Clinical trial NCT02787551: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-06-01
Enrollment: 514
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

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

Secondary Objectives:

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

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

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

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

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

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period
timeFrame: Week 26
measure: Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period
timeFrame: Week 52
measure: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
measure: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
measure: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
measure: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
measure: Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period
timeFrame: From Baseline to Week 26
measure: Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period
timeFrame: From Week 26 to Week 52
measure: Change From Baseline in Body Weight at Week 26: Core Period
timeFrame: Baseline, Week 26
measure: Change From Baseline in Body Weight to Week 52: Single Arm Extension Period
timeFrame: Baseline, Week 52
measure: Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period
timeFrame: From Baseline to Week 26
measure: Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period
timeFrame: From Baseline to Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number 8400064
state: Alabama
city: Fountain Hills
country: United States
facility: Investigational Site Number 8400073
state: Arizona
city: Phoenix
country: United States
facility: Investigational Site Number 8400047
state: Arizona
city: Bakersfield
country: United States
facility: Investigational Site Number 8400103
state: California
city: Fresno
country: United States
facility: Investigational Site Number 8400137
state: California
city: Huntington Park
country: United States
facility: Investigational Site Number 8400043
state: California
city: Lamont
country: United States
facility: Investigational Site Number 8400124
state: California
city: Lancaster
country: United States
facility: Investigational Site Number 8400027
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 8400098
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 8400013
state: California
city: Mission Hills
country: United States
facility: Investigational Site Number 8400042
state: California
city: Northridge
country: United States
facility: Investigational Site Number 8400006
state: California
city: Orange
country: United States
facility: Investigational Site Number 8400021
state: California
city: Rialto
country: United States
facility: Investigational Site Number 8400126
state: California
city: Santa Ana
country: United States
facility: Investigational Site Number 8400094
state: California
city: Ventura
country: United States
facility: Investigational Site Number 8400009
state: California
city: Denver
country: United States
facility: Investigational Site Number 8400071
state: Colorado
city: Denver
country: United States
facility: Investigational Site Number 8400036
state: Colorado
city: Jacksonville
country: United States
facility: Investigational Site Number 8400114
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 8400133
state: Florida
city: Port Charlotte
country: United States
facility: Investigational Site Number 8400058
state: Florida
city: Tampa
country: United States
facility: Investigational Site Number 8400084
state: Florida
city: West Palm Beach
country: United States
facility: Investigational Site Number 8400112
state: Florida
city: Lawrenceville
country: United States
facility: Investigational Site Number 8400045
state: Georgia
city: Snellville
country: United States
facility: Investigational Site Number 8400096
state: Georgia
city: Springfield
country: United States
facility: Investigational Site Number 8400023
state: Illinois
city: Avon
country: United States
facility: Investigational Site Number 8400049
state: Indiana
city: Avon
country: United States
facility: Investigational Site Number 8400053
state: Indiana
city: Avon
country: United States
facility: Investigational Site Number 8400085
state: Indiana
city: Avon
country: United States
facility: Investigational Site Number 8400120
state: Indiana
city: Evansville
country: United States
facility: Investigational Site Number 8400041
state: Indiana
city: Indianapolis
country: United States
facility: Investigational Site Number 8400038
state: Indiana
city: Council Bluffs
country: United States
