Download PDF

Clinical Trial Results:
A 26-Week Randomized, Open-label, Active Controlled, Parallel-group, Study Assessing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination in Adults With Type 2 Diabetes Inadequately Controlled on GLP-1 Receptor Agonist and Metformin (Alone or With Pioglitazone and/or SGLT2 Inhibitors), Followed by a Fixed Ratio Combination Single-arm 26-Week Extension Period

Summary
EudraCT number	2014-004850-32
Trial protocol	SK EE ES DE IT
Global end of trial date	17 Nov 2018

Results information
Results version number	v1(current)
This version publication date	02 Dec 2019
First version publication date	02 Dec 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

EFC13794

ISRCTN number

US NCT number

NCT02787551

WHO universal trial number (UTN)

U1111-1168-4639

Other trial identifiers

STUDY NAME: LixiLan-G

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Dec 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Nov 2018

Was the trial ended prematurely?

Main objective of the trial

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 from Baseline to Week 26.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Oral anti-diabetic (OAD) treatment metformin, pioglitazone, and sodium-glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) was used as background therapy.

Evidence for comparator

Actual start date of recruitment

06 Jul 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Romania: 62

Country: Number of subjects enrolled

Slovakia: 75

Country: Number of subjects enrolled

Spain: 48

Country: Number of subjects enrolled

Estonia: 13

Country: Number of subjects enrolled

Germany: 20

Country: Number of subjects enrolled

Canada: 23

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Italy: 33

Country: Number of subjects enrolled

United States: 223

Worldwide total number of subjects

514

EEA total number of subjects

251

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

334

From 65 to 84 years

180

85 years and over

Subject disposition

Top of page

Recruitment details

The study was conducted at 112 sites in 9 countries. A total of 840 subjects 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.

Screening details

A total of 514 subjects were randomized in 1:1 (Insulin Glargine/Lixisenatide FRC or GLP-1 RA) ratio. Randomization was stratified by values of HbA1c at screening (=8%) & GLP-1 RA subtype at screening (once/twice daily [QD/BID], once weekly [QW] formulations).

Period 1 title

Core Period: 26 Weeks

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

Arm description

FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.

Arm type

Experimental

Investigational medicinal product name

Insulin glargine/lixisenatide fixed-ratio combination

Investigational medicinal product code

HOE901/AVE0010

Other name

Soliqua

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

FRC was self-administered with a pre-filled disposable SoloStar® pen-injector. Dose of the combination was titrated according to the subject’s need for insulin. FRC was given QD in the morning in the hour (0 to 60 minutes) before breakfast. Dose was individually titrated throughout the study to reach and maintain fasting SMPG: 80-100 milligrams per deciliter (mg/dL) (4.4 - 5.6 millimoles per litre [mmol/L]) avoiding hypoglycemia.

GLP-1 Receptor Agonist

Arm description

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 randomisation.

Arm type

Active comparator

Investigational medicinal product name

Liraglutide

Investigational medicinal product code

Other name

Victoza®

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

QD at any time of day, independently of meals. Victoza is a marketed product and the dose used was in accordance with labeling document.

Investigational medicinal product name

Exenatide

Investigational medicinal product code

Other name

Byetta®

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

BID at any time within the 60 minute period before the morning and evening meal. Byetta is a marketed product and the dose used was in accordance with labeling document.

Investigational medicinal product name

Exenatide extended-release

Investigational medicinal product code

Other name

Bydureon®

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

QW at any time of day, independently of meals. Bydureon is a marketed product and the dose used was in accordance with labeling document.

Investigational medicinal product name

Albiglutide

Investigational medicinal product code

Other name

Tanzeum®

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

QW at any time of day, independently of meals. Tanzeum is a marketed product and the dose used was in accordance with labeling document.

Investigational medicinal product name

Dulaglutide

Investigational medicinal product code

Other name

Trulicity®

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

QW at any time of day, independently of meals. Trulicity is a marketed product and the dose used was in accordance with labeling document.

Number of subjects in period 1	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Started	257	257
Treated	255	256
Completed	230	246
Not completed	27	11
Randomized but not treated	2	1
Adverse event	10	-
Withdrawal by Subject	9	9
Other than specified	3	1
Poor compliance to protocol	2	-
Lack of efficacy	1	-

Period 2 title

Extension Period:26 Weeks(Upto 52 Weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Insulin glargine/lixisenatide fixed-ratio combination

Investigational medicinal product code

HOE901/AVE0010

Other name

Soliqua

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 2 ^[1]	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Started	206
Completed	197
Not completed	9
Adverse event	1
Other than specified	5
Poor compliance to protocol	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Out of 230 subjects, 206 subjects completed core period and met eligibility criteria for extension period.

