Efficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Pen auto-injector; Metformin; Sulfonylurea
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 1.0 gram per day and not more than 1.5 gram per day) up to Week 24.; Sulfonylurea if given at screening, to be continued up to Week 24. In patients with a screening HbA1c <8% the dose is decreased by 25% to 50% at randomization and then increased up to the screening dose between Week 4 and 12 as per fasting self-monitored plasma glucose (SMPG) values. In patients with a screening HbA1c >=8%, the dose is not to be changed at randomization. In any case, after Week 12, sulfonylurea is to be continued at a stable dose.
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: 391.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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 with or without sulfonylurea, over
      a period of 24 weeks of treatment.

      The primary objective is to assess the effects on glycemic control of lixisenatide (AVE0010)
      in comparison to placebo as an add-on treatment to metformin with or without sulfonylurea in
      terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24.

      The secondary objectives are to assess the effects of lixisenatide over 24 weeks on
      percentage of patients reaching HbA1c less than (< ) 7 percent (%) or HbA1c less than or
      equal to (<=) 6.5%, fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG)
      and glucose excursion during standardized meal test, body weight; to evaluate safety,
      tolerability, pharmacokinetic (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 metformin alone or metformin with sulfonylurea at the time
        of the screening visit

        Exclusion criteria:

          -  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 metformin not at a stable dose of at least 1.0 gram per day or more
             than 1.5 gram per day for at least 3 months prior to screening visit

          -  In case of treatment with sulfonylurea, if the sulfonylurea dosage is less than the
             maximum effective dose (that is, half of the maximum recommended dose according to
             local labeling), or is not at a stable (unchanged) dose for at least 3 months prior to
             screening

          -  FPG at screening >250 milligram per deciliter (mg/dL) (>13.9 millimole per liter
             [mmol/L])

          -  History of hypoglycemia unawareness

          -  Body mass index <=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, or inflammatory bowel disease or patients considered by the
             investigator at high risk for acute pancreatitis (for example, with known history of
             biliary gallstone[s], or with very high triglyceride level [>=5.65 mmol/L]) at the
             time of screening

          -  Personal or family history of medullary thyroid cancer or genetic conditions that
             predispose to medullary thyroid cancer (for example, multiple endocrine neoplasia
             syndromes);

          -  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: amylase and/or lipase: >3 times upper
             limit of normal (ULN); hemoglobin <11 gram/deciliter and/or neutrophils <1500 per
             cubic millimeter (mm^3) and/or platelets <100 000/mm^3; calcitonin >20 picogram per
             milliliter (5.9 picomole per liter) ; and positive test for Hepatitis B surface
             antigen and/or Hepatitis C antibody

          -  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 attending 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 and
             sulfonylurea (for example, alpha-glucosidase inhibitor, thiazolidinedione,
             glucagon-like peptide -1 [GLP-1], receptor agonist, 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 screening;

          -  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, unstable (that is,
             worsening) and not controlled (that is, prolonged nausea and vomiting)
             gastroesophageal reflux disease requiring medical treatment, within 6 months prior to
             the time of screening

          -  Allergic reaction to any 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