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

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: liraglutide
Drug: Insulin glargine/lixisenatide fixed ratio combination
Drug: exenatide
Drug: exenatide extended-release
Drug: albiglutide
Drug: dulaglutide

Registration Number: NCT02787551

Lead Sponsor: Sanofi

Brief Summary: Primary Objective:

To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) versus GLP-1 receptor agonist (GLP-1 RA) in hemoglobin A1c (HbA1c) change.

Secondary Objectives:

To compare the overall efficacy and safety of the insulin glargine/lixisenatide FRC to GLP-1 RA on top of metformin (with or without pioglitazone, with or without sodium-glucose co-transporter 2 \[SGLT2\] inhibitor) in participants with type 2 diabetes.

To evaluate safety, efficacy and other endpoints of FRC up to the end of the extension period.

Detailed Description: The maximum duration for GLP1-RA participants was approximately 29 weeks: up to 2 week screening period, a 26 week treatment period (either randomized or uncontrolled), and a 3 or 9 day post-treatment safety follow-up period.

Maximum duration for FRC participants was approximately 55 weeks: up to 2-week screening period, a 26-week randomized treatment period, a 26-week extension period and a 3-day post-treatment safety follow-up period.

All primary and secondary efficacy, safety and other outcome measures were assessed at the end of the extension period.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 514

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GLP-1 Receptor Agonist	exenatide	Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily \[BID\], 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.
GLP-1 Receptor Agonist	albiglutide	Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily \[BID\], 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.
GLP-1 Receptor Agonist	liraglutide	Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily \[BID\], 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.
GLP-1 Receptor Agonist	exenatide extended-release	Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily \[BID\], 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.
Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	Insulin glargine/lixisenatide fixed ratio combination	Core period: FRC injected subcutaneously once daily (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	dulaglutide	Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily \[BID\], 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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period	Baseline, Week 26	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.
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period	Baseline, Week 52	Change in HbA1c was calculated by subtracting baseline value from Week 52 value.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period	Week 52	Participants without any available HbA1c assessment at Week 52 were considered as non-responders.
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period	Baseline, Week 26	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.
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period	Baseline, Week 52	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.
Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period	From Baseline to Week 26	Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.
Change From Baseline in Body Weight at Week 26: Core Period	Baseline, Week 26	Change in body weight was calculated by subtracting baseline value from Week 26 value.
Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period	Week 26	Participants without any available HbA1c assessment at Week 26 were considered as non-responders.
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period	Baseline, Week 26	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.
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period	Baseline, Week 52	Change in FPG was calculated by subtracting baseline value from Week 52 value.
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period	Baseline, Week 26	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).
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period	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.
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period	Baseline, Week 52	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.
Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period	From Week 26 to Week 52	Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period	Baseline, Week 26	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.
Change From Baseline in Body Weight to Week 52: Single Arm Extension Period	Baseline, Week 52	Change in body weight was calculated by subtracting baseline value from Week 52 value.
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period	From Baseline to Week 26	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.
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period	From Baseline to Week 52	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.

Trial Locations

Locations (124): Investigational Site Number 8400064
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Birmingham, Alabama, United States
Investigational Site Number 8400073
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Fountain Hills, Arizona, United States
Investigational Site Number 8400047
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Phoenix, Arizona, United States
Investigational Site Number 8400103
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Bakersfield, California, United States
Investigational Site Number 8400137
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Fresno, California, United States
Investigational Site Number 8400043
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Huntington Park, California, United States
Investigational Site Number 8400124
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Lamont, California, United States
Investigational Site Number 8400027
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Lancaster, California, United States
Investigational Site Number 8400098
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Los Angeles, California, United States
Investigational Site Number 8400013
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Los Angeles, California, United States
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Investigational Site Number 8400064
🇺🇸Birmingham, Alabama, United States