Baseline characteristics

Top of page

Reporting group title

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

Reporting group description

FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.

Reporting group title

GLP-1 Receptor Agonist

Reporting group description

Reporting group values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist	Total
Number of subjects	257	257	514
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.2 ( 9.6 )	60.0 ( 10.3 )	-
Gender categorical
Units: Subjects
Female	131	113	244
Male	126	144	270
Race/Ethnicity
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian/Oriental	3	4	7
Native Hawaiian or Other Pacific Islander	1	0	1
White	241	244	485
Black	12	7	19
Unknown or Not Reported	0	2	2
Body Mass Index (BMI)
Units: Subjects
<30	71	69	140
>=30	186	188	374
GLP-1 receptor agonist use by type at screening
Units: Subjects
Once/twice daily formulation	153	154	307
Once weekly formulation	104	103	207
Duration of diabetes
Units: years
arithmetic mean (standard deviation)	11.23 ( 7.42 )	10.95 ( 6.08 )	-
Hemoglobin A1C (HbA1C)
Units: percentage of HbA1c
arithmetic mean (standard deviation)	7.78 ( 0.62 )	7.80 ( 0.56 )	-
Daily dose of metformin at baseline
Units: milligrams (mg)
arithmetic mean (standard deviation)	1966.93 ( 434.56 )	2030.74 ( 497.15 )	-
Daily dose of pioglitazone at baseline
Data for Daily dose of pioglitazone at baseline is reported for 34 subjects.
Units: mg
arithmetic mean (standard deviation)	31.25 ( 10.03 )	32.73 ( 8.83 )	-
Daily dose of SGLT2 inhibitor (Canagliflozin) at baseline
Data for daily dose of Canagliflozin at baseline is reported for 19 subjects.
Units: mg
arithmetic mean (standard deviation)	214.29 ( 106.90 )	283.33 ( 57.74 )	-
Daily dose of SGLT2 inhibitor (Empagliflozin) at baseline
Data for daily dose of Empagliflozin at baseline is reported for 15 subjects.
Units: mg
arithmetic mean (standard deviation)	15.42 ( 7.49 )	16.67 ( 8.20 )	-
Daily dose of SGLT2 inhibitor (Dapagliflozin) at baseline
Data for daily dose of Dapagliflozin at baseline is reported for 18 subjects.
Units: mg
arithmetic mean (standard deviation)	9.62 ( 3.80 )	9.00 ( 2.24 )	-
Duration of GLP-1 receptor agonist treatment
Units: years
arithmetic mean (standard deviation)	1.89 ( 1.76 )	1.92 ( 1.85 )	-

End points

Top of page

Reporting group title

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

Reporting group description

FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.

Reporting group title

GLP-1 Receptor Agonist

Reporting group description

Reporting group title

Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period

Reporting group description

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period

Top of page

End point title

Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period

End point 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. Modified Intent-To-Treat (mITT) population:all randomised subjects who had a baseline and at least 1 post-baseline assessment of any primary/secondary endpoints, irrespective of compliance with study protocol and procedures. Here, “number of subjects analysed” = subjects with baseline and at least 1 post-baseline HbA1c assessment.

End point type

Primary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	250	253
Units: percentage of HbA1c
least squares mean (standard error)	-1.02 ( 0.048 )	-0.38 ( 0.048 )

FRC vs. GLP-1 RA

Statistical analysis description

Analysis was performed using MMRM with treatment groups, randomisation 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 randomised treatment period, including those obtained after IMP discontinuation/introduction of rescue medication.

Comparison groups

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) v GLP-1 Receptor Agonist

Number of subjects included in analysis

503

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Mixed models analysis

Parameter type

Least square (LS) mean difference

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

-0.508

Variability estimate

Standard error of the mean

Dispersion value

0.067

Notes
[1] - Threshold for significance at 0.05 level.

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period ^[2]

End point description

Change in HbA1c was calculated by subtracting baseline value from Week 52 value. Analysis was performed on mITT population who entered the extension period. Here, “number of subjects analysed”= subjects with baseline and at least 1 post-baseline HbA1c assessment.