facility: Investigational Site Number 8400130
state: Iowa
city: Lexington
country: United States
facility: Investigational Site Number 8400034
state: Kentucky
city: Lexington
country: United States
facility: Investigational Site Number 8400091
state: Kentucky
city: Marrero
country: United States
facility: Investigational Site Number 8400078
state: Louisiana
city: Metairie
country: United States
facility: Investigational Site Number 8400032
state: Louisiana
city: New Orleans
country: United States
facility: Investigational Site Number 8400088
state: Louisiana
city: Baltimore
country: United States
facility: Investigational Site Number 8400033
state: Maryland
city: Jefferson City
country: United States
facility: Investigational Site Number 8400051
state: Missouri
city: Papillion
country: United States
facility: Investigational Site Number 8400083
state: Nebraska
city: Henderson
country: United States
facility: Investigational Site Number 8400044
state: Nevada
city: Albany
country: United States
facility: Investigational Site Number 8400079
state: New York
city: New York
country: United States
facility: Investigational Site Number 8400061
state: New York
city: North Massapequa
country: United States
facility: Investigational Site Number 8400123
state: New York
city: Staten Island
country: United States
facility: Investigational Site Number 8400095
state: New York
city: West Seneca
country: United States
facility: Investigational Site Number 8400067
state: New York
city: Yonkers
country: United States
facility: Investigational Site Number 8400111
state: New York
city: Morehead City
country: United States
facility: Investigational Site Number 8400020
state: North Carolina
city: Wilmington
country: United States
facility: Investigational Site Number 8400065
state: North Carolina
city: Fargo
country: United States
facility: Investigational Site Number 8400018
state: North Dakota
city: Columbus
country: United States
facility: Investigational Site Number 8400019
state: Ohio
city: Dayton
country: United States
facility: Investigational Site Number 8400056
state: Ohio
city: Mentor
country: United States
facility: Investigational Site Number 8400125
state: Ohio
city: Oklahoma City
country: United States
facility: Investigational Site Number 8400099
state: Oklahoma
city: Scottdale
country: United States
facility: Investigational Site Number 8400129
state: Pennsylvania
city: Smithfield
country: United States
facility: Investigational Site Number 8400076
state: Pennsylvania
city: Warwick
country: United States
facility: Investigational Site Number 8400104
state: Rhode Island
city: Columbia
country: United States
facility: Investigational Site Number 8400090
state: South Carolina
city: Austin
country: United States
facility: Investigational Site Number 8400139
state: Texas
city: Dallas
country: United States
facility: Investigational Site Number 8400001
state: Texas
city: Edinburg
country: United States
facility: Investigational Site Number 8400118
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 8400008
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 8400109
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 8400063
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 8400106
state: Texas
city: North Richland Hills
country: United States
facility: Investigational Site Number 8400014
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number 8400089
state: Texas
city: Schertz
country: United States
facility: Investigational Site Number 8400135
state: Texas
city: Shavano Park
country: United States
facility: Investigational Site Number 8400075
state: Texas
city: Sugar Land
country: United States
facility: Investigational Site Number 8400107
state: Texas
city: Orem
country: United States
facility: Investigational Site Number 8400054
state: Utah
city: Salt Lake City
country: United States
facility: Investigational Site Number 8400025
state: Utah
city: Weber City
country: United States
facility: Investigational Site Number 8400092
state: Virginia
city: Burlington
country: Canada
facility: Investigational Site Number 1240003
city: Corunna
country: Canada
facility: Investigational Site Number 1240006
city: Red Deer
country: Canada
facility: Investigational Site Number 1240002
city: Vancouver
country: Canada
facility: Investigational Site Number 1240001
city: Pärnu
country: Estonia
facility: Investigational Site Number 2330002
city: Tallinn
country: Estonia
facility: Investigational Site Number 2330003
city: Tallinn
country: Estonia
facility: Investigational Site Number 2330001
city: Viljandi
country: Estonia
facility: Investigational Site Number 2330004
city: Dresden
country: Germany
facility: Investigational Site Number 2760001
city: Oldenburg In Holstein
