Outcomes & Findings for Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Versus GLP-1 Receptor Agonist in Patients With Type 2 Diabetes, With a FRC Extension Period (NCT NCT02787551)

Last Updated: 2022-03-25

Results Overview

Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Adjusted least squares (LS) mean and standard error (SE) were obtained from Mixed-effect model with repeated measures (MMRM) to account for missing data using all available post baseline data during the 26 week treatment period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

514 participants

Primary outcome timeframe

Baseline, Week 26

Results posted on

2022-03-25

Participant Flow

The study was conducted at 112 sites in 9 countries. A total of 840 participants were screened between 06 July 2016 and 01 November 2017, of which 326 were screen failures. Screen failures were mainly due to glycated hemoglobin (HbA1c) level lesser than (\<)7% or more than (\>)9% at screening visit.

A total of 514 participants were randomized in 1:1 (Insulin Glargine/Lixisenatide fixed ratio combination \[FRC\] or glucagon-like peptide-1 receptor agonist \[GLP-1 RA\]) ratio. Randomization was stratified by values of HbA1c at screening (\<8%, \>=8%) \& GLP-1 RA subtype at screening (once/twice daily \[QD/BID\], once weekly \[QW\] formulations).

Participant milestones

Participant milestones
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Core period: FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted. Single arm extension period: participants who completed core treatment period and met eligibility criteria entered in extension treatment period and received same treatment (FRC injected subcutaneously QD on top of OAD therapy) for 26 weeks (up to Week 52). Dose individually adjusted.	GLP-1 Receptor Agonist Core Period: GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Core Period: 26 Weeks STARTED	257	257
Core Period: 26 Weeks Treated	255	256
Core Period: 26 Weeks COMPLETED	230	246
Core Period: 26 Weeks NOT COMPLETED	27	11
Extension Period:26 Weeks(Upto 52 Weeks) STARTED	206	0
Extension Period:26 Weeks(Upto 52 Weeks) COMPLETED	197	0
Extension Period:26 Weeks(Upto 52 Weeks) NOT COMPLETED	9	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Core period: FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted. Single arm extension period: participants who completed core treatment period and met eligibility criteria entered in extension treatment period and received same treatment (FRC injected subcutaneously QD on top of OAD therapy) for 26 weeks (up to Week 52). Dose individually adjusted.	GLP-1 Receptor Agonist Core Period: GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Core Period: 26 Weeks Adverse Event	10	0
Core Period: 26 Weeks Lack of Efficacy	1	0
Core Period: 26 Weeks Poor compliance to protocol	2	0
Core Period: 26 Weeks Withdrawal by Subject	9	9
Core Period: 26 Weeks Randomized but not treated	2	1
Core Period: 26 Weeks Other than specified	3	1
Extension Period:26 Weeks(Upto 52 Weeks) Adverse Event	1	0
Extension Period:26 Weeks(Upto 52 Weeks) Poor compliance to protocol	3	0
Extension Period:26 Weeks(Upto 52 Weeks) Other than specified	5	0