End point type

Primary

End point timeframe

Baseline, Week 52

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	202
Units: percentage of HbA1c
arithmetic mean (standard error)	-1.01 ( 0.063 )

No statistical analyses for this end point

Secondary: Percentage of Subjects Reaching HbA1c <7% or <=6.5% at Week 26: Core Period

Top of page

End point title

Percentage of Subjects Reaching HbA1c <7% or <=6.5% at Week 26: Core Period

End point description

Subjects without any available HbA1c assessment at Week 26 were considered as non-responders. Analysis was performed on mITT population.

End point type

Secondary

End point timeframe

Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	252	253
Units: percentage of subjects
number (not applicable)
HbA1c <7%	61.9	25.7
HbA1c <=6.5%	40.5	9.9

FRC vs. GLP-1 RA

Statistical analysis description

HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs GLP-1 Receptor Agonist. Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomisation strata of Week -2 HbA1c (<8.0%, >=8.0%), and randomisation 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).

Comparison groups

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) v GLP-1 Receptor Agonist

Number of subjects included in analysis

505

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in percentage

Point estimate

36.05

Confidence interval

level

95%

sides

2-sided

lower limit

28.11

upper limit

43.99

Notes
[3] - Threshold for significance <=0.05

Secondary: Percentage of Subjects Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period

Top of page

End point title

Percentage of Subjects Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period

End point description

Subjects without any available HbA1c assessment at Week 52 were considered as non-responders. Analysis was performed on mITT population who entered the extension period.

End point type

Secondary

End point timeframe

Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	206
Units: percentage of subjects
number (not applicable)
HbA1c <7%	64.1
HbA1c <=6.5%	42.7

No statistical analyses for this end point

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period

Top of page

End point title

Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period

End point 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. Analysis was performed using mITT population. Here, "number of subjects analysed"= subjects with baseline and at least one post-baseline FPG assessment.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	251	253
Units: millimoles per litre (mmol/L)
least squares mean (standard error)	-2.28 ( 0.120 )	-0.60 ( 0.119 )

FRC vs. GLP-1 RA

Statistical analysis description

Analysis was performed using MMRM with treatment groups, randomisation strata of Week -2 HbA1c (<8.0%, >=8.0%), randomisation 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 end points were statistically significant).

Comparison groups

GLP-1 Receptor Agonist v Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

Number of subjects included in analysis

504

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-1.67

Confidence interval

level

95%

sides

2-sided

lower limit

-2.001

upper limit

-1.341

Variability estimate

Standard error of the mean

Dispersion value

0.168

Notes
[4] - Threshold for significance at 0.05 level.

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period

End point description

Change in FPG was calculated by subtracting baseline value from Week 52 value. Analysis was performed on mITT population who entered the extension period. Here, "number of subjects analysed"= subjects with baseline and at least one post-baseline FPG assessment.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	196
Units: mmol/L
arithmetic mean (standard error)	-2.27 ( 0.173 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period

Top of page

End point title

Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period

End point 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. Analysis was performed using mITT population. Here, "number of subjects analysed"= subjects with baseline and at least one post-baseline 7-point SMPG assessment.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	216	220
Units: mmol/L
least squares mean (standard error)	-1.69 ( 0.114 )	-0.67 ( 0.112 )

FRC vs. GLP-1 RA

Statistical analysis description

Analysis was performed using MMRM with treatment groups, randomisation strata of Week -2 HbA1c (<8.0%, >=8.0%), randomisation 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 end points were statistically significant).

Comparison groups

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) v GLP-1 Receptor Agonist

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-1.02

Confidence interval

level

95%

sides

2-sided

lower limit

-1.325

upper limit

-0.708

Variability estimate

Standard error of the mean

Dispersion value

0.157

Notes
[5] - Threshold for significance at 0.05 level.

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period

End point 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. Analysis was performed on mITT population who entered the extension period. Here, "number of subjects analysed"= subjects with baseline and at least one post-baseline 7-point SMPG assessment.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	142
Units: mmol/L
arithmetic mean (standard error)	-1.68 ( 0.176 )

No statistical analyses for this end point

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period

Top of page

End point title

Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period

End point 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 LOCF. Analysis was performed on mITT population. Here, "number of subjects analysed"= subjects with baseline and at least one post-baseline plasma glucose assessment.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	215	222
Units: mmol/L
least squares mean (standard error)	-3.96 ( 0.211 )	-1.11 ( 0.205 )

FRC vs. GLP-1 RA

Statistical analysis description

Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomisation strata of Week -2 HbA1c (<8.0%, >=8.0%), randomisation 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).

