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

Type 2 Diabetes Mellitus Clinical Trial

— LixiLan-G  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02787551
• Other study ID #: EFC13794
• Secondary ID: 2014-004850-32U1
• Status: Completed
• Phase: Phase 3
• Start date: July 6, 2016
• Est. completion date: November 17, 2018

Study information

• Verified date: March 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

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

Secondary Objectives:

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

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

Description:

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

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 514
• Est. completion date: November 17, 2018
• Est. primary completion date: May 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria :

• Participants with type 2 diabetes mellitus diagnosed at least 1 year prior to screening visit.

• Participants who were treated with one of the following GLP-1 receptor agonists for at least 4 months prior to screening visit 1 (V1), and with stable dose for at least 3 months prior to screening visit (V1):

• Liraglutide (Victoza®) 1.8 milligram (mg) QD or 1.2 mg QD, if the 1.8 mg QD dose was not well tolerated according to the Investigator's judgment or

• Exenatide (Byetta®) 10 microgram (µg) BID or of 5 µg BID, if 10 µg BID dose was not well tolerated according to the Investigator's judgment

in combination with metformin (daily dose greater than equal to [>=] 1500 mg/day or maximum tolerated dose [MTD]), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening.

or

Participants who were treated with stable dose of one of the following GLP-1 receptor agonists for at least 6 months prior to screening visit (V1):

• Exenatide extended-release (Bydureon®) 2 mg once weekly (QW), if well tolerated according to Investigator's judgment,

• Albiglutide (Tanzeum®) 50 mg QW or 30 mg QW, if 50 mg QW was not well tolerated according to Investigator's judgment,

• Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW was not well tolerated according to Investigator's judgment

in combination with metformin (daily dose =1500 mg/day or MTD), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening;

-Signed written informed consent.

Exclusion criteria:

• At screening visit, age <18.

• Screening HbA1c <7% and >9%.

• Pregnancy or lactation, women of childbearing potential with no effective contraceptive method.

• Any use of antidiabetic drugs within 3 months prior to the screening visit other than those described in the inclusion criteria.

• Previous treatment with insulin in the year prior to screening visit (note: short-term treatment with insulin [<=10 days] due to intercurrent illness including gestational diabetes was allowed at the discretion of the study physician).

• Laboratory findings at the time of screening, including:

• Fasting plasma glucose (FPG) >250 mg/dL (13.9 millimoles per litre [mmol/L]),

• Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN),

• Alanine transaminase or aspartate transaminase >3 ULN,

• Calcitonin >=20 pg/mL (5.9 pmol/L),

• Positive pregnancy test.

• Participant who had renal function impairment with estimated glomerular filtration rate <30mL/min/1.73m^2 (using the Modification of Diet in Renal Disease formula) or end-stage renal disease.

• Contraindication to use of insulin glargine, or lixisenatide or GLP-1 receptor agonist (Victoza®, Byetta®, Bydureon®, Tanzeum® or Trulicity®) according to local labeling.

• Any contraindication to metformin or pioglitazone or SGLT2 inhibitor use, according to local labeling.

• History of hypersensitivity to insulin glargine, or to any of the excipients.

• History of allergic reaction to any GLP-1 receptor agonist or to meta-cresol.

• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia type 2 syndromes).

• History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy.

• Body mass index <=20 or >40 kg/m^2.

Exclusion criteria for the extension period:

• Participants in the FRC arm with a rescue therapy and HbA1c >8% at week 22.

• Participants in the FRC arm who discontinued prematurely from FRC treatment before week 26.

• Participants in the GLP-1 RA treatment arm after randomization.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Insulin glargine/lixisenatide fixed ratio combination
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• liraglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• exenatide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• exenatide extended-release
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• albiglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• dulaglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• Background therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
Pharmaceutical form: tablet Route of administration: oral If previously taken, doses to remain stable through the study.