country: Germany
facility: Investigational Site Number 2760003
city: Haifa
country: Israel
facility: Investigational Site Number 3760001
city: Haifa
country: Israel
facility: Investigational Site Number 3760002
city: Jerusalem
country: Israel
facility: Investigational Site Number 3760005
city: Jerusalem
country: Israel
facility: Investigational Site Number 3760006
city: Tel Aviv
country: Israel
facility: Investigational Site Number 3760004
city: Bergamo
country: Italy
facility: Investigational Site Number 3800008
city: Bologna
country: Italy
facility: Investigational Site Number 3800002
city: Milano
country: Italy
facility: Investigational Site Number 3800001
city: Milano
country: Italy
facility: Investigational Site Number 3800006
city: Napoli
country: Italy
facility: Investigational Site Number 3800005
city: Roma
country: Italy
facility: Investigational Site Number 3800004
city: Roma
country: Italy
facility: Investigational Site Number 3800003
city: Bacau
country: Romania
facility: Investigational Site Number 6420004
city: Brasov
country: Romania
facility: Investigational Site Number 6420006
city: Bucuresti
country: Romania
facility: Investigational Site Number 6420001
city: Buzau
country: Romania
facility: Investigational Site Number 6420008
city: Cluj Napoca
country: Romania
facility: Investigational Site Number 6420003
city: Oradea
country: Romania
facility: Investigational Site Number 6420002
city: Targoviste
country: Romania
facility: Investigational Site Number 6420009
city: Timisoara
country: Romania
facility: Investigational Site Number 6420005
city: Târgu-Mureş
country: Romania
facility: Investigational Site Number 6420007
city: Bratislava
country: Slovakia
facility: Investigational Site Number 7030006
city: Lubochna
country: Slovakia
facility: Investigational Site Number 7030009
city: Lucenec
country: Slovakia
facility: Investigational Site Number 7030002
city: Malacky
country: Slovakia
facility: Investigational Site Number 7030005
city: Presov
country: Slovakia
facility: Investigational Site Number 7030007
city: Roznava
country: Slovakia
facility: Investigational Site Number 7030001
city: Sabinov
country: Slovakia
facility: Investigational Site Number 7030008
city: Trencin
country: Slovakia
facility: Investigational Site Number 7030004
city: Zilina
country: Slovakia
facility: Investigational Site Number 7030003
city: Alzira
country: Spain
facility: Investigational Site Number 7240012
city: Barcelona
country: Spain
facility: Investigational Site Number 7240005
city: Ferrol
country: Spain
facility: Investigational Site Number 7240002
city: Málaga
country: Spain
facility: Investigational Site Number 7240008
city: Pozuelo De Alarcón
country: Spain
facility: Investigational Site Number 7240011
city: Quart De Poblet
country: Spain
facility: Investigational Site Number 7240003
city: Sabadell
country: Spain
facility: Investigational Site Number 7240006
city: Sevilla
country: Spain
facility: Investigational Site Number 7240007
city: sEVILLA
country: Spain
facility: Investigational Site Number 7240009
city: Sevilla
country: Spain
facility: Investigational Site Number 7240004
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Kuruvilla DE, Mann JI, Tepper SJ, Starling AJ, Panza G, Johnson MAL. Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). Sci Rep. 2022 Mar 24;12(1):5110. doi: 10.1038/s41598-022-09071-6.
citation: Ferrannini E, Niemoeller E, Dex T, Servera S, Mari A. Fixed-ratio combination of insulin glargine plus lixisenatide (iGlarLixi) improves ss-cell function in people with type 2 diabetes. Diabetes Obes Metab. 2022 Jun;24(6):1159-1165. doi: 10.1111/dom.14688. Epub 2022 Mar 28.
citation: Guja C, Giorgino F, Blonde L, Ali A, Prazny M, Meier JJ, Souhami E, Lubwama R, Ji C, Rosenstock J. Concomitant iGlarLixi and Sodium-Glucose Co-transporter-2 Inhibitor Therapy in Adults with Type 2 Diabetes: LixiLan-G Trial and Real-World Evidence Results. Diabetes Ther. 2022 Jan;13(1):205-215. doi: 10.1007/s13300-021-01180-1. Epub 2021 Dec 11.
citation: Blonde L, Rosenstock J, Frias J, Birkenfeld AL, Niemoeller E, Souhami E, Ji C, Del Prato S, Aroda VR. Durable Effects of iGlarLixi Up to 52 Weeks in Type 2 Diabetes: The LixiLan-G Extension Study. Diabetes Care. 2021 Mar;44(3):774-780. doi: 10.2337/dc20-2023. Epub 2021 Jan 19.
citation: Blonde L, Rosenstock J, Del Prato S, Henry R, Shehadeh N, Frias J, Niemoeller E, Souhami E, Ji C, Aroda VR. Switching to iGlarLixi Versus Continuing Daily or Weekly GLP-1 RA in Type 2 Diabetes Inadequately Controlled by GLP-1 RA and Oral Antihyperglycemic Therapy: The LixiLan-G Randomized Clinical Trial. Diabetes Care. 2019 Nov;42(11):2108-2116. doi: 10.2337/dc19-1357. Epub 2019 Sep 17.