Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to Week 30. Secondary Objective: To compare the overall efficacy and safety of insulin glargine/lixisenatide FRC to insulin glargine (with or without metformin) over a 30 week treatment period in participants with type 2 diabetes.

Detailed Description
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Maximum duration of approximately 39 weeks: an up to 8-week screening period, a 30-week randomized treatment period and 3 days 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 the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine With or Without Metformin in Patients With Type 2 Diabetes Mellitus (T2DM)

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Insulin glargine/lixisenatide (HOE901/AVE0010)
* Drug: Insulin glargine (HOE901)
* Drug: Metformin (Background Drug)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Type 2 diabetes mellitus diagnosed at least 1 year before the screening visit. Treatment with basal insulin for at least 6 months before the screening visit. Stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection) for at least 3 months before the screening visit. Stable (plus/minus 20 percent) total daily basal insulin dose between 15 and 40 Units/day for at least 2 months prior to the screening visit. For participants receiving basal insulin and 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 could be 1 to 2 out of: metformin (more than or equal to 1500 mg/day or maximal tolerated dose), a sulfonylurea, a glinide, a dipeptidyl-peptidase-4 inhibitor, a sodium glucose co-transporter 2 inhibitor, Fasting Plasma Glucose (FPG) less than or equal to 180 mg/dL(10.0 mmol/L) at screening visit for participants receiving basal insulin in combination with 2 OADs or with 1 OAD other than metformin; FPG less than or equal to 200 mg/dL (11.1 mmol/L) at screening visit for participants on basal insulin only or basal insulin plus metformin at screening visit. Signed written informed consent. Exclusion criteria: Age under legal age of adulthood at screening visit. HbA1c at screening visit less than 7.5% or above 10%. Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. Use of other oral or injectable glucose-lowering agents than stated in the inclusion criteria in a period of 3 months prior to screening. Previous use of insulin other than basal insulin eg, prandial or pre-mixed insulin, in the year prior to screening. Note: Short term treatment (≤10 days) due to intercurrent illness is allowed. History discontinuation of a previous treatment with Glucagon Like Peptide -1 Receptor Agonists for safety/tolerability or lack of efficacy. Participant who had previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide FRC or had previously received lixisenatide. 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 (eg, 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). Any contraindication to metformin use, according to local labeling, if the participant was taking metformin. Participant who had a renal function impairment with creatinine clearance less than 30 mL/min (using the Cockcroft and Gault formula) or end-stage renal disease for participants, not treated with metformin. Exclusion criteria for randomization: HbA1c less than 7% or above 10% . Mean fasting SMPG calculated from the self-measurements for 7 days the week before randomization visit was above 140 mg/dL (7.8 mmol/L). Average insulin glargine daily dose less than 20 Units or above 50 Units (in the week before randomization visit). 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
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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 once daily (QD) for 30 weeks. Dose individually adjusted. | Drug: Insulin glargine/lixisenatide (HOE901/AVE0010)<br>* Insulin glargine/lixisenatide FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using one of 2 SoloStar® pen-injectors: Pen A (ratio of 2 Units (U) of insulin glargine U 100:1 mcg of lixisenatide) or Pen B (ratio of 3 U of insulin glargine U 100:1 mcg of lixisenatide). After run-in, the FRC was initiated at a dose of either 20 U/10 mcg with Pen A or 30 U/10 mcg with Pen B, depending on participant's dose of Insulin glargine on the day prior to randomization. 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). Pen A was used for administration of doses up to 40 U/20 mcg and Pen B for administration of doses from 30 U/10 mcg up to 60 U/20 mcg.<br>Drug: Metformin (Background Drug)<br>* Pharmaceutical form: Tablet; Route of administration: Oral administration<br>|
| Active Comparator: Insulin glargine<br>Insulin glargine 100 U/mL QD for 30 weeks. Dose individually adjusted. | Drug: Insulin glargine (HOE901)<br>* Insulin glargine was self-administered QD by SC injection at approximately the same time every day. After screening, eligible participants entered 6 week run-in phase during which they were switched (if necessary) to insulin glargine and dose was stabilized. The first dose after randomization was same as the one administered on the day prior to randomization 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 | 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 |  | Week 30 | 
| Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 | Plasma glucose excursion = 2-hour postprandial glucose (PPG) minus plasma glucose value obtained 30 minutes prior to the start of the meal and before investigational medicinal product (IMP) administration, if IMP was injected before breakfast. Change in plasma glucose excursions was calculated by subtracting baseline value from Week 30 value. | 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 | 
| 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 | 
| Change in Daily Insulin Glargine Dose From Baseline to Week 30 |  | Baseline, 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 | 
| Change in FPG From Baseline to Week 30 | Change in FPG was calculated by subtracting baseline value from Week 30 value. | Baseline, Week 30 | 
| Change in 2-hour PPG From Baseline to Week 30 | Change in PPG was calculated by subtracting baseline value from Week 30 value. | Baseline, Week 30 | 
| Percentage of Participants Reaching HbA1c <7.0% 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). | 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) 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 30 | 
| Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | 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). | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) | 
| Percentage of Participants With Documented 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). | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) | 
| 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 had 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 for injury to themselves or others. | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) |