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

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

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.

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.

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.