Baseline Characteristics

Here, number analyzed=number of participants with available data for specified measure.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=257 Participants FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=257 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.	Total n=514 Participants Total of all reporting groups
Age, Continuous	59.2 years STANDARD_DEVIATION 9.6 • n=257 Participants	60.0 years STANDARD_DEVIATION 10.3 • n=257 Participants	59.6 years STANDARD_DEVIATION 10.0 • n=514 Participants
Sex: Female, Male Female	131 Participants n=257 Participants	113 Participants n=257 Participants	244 Participants n=514 Participants
Sex: Female, Male Male	126 Participants n=257 Participants	144 Participants n=257 Participants	270 Participants n=514 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=257 Participants	0 Participants n=257 Participants	0 Participants n=514 Participants
Race/Ethnicity, Customized Asian/Oriental	3 Participants n=257 Participants	4 Participants n=257 Participants	7 Participants n=514 Participants
Race/Ethnicity, Customized Black	12 Participants n=257 Participants	7 Participants n=257 Participants	19 Participants n=514 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=257 Participants	0 Participants n=257 Participants	1 Participants n=514 Participants
Race/Ethnicity, Customized White	241 Participants n=257 Participants	244 Participants n=257 Participants	485 Participants n=514 Participants
Race/Ethnicity, Customized Unknown or Not Reported'	0 Participants n=257 Participants	2 Participants n=257 Participants	2 Participants n=514 Participants
Body Mass Index (BMI) <30	71 Participants n=257 Participants	69 Participants n=257 Participants	140 Participants n=514 Participants
Body Mass Index (BMI) >=30	186 Participants n=257 Participants	188 Participants n=257 Participants	374 Participants n=514 Participants
Duration of diabetes	11.23 years STANDARD_DEVIATION 7.42 • n=257 Participants	10.95 years STANDARD_DEVIATION 6.08 • n=257 Participants	11.09 years STANDARD_DEVIATION 6.78 • n=514 Participants
Hemoglobin A1C (HbA1C)	7.78 percentage of HbA1c STANDARD_DEVIATION 0.62 • n=257 Participants	7.80 percentage of HbA1c STANDARD_DEVIATION 0.56 • n=257 Participants	7.79 percentage of HbA1c STANDARD_DEVIATION 0.59 • n=514 Participants
Daily dose of metformin at baseline	1966.93 milligrams (mg) STANDARD_DEVIATION 434.56 • n=257 Participants	2030.74 milligrams (mg) STANDARD_DEVIATION 497.15 • n=257 Participants	1998.83 milligrams (mg) STANDARD_DEVIATION 467.54 • n=514 Participants
Daily dose of pioglitazone at baseline	31.25 mg STANDARD_DEVIATION 10.03 • n=12 Participants • Here, number analyzed=number of participants with available data for specified measure.	32.73 mg STANDARD_DEVIATION 8.83 • n=22 Participants • Here, number analyzed=number of participants with available data for specified measure.	32.21 mg STANDARD_DEVIATION 9.14 • n=34 Participants • Here, number analyzed=number of participants with available data for specified measure.
Daily dose of SGLT2 inhibitor at baseline Canagliflozin	214.29 mg STANDARD_DEVIATION 106.90 • n=7 Participants • Here, number analyzed=number of participants with available data for specified categories.	283.33 mg STANDARD_DEVIATION 57.74 • n=12 Participants • Here, number analyzed=number of participants with available data for specified categories.	257.89 mg STANDARD_DEVIATION 83.77 • n=19 Participants • Here, number analyzed=number of participants with available data for specified categories.
Daily dose of SGLT2 inhibitor at baseline Empagliflozin	15.42 mg STANDARD_DEVIATION 7.49 • n=6 Participants • Here, number analyzed=number of participants with available data for specified categories.	16.67 mg STANDARD_DEVIATION 8.20 • n=9 Participants • Here, number analyzed=number of participants with available data for specified categories.	16.17 mg STANDARD_DEVIATION 7.67 • n=15 Participants • Here, number analyzed=number of participants with available data for specified categories.
Daily dose of SGLT2 inhibitor at baseline Dapagliflozin	9.62 mg STANDARD_DEVIATION 3.80 • n=13 Participants • Here, number analyzed=number of participants with available data for specified categories.	9.00 mg STANDARD_DEVIATION 2.24 • n=5 Participants • Here, number analyzed=number of participants with available data for specified categories.	9.44 mg STANDARD_DEVIATION 3.38 • n=18 Participants • Here, number analyzed=number of participants with available data for specified categories.
Duration of GLP-1 receptor agonist treatment	1.89 years STANDARD_DEVIATION 1.76 • n=257 Participants	1.92 years STANDARD_DEVIATION 1.85 • n=257 Participants	1.90 years STANDARD_DEVIATION 1.81 • n=514 Participants
GLP-1 receptor agonist use by type at screening Once/twice daily formulation	153 Participants n=257 Participants	154 Participants n=257 Participants	307 Participants n=514 Participants
GLP-1 receptor agonist use by type at screening Once weekly formulation	104 Participants n=257 Participants	103 Participants n=257 Participants	207 Participants n=514 Participants

PRIMARY outcome

Timeframe: Baseline, Week 26

Population: Modified Intent-To-Treat (mITT) population:all randomized participants who had a baseline and at least 1 post-baseline assessment of any primary/secondary outcome measures, irrespective of compliance with study protocol and procedures."Overall number of participants analyzed"=participants with baseline and at least 1 post-baseline HbA1c assessment.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=250 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=253 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period	-1.02 percentage of HbA1c Standard Error 0.048	-0.38 percentage of HbA1c Standard Error 0.048

PRIMARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population who entered the extension period. Here, "Overall number of participants analyzed" = participants with baseline and at least 1 post-baseline HbA1c assessment.

Change in HbA1c was calculated by subtracting baseline value from Week 52 value.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=202 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period	-1.01 percentage of HbA1c Standard Error 0.063	—

SECONDARY outcome

Timeframe: Week 26

Population: Analysis was performed on mITT population.

Participants without any available HbA1c assessment at Week 26 were considered as non-responders.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=252 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=253 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period HbA1c <7%	61.9 percentage of participants	25.7 percentage of participants
Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period HbA1c <=6.5%	40.5 percentage of participants	9.9 percentage of participants

SECONDARY outcome

Timeframe: Week 52

Population: Analysis was performed on mITT population who entered the extension period.

Participants without any available HbA1c assessment at Week 52 were considered as non-responders.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=206 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period HbA1c <7%	64.1 percentage of participants	—
Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period HbA1c <=6.5%	42.7 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline FPG assessment.

Change in FPG was calculated by subtracting baseline value from Week 26 value. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=251 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=253 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period	-2.28 millimoles per litre (mmol/L) Standard Error 0.120	-0.60 millimoles per litre (mmol/L) Standard Error 0.119

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline FPG assessment.

