24-week Treatment With Lixisenatide in Type 2 Diabetes Insufficiently Controlled With Metformin and Insulin Glargine
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Insulin glargine; Pen auto-injector; Metformin; Thiazolidinedione (TZD)
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 adjusted to maintain a fasting SMPG between 100 and 80 mg/dL (5.6 and 4.4 mmol/L), inclusive.; Lantus® SoloStar® OptiClik®; Metformin to be continued at stable dose (at least 1.5 gram per day) up to Week 24.; TZD (either rosiglitazone or pioglitazone) if given, to be continued at stable dose up to Week 24.
Intervention MeSH terms: Metformin; Insulin Glargine; Lixisenatide; 2,4-thiazolidinedione
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 446.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of the study is to evaluate the benefits and risks of lixisenatide (AVE0010), in
      comparison to placebo, as an add-on treatment to insulin glargine and metformin with or
      without thiazolidinediones (TZDs), over a period of 24 weeks of treatment.

      The primary objective is to assess the effects of lixisenatide in comparison to placebo, when
      added to insulin glargine and 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 the percentage of
      patients reaching HbA1c less than (<) 7 percent (%) and less than or equal to (<=) 6.5%,
      plasma glucose (fasting, postprandial during a standardized meal challenge test, 7-point self
      monitored profiles), body weight, insulin glargine doses, to evaluate safety and tolerability
      (including anti-lixisenatide antibody assessment), and to assess the impact on treatment
      satisfaction using the Diabetes Treatment Satisfaction Questionnaire (state) (DTSQs) in the
      participating countries where it is validated.
    

Eligibility criteria:

        Inclusion criteria:

        - Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit,
        insufficiently controlled with insulin glargine and metformin

        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

          -  Metformin not at a stable dose of at least 1.5 gram per day for at least 3 months
             prior to the screening visit

          -  Use of oral or injectable antidiabetic or hypoglycemic agents other than metformin,
             sulfonylurea (SU) and TZDs (for example, alpha glucosidase inhibitor, other glucagon
             like peptide-1 [GLP-1] receptor agonists, dipeptidyl peptidase-IV [DPP-IV] inhibitors,
             insulin etc.) within 3 months prior to the time of screening, use of weight loss drugs
             if not at a stable dose for at least 3 months prior to the screening visit

          -  History of hypoglycemia unawareness

          -  Body Mass Index (BMI) less than or equal to (<=) 20 kilogram per square meter (kg/m^2)

          -  History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy,
             stomach/gastric surgery, inflammatory bowel disease, personal or family history of
             medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (for
             example, multiple endocrine neoplasia syndromes)

          -  History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to
             screening

          -  Hemoglobinopathy or hemolytic anemia, blood or plasma products transfusion 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

          -  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 such as active malignant tumor or other major systemic
             diseases, presence of clinically significant diabetic retinopathy 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 or diastolic blood pressure >180 millimeter of mercury (mmHg) or >110
             mmHg, respectively

          -  Laboratory findings at the time of screening: amylase and/or lipase, alanine
             aminotransferase >3 times upper limit of the normal (ULN) laboratory range; 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 childbearing potential; and
             calcitonin >=20 picogram per milliliter (pg/mL) (5.9 picomole per milliliter [pmol/L])

          -  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, patient being
             investigator or any sub investigator, pharmacist, study coordinator, other study staff
             or relative thereof directly involved in the conduct of the protocol etc.)

          -  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 screening

          -  Renal impairment defined with serum creatinine > 1.4 mg/dL in women and > 1.5 mg/dL in
             men

          -  History of hypersensitivity to insulin glargine or to any of the excipients

          -  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

          -  Any previous treatment with lixisenatide (for example, participation in a previous
             study with lixisenatide)

          -  Allergic reaction to any GLP-1 receptor agonist in the past (for example, exenatide,
             liraglutide) or to metacresol

          -  Additional exclusion criteria during or at the end of the run-in phase before
             randomization: informed consent withdrawal (patient who was not willing to continue or
             failed to return), mean fasting SMPG calculated from the self-measurements for the 7
             days prior to Visit 12 (Week -1) was >140 mg/dL (7.8 mmol/L) and HbA1c measured at
             Visit 12 (Week -1) is <7% or >9%, amylase and/or lipase > 3 times the ULN at Visit 12
             (Week -1), patients with fasting plasma glucose (FPG) above the threshold value
             described for rescue (that is, FPG >240 mg/dL [13.3 mmol/L]), patients with any
             adverse event, which, by the judgment of the Investigator precludes the inclusion in
             the double-blind randomized treatment phase, and lack of compliance to protocol or to
             insulin glargine treatment during the run-in phase