Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Insulin glargine/lixisenatide (HOE901/AVE0010); Insulin glargine (HOE901); Metformin (Background Drug)
Intervention description: Insulin glargine/lixisenatide FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using one of 2 SoloStar® pen-injectors: Pen A (ratio of 2 Units (U) of insulin glargine U 100:1 mcg of lixisenatide) or Pen B (ratio of 3 U of insulin glargine U 100:1 mcg of lixisenatide). After run-in, the FRC was initiated at a dose of either 20 U/10 mcg with Pen A or 30 U/10 mcg with Pen B, depending on participant's dose of Insulin glargine on the day prior to randomization.
Dose was adjusted weekly to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L). Pen A was used for administration of doses up to 40 U/20 mcg and Pen B for administration of doses from 30 U/10 mcg up to 60 U/20 mcg.; Insulin glargine was self-administered QD by SC injection at approximately the same time every day.
After screening, eligible participants entered 6 week run-in phase during which they were switched (if necessary) to insulin glargine and dose was stabilized. The first dose after randomization was same as the one administered on the day prior to randomization and then dose was adjusted weekly to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L).; Pharmaceutical form: Tablet; Route of administration: Oral administration
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Lixisenatide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 736.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objective:

      To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination
      (FRC) to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to Week 30.

      Secondary Objective:

      To compare the overall efficacy and safety of insulin glargine/lixisenatide FRC to insulin
      glargine (with or without metformin) over a 30 week treatment period in participants with
      type 2 diabetes.
    

Eligibility criteria:

        Inclusion criteria :

          -  Type 2 diabetes mellitus diagnosed at least 1 year before the screening visit.

          -  Treatment with basal insulin for at least 6 months before the screening visit.

          -  Stable basal insulin regimen (i.e. type of insulin and time/frequency of the
             injection) for at least 3 months before the screening visit.

          -  Stable (plus/minus 20 percent) total daily basal insulin dose between 15 and 40
             Units/day for at least 2 months prior to the screening visit.

          -  For participants receiving basal insulin and 1 or 2 oral anti-diabetic drugs (OADs):
             the OAD dose(s) must be stable during the 3 months before the screening visit. The
             OADs could be 1 to 2 out of:

               -  metformin (more than or equal to 1500 mg/day or maximal tolerated dose),

               -  a sulfonylurea,

               -  a glinide,

               -  a dipeptidyl-peptidase-4 inhibitor,

               -  a sodium glucose co-transporter 2 inhibitor,

          -  Fasting Plasma Glucose (FPG) less than or equal to 180 mg/dL(10.0 mmol/L) at screening
             visit for participants receiving basal insulin in combination with 2 OADs or with 1
             OAD other than metformin; FPG less than or equal to 200 mg/dL (11.1 mmol/L) at
             screening visit for participants on basal insulin only or basal insulin plus metformin
             at screening visit.

          -  Signed written informed consent.

        Exclusion criteria:

          -  Age under legal age of adulthood at screening visit.

          -  HbA1c at screening visit less than 7.5% or above 10%.

          -  Pregnancy or lactation, women of childbearing potential with no effective
             contraceptive method.

          -  Use of other oral or injectable glucose-lowering agents than stated in the inclusion
             criteria in a period of 3 months prior to screening.

          -  Previous use of insulin other than basal insulin eg, prandial or pre-mixed insulin, in
             the year prior to screening. Note: Short term treatment (≤10 days) due to intercurrent
             illness is allowed.

          -  History discontinuation of a previous treatment with Glucagon Like Peptide -1 Receptor
             Agonists for safety/tolerability or lack of efficacy.

          -  Participant who had previously participated in any clinical trial with lixisenatide or
             the insulin glargine/lixisenatide FRC or had previously received lixisenatide.

          -  Use of weight loss drugs within 3 months prior to screening visit.

          -  Within the last 6 months prior to screening visit: history of stroke, myocardial
             infarction, unstable angina, or heart failure requiring hospitalization. Planned
             coronary, carotid or peripheral artery revascularisation procedures to be performed
             during the study period.

          -  History of pancreatitis (unless pancreatitis was related to gallstones and
             cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a
             previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery.

          -  Personal or immediate family history of medullary thyroid cancer (MTC) or genetic
             conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes).

          -  Uncontrolled or inadequately controlled hypertension (systolic blood pressure above
             180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit.

          -  At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m^2.

          -  At screening visit amylase and/or lipase more than 3 times the upper limit of the
             normal (ULN) laboratory range.

          -  At screening visit alanine aminotransferase (ALT) or alkaline phosphatase (AST) more
             than 3 ULN.

          -  At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L).

          -  Any contraindication to metformin use, according to local labeling, if the participant
             was taking metformin.

          -  Participant who had a renal function impairment with creatinine clearance less than 30
             mL/min (using the Cockcroft and Gault formula) or end-stage renal disease for
             participants, not treated with metformin.

        Exclusion criteria for randomization:

          -  HbA1c less than 7% or above 10% .

          -  Mean fasting SMPG calculated from the self-measurements for 7 days the week before
             randomization visit was above 140 mg/dL (7.8 mmol/L).

          -  Average insulin glargine daily dose less than 20 Units or above 50 Units (in the week
             before randomization visit).

          -  Amylase and/or lipase more than 3 ULN .

        The above information is not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.