GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Basal Insulin
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Lixisenatide (AVE0010); Placebo; Basal Insulin; Metformin; Pen auto-injector
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 (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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 496.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: hyperglycemia, GLP-1, metformin, insulin

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 basal insulin 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 basal insulin on
      glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction at Week 24.

      The secondary objectives are to assess the effects of lixisenatide when added to basal
      insulin on body weight, 2-hour postprandial plasma glucose (PPG) after standardized meal
      challenge test, percentage of patients reaching HbA1c less than 7 percent (%), percentage of
      patients reaching HbA1c less than or equal to 6.5%, fasting plasma glucose (FPG), change in
      7-point self-monitored plasma glucose (SMPG) profiles, change in basal insulin and total
      insulin doses; 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 basal insulin with or without metformin

        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 basal insulin for less than 3 months prior to screening or insulin
             regimen changed during the last 3 months prior to screening

          -  Basal insulin dose at screening <30 units/day and/or not at a stable dose (+/- 20
             percent [%]) during the last 2 months

          -  If treatment with metformin, no stable dose of at least 1.5 gram/day (except for South
             Korea: at least 1.0 gram/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])

          -  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, or 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 and positive serum
             pregnancy test in females of childbearing potential

          -  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 other oral or injectable antidiabetic or hypoglycemic agents other than
             metformin or basal insulin (for example, sulfonylurea, alpha-glucosidase inhibitor,
             thiazolidinedione, rimonabant, exenatide, dipeptidyl-peptidase-4 inhibitors,
             fast-acting insulin for 1 week or more) 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

          -  Any previous treatment with lixisenatide or participation in any previous study with
             lixisenatide

          -  Use of any investigational drug within 3 months prior to study

          -  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)

          -  End-stage renal disease as defined by a calculated serum creatinine clearance of <15
             milliliter/minute 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 the previous 6 months

          -  History of 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