GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Pen auto-injector; Sulfonylurea; 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.; Sulfonylurea to be continued at maximum effective dose according to local labeling up to end of treatment.; Metformin if given to be continued at stable dose (at least 1.5 gram per day [except at least 0.75 gram per day in Japan and 1.0 gram per day in South Korea]) 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: 859.0
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 sulfonylurea without or with 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 sulfonylurea
      with or without metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c)
      reduction (absolute change) at Week 24.

      The secondary objectives are to assess the effects of lixisenatide on percentage of patients
      reaching HbA1c less than (<) 7 percent (%); percentage of patients reaching HbA1c less than
      or equal to (<=) 6.5%; body weight; fasting plasma glucose (FPG); beta-cell function assessed
      by homeostasis model assessment (HOMA) beta; 2-hour postprandial plasma glucose (PPG),
      glucagon, insulin, proinsulin, and C-peptide after a standardized meal challenge test in a
      sub-study in all patients in selected centers; to evaluate safety, tolerability,
      pharmacokinetics (PK) and anti-lixisenatide antibody development.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit,
             insufficiently controlled with a sulfonylurea alone or a sulfonylurea in association
             with metformin

        Exclusion Criteria:

          -  HbA1c less than (<) 7% or greater than (>) 10% at screening

          -  At the time of screening age less than legal age of majority

          -  Pregnant or breastfeeding women or women of childbearing potential with no effective
             contraceptive method

          -  Type 1 diabetes mellitus

          -  Sulfonylurea less than the maximum effective dose according to local labeling

          -  Sulfonylurea not at a stable (unchanged) dose for at least 3 months prior to screening

          -  In case of treatment with metformin in association with sulfonylurea, no stable
             (unchanged) treatment with metformin of at least 1.5 gram per day (except at least
             0.75 gram per day in Japan and at least 1.0 gram per day in South Korea), 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])

          -  History of hypoglycemia unawareness

          -  Body mass index less than or equal to (<=) 20 kilogram per square meter (kg/m^2)

          -  Weight change of >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 systolic blood pressure (SBP) or diastolic blood pressure (DBP) >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 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 <100 000/mm^3; positive
             test for Hepatitis B surface antigen and/or Hepatitis C antibody

          -  Any clinically significant abnormality identified on physical examination, laboratory
             tests 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)

          -  Patients with condition/concomitant diseases making them non-evaluable for the
             efficacy assessment

          -  Use of oral or injectable antidiabetic or hypoglycemic agents other than sulfonylurea
             and metformin (for example, alpha glucosidase inhibitor, thiazolidinedione,
             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 (for example, participation in a previous
             study with lixisenatide)

          -  Renal impairment defined with serum creatinine >1.4 mg/dL in women and serum
             creatinine >1.5 mg/dL in men (applicable only for patients with metformin treatment)

          -  End-stage renal disease as defined by a serum creatinine clearance of <15
             milliliter/minute (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