Comparison of the Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine in Patients With Type 2 Diabetes Insufficiently Controlled on Basal Insulin

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the superiority of iGlarLixi (fixed ratio combination of insulin glargine and lixisenatide) to insulin glargine on glycemic control as assessed by glycated hemoglobin A1c (HbA1c) change in patients with type 2 diabetes mellitus (T2DM) who are not sufficiently controlled with basal insulin. Secondary Objectives: To assess the effects of iGlarLixi in comparison with insulin glargine To assess the safety in each treatment group

Detailed Description
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The maximum study duration per patient will be approximately 33 weeks: an up to 2-week screening period (it can be exceptionally extended up to one additional week), a 30-week, open label randomized treatment period comparing iGlarLixi to insulin glargine (± metformin for both treatments), and a 3-day post-treatment safety follow-up period.

Official Title
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A Randomized, 30-week, Active-controlled, Open-label, 2 Treatment-arm, Parallel Group, Multicenter Study Comparing Efficacy and Safety of iGlarLixi to Insulin Glargine With or Without Metformin in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled on Basal Insulin With or Without 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: Metformin


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 and treated with basal insulin for at least 6 months before screening visit (V1). Patients who have been treated with a stable basal insulin regimen (ie, type of insulin and time/frequency of the injection), for at least 3 months before screening visit (V1). Stable total daily basal insulin dose (±20 %) in the range of 10 and 25 U/day for at least 2 months before screening visit (V1). Total daily dose should be within the range of 10-25 U, both inclusive, on the day of screening, but individual fluctuations of ±20% within 2 months prior to screening are acceptable. For patients receiving basal insulin AND 1 or 2 oral anti-diabetic drugs (OADs): the OAD dose(s) must be stable during the 3 months prior to screening. The OAD(s) can be 1 to 2 out of: Metformin (≥1500 mg/day or maximal tolerated dose). Sulfonylurea (SU)/glinide. Alpha-glucosidase inhibitor (alpha-GI). Sodium-glucose co-transporter 2 (SGLT2) inhibitor. Dipeptidyl-peptidase-4 (DPP-4) inhibitor. Fasting plasma glucose (FPG) ≤160 mg/dL (8.9 mmol/L) at screening visit (V1) (can be repeated once to confirm). Signed written informed consent. Exclusion criteria: Age <18 years at screening visit (V1). Screening glycated hemoglobin A1c(HbA1c) <7.0% or >10.5%. History of hypoglycemia unawareness. History of metabolic acidosis, including diabetic ketoacidosis within one 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 use of insulin regimen other than basal insulin, eg, prandial or pre-mixed insulin, within one year prior to screening (Note: Short term treatment [≤10 days] due to intercurrent illness is allowed). History of discontinuation of a previous treatment with glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) due to safety/tolerability reason 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 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 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: 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 test for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibody (HCAb). Positive urine pregnancy test in female of childbearing potential. For patient not treated with metformin at screening: severe renal function impairment with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 or end-stage renal disease. Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including (but not limited to): gastroparesis, unstable (ie, worsening) or not controlled (ie, prolonged nausea and vomiting) gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening visit; or history of surgery affecting gastric emptying. 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). Mean fasting self-monitored plasma glucose (SMPG) is >160 mg/dL (8.9 mmol/L), calculated from all available (minimum of 4 self-measurements) values during the 7 days prior to randomization. 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 with or without metformin for 30 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>|
| Active Comparator: Lantus (insulin glargine)<br>Insulin glargine will be self-administered subcutaneously once daily at any time of the day with or without metformin for 30 weeks | 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>|

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 30 | From Baseline to Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients with HbA1c <7.0% | Percentage of patients reaching HbA1c <7% at Week 30 | At Week 30 | 
| Patients with HbA1c ≤ 6.5% | Percentage of patients reaching HbA1c ≤ 6.5% at Week 30 | At Week 30 | 
| Change in postprandial plasma glucose (PPG) | Absolute change in 2-hour blood glucose excursion and PPG during meal test from baseline to Week 30 | From Baseline to Week 30 | 
| Change in self-monitored plasma glucose (SMPG) profile | Absolute change in 7-point SMPG profiles from baseline to Week 30 (each time point and average daily value) | From Baseline to Week 30 | 
| Patients with HbA1c <7.0% with no body weight gain | Percentage of patients reaching HbA1c <7% with no body weight gain at Week 30 | At Week 30 | 
| Change in body weight | Absolute change in body weight from baseline to Week 30 | From Baseline to Week 30 | 
| 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 30 and no documented (plasma glucose [PG] ≤70 mg/dL [3.9mmol/L]) symptomatic hypoglycemia during the 30-week randomized treatment period | At Week 30 | 
| Patients requiring rescue therapy | Percentage of patients requiring rescue therapy during the 30-week randomized treatment period | From Baseline to Week 30 | 
| Change in fasting plasma glucose (FPG) | Absolute change in FPG from baseline to Week 30 | From Baseline to Week 30 | 
| Confirmed hypoglycemia | Severe hypoglycemia and episodes of hypoglycemia documented with PG ≤ 70 mg/dL (3.9mmol/L) regardless of symptoms | From Baseline to Week 30 | 
| Adverse events (AEs) | Number of AEs, Serious AEs, AEs of Special Interest, and AEs requiring specific monitoring from baseline to Week 30 | From Baseline to Week 30 | 
| Immunogenicity (antibody variables) | Anti-lixisenatide antibodies (in iGlarLixi group) and anti-insulin antibodies from baseline to Week 30 | From Baseline to Week 30 |