Comparison groups

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) v GLP-1 Receptor Agonist

Number of subjects included in analysis

437

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

ANCOVA

Parameter type

LS Mean Difference]

Point estimate

-2.85

Confidence interval

level

95%

sides

2-sided

lower limit

-3.42

upper limit

-2.279

Variability estimate

Standard error of the mean

Dispersion value

0.29

Notes
[6] - Threshold for significance at 0.05 level.

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period

End point 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. Analysis was performed on mITT population who entered the extension period. Here, "number of subjects analysed"=subjects with baseline and at least one post-baseline plasma glucose assessment.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	192
Units: mmol/L
arithmetic mean (standard error)	-4.30 ( 0.284 )

No statistical analyses for this end point

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period

Top of page

End point title

Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period

End point 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. Analysis was performed using mITT population. Here, "number of subjects analysed"= subjects with baseline and Week 26 assessments.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	215	220
Units: mmol/L
least squares mean (standard error)	-1.51 ( 0.177 )	-0.52 ( 0.173 )

FRC vs. GLP-1 RA

Statistical analysis description

Analysis was performed using ANCOVA model with treatment groups, randomisation strata of Week -2 HbA1c (<8.0%, >=8.0%), randomisation 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).

Comparison groups

Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) v GLP-1 Receptor Agonist

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[7]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.99

Confidence interval

level

95%

sides

2-sided

lower limit

-1.468

upper limit

-0.508

Variability estimate

Standard error of the mean

Dispersion value

0.244

Notes
[7] - Threshold for significance at 0.05 level.

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period

End point 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. Analysis was performed on mITT population who entered the extension period. Here, "number of subjects analysed"= subjects with baseline and Week 52 assessments.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	192
Units: mmol/L
arithmetic mean (standard error)	-1.85 ( 0.209 )

No statistical analyses for this end point

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period

Top of page

End point title

Percentage of Subjects Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period

End point 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%. Analysis was performed using mITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	252	253
Units: percentage of subjects
number (not applicable)	4.8	15.0

No statistical analyses for this end point

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period

Top of page

End point title

Percentage of Subjects Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period

End point 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%. Analysis was performed on mITT population who entered the extension period.

End point type

Secondary

End point timeframe

From Week 26 to Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	206
Units: percentage of subjects
number (not applicable)	1.5

No statistical analyses for this end point

Secondary: Change From Baseline in Body Weight at Week 26: Core Period

Top of page

End point title

Change From Baseline in Body Weight at Week 26: Core Period

End point description

Change in body weight was calculated by subtracting baseline value from Week 26 value. Analysis was performed using mITT population. Here, "number of subjects analysed" = subjects with baseline and at least one post-baseline body weight assessment.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	251	253
Units: kilogram (kg)
least squares mean (standard error)	1.89 ( 0.222 )	-1.14 ( 0.220 )

No statistical analyses for this end point

Secondary: Change From Baseline in Body Weight to Week 52: Single Arm Extension Period

Top of page

End point title

Change From Baseline in Body Weight to Week 52: Single Arm Extension Period

End point description

Change in body weight was calculated by subtracting baseline value from Week 52 value. Analysis was performed using mITT population who entered the extension period. Here, "number of subjects analysed"=subjects with baseline and at least one post-baseline body weight assessment.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	202
Units: kg
arithmetic mean (standard error)	2.78 ( 0.294 )

No statistical analyses for this end point

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Core Period

Top of page

End point title

Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Core Period

End point 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 analysed. Analysis was performed on safety population which included all randomised subjects who received at least one dose of open-label IMP, regardless of the amount of treatment administered. Subjects were analysed according to the treatment actually received (as treated).

End point type

Secondary

End point timeframe

From Baseline to Week 26

End point values	Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)	GLP-1 Receptor Agonist
Number of subjects analysed	255	256
Units: events per subject-year
number (not applicable)
Documented symptomatic hypoglycemia(<=3.9 mmol/ L)	1.54	0.08
Documented symptomatic hypoglycemia (<3.0 mmol/ L)	0.25	0.01

No statistical analyses for this end point

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Single Arm Extension Period

Top of page

End point title

Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Single Arm Extension Period

End point 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 analysed. Analysis was performed on safety population who entered the extension period and their data for whole study duration was analysed and reported.

End point type

Secondary

End point timeframe

From Baseline to Week 52

End point values	Insulin Glargine/Lixisenatide FRC- Single Arm Extension Period
Number of subjects analysed	206
Units: events per subject-year
number (not applicable)
Documented symptomatic hypoglycemia(<=3.9 mmol/ L)	1.59
Documented symptomatic hypoglycemia (<3.0 mmol/ L)	0.24

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks).

