GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Metformin
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Pen auto-injector; Metformin
Intervention description: Self-administered by subcutaneous injections once daily within the hour preceding breakfast.; Self-administered by subcutaneous injections once daily within the hour preceding breakfast.; Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.
Intervention MeSH terms: Metformin; Lixisenatide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 484.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: hyperglycemia, GLP-1

Summary:

      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.
    

Eligibility criteria:

        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