Evaluation of Insulin Glargine/Lixisenatide Fixed Ratio Combination in Patients With Type 2 Diabetes Insufficiently Controlled With Oral Antidiabetic Drug(s)

Study Overview
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Brief Summary
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Primary Objectives: The co-primary objective of this study is: To demonstrate the superiority of iGlarLixi (fixed ratio combination of insulin glargine and lixisenatide) versus lixisenatide on glycemic control as assessed by glycated hemoglobin A1c (HbA1c) change. To demonstrate the non-inferiority of iGlarLixi versus insulin glargine on glycemic control as assessed by HbA1c change. Secondary Objectives: To assess the effects of iGlarLixi in comparison with insulin glargine alone and lixisenatide alone. To assess the safety in each treatment group.

Detailed Description
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The maximum study duration per patient will be approximately 31 weeks: an up-to 6-week screening and run-in period (with an up-to 2-week screening phase and a 4-week run-in phase), followed by a 24-week randomized treatment period and a 3-day post-treatment safety follow up period.

Official Title
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A Randomized, 24 Week, Active-controlled, Open-label, 3-arm, Parallel-group Multicenter Study Comparing the Efficacy and Safety of iGlarLixi to Insulin Glargine and Lixisenatide in Type 2 Diabetes Mellitus Patients Insufficiently Controlled With Oral Antidiabetic Drug(s)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010)
* Drug: Insulin glargine (HOE901)
* Drug: Lixisenatide (AVE0010)
* Drug: Metformin
* Drug: SGLT2 inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Patients with type 2 diabetes mellitus (T2DM) diagnosed for at least 1 year before the screening visit (V1), treated for at least 3 months prior to the screening visit (V1) with metformin alone or metformin and a second oral antidiabetic treatment that can be a sulfonylurea (SU), a glinide, an alpha-glucosidase inhibitor (alpha-GI), a dipeptidyl peptidase-4 (DPP-4) inhibitor or a sodium-glucose co transporter 2 (SGLT-2) inhibitor and who are not adequately controlled with this treatment. Signed written informed consent. Exclusion criteria: Age < legal age of majority at the screening visit (V1). Body mass index (BMI) >40 kg/m² at screening. Glycated hemoglobin A1c (HbA1c) at screening visit: <7.5% or >11% for patients previously treated with metformin alone; <7.0% or >10% for patients previously treated with metformin and a second oral antidiabetic treatment. History of hypoglycemia unawareness. History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening. Use of oral or injectable glucose-lowering agents other than those stated in the inclusion criteria within 3 months prior to screening. Previous treatment with insulin (except for short-term treatment due to intercurrent illness at the discretion of the Investigator) within 1 year prior to screening. History of discontinuation of a previous treatment with glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) due to safety/tolerability reasons or lack of efficacy. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 week or more within 3 months prior to screening. Use of weight loss drugs within 3 months prior to screening. Use of any investigational drug other than specified in this protocol within 1 month or 5 half-lives, whichever is longer, prior to screening. Within 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization. Planned coronary, carotid, or peripheral artery revascularization procedures to be performed during the study period. Known history of drug or alcohol abuse within 6 months prior to screening. Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic blood pressure >180 mmHg or diastolic blood pressure >95 mmHg. Laboratory findings at screening visit (V1): Amylase and/or lipase >3 times the upper limit of normal (ULN) laboratory range. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN. Total bilirubin >1.5 ULN (except in case of Gilbert's syndrome). Calcitonin ≥20 pg/mL (5.9 pmol/L). Hemoglobin <10.5 g/dL and/or neutrophils <1500/mm3 and/or platelets <100 000/mm3. Positive urine pregnancy test in female of childbearing potential. Patient who has a severe renal function impairment with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 or end-stage renal disease. History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy has been performed), pancreatitis during previous treatment with incretin therapies, chronic pancreatitis, pancreatectomy. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes). Use of SU, glinide, alpha-GI, DPP-4 inhibitor, and SGLT-2 inhibitor after start of run-in (from V2 [Week -4]). HbA1c at V4 (Week -1) : <7.0% or >10%. Fasting plasma glucose >250 mg/dL (13.9 mmol/L) at V4 (Week-1) (can be repeated once to confirm). Metformin maximal tolerated dose <1500 mg/day. Amylase and/or lipase >3 ULN at V4 (Week-1). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Soliqua (insulin glargine/lixisenatide)<br>iGlarLixi (insulin glargine/lixisenatide) will be self-administered subcutaneously once daily in the morning on top of metformin for 24 weeks. | Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: iGlarLixi;Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: SGLT2 inhibitor<br>* Pharmaceutical form:tablet Route of administration: oral<br>|
| Active Comparator: Lantus (insulin glargine)<br>Insulin glargine will be self-administered subcutaneously once daily at any time of the day on top of metformin for 24 weeks. Injection time should be determined on the day of randomization, and should remain about the same until the end of the treatment period. | Drug: Insulin glargine (HOE901)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: Lantus;Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: SGLT2 inhibitor<br>* Pharmaceutical form:tablet Route of administration: oral<br>|
| Active Comparator: Lyxumia (lixisenatide)<br>Lixisenatide will be self-administered subcutaneously once daily according to the locally approved label on top of metformin for 24 weeks. Injection time should be determined on the day of randomization, and should remain about the same until the end of the treatment period. | Drug: Lixisenatide (AVE0010)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: Lyxumia;Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: SGLT2 inhibitor<br>* Pharmaceutical form:tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change in glycated hemoglobin (HbA1c) from baseline to Week 24 | From Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in postprandial plasma glucose (PPG) | Absolute change in 2-hour blood glucose excursion and PPG during meal test from baseline to Week 24 (for all patients in iGlarLixi or insulin glargine group and patients who receive morning injection in the lixisenatide group) | From Baseline to Week 24 | 
| Change in fasting plasma glucose (FPG) | Absolute change in FPG from baseline to Week 24 | From Baseline to Week 24 | 
| Change in self-monitored plasma glucose (SMPG) profile | Absolute change in 7-point SMPG profiles from baseline to Week 24 (each time point and average daily value) | From Baseline to Week 24 | 
| Patients with HbA1c <7.0% | Percentage of patients reaching HbA1c <7% at Week 24 | At Week 24 | 
| Patients with HbA1c ≤ 6.5% | Percentage of patients reaching HbA1c ≤ 6.5% at Week 24 | At Week 24 | 
| Change in body weight | Absolute change in body weight from baseline to Week 24 | From Baseline to Week 24 | 
| Patients with HbA1c <7.0% with no body weight gain | Percentage of patients reaching HbA1c <7% with no body weight gain at Week 24 | At Week 24 | 
| Patients with HbA1c <7.0% with no body weight gain and no documented symptomatic hypoglycemia | Percentage of patients reaching HbA1c <7% with no body weight gain at Week 24 and no documented (plasma glucose [PG] ≤70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia during the 24 week treatment period | At Week 24 | 
| Confirmed hypoglycemia | Including severe hypoglycemia and episodes of hypoglycemia documented with PG ≤70 mg/dL (3.9 mmol/L) regardless of symptoms from baseline to Week 24 | From Baseline to Week 24 | 
| Adverse events (AEs) | Number of AEs, serious AEs, AEs of Special Interest, and AEs requiring specific monitoring from baseline to Week 24 | From Baseline to Week 24 | 
| Immunogenicity (antibody variables) | Anti-lixisenatide antibodies and anti-insulin antibodies (depending on the treatment group) from baseline to Week 24 | From Baseline to Week 24 |