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

Study Description

Brief Summary

Detailed Description

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: insulin glargine/lixisenatide fixed ratio combination Other Names HOE901/AVE0010 Drug: liraglutide Other Names Victoza Drug: exenatide Other Names Byetta Drug: exenatide extended-release Other Names Bydureon Drug: albiglutide Other Names Tanzeum Drug: dulaglutide Other Names Trulicity Drug: metformin Other Names Drug: pioglitazone Other Names Drug: SGLT2 inhibitor Other Names	Phase 3

Tracking Information

First Submitted Date	May 26, 2016
Last Update Posted Date	February 22, 2018
Start Date	July 06, 2016
Anticipated Completion Date	November 01, 2018
Primary Completion Date	May 24, 2018
Results First Submitted Date	N/A
Received Results Disposit Date	N/A

Current Primary Outcome Measures

• Change from baseline in HbA1c [Time Frame: Baseline to 26 weeks]

Original Primary Outcome Measures

Current Secondary Outcome Measures

• Percentage of participants reaching HbA1c targets [Time Frame: Baseline to 26 weeks]

• Change from baseline in fasting plasma glucose (FPG) [Time Frame: Baseline to 26 weeks]

• Change from baseline in 7-point self-monitored plasma glucose (SMPG) profiles [Time Frame: Baseline to 26 weeks]

• Change from baseline in 2-hour postprandial glucose (PPG) during standardized meal test [Time Frame: Baseline to 26 weeks]

• Change from baseline in blood glucose excursion during standardized meal test [Time Frame: Baseline to 26 weeks]

• Change from baseline in body weight [Time Frame: Baseline to 26 weeks]

• Percentage of participants with symptomatic hypoglycemia [Time Frame: 26 weeks]

• Number of adverse events [Time Frame: 26 weeks]

• Percentage of patients requiring rescue therapy [Time Frame: Baseline to 26 weeks]

Original Secondary Outcome Measures

Study Design

Brief Title	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
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 fixed ratio combination (FRC) to GLP-1 receptor agonist (GLP-1 RA) on top of metformin (with or without pioglitazone, with or without SGLT2 inhibitor) in patients 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 patients will be approximately 29 weeks: an up to 2 week screening period, a 26 week treatment period (either randomized or uncontrolled), and a 3 or 9 day post-treatment safety followup period. Maximum duration for FRC patients will be approximately 55 weeks: an 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 endpoints will be also assessed at the end of the extension period.
Study Type	Interventional
Study Phase	Phase 3
Estimated Enrollment	500
Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Conditions	Type 2 Diabetes Mellitus
Target Follow-Up Duration	N/A
Biospecimen:	N/A
Sampling Method	N/A
Study Population	N/A
Intervention	Drug: insulin glargine/lixisenatide fixed ratio combination Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names HOE901/AVE0010 Drug: liraglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names Victoza Drug: exenatide Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names Byetta Drug: exenatide extended-release Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names Bydureon Drug: albiglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names Tanzeum Drug: dulaglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous Other Names Trulicity Drug: metformin Pharmaceutical form: tablet Route of administration: oral Other Names Drug: pioglitazone Pharmaceutical form: tablet Route of administration: oral Other Names Drug: SGLT2 inhibitor Pharmaceutical form: tablet Route of administration: oral Other Names
Study Groups/Cohorts	Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.
Study Arms	Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : insulin glargine/lixisenatide fixed ratio combination Pharmaceutical form: solution for injection Route of administration: subcutaneous Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : metformin Pharmaceutical form: tablet Route of administration: oral Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : pioglitazone Pharmaceutical form: tablet Route of administration: oral Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : SGLT2 inhibitor Pharmaceutical form: tablet Route of administration: oral Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : SGLT2 inhibitor Pharmaceutical form: tablet Route of administration: oral Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : pioglitazone Pharmaceutical form: tablet Route of administration: oral Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : metformin Pharmaceutical form: tablet Route of administration: oral Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : liraglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : exenatide Pharmaceutical form: solution for injection Route of administration: subcutaneous Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : exenatide extended-release Pharmaceutical form: solution for injection Route of administration: subcutaneous Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : albiglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued. Drug : dulaglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous

Arm	Intervention/Treatment
Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : insulin glargine/lixisenatide fixed ratio combination Pharmaceutical form: solution for injection Route of administration: subcutaneous
Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : metformin Pharmaceutical form: tablet Route of administration: oral
Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : pioglitazone Pharmaceutical form: tablet Route of administration: oral
Experimental Insulin glargine/lixisenatide fixed ratio combination Insulin glargine/lixisenatide fixed ratio combination (FRC) is injected subcutaneously (SC, under the skin) once daily (QD). Dose individually adjusted. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : SGLT2 inhibitor Pharmaceutical form: tablet Route of administration: oral
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : SGLT2 inhibitor Pharmaceutical form: tablet Route of administration: oral
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : pioglitazone Pharmaceutical form: tablet Route of administration: oral
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : metformin Pharmaceutical form: tablet Route of administration: oral
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : liraglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : exenatide Pharmaceutical form: solution for injection Route of administration: subcutaneous
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : exenatide extended-release Pharmaceutical form: solution for injection Route of administration: subcutaneous
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : albiglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous
Active Comparator Liraglutide/Exenatide/Exenatide ER/Albiglutide/Dulaglutide Liraglutide will be injected SC (under the skin) QD, and exenatide will be injected SC (under the skin) twice daily (BID). Exenatide extended-release, albiglutide, and dulaglutide are injected SC (under the skin) once weekly. Metformin, pioglitazone (if taken prior to entry in the trial), and SGLT2 inhibitor (if taken prior to entry in the trial) treatments should be continued.	Drug : dulaglutide Pharmaceutical form: solution for injection Route of administration: subcutaneous

Recruitment Information

Recruitment Status:	Recruiting
Enrollment	500
Completion Date	November 01, 2018
Eligibility Criteria:	Inclusion criteria : - Patients with type 2 diabetes mellitus diagnosed at least 1 year prior to screening visit. - Patients who have been treated with one of the following glucagon-like peptide 1 (GLP-1) receptor agonists for at least 4 months prior to screening visit (V1), and with stable dose for at least 3 months prior to screening visit (V1): - Liraglutide (Victoza®) 1.8 mg QD or 1.2 mg QD, if the 1.8 mg QD dose is not well tolerated according to the Investigator's judgment or - Exenatide (Byetta®) 10 µg BID or of 5 µg BID, if 10 µg BID dose is not well tolerated according to the Investigator's judgment in combination with metformin (daily dose ≥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 Patients who have been 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 is not well tolerated according to Investigator's judgment, - Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW is 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 is 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 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. - Patient who has renal function impairment with estimated glomerular filtration rate <30mL/min/1.73m2 (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: - Patients in the FRC arm with a rescue therapy and HbA1c >8% at week 22. - Patients in the FRC arm who discontinued prematurely from FRC treatment before week 26. - Patients 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.
Gender	All
Age	18 Years to N/A
Accepts Healthy Volunteers	No
Contacts	For site information, send an email with site number to [email protected]
Listed Location Countries	Canada Estonia Germany Israel Italy Romania Slovakia Spain United States

Administrative Information

NCT Number:	NCT02787551
Other Study ID Numbers	EFC13794 2014-004850-32 U1111-1168-4639
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement	Not Available
Responsible Party	,
Study Sponsor	Sanofi
Collaborators	Not Available
Investigators	Study Director Clinical Sciences & Operations Sanofi