GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Pioglitazone
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Pen auto-injector; Pioglitazone; 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.; Dose to be kept stable.; Metformin, if given to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.
Intervention MeSH terms: Metformin; Pioglitazone; 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 pioglitazone

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 pioglitazone with or without 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 pioglitazone on
      glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at
      Week 24.

      Secondary objectives are to assess the effects of lixisenatide when added to pioglitazone on
      the percentage of patients reaching HbA1c less than 7 percent (%) and less than or equal to
      6.5%, fasting plasma glucose (FPG), body weight, beta-cell function (assessed by homeostatic
      model assessment of beta-cell function [HOMA-beta]), and on fasting plasma insulin (FPI), 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 the screening
             visit, insufficiently controlled with pioglitazone

        Exclusion Criteria:

          -  HbA1c less than (<) 7 percent (%) or greater than (>) 10% at screening

          -  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

          -  Pioglitazone not at a stable dose of at least 30 milligram per day (mg/day) for at
             least 3 months prior to screening

          -  If treatment with metformin, no stable dose of at least 1.5 gram per day (g/day) for
             at least 3 months prior to screening visit

          -  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, or inflammatory bowel disease

          -  History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to
             screening

          -  Hemoglobinopathy or hemolytic anemia, or receipt of blood or plasma products within3
             months prior to the time of screening

          -  History of myocardial infarction or stroke within the last 6 months prior to screening

          -  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 systolic blood pressure or diastolic blood pressure (DBP) >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
             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 (HBsAg) and/or Hepatitis C antibody
             (HCAb); 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 other oral or injectable antidiabetic or hypoglycemic agents other than
             metformin or pioglitazone (for example, sulfonylurea, alpha-glucosidase inhibitor,
             other thiazolidinediones, rimonabant, exenatide, dipeptidyl peptidase-4 [DPP-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 (applicable only for patients with metformin treatment)

          -  Patients with cardiac failure or history of cardiac failure (New York Heart
             Association class I to IV)

          -  End-stage renal disease defined by a serum creatinine clearance of <15 milliliter per
             minute (mL/min) (calculated by the Cockcroft and Gault formula) and/or patients on
             dialysis, if no treatment with metformin

          -  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