GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Metformin

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the benefits and risks of lixisenatide (AVE0010), in comparison to placebo, as an add-on treatment to metformin, over a period of 24 weeks of treatment, followed by an extension. The primary objective is to assess the effects of lixisenatide when added to metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction when it is used in two steps dose titration regimen at Week 24. Secondary objectives are to assess the effects of lixisenatide when added to metformin on glycemic control in comparison to placebo in terms of HbA1c reduction when it is used in a one-step dose titration regimen, the percentage of patients with HbA1c less than 7 percent or less than or equal to 6.5%, body weight, fasting plasma glucose (FPG); to assess the safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.

Detailed Description
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Patients who complete the 24-week main double-blind treatment would undergo a variable double-blind extension treatment, which ends for all patients at approximately the scheduled date of Week 76 visit (Visit 25) for the last randomized patients.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, 24-week Study Followed by an Extension Assessing the Efficacy and Safety of AVE0010 in Two Titration Regimens on Top of Metformin in Patients With Type 2 Diabetes Not Adequately Controlled With Metformin

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Lixisenatide (AVE0010)
* Drug: Placebo
* Device: Pen auto-injector
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of screening visit, insufficiently controlled with metformin at a stable dose of at least 1.5 gram/day for at least 3 months prior to screening visit Exclusion Criteria: HbA1c less than (<) 7% or greater than (>) 10% at screening At the time of screening age <legal age of majority Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method Type 1 diabetes mellitus Treatment with an antidiabetic pharmacological agent other than metformin within the 3 months preceding the screening FPG at screening >250 milligram per deciliter (mg/dL) (>13.9 millimole per liter [mmol/L]) Body mass index less than or equal to (<)20 kilogram per square meter (kg/m^2) Weight change of more than 5 kg during the 3 months preceding the screening visit History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening Hemoglobinopathy or hemolytic anemia, receipt of blood or plasma products within 3 months prior to the time of screening Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization Known history of drug or alcohol abuse within 6 months prior to the time of screening Cardiovascular, hepatic, neurological, endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult, history or presence of clinically significant diabetic retinopathy, history or presence of macular edema likely to require laser treatment within the study period Uncontrolled or inadequately controlled hypertension at the time of screening with a resting supine systolic or diastolic blood pressure >180 millimeter of mercury (mmHg) or >95 mmHg, respectively Laboratory findings at the time of screening: aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP): >2 times upper limit of the normal (ULN) laboratory range; amylase and/or lipase: >3 times ULN; total bilirubin: >1.5 times ULN (except in case of Gilbert's syndrome); hemoglobin <11 gram/deciliter and/or neutrophils <1500 per cubic millimeter (mm^3) and/or platelets <100000/mm^3; positive test for Hepatitis B surface antigen (HBsAg) and/or Hepatitis C antibody (HCAb) and positive serum pregnancy test in females of childbearing potential Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram (ECG) or vital signs at the time of screening that in the judgment of the investigator or any sub-investigator precludes safe completion of the study or constrains efficacy assessment Patients who are considered by the investigator or any sub-investigator as inappropriate for this study for any reason (for example, impossibility to meet specific protocol requirements, such as scheduled visits, being able to do self-injections), likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol; investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol) Use of oral or injectable antidiabetic or hypoglycemic agents other than metformin (for example, sulfonylurea, alpha glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidylpeptidase-4 (DPP-IV) inhibitor, insulin) within 3 months prior to the time of screening Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one week or more within 3 months prior to the time of screening Use of any investigational drug within 3 months prior to study Any previous treatment with lixisenatide or participation in any previous study with lixisenatide Renal impairment defined with creatinine >1.4 mg/dL in women and creatinine >1.5 mg/dL in men Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to gastroparesis and gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening Allergic reaction to any glucagon like peptide-1 (GLP-1) agonist in the past (for example, exenatide, liraglutide) or to metacresol Additional exclusion criteria at the end of the run-in phase: informed consent withdrawal; lack of compliance during the single-blind placebo run-in phase (>2 injections missed); and patient with any adverse event which precludes the inclusion in the study, as assessed by the investigator

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lixisenatide (Two-Step Titration)<br>2-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment. | Drug: Lixisenatide (AVE0010)<br>* Self-administered by subcutaneous injections once daily within the hour preceding breakfast.<br>Device: Pen auto-injector<br> <br> * Other names: OptiClik®;Drug: Metformin<br>* Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.<br>|
| Experimental: Lixisenatide (One-Step Titration)<br>1-step initiation regimen of lixisenatide: 10 mcg QD for 2 weeks, then 20 mcg QD up to the end of treatment. | Drug: Lixisenatide (AVE0010)<br>* Self-administered by subcutaneous injections once daily within the hour preceding breakfast.<br>Device: Pen auto-injector<br> <br> * Other names: OptiClik®;Drug: Metformin<br>* Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.<br>|
| Placebo Comparator: Placebo (Two-Step Titration)<br>2-step initiation regimen of volume matching placebo: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment. | Drug: Placebo<br>* Self-administered by subcutaneous injections once daily within the hour preceding breakfast.<br>Device: Pen auto-injector<br> <br> * Other names: OptiClik®;Drug: Metformin<br>* Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.<br>|
| Placebo Comparator: Placebo (One-Step Titration)<br>1-step initiation regimen of volume matching placebo: 10 mcg QD for 2 weeks, then 20 mcg QD up to the end of treatment. | Drug: Placebo<br>* Self-administered by subcutaneous injections once daily within the hour preceding breakfast.<br>Device: Pen auto-injector<br> <br> * Other names: OptiClik®;Drug: Metformin<br>* Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. The Placebo (Two-step Titration) and Placebo (One-step Titration) Arms/Groups were combined as pre-specified in the study protocol | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. | Baseline, Week 24 | 
| Change From Baseline in Body Weight at Week 24 | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. | Baseline, Week 24 | 
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. | Week 24 | 
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. | Week 24 | 
| Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period | Routine fasting self-measured plasma glucose (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 baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. | Baseline up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperglycemia, GLP-1