Locations

Country	Name	City	State
Canada	Investigational Site Number 1240003	Burlington
Canada	Investigational Site Number 1240006	Corunna
Canada	Investigational Site Number 1240002	Red Deer
Canada	Investigational Site Number 1240001	Vancouver
Estonia	Investigational Site Number 2330002	Pärnu
Estonia	Investigational Site Number 2330001	Tallinn
Estonia	Investigational Site Number 2330003	Tallinn
Estonia	Investigational Site Number 2330004	Viljandi
Germany	Investigational Site Number 2760001	Dresden
Germany	Investigational Site Number 2760003	Oldenburg In Holstein
Israel	Investigational Site Number 3760001	Haifa
Israel	Investigational Site Number 3760002	Haifa
Israel	Investigational Site Number 3760005	Jerusalem
Israel	Investigational Site Number 3760006	Jerusalem
Israel	Investigational Site Number 3760004	Tel Aviv
Italy	Investigational Site Number 3800008	Bergamo
Italy	Investigational Site Number 3800002	Bologna
Italy	Investigational Site Number 3800001	Milano
Italy	Investigational Site Number 3800006	Milano
Italy	Investigational Site Number 3800005	Napoli
Italy	Investigational Site Number 3800003	Roma
Italy	Investigational Site Number 3800004	Roma
Romania	Investigational Site Number 6420004	Bacau
Romania	Investigational Site Number 6420006	Brasov
Romania	Investigational Site Number 6420001	Bucuresti
Romania	Investigational Site Number 6420008	Buzau
Romania	Investigational Site Number 6420003	Cluj Napoca
Romania	Investigational Site Number 6420002	Oradea
Romania	Investigational Site Number 6420009	Targoviste
Romania	Investigational Site Number 6420007	Târgu-Mures
Romania	Investigational Site Number 6420005	Timisoara
Slovakia	Investigational Site Number 7030006	Bratislava
Slovakia	Investigational Site Number 7030009	Lubochna
Slovakia	Investigational Site Number 7030002	Lucenec
Slovakia	Investigational Site Number 7030005	Malacky
Slovakia	Investigational Site Number 7030007	Presov
Slovakia	Investigational Site Number 7030001	Roznava
Slovakia	Investigational Site Number 7030008	Sabinov
Slovakia	Investigational Site Number 7030004	Trencin
Slovakia	Investigational Site Number 7030003	Zilina
Spain	Investigational Site Number 7240012	Alzira
Spain	Investigational Site Number 7240005	Barcelona
Spain	Investigational Site Number 7240002	Ferrol
Spain	Investigational Site Number 7240008	Málaga
Spain	Investigational Site Number 7240011	Pozuelo De Alarcón
Spain	Investigational Site Number 7240003	Quart De Poblet
Spain	Investigational Site Number 7240006	Sabadell
Spain	Investigational Site Number 7240004	Sevilla
Spain	Investigational Site Number 7240007	Sevilla
Spain	Investigational Site Number 7240009	sEVILLA
United States	Investigational Site Number 8400079	Albany	New York
United States	Investigational Site Number 8400139	Austin	Texas
United States	Investigational Site Number 8400049	Avon	Indiana
United States	Investigational Site Number 8400053	Avon	Indiana
United States	Investigational Site Number 8400085	Avon	Indiana
United States	Investigational Site Number 8400120	Avon	Indiana
United States	Investigational Site Number 8400103	Bakersfield	California
United States	Investigational Site Number 8400033	Baltimore	Maryland
United States	Investigational Site Number 8400064	Birmingham	Alabama
United States	Investigational Site Number 8400090	Columbia	South Carolina
United States	Investigational Site Number 8400019	Columbus	Ohio
United States	Investigational Site Number 8400130	Council Bluffs	Iowa
United States	Investigational Site Number 8400001	Dallas	Texas
United States	Investigational Site Number 8400056	Dayton	Ohio
United States	Investigational Site Number 8400036	Denver	Colorado
United States	Investigational Site Number 8400071	Denver	Colorado
United States	Investigational Site Number 8400118	Edinburg	Texas
United States	Investigational Site Number 8400041	Evansville	Indiana
United States	Investigational Site Number 8400018	Fargo	North Dakota
United States	Investigational Site Number 8400073	Fountain Hills	Arizona
