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Trial record 46 of 63 for:    Lixisenatide

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 (LixiLan-G)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02787551
Recruitment Status : Completed
First Posted : June 1, 2016
Results First Posted : June 12, 2019
Last Update Posted : November 27, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Insulin glargine/lixisenatide fixed ratio combination
Drug: liraglutide
Drug: exenatide
Drug: exenatide extended-release
Drug: albiglutide
Drug: dulaglutide
Drug: Background therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
Enrollment 514
Recruitment Details 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.
Pre-assignment Details 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).
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description

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.

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.
Period Title: Core Period: 26 Weeks
Started 257 257
Treated 255 256
Completed 230 [1] 246
Not Completed 27 11
Reason Not Completed
Adverse Event             10             0
Lack of Efficacy             1             0
Poor compliance to protocol             2             0
Withdrawal by Subject             9             9
Randomized but not treated             2             1
Other than specified             3             1
[1]
Out of 230 participants, 206 participants entered in single arm extension period.
Period Title: Extension Period:26 Weeks(Upto 52 Weeks)
Started 206 [1] 0
Completed 197 0
Not Completed 9 0
Reason Not Completed
Adverse Event             1             0
Poor compliance to protocol             3             0
Other than specified             5             0
[1]
Participants who completed core period and met eligibility criteria for extension period.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist Total
Hide Arm/Group Description FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. 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 of all reporting groups
Overall Number of Baseline Participants 257 257 514
Hide Baseline Analysis Population Description
Analysis was performed on randomized population.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 257 participants 257 participants 514 participants
59.2  (9.6) 60.0  (10.3) 59.6  (10.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 257 participants 257 participants 514 participants
Female
131
  51.0%
113
  44.0%
244
  47.5%
Male
126
  49.0%
144
  56.0%
270
  52.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
American Indian or Alaska Native Number Analyzed 257 participants 257 participants 514 participants
0 0 0
Asian/Oriental Number Analyzed 257 participants 257 participants 514 participants
3 4 7
Black Number Analyzed 257 participants 257 participants 514 participants
12 7 19
Native Hawaiian or Other Pacific Islander Number Analyzed 257 participants 257 participants 514 participants
1 0 1
White Number Analyzed 257 participants 257 participants 514 participants
241 244 485
Unknown or Not Reported’ Number Analyzed 257 participants 257 participants 514 participants
0 2 2
Body Mass Index (BMI)  
Measure Type: Count of Participants
Unit of measure:  Participants
<30 Number Analyzed 257 participants 257 participants 514 participants
71
  27.6%
69
  26.8%
140
  27.2%
>=30 Number Analyzed 257 participants 257 participants 514 participants
186
  72.4%
188
  73.2%
374
  72.8%
Duration of diabetes  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 257 participants 257 participants 514 participants
11.23  (7.42) 10.95  (6.08) 11.09  (6.78)
Hemoglobin A1C (HbA1C)  
Mean (Standard Deviation)
Unit of measure:  Percentage of HbA1c
Number Analyzed 257 participants 257 participants 514 participants
7.78  (0.62) 7.80  (0.56) 7.79  (0.59)
Daily dose of metformin at baseline  
Mean (Standard Deviation)
Unit of measure:  Milligrams (mg)
Number Analyzed 257 participants 257 participants 514 participants
1966.93  (434.56) 2030.74  (497.15) 1998.83  (467.54)
Daily dose of pioglitazone at baseline   [1] 
Mean (Standard Deviation)
Unit of measure:  Mg
Number Analyzed 12 participants 22 participants 34 participants
31.25  (10.03) 32.73  (8.83) 32.21  (9.14)
[1]
Measure Analysis Population Description: Here, number analyzed=number of participants with available data for specified measure.
