GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation in Monotherapy

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, used in a 2-step dose titration regimen in monotherapy, over a period of 12 weeks of treatment. The primary objective is to assess the effects of lixisenatide, in comparison to placebo, on glycemic control using a 2-step dose titration regimen in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 12. Secondary objectives are to assess the effects of lixisenatide, in comparison to placebo, on glycemic control in terms of HbA1c reduction when it is used in a one-step dose titration regimen over a period of 12 weeks, body weight, fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG) after a standardized meal, to assess the safety and tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.

Detailed Description
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This is a double-blind, randomized, placebo-controlled, 4-arm, unbalanced design, parallel group study with a two-step titration regimen or a one-step titration regimen. The study is double-blind with regard to active and placebo treatments; however neither the study drug volume nor the titration regimens (that is, two-step or one-step) are blinded.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 12-week Study Assessing the Efficacy and Safety of AVE0010 in Patients With Type 2 Diabetes Not Treated With Antidiabetic Agents

Conditions
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Diabetes Mellitus, Type 2

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus, diagnosed for at least 2 months at the time of the screening visit, not treated with any antidiabetic agent Exclusion Criteria: HbA1c less than (<) 7 percent (%) or greater than (>) 10% At the time of screening age < legal age of majority Pregnant or breastfeeding women and women of childbearing potential without effective contraceptive method of birth control Type 1 diabetes mellitus Type 2 diabetes treated by an antidiabetic agent within the 3 months preceding the study Fasting plasma glucose 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 previous 3 months History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease History of metabolic acidosis, including diabetic ketoacidosis within the previous year Hemoglobinopathy or hemolytic anemia, receipt of blood or plasma products within the previous 3 months History of myocardial infarction, stroke, or heart failure requiring hospitalization within the previous 6 months Known history of drug or alcohol abuse within the previous 6 months 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 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, alanine aminotransferase or alkaline phosphatase: >2 times the upper limit of the normal (ULN) laboratory range; amylase and/or lipase: >3 ULN; total bilirubin: >1.5 ULN (except in case of Gilbert's syndrome); hemoglobin <11 gram/deciliter (g/dL) and/or neutrophils <1,500 per cubic mm (mm^3) and/or platelets <100,000/mm^3; positive test for Hepatitis B surface antigen and/or hepatitis C antibody Any clinically significant abnormality identified by physical examination, laboratory tests, electrocardiogram or vital sign at the time of screening that in the judgment of the investigator or any sub investigator precludes safe completion of the study or hinders the efficacy assessment Patients who are considered by the investigator or any sub-investigator as inappropriate for this study for any reason Use of systemic glucocorticoids (excluding topical application or inhaled forms) within the previous 3 months Participation in any previous study with lixisenatide Use of any investigational drug within 3 months prior to study End-stage renal disease as defined by a calculated serum creatinine clearance of <15 milliliter/minute and/or patients on dialysis 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 the previous 6 months History of allergic reaction to any glucagon like peptide-1 (GLP-1) agonist in the past 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: more than 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Two-Step Titration)<br>2-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 12. | 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®;|
| 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 Week 12. | 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®;|
| Experimental: Lixisenatide (Two-Step Titration)<br>2-step initiation regimen of lixisenatide: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 12. | 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®;|
| Experimental: Lixisenatide (One-Step Titration)<br>1-step initiation regimen of lixisenatide: 10 mcg QD for 2 weeks, then 20 mcg QD up to Week 12. | 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®;|

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 12 | Absolute change = HbA1c value at Week 12 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 12 | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal (performed in selected sites). Change was calculated by subtracting baseline value from Week 12 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 
| Change From Baseline in Body Weight at Week 12 | Change was calculated by subtracting baseline value from Week 12 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | Change was calculated by subtracting baseline value from Week 12 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 12 | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 12 | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 12 | 
| Percentage of Patients Requiring Rescue Therapy During the Double-Blind Treatment Period | Routine fasting self monitored plasma glucose (SMPG) and central laboratory FPG 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 was performed. Threshold values for fasting SMPG/FPG: from baseline to Week 8: >270 milligram/deciliter (mg/dL) (15 mmol/L) and from Week 8 to Week 12: >240 mg/dL (13.3 mmol/L). 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 12 | 

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