Adverse event reporting additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Fixed Ratio Combination

Reporting group description

FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted (median exposure: 183 days).

Reporting group title

GLP-1 Receptor Agonist

Reporting group description

GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extendedrelease 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).

Reporting group title

Fixed Ratio Combination Whole Study period

Reporting 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 (median exposure: 365 days).

Serious adverse events	Fixed Ratio Combination	GLP-1 Receptor Agonist	Fixed Ratio Combination Whole Study period
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 255 (3.92%)	9 / 256 (3.52%)	21 / 206 (10.19%)
number of deaths (all causes)	0	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenosquamous Cell Lung Cancer
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder Papilloma
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial Adenocarcinoma
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hepatic Neoplasm
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive Ductal Breast Carcinoma
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Papillary Thyroid Cancer
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal Cell Carcinoma
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Vasculitis Necrotising
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema Peripheral
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia Aspiration
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle Fracture
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 255 (0.78%)	0 / 256 (0.00%)	2 / 206 (0.97%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot Fracture
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip Fracture
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib Fracture
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin Laceration
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid Haemorrhage
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous Haematoma
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arteriosclerosis Coronary Artery
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Failure
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Failure Congestive
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	2 / 206 (0.97%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary Artery Disease
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	2 / 206 (0.97%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic Cardiomyopathy
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral Infarction
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic Neuropathy
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemic Unconsciousness
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intraventricular Haemorrhage
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid Haemorrhage
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	2 / 206 (0.97%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Duodenal Ulcer
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large Intestine Polyp
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal Haemorrhage
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermal Cyst
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	1 / 255 (0.39%)	1 / 256 (0.39%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary Retention
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 255 (0.39%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal Column Stenosis
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected Skin Ulcer
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative Abscess
subjects affected / exposed	0 / 255 (0.00%)	0 / 256 (0.00%)	1 / 206 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Electrolyte Imbalance
subjects affected / exposed	0 / 255 (0.00%)	1 / 256 (0.39%)	0 / 206 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Fixed Ratio Combination	GLP-1 Receptor Agonist	Fixed Ratio Combination Whole Study period
Total subjects affected by non serious adverse events
subjects affected / exposed	69 / 255 (27.06%)	48 / 256 (18.75%)	75 / 206 (36.41%)
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	14 / 255 (5.49%)	6 / 256 (2.34%)	15 / 206 (7.28%)
occurrences all number	14	6	17
Nausea
subjects affected / exposed	22 / 255 (8.63%)	6 / 256 (2.34%)	19 / 206 (9.22%)
occurrences all number	30	6	30
Infections and infestations
Influenza
subjects affected / exposed	11 / 255 (4.31%)	6 / 256 (2.34%)	15 / 206 (7.28%)
occurrences all number	12	6	19
Nasopharyngitis
subjects affected / exposed	25 / 255 (9.80%)	23 / 256 (8.98%)	32 / 206 (15.53%)
occurrences all number	27	26	37
Upper Respiratory Tract Infection
subjects affected / exposed	9 / 255 (3.53%)	12 / 256 (4.69%)	13 / 206 (6.31%)
occurrences all number	11	15	17

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

22 Sep 2016

Main changes were the following: - A single-arm FRC 26-week extension period was introduced to provide additional assessment of all safety, efficacy and other endpoints over 52 weeks in total. - Pharmacokinetic and antibody assessments were added in the FRC treatment group to gain information about exposure to lixisenatide and to assess the immunogenicity of insulin glargine and lixisenatide. - Minor clarifications and corrections were also made.

12 May 2017

Main change was to allow inclusion of subjects receiving background treatment of SGLT2 inhibitors. - Minor clarifications and corrections were also made.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period

Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period

Secondary: Percentage of Subjects Reaching HbA1c <7% or <=6.5% at Week 26: Core Period

Secondary: Percentage of Subjects Reaching HbA1c <7% or <=6.5% at Week 26: Core Period

Secondary: Percentage of Subjects Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period

Secondary: Percentage of Subjects Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period

Secondary: Percentage of Subjects Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period

Secondary: Change From Baseline in Body Weight at Week 26: Core Period

Secondary: Change From Baseline in Body Weight at Week 26: Core Period

Secondary: Change From Baseline in Body Weight to Week 52: Single Arm Extension Period

Secondary: Change From Baseline in Body Weight to Week 52: Single Arm Extension Period

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Core Period

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Core Period

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Single Arm Extension Period

Secondary: Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year: Single Arm Extension Period

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information