Daily dose of SGLT2 inhibitor at baseline   [1] 
Mean (Standard Deviation)
Unit of measure:  Mg
Canagliflozin Number Analyzed 7 participants 12 participants 19 participants
214.29  (106.90) 283.33  (57.74) 257.89  (83.77)
Empagliflozin Number Analyzed 6 participants 9 participants 15 participants
15.42  (7.49) 16.67  (8.20) 16.17  (7.67)
Dapagliflozin Number Analyzed 13 participants 5 participants 18 participants
9.62  (3.80) 9.00  (2.24) 9.44  (3.38)
[1]
Measure Analysis Population Description: Here, number analyzed=number of participants with available data for specified categories.
Duration of GLP-1 receptor agonist treatment  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 257 participants 257 participants 514 participants
1.89  (1.76) 1.92  (1.85) 1.90  (1.81)
GLP-1 receptor agonist use by type at screening  
Measure Type: Count of Participants
Unit of measure:  Participants
Once/twice daily formulation Number Analyzed 257 participants 257 participants 514 participants
153
  59.5%
154
  59.9%
307
  59.7%
Once weekly formulation Number Analyzed 257 participants 257 participants 514 participants
104
  40.5%
103
  40.1%
207
  40.3%
1.Primary Outcome
Title Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period
Hide Description 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.
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 250 253
Least Squares Mean (Standard Error)
Unit of Measure: percentage of HbA1c
-1.02  (0.048) -0.38  (0.048)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), GLP-1 RA subtype at screening, visits, treatment-by-visit interaction, world region as fixed effects, baseline HbA1c value-by-visit interaction as a covariate. Analysis included all scheduled measurements obtained during 26-week randomized treatment period, including those obtained after IMP discontinuation/introduction of rescue medication.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.05 level.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least square (LS) mean difference
Estimated Value -0.64
Confidence Interval (2-Sided) 95%
-0.770 to -0.508
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.067
Estimation Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period
Hide Description Change in HbA1c was calculated by subtracting baseline value from Week 52 value.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 202
Mean (Standard Error)
Unit of Measure: percentage of HbA1c
-1.01  (0.063)
3.Secondary Outcome
Title Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period
Hide Description Participants without any available HbA1c assessment at Week 26 were considered as non-responders.
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on mITT population.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 252 253
Measure Type: Number
Unit of Measure: percentage of participants
HbA1c <7% 61.9 25.7
HbA1c <=6.5% 40.5 9.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs GLP-1 Receptor Agonist. Analysis was performed using Cochran-Mantel-Haenszel method method stratified on randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), and randomization strata of GLP-1 receptor agonist subtype at screening. Hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially per pre-specified order (only HbA1c < 7% was part of testing).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments Threshold for significance <=0.05
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 36.05
Confidence Interval (2-Sided) 95%
28.11 to 43.99
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period
Hide Description Participants without any available HbA1c assessment at Week 52 were considered as non-responders.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on mITT population who entered the extension period.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 206
Measure Type: Number
Unit of Measure: percentage of participants
HbA1c <7% 64.1
HbA1c <=6.5% 42.7
5.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period
Hide Description 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.
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline FPG assessment.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 251 253
Least Squares Mean (Standard Error)
Unit of Measure: millimoles per litre (mmol/L)
-2.28  (0.120) -0.60  (0.119)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and and baseline FPG value-by visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.05 level.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.67
Confidence Interval (2-Sided) 95%
-2.001 to -1.341
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.168
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period
Hide Description Change in FPG was calculated by subtracting baseline value from Week 52 value.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 196
Mean (Standard Error)
Unit of Measure: mmol/L
-2.27  (0.173)
7.Secondary Outcome
Title Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period
Hide Description 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.
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 216 220
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-1.69  (0.114) -0.67  (0.112)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and baseline average SMPG value-by-visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.05 level.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.02
Confidence Interval (2-Sided) 95%
-1.325 to -0.708
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.157
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period
Hide Description 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.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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 7-point SMPG assessment.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 142
Mean (Standard Error)
Unit of Measure: mmol/L
-1.68  (0.176)
9.Secondary Outcome
Title Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period
Hide Description 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).