Change in FPG was calculated by subtracting baseline value from Week 52 value.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=196 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period	-2.27 mmol/L Standard Error 0.173	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline 7-point SMPG assessment.

The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=216 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=220 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period	-1.69 mmol/L Standard Error 0.114	-0.67 mmol/L Standard Error 0.112

SECONDARY outcome

Timeframe: Baseline, Week 52

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=142 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period	-1.68 mmol/L Standard Error 0.176	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Analysis was performed on mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline plasma glucose assessment.

The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last observation carried forward (LOCF).

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=215 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=222 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period	-3.96 mmol/L Standard Error 0.211	-1.11 mmol/L Standard Error 0.205

SECONDARY outcome

Timeframe: Baseline, Week 52

The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=192 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period	-4.30 mmol/L Standard Error 0.284	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and Week 26 assessments.

2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=215 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=220 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period	-1.51 mmol/L Standard Error 0.177	-0.52 mmol/L Standard Error 0.173

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and Week 52 assessments.

2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before IMP administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=192 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period	-1.85 mmol/L Standard Error 0.209	—

SECONDARY outcome

Timeframe: From Baseline to Week 26

Population: Analysis was performed using mITT population.

Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=252 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=253 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period	4.8 percentage of participants	15.0 percentage of participants

SECONDARY outcome

Timeframe: From Week 26 to Week 52

Population: Analysis was performed on mITT population who entered the extension period.

Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=206 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period	1.5 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline body weight assessment.

Change in body weight was calculated by subtracting baseline value from Week 26 value.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=251 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=253 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Body Weight at Week 26: Core Period	1.89 kilogram (kg) Standard Error 0.222	-1.14 kilogram (kg) Standard Error 0.220

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Analysis was performed using mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline body weight assessment.

Change in body weight was calculated by subtracting baseline value from Week 52 value.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=202 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Change From Baseline in Body Weight to Week 52: Single Arm Extension Period	2.78 kg Standard Error 0.294	—

SECONDARY outcome

Timeframe: From Baseline to Week 26

Population: Analysis was performed on safety population which included all randomized participants who received at least one dose of open-label IMP, regardless of the amount of treatment administered. Participants were analyzed according to the treatment actually received (as treated).

Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of \<3.0 mmol/L (54 mg/dL) were also analyzed.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=255 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist n=256 Participants GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period Documented symptomatic hypoglycemia(<=3.9 mmol/L)	1.54 events per participant-year	0.08 events per participant-year
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period Documented symptomatic hypoglycemia (<3.0 mmol/L)	0.25 events per participant-year	0.01 events per participant-year

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Analysis was performed on safety population who entered the extension period and their data for whole study duration was analyzed and reported.

Outcome measures

Outcome measures
Measure	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) n=206 Participants FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.	GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period Documented symptomatic hypoglycemia(<=3.9 mmol/L)	1.59 events per participant-year	—
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period Documented symptomatic hypoglycemia (<3.0 mmol/L)	0.24 events per participant-year	—

Adverse Events

Fixed Ratio Combination

Serious events: 10 serious events

Other events: 69 other events

Deaths: 0 deaths

GLP-1 Receptor Agonist

Serious events: 9 serious events

Other events: 48 other events

Deaths: 0 deaths

Fixed Ratio Combination Whole Study Period

Serious events: 21 serious events

Other events: 75 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Fixed Ratio Combination n=255 participants at risk FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted (median exposure: 183 days).	GLP-1 Receptor Agonist n=256 participants at risk GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization (median exposure: 183 days).	Fixed Ratio Combination Whole Study Period n=206 participants at risk Participants who completed core treatment period and met eligibility criteria entered in extension treatment period and received same treatment (FRC injected subcutaneously QD on top of OAD therapy) for 26 weeks (up to Week 52). Dose individually adjusted (median exposure: 365 days).
Gastrointestinal disorders Diarrhoea	5.5% 14/255 • Number of events 14 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	2.3% 6/256 • Number of events 6 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	7.3% 15/206 • Number of events 17 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.
Gastrointestinal disorders Nausea	8.6% 22/255 • Number of events 30 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	2.3% 6/256 • Number of events 6 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	9.2% 19/206 • Number of events 30 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.
Infections and infestations Influenza	4.3% 11/255 • Number of events 12 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	2.3% 6/256 • Number of events 6 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	7.3% 15/206 • Number of events 19 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.
Infections and infestations Nasopharyngitis	9.8% 25/255 • Number of events 27 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	9.0% 23/256 • Number of events 26 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	15.5% 32/206 • Number of events 37 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.
Infections and infestations Upper Respiratory Tract Infection	3.5% 9/255 • Number of events 11 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	4.7% 12/256 • Number of events 15 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.	6.3% 13/206 • Number of events 17 • All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population.

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