Efficacy and Safety of Lixisenatide Versus Insulin Glulisine on Top of Insulin Glargine With or Without Metformin in Type 2 Diabetic Patients

Study Overview
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Brief Summary
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Primary Objective: - To compare lixisenatide versus insulin glulisine in terms of glycosylated hemoglobin (HbA1c) reduction and body weight change at Week 26 in type 2 diabetic participants not adequately controlled on insulin glargine ± metformin. Secondary Objectives: - To compare the treatments/regimens on: The percentage of participants reaching the target of HbA1c <7% or ≤6.5%, Body weight, Self-Monitored Glucose profiles, Fasting Plasma Glucose (FPG), Post-prandial plasma glucose (PPG) /glucose excursions during a standardized meal test (subset of participants), Daily doses of insulins, Safety and tolerability.

Detailed Description
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Approximately 41 weeks including a 26 week treatment period.

Official Title
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A Randomized, Open-label, Active-controlled, 3-arm Parallel-group, 26-week Study Comparing the Efficacy and Safety of Lixisenatide to That of Insulin Glulisine Once Daily and Insulin Glulisine Three Times Daily in Patients With Type 2 Diabetes Insufficiently Controlled With Insulin Glargine With or Without Metformin

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Lixisenatide (AVE0010)
* Drug: Insulin glulisine QD
* Drug: Insulin glulisine TID
* Drug: Insulin Glargine (Mandatory background drug)
* Drug: Metformin (Background drug)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with type 2 diabetes mellitus diagnosed at least 1 year before screening visit (V1). Participants treated with basal insulin for at least 6 months. Participants treated for at least 3 months prior to visit 1 with a stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection). The insulin dose should be stable (± 20%) and ≥20 U/day for at least 2 months prior to visit 1. Participants treated with basal insulin alone or in combination with 1 to 3 oral anti-diabetic drugs (OADs) that could be: metformin (≥1.5 g/day or maximal tolerated dose), a sulfonylurea (SU), a dipeptidyl-peptidase-4 (DPP-4) inhibitor, a glinide. The dose of OADs should be stable for at least 3 months prior to visit 1. Exclusion criteria: At screening: age < legal age of majority. At screening, HbA1c: <7.5% and >10.0% for participants treated with basal insulin alone or in combination with metformin only; < 7.0% and > 10.0% for participants treated with basal insulin and a combination of oral anti-diabetic drugs which included a SU and/or a DPP-4 inhibitor and/or a glinide. Women of childbearing potential with no effective contraceptive method, pregnancy or lactation. Type 1 diabetes mellitus. Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 3 months prior to screening. Previous treatment with short or rapid acting insulin other than in relation to hospitalization or an acute illness. Any previous treatment with lixisenatide, or any discontinuation from another glucagon-like peptide 1 (GLP-1) receptor agonist due to safety/tolerability issue or lack of efficacy. At screening, Body Mass Index (BMI) ≤20 or >40 kg/m^2. Weight change of more than 5 kg during the 3 months prior to the screening visit; use of weight loss drugs within 3 months prior to screening. Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery. At screening resting systolic blood pressure >180 mmHg or diastolic blood pressure >95 mmHg. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposed to MTC (e.g. multiple endocrine neoplasia syndromes). Contraindication related to metformin (for participant receiving this treatment), insulin glargine, insulin glulisine or lixisenatide. Participants with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease. At screening, amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN). At screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN. At screening calcitonin ≥20 pg/ml (5.9 pmol/L). Exclusion Criteria for randomization at the end of the screening period before randomization: HbA1c <7.0% or >9.0%. 7-day mean fasting SMPG >140 mg/dl (7.8 mmol/L). Amylase and/or lipase >3 times ULN. The above information is not intended to contain all considerations relevant to a participant'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: Lixisenatide<br>Lixisenatide 10 mcg once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin. | Drug: Lixisenatide (AVE0010)<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection 30 to 60 minutes before breakfast or dinner.<br>* Other names: Device: Disposable self-injector prefilled pen (Delta 14®);Drug: Insulin Glargine (Mandatory background drug)<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).<br>* Other names: Device: Disposable self-injector prefilled pen (Lantus® Solostar®);Drug: Metformin (Background drug)<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.<br>|
| Active Comparator: Insulin Glulisine QD<br>Insulin glulisine QD from randomization up to Week 26 on top of Insulin glargine with or without metformin. | Drug: Insulin glulisine QD<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before breakfast or dinner. The initial dose was 3-5 units and then individually titrated to obtain the SMPG value >5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before lunch (if administered at breakfast) or at bedtime (if administered at dinner).<br>* Other names: Device: Disposable self-injector prefilled pen (Apidra® Solostar®);Drug: Insulin Glargine (Mandatory background drug)<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).<br>* Other names: Device: Disposable self-injector prefilled pen (Lantus® Solostar®);Drug: Metformin (Background drug)<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.<br>|
| Active Comparator: Insulin Glulisine TID<br>Insulin glulisine thrice daily (TID) from randomization up to Week 26 on top of Insulin glargine with or without metformin. | Drug: Insulin glulisine TID<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before each meal. The initial dose was 3-5 units for each meal and then individually titrated to obtain the SMPG value >5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before the next meal or at bedtime (for injection at dinner).<br>* Other names: Device: Disposable self-injector prefilled pen (Apidra® Solostar®);Drug: Insulin Glargine (Mandatory background drug)<br>* Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).<br>* Other names: Device: Disposable self-injector prefilled pen (Lantus® Solostar®);Drug: Metformin (Background drug)<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 26 | Change in HbA1C was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period. | Baseline, Week 26 | 
| Change in Body Weight From Baseline to Week 26 | Primary outcome was the comparison between Lixisenatide versus Insulin Glulisine TID. Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Missing data was imputed using LOCF. | Week 26 | 
| Percentage of Participants With no Weight Gain at Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 3 days after the last dose of study drug. | Week 26 | 
| Change in Average 7-point SMPG Profiles From Baseline to Week 26 | Participants recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime three times in a week before baseline, before visit Week 12 and before visit week 26 and the average value across the profiles performed in the week a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug. | Baseline, Week 26 | 
| Change in FPG From Baseline to Week 26 | Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug. | Baseline, Week 26 | 
| Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast) | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. | Baseline, Week 26 | 
| Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast) | Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change in glucose excursions was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. | Baseline, Week 26 | 
| Change in Insulin Glargine Dose From Baseline to Week 26 | Change in Insulin glargine dose was calculated by subtracting the baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. | Baseline, Week 26 | 
| Insulin Glulisine Dose at Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. | Week 26 | 
| Total Insulin Dose at Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. The outcome is reporting results of total insulin (amounts of Insulin Glargine plus Insulin Glulisine ) only for the arms in which Insulin Glulisine was administered and is not applicable for the lixisenatide arm in which only Insulin Glargine is administered. Change in dose of the insulin used by patients in the Lixisenatide arm (i.e. Insulin Glargine) is reported in the secondary Outcome Measure 9. | Week 26 | 
| Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <60 mg/dL (3.3 mmol/L). Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the participant required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. | First dose of study drug up to 3 days after the last dose administration (maximum of 185 days) | 
| Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. | Week 26 | 
| Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26 | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. | Week 26 | 
| Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. Participants without post-baseline on-treatment values (HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response, or if they experienced at least one documented symptomatic hypoglycemia during the on-treatment period. Otherwise, they were counted as missing data. | Week 26 |