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline plasma glucose assessment.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 215 222
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-3.96  (0.211) -1.11  (0.205)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour PPG value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.05 level.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -2.85
Confidence Interval (2-Sided) 95%
-3.420 to -2.279
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.290
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period
Hide Description 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.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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 plasma glucose assessment.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 192
Mean (Standard Error)
Unit of Measure: mmol/L
-4.30  (0.284)
11.Secondary Outcome
Title Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period
Hide Description 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.
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and Week 26 assessments.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 215 220
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-1.51  (0.177) -0.52  (0.173)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist
Comments Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 receptor agonist subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.05 level.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.99
Confidence Interval (2-Sided) 95%
-1.468 to -0.508
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.244
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period
Hide Description 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.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and Week 52 assessments.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 192
Mean (Standard Error)
Unit of Measure: mmol/L
-1.85  (0.209)
13.Secondary Outcome
Title Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period
Hide Description Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%.
Time Frame From Baseline to Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed using mITT population.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 252 253
Measure Type: Number
Unit of Measure: percentage of participants
4.8 15.0
14.Secondary Outcome
Title Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period
Hide Description Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%.
Time Frame From Week 26 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on mITT population who entered the extension period.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 206
Measure Type: Number
Unit of Measure: percentage of participants
1.5
15.Secondary Outcome
Title Change From Baseline in Body Weight at Week 26: Core Period
Hide Description Change in body weight was calculated by subtracting baseline value from Week 26 value.
Time Frame Baseline, Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline body weight assessment.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 251 253
Least Squares Mean (Standard Error)
Unit of Measure: kilogram (kg)
1.89  (0.222) -1.14  (0.220)
16.Secondary Outcome
Title Change From Baseline in Body Weight to Week 52: Single Arm Extension Period
Hide Description Change in body weight was calculated by subtracting baseline value from Week 52 value.
Time Frame Baseline, Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 202
Mean (Standard Error)
Unit of Measure: kg
2.78  (0.294)
17.Secondary Outcome
Title Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period
Hide Description 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.
Time Frame From Baseline to Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) GLP-1 Receptor Agonist
Hide Arm/Group Description:
FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted.
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.
Overall Number of Participants Analyzed 255 256
Measure Type: Number
Unit of Measure: events per participant-year
Documented symptomatic hypoglycemia(<=3.9 mmol/L) 1.54 0.08
Documented symptomatic hypoglycemia (<3.0 mmol/L) 0.25 0.01
18.Secondary Outcome
Title Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period
Hide Description 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.
Time Frame From Baseline to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety population who entered the extension period and their data for whole study duration was analyzed and reported.
Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 206
Measure Type: Number
Unit of Measure: events per participant-year
Documented symptomatic hypoglycemia(<=3.9 mmol/L) 1.59
Documented symptomatic hypoglycemia (<3.0 mmol/L) 0.24
Time Frame All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks).
Adverse Event Reporting Description 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.
 
Arm/Group Title Fixed Ratio Combination GLP-1 Receptor Agonist Fixed Ratio Combination Whole Study Period
Hide Arm/Group Description FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted (median exposure: 183 days). 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). 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).
