A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 24-week Study Followed by an Extension Assessing the Efficacy and Safety of AVE0010 on Top of Metformin in Patients With Type 2 Diabetes Not Adequately Controlled With Metformin
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Sanofi
- 入组人数
- 680
- 试验地点
- 2
- 主要终点
- Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
研究概览
简要总结
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 as an add-on treatment to metformin in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24.
The secondary objectives are to assess the effect of lixisenatide, in comparison to placebo, when administered in the evening within 1 hour prior to the meal in terms of HbA1c reduction, percentage of patients reaching HbA1c less than (<) 7 percent (%), percentage of patients reaching HbA1c less than or equal to 6.5%, fasting plasma glucose (FPG), plasma glucose, plasma insulin, C-peptide, glucagon, and proinsulin during a 2-hour standardized meal test (only in morning injection arms), body weight, beta-cell function assessed by homeostasis model assessment (HOMA)-beta, fasting plasma insulin (FPI) and adiponectin; to evaluate safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development, beta-cell function 4 weeks after study drug discontinuation (only in patients from the morning injection arms in some selected centers).
详细描述
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 patient.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit, insufficiently controlled with metformin at a stable dose of at least 1.5 gram/ day (g/day) for at least 3 months prior to screening visit
排除标准
- •HbA1c <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 (BMI) <=20 kilogram per square meter (kg/m^2)
- •Weight change of >5 kg during the 3 months preceding the study 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 blood pressure 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 upper limit of 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 <100 000/mm^3; positive test for Hepatitis B surface antigen and/or Hepatitis C antibody; positive serum pregnancy test in females of child bearing potential
- •Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram, 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 other oral or injectable antidiabetic or hypoglycemic agents other than metformin (for example, sulfonylurea, alpha glucosidase inhibitor, other thiazolidinediones, rimonabant, exenatide, dipeptidyl-peptidase-4 inhibitors, insulin) within 3 months prior to the time of screening
- •Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 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 a 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
研究组 & 干预措施
Lixisenatide (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Lixisenatide (AVE0010) (Drug)
Lixisenatide (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Pen auto-injector (Device)
Lixisenatide (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Metformin (Drug)
Lixisenatide (Evening Injection)
2-step initiation evening regimen of lixisenatide: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to end of treatment.
干预措施: Lixisenatide (AVE0010) (Drug)
Lixisenatide (Evening Injection)
2-step initiation evening regimen of lixisenatide: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to end of treatment.
干预措施: Pen auto-injector (Device)
Lixisenatide (Evening Injection)
2-step initiation evening regimen of lixisenatide: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to end of treatment.
干预措施: Metformin (Drug)
Placebo (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Placebo (Drug)
Placebo (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Pen auto-injector (Device)
Placebo (Morning Injection)
2-step initiation morning 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 end of treatment.
干预措施: Metformin (Drug)
Placebo (Evening Injection)
2-step initiation evening 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 end of treatment.
干预措施: Placebo (Drug)
Placebo (Evening Injection)
2-step initiation evening 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 end of treatment.
干预措施: Pen auto-injector (Device)
Placebo (Evening Injection)
2-step initiation evening 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 end of treatment.
干预措施: Metformin (Drug)
结局指标
主要结局
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
时间窗: Baseline, 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 Modified Intent-to-treat (mITT) population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
次要结局
- Change From Baseline in Fasting Plasma Insulin (FPI) at Week 24(Baseline, Week 24)
- Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24(Week 24)
- Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24(Baseline, Week 24)
- Change From Baseline in 2-Hour Postprandial Plasma Insulin (PPI) at Week 24(Baseline, Week 24)
- Change From Baseline in Fasting Glucagon at Week 24(Baseline, Week 24)
- Change From Baseline in 2-Hour Postprandial Glucagon at Week 24(Baseline, Week 24)
- Change From Baseline in Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) at Week 24(Baseline, Week 24)
- Percentage of Patients Requiring Rescue Therapy During the Main 24-Week Period(Baseline up to Week 24)
- Change From Baseline in Body Weight at Week 24(Baseline, Week 24)
- Change From Baseline in Fasting Proinsulin at Week 24(Baseline, Week 24)
- Change From Baseline in 2-Hour Postprandial Proinsulin at Week 24(Baseline, Week 24)
- Change From Baseline in 2-Hour Postprandial C-Peptide at Week 24(Baseline, Week 24)
- Change From Baseline in Adiponectin at Week 24(Baseline, Week 24)
- Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24(Baseline, Week 24)
- Change From Baseline in Fasting C-Peptide at Week 24(Baseline, Week 24)
- Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24(Week 24)