Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination Compared to Insulin Glargine Alone and Lixisenatide Alone on Top of Metformin in Patients With T2DM

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To compare the insulin glargine/lixisenatide fixed ratio combination to lixisenatide alone and to insulin glargine alone (on top of metformin treatment) in glycated hemoglobin (HbA1c) change from baseline to Week 30. Secondary Objective: To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio combination (FRC) to insulin glargine alone and to lixisenatide alone (on top of metformin treatment) over a 30 week treatment period in participants with type 2 diabetes.

Detailed Description
-----------------
Approximately 37 weeks including up to 6 weeks of screening, 30-week treatment period, and a 3 days follow-up period.

Official Title
-----------------
A Randomized, 30 Week, Active-controlled, Open-label, 3-treatment Arm, Parallel-group Multicenter Study Comparing the Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination to Insulin Glargine Alone and to Lixisenatide Alone on Top of Metformin in Patients With Type 2 Diabetes Mellitus (T2DM)

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Insulin glargine/lixisenatide Fixed Ratio Combination
* Drug: Insulin glargine (HOE901)
* Drug: Lixisenatide (AVE0010)
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Participants with type 2 diabetes mellitus diagnosed for at least 1 year before the screening visit, treated for at least 3 months prior to visit 1 with metformin alone or metformin and a second oral anti-diabetic treatment that could be a sulfonylurea, a glinide, a sodium glucose co-transporter-2 inhibitor or a di-peptidyl peptidase 4 (DPP-4) inhibitors, and who were not adequately controlled with this treatment. Signed written informed consent. Exclusion criteria: HbA1c at screening visit: less than 7.5% or more than 10% for participants previously treated with metformin alone, less than 7.0% or more than 9% for participants previously treated with metformin and a second oral anti-diabetic treatment. Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. Use of oral glucose-lowering agents other than those stated in the inclusion criteria or any injectable glucose-lowering agents during the 3 months before screening. Previous Treatment with insulin (except for short-term treatment due to intercurrent illness including gestational diabetes, at the discretion of the trial physician). History of discontinuation of a previous treatment with a glucagon-like peptide (GLP-1) receptor agonist (GLP-1 RA) due to safety/tolerability issue or lack of efficacy. Participant who previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide fixed ratio combination or had previously received lixisenatide. Any contraindication to metformin use, according to local labeling. Use of weight loss drugs within 3 months prior to screening visit. Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be performed during the study period. History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (e.g, multiple endocrine neoplasia syndromes). Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit. At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m^2. At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN) laboratory range. At screening visit alanine aminotransferase (ALT) or alkaline phosphatase (AST) more than 3 ULN. At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L). Exclusion Criteria for randomization at the end of the screening period: HbA1c less than 7% or above 10%; Fasting Plasma glucose above 250 mg/dL (13.9 mmol/L); Metformin maximal tolerated dose less than 1500 mg/day; Amylase and/or lipase more than 3 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 once daily (QD) for 30 weeks. Dose individually adjusted. | Drug: Insulin glargine/lixisenatide Fixed Ratio Combination<br>* Insulin glargine/Lixisenatide FRC was self-administered by subcutaneous (SC) injection in the morning within one hour before breakfast using one of the 2 prefilled disposable SoloStar® pen-injectors: Pen A containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 50 mcg/mL lixisenatide in a ratio of 2 U:1 mcg, used for administration of doses from 10 U to 40 U (10 U/5mcg to 40 U/20mcg). Pen B containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 33 mcg/mL lixisenatide in a ratio of 3 U:1 mcg, used to administer doses from 41 U to 60 U (41 U/13 mcg to 60 U/20 mcg). The starting dose was 10 U/5 mcg. Dose was then adjusted individually 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) while avoiding hypoglycemia.<br>* Other names: (HOE901/AVE0010);Drug: Metformin<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration.<br>|
| Active Comparator: Insulin Glargine<br>Insulin glargine QD for 30 weeks. Dose individually adjusted. | Drug: Insulin glargine (HOE901)<br>* Insulin glargine (100 U/mL) was self-administered by SC injection at approximately the same time every day. Dose was adjusted individually to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) while avoiding hypoglycemia.<br>* Other names: Lantus;Drug: Metformin<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration.<br>|
| Active Comparator: Lixisenatide<br>Lixisenatide 10 mcg QD for 2 weeks, then 20 mcg QD (maintenance dose). | Drug: Lixisenatide (AVE0010)<br>* Lixisenatide was self-administered by SC injection within 0 to 60 minutes before breakfast or evening meal. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.<br>* Other names: Lyxumia;Drug: Metformin<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 30 | Primary outcome was to test superiority of FRC versus Lixisenatide and non-inferiority versus Insulin glargine. Change in HbA1c was calculated by subtracting baseline value from Week 30 value. | Baseline, Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | Participants without Week 30 value for HbA1c were counted as non-responders. | Week 30 | 
| Change in Plasma Glucose Excursion From Baseline to Week 30 | Plasma glucose excursion = 2-hour postprandial plasma glucose (PPG) value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 30 value. Missing data was imputed using last observation carried forward (LOCF). | Baseline, Week 30 | 
| Change in Body Weight From Baseline to Week 30 | Change in body weight was calculated by subtracting baseline value from Week 30 value. | Baseline, Week 30 | 
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30 | Change in FPG was calculated by subtracting baseline value from Week 30 value. | Baseline, Week 30 | 
| Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | Participants recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime two times in a week before baseline, before visit Week 12 and before visit Week 30 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 30 value. The analysis included all scheduled measurements obtained during the study. The missing data was handled by mixed effect model with repeated measures (MMRM) approach. | Baseline, Week 30 | 
| Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 |  | Week 30 | 
| Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-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). | Baseline up to Week 30 | 
| Average Daily Insulin Glargine Dose at Week 30 | The analysis included scheduled measurements obtained up to the date of last injection of the IMP, including those obtained after introduction of rescue therapy. | Week 30 | 
| Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30 | The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 30 value. Missing data was imputed using LOCF. | Baseline, Week 30 | 
| Percentage of Participants Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-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). The analysis included all HbA1c measurements at Week 30, including those obtained after the IMP discontinuation or the introduction of rescue medication. | Baseline up to Week 30 | 
| Percentage of Participants Requiring Rescue Therapy During 30-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 exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) was 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 30 | 
| Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤ 70 mg/dL (3.9 mmol/L). | First dose of study drug up to 1 day after the last dose administration (median treatment exposure: 211 days) | 
| Percentage of Participants With Documented Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤ 70 mg/dL (3.9 mmol/L). | First dose of study drug up to 1 day after the last dose administration (median treatment exposure: 211 days) | 
| Percentage of Participants With Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not have been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place participants at risk of injury to themselves or others. | First dose of study drug up to 1 day after the last dose administration (median treatment exposure: 211 days) |