All-Cause Mortality
Fixed Ratio Combination GLP-1 Receptor Agonist Fixed Ratio Combination Whole Study Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/255 (0.00%)      0/256 (0.00%)      1/206 (0.49%)    
Hide Serious Adverse Events
Fixed Ratio Combination GLP-1 Receptor Agonist Fixed Ratio Combination Whole Study Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/255 (3.92%)      9/256 (3.52%)      21/206 (10.19%)    
Cardiac disorders       
Arteriosclerosis Coronary Artery  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Atrial Fibrillation  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Cardiac Failure  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Cardiac Failure Congestive  1  0/255 (0.00%)  0 0/256 (0.00%)  0 2/206 (0.97%)  2
Coronary Artery Disease  1  0/255 (0.00%)  0 0/256 (0.00%)  0 2/206 (0.97%)  2
Ischaemic Cardiomyopathy  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Gastrointestinal disorders       
Duodenal Ulcer  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Large Intestine Polyp  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Rectal Haemorrhage  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
General disorders       
Non-Cardiac Chest Pain  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Oedema Peripheral  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Infections and infestations       
Cellulitis  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Diverticulitis  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Infected Skin Ulcer  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Peritonitis  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Pneumonia  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Postoperative Abscess  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Injury, poisoning and procedural complications       
Ankle Fracture  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Fall  1  2/255 (0.78%)  2 0/256 (0.00%)  0 2/206 (0.97%)  2
Foot Fracture  1  1/255 (0.39%)  1 0/256 (0.00%)  0 0/206 (0.00%)  0
Hip Fracture  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Laceration  1  1/255 (0.39%)  1 0/256 (0.00%)  0 0/206 (0.00%)  0
Rib Fracture  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Skin Laceration  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Subarachnoid Haemorrhage  1  1/255 (0.39%)  2 0/256 (0.00%)  0 0/206 (0.00%)  0
Subcutaneous Haematoma  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Metabolism and nutrition disorders       
Electrolyte Imbalance  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Intervertebral Disc Protrusion  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Musculoskeletal Chest Pain  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Osteoarthritis  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Spinal Column Stenosis  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenosquamous Cell Lung Cancer  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Basal Cell Carcinoma  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Bladder Papilloma  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Endometrial Adenocarcinoma  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Glioblastoma  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Hepatic Neoplasm  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Invasive Ductal Breast Carcinoma  1  0/255 (0.00%)  0 1/256 (0.39%)  1 1/206 (0.49%)  1
Papillary Thyroid Cancer  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Renal Cell Carcinoma  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Nervous system disorders       
Cerebral Infarction  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Diabetic Neuropathy  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Hypoglycaemic Unconsciousness  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Intraventricular Haemorrhage  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Subarachnoid Haemorrhage  1  0/255 (0.00%)  0 0/256 (0.00%)  0 2/206 (0.97%)  3
Renal and urinary disorders       
Acute Kidney Injury  1  1/255 (0.39%)  1 1/256 (0.39%)  1 1/206 (0.49%)  1
Urinary Retention  1  1/255 (0.39%)  1 0/256 (0.00%)  0 0/206 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute Pulmonary Oedema  1  1/255 (0.39%)  1 0/256 (0.00%)  0 1/206 (0.49%)  1
Pneumonia Aspiration  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
Skin and subcutaneous tissue disorders       
Dermal Cyst  1  0/255 (0.00%)  0 1/256 (0.39%)  1 0/206 (0.00%)  0
Vascular disorders       
Vasculitis Necrotising  1  0/255 (0.00%)  0 0/256 (0.00%)  0 1/206 (0.49%)  1
1
Term from vocabulary, MedDRA 21.0 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Fixed Ratio Combination GLP-1 Receptor Agonist Fixed Ratio Combination Whole Study Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   69/255 (27.06%)      48/256 (18.75%)      75/206 (36.41%)    
Gastrointestinal disorders       
Diarrhoea  1  14/255 (5.49%)  14 6/256 (2.34%)  6 15/206 (7.28%)  17
Nausea  1  22/255 (8.63%)  30 6/256 (2.34%)  6 19/206 (9.22%)  30
Infections and infestations       
Influenza  1  11/255 (4.31%)  12 6/256 (2.34%)  6 15/206 (7.28%)  19
Nasopharyngitis  1  25/255 (9.80%)  27 23/256 (8.98%)  26 32/206 (15.53%)  37
Upper Respiratory Tract Infection  1  9/255 (3.53%)  11 12/256 (4.69%)  15 13/206 (6.31%)  17
1
Term from vocabulary, MedDRA 21.0 21.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Sanofi aventis recherche & développement
Phone: 800-633-1610 ext 1#
EMail: Contact-US@sanofi.com
Layout table for additonal information
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT02787551    
Other Study ID Numbers: EFC13794
2014-004850-32
U1111-1168-4639 ( Other Identifier: UTN )
First Submitted: May 26, 2016
First Posted: June 1, 2016
Results First Submitted: May 23, 2019
Results First Posted: June 12, 2019
Last Update Posted: November 27, 2019