Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Combination Versus Insulin Glargine Alone on Top of Metformin in Type 2 Diabetic Patients

Study Overview
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Brief Summary
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Primary Objective: The purpose of this study was to compare insulin glargine/ lixisenatide fixed ratio combination (FRC) versus insulin glargine on glycemic control over 24 weeks, as evaluated by glycosylated hemoglobin (HbA1c) reduction in type 2 diabetic participants treated with metformin. Secondary Objectives: To compare insulin glargine/lixisenatide FRC versus insulin glargine over 24 weeks on: Glycemic control in relation to a meal as evaluated by post-prandial plasma glucose and glucose excursions during a standardized meal test; Percentage of participants reaching HbA1c <7% or ≤6.5%; 7-point Self-Monitored Plasma Glucose (SMPG) profile; Body weight; Insulin glargine dose Fasting Plasma Glucose (FPG); Percentage of participants requiring rescue therapy during the 24-week open label treatment period; To assess safety and tolerability of insulin glargine/lixisenatide FRC.

Detailed Description
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Approximately 27 weeks including a 24-week treatment period.

Official Title
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A Randomized, 24-week, Open-label, 2-arm Parallel-group, Multicenter Study Comparing the Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine on Top of Metformin in Type 2 Diabetic Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin glargine /lixisenatide Fixed Ratio Combination
* Drug: Insulin glargine
* 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 for at least 1 year. Metformin treatment at a stable dose of at least 1.5 g/day for at least 3 months prior to screening. Exclusion criteria: Age < legal age of adulthood (18 years). Screening HbA1c <7% or >10%. Screening FPG >250 mg/dL (>13.9 mmol/L). Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. Type 1 diabetes mellitus. Treatment with glucose-lowering agent(s) other than metformin in a period of 3 months prior to screening. Use of insulin within the last 6 months. Previous use of insulin, except for episode(s) of short-term treatment (≤15 consecutive days) due to intercurrent illness. Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN) at screening. Calcitonin ≥20 pg/ml (5.9 pmol/l) at screening. Alanine Transferase (ALT) >3 ULN at screening. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes). Uncontrolled or inadequately controlled hypertension at the time of screening with a resting supine systolic or diastolic blood pressure >180 mmHg or >110 mmHg, respectively. Within the last 6 months prior to screening: history of heart failure requiring hospitalization, myocardial infarction, or stroke. Planned coronary, carotid or peripheral artery revascularisation procedures. Body Mass Index (BMI) ≤20 or >40 kg/m^2. Any previous treatment with lixisenatide 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: Insulin glargine/Lixisenatide Fixed Ratio Combination (FRC)<br>FRC injected once daily (QD) for 24 weeks. Dose individually adjusted. | Drug: Insulin glargine /lixisenatide Fixed Ratio Combination<br>* FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using pen-type injector (Tactipen®): 100 U/ml insulin glargine and 50 mcg Lixisenatide (ratio of 2 U/1 mcg). The initial dose was 10 U/5 mcg and then dose was adjusted weekly to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L.<br>* Other names: (HOE901/AVE0010);Drug: Metformin (Background drug)<br>* Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept at stable dose (≥1.5 g/day) throughout the study.<br>|
| Active Comparator: Insulin glargine<br>Insulin glargine QD for 24 weeks. Dose individually adjusted. | Drug: Insulin glargine<br>* Insulin glargine (100 U/ml) was self-administered by SC injection before breakfast using pen-type injector (Lantus® Solostar®). The initial daily dose of insulin glargine was 10 U and then dose was adjusted weekly to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L).<br>* Other names: Lantus;Drug: Metformin (Background drug)<br>* Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept 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 24 | Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP). | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24 | 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 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Baseline, Week 24 | 
| Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24 | 2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Baseline, Week 24 | 
| Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24 | Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 and the average value across the profiles performed in the week before a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Baseline, Week 24 | 
| Change in Body Weight From Baseline to Week 24 | Change in body weight was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 3 days after the last injection of IMP. | Baseline, Week 24 | 
| Average Daily Insulin Glargine Dose at Week 24 | 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Week 24 | 
| Change in FPG From Baseline to Week 24 | Change in FPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 1 day after the last injection of IMP. | Baseline, Week 24 | 
| Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period | Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceed the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8%. | Baseline up to Week 24 | 
| Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP. | Week 24 | 
| Change in 30-minute and 1-hour PPG From Baseline to Week 24 | The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Baseline, Week 24 | 
| Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | 30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. | Baseline, Week 24 | 
| Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP. | Baseline up to Week 24 | 
| Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24 | Participants without any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data. | Week 24 | 
| 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 ≤70 mg/dL (3.9 mmol/L).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others. | First dose of study drug up to 3 days after the last dose administration (maximum of 219 days) |