Efficacy and Safety of LixiLan Versus Insulin Glargine Alone Both With Metformin in Japanese With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antidiabetic Drugs

Study Overview
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Brief Summary
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Primary Objective: To compare LixiLan to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to week 26 in patients with type 2 diabetes mellitus. Secondary Objective: To compare overall efficacy and safety of LixiLan to insulin glargine over 26 weeks in patients with type 2 diabetes mellitus.

Detailed Description
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The maximum study duration per patient will be approximately 41 weeks: an up to 14-week screening period (consisting of an up to 2-week screening phase and a 12-week run-in phase), a 26-week randomized treatment period, and a 3-day post-treatment safety follow-up period.

Official Title
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A Randomized, Active-controlled, Open Label, 2-treatment Arm, and Multicenter Study Comparing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Combination to Insulin Glargine With Metformin in Japanese Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antidiabetic Drugs

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010)
* Drug: Insulin glargine U100 (HOE901)
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Patient with type 2 diabetes mellitus (T2DM) diagnosed for at least 1 year before the screening visit (V1). Patient treated with a stable, once a day basal insulin regimen (ie, type of insulin and time/frequency of the injection), for at least 3 months before the screening visit. The total daily basal insulin dose should be stable (± 20%) and <15 U/day for at least 1 month before the screening visit. Patient receiving 1 or 2 oral anti-diabetic drugs (OADs): the OAD dose(s) must be stable during the 3 months before the screening visit. The OADs can be 1 to 2 out of: Metformin; Sulfonylurea (SU); Glinide; Dipeptidyl-peptidase-4 (DPP-4) inhibitor; Sodium glucose co-transporter 2 (SGLT2) inhibitor; Alpha glucosidase inhibitor (alpha-GI). Signed written informed consent. Exclusion criteria: Age <20 years at screening visit. HbA1c at screening visit <7.5% or >9.5%. Fasting plasma glucose (FPG) >180 mg/dL (10.0 mmol/L) at screening visit. Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. Use of oral or injectable glucose-lowering agents other than those stated in the inclusion criteria in the 3 months before screening visit. Previous use of insulin regimen other than basal insulin, eg, prandial or pre-mixed insulin. Note: Short-term treatment (≤10 days) due to intercurrent illness including gestational diabetes is allowed at the discretion of the Investigator. Use of thiazolidinedione (TZD) within 6 months prior to screening visit. History of discontinuation of a previous treatment with a glucagon-like peptide-1(GLP-1) receptor agonist due to safety/ tolerability issues or lack of efficacy. Laboratory findings at the screening visit; including: Amylase and/or lipase >3 times the upper limit of the normal (ULN) laboratory range; Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN; Calcitonin ≥20 pg/mL (5.9 pmol/L); Positive serum pregnancy test. Any contraindication to metformin use according to local labeling. History of hypersensitivity to any GLP-1 receptor agonist or to metacresol. Contraindication to use of insulin glargine or lixisenatide according to local labeling. History of hypersensitivity to insulin glargine or to any of the excipients. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia syndromes). History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy has now been performed), pancreatitis during previous treatment with incretin therapies, chronic pancreatitis, pancreatectomy, stomach/gastric surgery. Exclusion criteria for randomization at the end of the run-in phase: HbA1c <7.5% or >9.5% at visit 6 (Week -1). Mean fasting self monitored plasma glucose (SMPG) >160 mg/dL (8.9 mmol/L), calculated from all available (minimum of 4 self-measurements) values during the 7 days prior to randomization. Note:fasting SMPG on the day of randomization can be included if assessed before randomization. Average insulin glargine daily dose ≥15 U/day or <5U/day calculated for the last 3 days before Visit 7. Metformin total daily dose <750 mg/day. Amylase and/or lipase >3 ULN at Visit 6 (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: 20 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: LixiLan<br>LixiLan (insulin glargine/lixisenatide fixed ratio combination) is injected subcutaneously (under the skin) once daily. Dose is individually adjusted. Metformin will be continued. | Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: LixiLan;Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Active Comparator: insulin glargine<br>Insulin glargine U100 (Lantus) will be injected subcutaneously (under skin) once daily. Dose will be individually adjusted. Metformin will be continued. | Drug: Insulin glargine U100 (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 from baseline in HbA1c |  | Baseline, 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients reaching HbA1c <7% or ≤6.5% |  | 26 weeks | 
| Change from baseline in 2-hour postprandial plasma glucose (PPG) during standardized meal test |  | Baseline, 26 weeks | 
| Change from baseline in blood glucose excursion during standardized meal test |  | Baseline, 26 weeks | 
| Change from baseline in 7-point self-monitoring plasma glucose (SMPG) profiles (each time point and average daily value) |  | Baseline, 26 weeks | 
| Change from baseline in body weight |  | Baseline, 26 weeks | 
| Change from baseline in FPG |  | Baseline, 26 weeks | 
| Change from baseline in daily dose of insulin glargine |  | Baseline, 26 weeks | 
| Percentage of patients reaching HbA1c <7% with no body weight gain |  | 26 weeks | 
| Percentage of patients reaching HbA1c <7% with no body weight gain and with no documented (PG ≤70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia |  | 26 weeks | 
| Percentage of patients reaching HbA1c <7% with no documented (PG ≤70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia |  | 26 weeks | 
| Percentage of patients requiring a rescue therapy |  | 26 weeks | 
| Number of hypoglycemic events |  | 26 weeks | 
| Number of adverse events |  | 26 weeks | 
| Measurement of anti-lixisenatide antibodies from baseline |  | Baseline, 26 weeks | 
| Measurement of anti-insulin antibodies from baseline |  | Baseline, 26 weeks |