United States	Investigational Site Number 8400137	Fresno	California
United States	Investigational Site Number 8400044	Henderson	Nevada
United States	Investigational Site Number 8400008	Houston	Texas
United States	Investigational Site Number 8400063	Houston	Texas
United States	Investigational Site Number 8400106	Houston	Texas
United States	Investigational Site Number 8400109	Houston	Texas
United States	Investigational Site Number 8400043	Huntington Park	California
United States	Investigational Site Number 8400038	Indianapolis	Indiana
United States	Investigational Site Number 8400114	Jacksonville	Florida
United States	Investigational Site Number 8400051	Jefferson City	Missouri
United States	Investigational Site Number 8400124	Lamont	California
United States	Investigational Site Number 8400027	Lancaster	California
United States	Investigational Site Number 8400045	Lawrenceville	Georgia
United States	Investigational Site Number 8400034	Lexington	Kentucky
United States	Investigational Site Number 8400091	Lexington	Kentucky
United States	Investigational Site Number 8400013	Los Angeles	California
United States	Investigational Site Number 8400098	Los Angeles	California
United States	Investigational Site Number 8400078	Marrero	Louisiana
United States	Investigational Site Number 8400125	Mentor	Ohio
United States	Investigational Site Number 8400032	Metairie	Louisiana
United States	Investigational Site Number 8400133	Miami	Florida
United States	Investigational Site Number 8400042	Mission Hills	California
United States	Investigational Site Number 8400020	Morehead City	North Carolina
United States	Investigational Site Number 8400088	New Orleans	Louisiana
United States	Investigational Site Number 8400061	New York	New York
United States	Investigational Site Number 8400123	North Massapequa	New York
United States	Investigational Site Number 8400014	North Richland Hills	Texas
United States	Investigational Site Number 8400006	Northridge	California
United States	Investigational Site Number 8400099	Oklahoma City	Oklahoma
United States	Investigational Site Number 8400021	Orange	California
United States	Investigational Site Number 8400054	Orem	Utah
United States	Investigational Site Number 8400083	Papillion	Nebraska
United States	Investigational Site Number 8400047	Phoenix	Arizona
United States	Investigational Site Number 8400058	Port Charlotte	Florida
United States	Investigational Site Number 8400126	Rialto	California
United States	Investigational Site Number 8400025	Salt Lake City	Utah
United States	Investigational Site Number 8400089	San Antonio	Texas
United States	Investigational Site Number 8400094	Santa Ana	California
United States	Investigational Site Number 8400135	Schertz	Texas
United States	Investigational Site Number 8400129	Scottdale	Pennsylvania
United States	Investigational Site Number 8400075	Shavano Park	Texas
United States	Investigational Site Number 8400076	Smithfield	Pennsylvania
United States	Investigational Site Number 8400096	Snellville	Georgia
United States	Investigational Site Number 8400023	Springfield	Illinois
United States	Investigational Site Number 8400095	Staten Island	New York
United States	Investigational Site Number 8400107	Sugar Land	Texas
United States	Investigational Site Number 8400084	Tampa	Florida
United States	Investigational Site Number 8400009	Ventura	California
United States	Investigational Site Number 8400104	Warwick	Rhode Island
United States	Investigational Site Number 8400092	Weber City	Virginia
United States	Investigational Site Number 8400112	West Palm Beach	Florida
United States	Investigational Site Number 8400067	West Seneca	New York
United States	Investigational Site Number 8400065	Wilmington	North Carolina
United States	Investigational Site Number 8400111	Yonkers	New York

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Canada,  Estonia,  Germany,  Israel,  Italy,  Romania,  Slovakia,  Spain, 

Outcome

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