Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination Compared to Insulin Glargine Alone and Lixisenatide Alone on Top of Metformin in Patients With T2DM
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Insulin glargine/lixisenatide Fixed Ratio Combination; Insulin glargine (HOE901); Lixisenatide (AVE0010); Metformin
Intervention description: Insulin glargine/Lixisenatide FRC was self-administered by subcutaneous (SC) injection in the morning within one hour before breakfast using one of the 2 prefilled disposable SoloStar® pen-injectors: Pen A containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 50 mcg/mL lixisenatide in a ratio of 2 U:1 mcg, used for administration of doses from 10 U to 40 U (10 U/5mcg to 40 U/20mcg). Pen B containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 33 mcg/mL lixisenatide in a ratio of 3 U:1 mcg, used to administer doses from 41 U to 60 U (41 U/13 mcg to 60 U/20 mcg). The starting dose was 10 U/5 mcg. Dose was then adjusted individually 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) while avoiding hypoglycemia.; Insulin glargine (100 U/mL) was self-administered by SC injection at approximately the same time every day. Dose was adjusted individually to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) while avoiding hypoglycemia.; Lixisenatide was self-administered by SC injection within 0 to 60 minutes before breakfast or evening meal. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.; 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: 1170.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objective:

      To compare the insulin glargine/lixisenatide fixed ratio combination to lixisenatide alone
      and to insulin glargine alone (on top of metformin treatment) in glycated hemoglobin (HbA1c)
      change from baseline to Week 30.

      Secondary Objective:

      To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio
      combination (FRC) to insulin glargine alone and to lixisenatide alone (on top of metformin
      treatment) over a 30 week treatment period in participants with type 2 diabetes.
    

Eligibility criteria:

        Inclusion criteria:

          -  Participants with type 2 diabetes mellitus diagnosed for at least 1 year before the
             screening visit, treated for at least 3 months prior to visit 1 with metformin alone
             or metformin and a second oral anti-diabetic treatment that could be a sulfonylurea, a
             glinide, a sodium glucose co-transporter-2 inhibitor or a di-peptidyl peptidase 4
             (DPP-4) inhibitors, and who were not adequately controlled with this treatment.

          -  Signed written informed consent.

        Exclusion criteria:

          -  HbA1c at screening visit:

               -  less than 7.5% or more than 10% for participants previously treated with
                  metformin alone,

               -  less than 7.0% or more than 9% for participants previously treated with metformin
                  and a second oral anti-diabetic treatment.

          -  Pregnancy or lactation, women of childbearing potential with no effective
             contraceptive method.

          -  Use of oral glucose-lowering agents other than those stated in the inclusion criteria
             or any injectable glucose-lowering agents during the 3 months before screening.

          -  Previous Treatment with insulin (except for short-term treatment due to intercurrent
             illness including gestational diabetes, at the discretion of the trial physician).

          -  History of discontinuation of a previous treatment with a glucagon-like peptide
             (GLP-1) receptor agonist (GLP-1 RA) due to safety/tolerability issue or lack of
             efficacy.

          -  Participant who previously participated in any clinical trial with lixisenatide or the
             insulin glargine/lixisenatide fixed ratio combination or had previously received
             lixisenatide.

          -  Any contraindication to metformin use, according to local labeling.

          -  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 (e.g, 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).

        Exclusion Criteria for randomization at the end of the screening period:

          -  HbA1c less than 7% or above 10%;

          -  Fasting Plasma glucose above 250 mg/dL (13.9 mmol/L);

          -  Metformin maximal tolerated dose less than 1500 mg/day;

          -  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.