Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-naive Patients

Study Overview
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Brief Summary
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The primary objective was to demonstrate the superiority of insulin glargine over sitagliptin in reducing Glycosylated Hemoglobin A1c (HbA1c) from baseline to the end of the treatment period. Secondary objective was to assess the effect of insulin glargine in comparison with sitagliptin on: HbA1c level Fasting Plasma Glucose (FPG) 7-point plasma glucose (PG) profiles Percentage of patients with HbA1c <7% and <6.5% Safety objectives consisted of: Hypoglycemia occurrence Body weight Overall safety

Official Title
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Superiority Study of Insulin Glargine Over Sitagliptin in Insulin-naïve Patients With Type 2 Diabetes Treated With Metformin and Not Adequately Controlled

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Insulin Glargine
* Drug: Sitagliptin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: With type 2 diabetes diagnosed for at least 6 months, Not previously treated with insulin, On metformin for at least 3 months and a stable minimal dose of 1 g/day for at least 2 months HbA1c ≥ 7 and < 11 %, Body Mass Index (BMI) between 25 and 45 kg/m² inclusively, Ability and willingness to perform plasma glucose (PG) monitoring using the Sponsor-provided PG meter and to complete the patient diary, Signed informed consent obtained prior any study procedures, Willingness and ability to comply with the study protocol. Exclusion Criteria: Treatment with oral antidiabetic drugs other than metformin within the last 3 months, Previous treatment with the combination of metformin + sulfonylurea for more than 1 year, Previous treatment with Glucagon Like Peptide-1 (GLP-1) agonists or DiPeptidyl Peptidase (DPP) IV inhibitors, FPG (assessed by central laboratory measurement) ≥ 280 mg/dL (15.4 mmol/L), Diabetes other than type 2 diabetes (e.g. secondary to pancreatic disorders, drug or chemical agents intake...), Pregnant or lactating women (women of childbearing potential must have a negative pregnancy test at study entry and a medically approved contraception method), In-patient care, Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence in the 6 months prior to visit 1, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the study (an optic fundus examination should have been performed within the 2 years prior to study entry), Impaired renal function: serum creatinine ≥ 1.5 mg/dL (≥ 133µmol/L) or ≥ 1.4 mg/dL (≥ 124 µmol/L) in men and women, respectively, History of sensitivity to the study drugs or to drugs with a similar chemical structure, Impaired hepatic function: alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 3 x upper limit of normal range, Treatment with systemic corticosteroids within the 3 months prior to study entry or likelihood of requiring treatment during the study that are not permitted during the study (exception: in case of chronic adrenal insufficiency, systemic glucosteroids are accepted only if the disease is stable and the treatment dose stable for at least 3 months before study entry), Alcohol or drug abuse within the last year, Night shift worker, Presence of any condition (medical, psychological, social or geographical), current or anticipated that the investigator feels would compromise the patient's safety or limit the patient successful participation in the study, Treatment with weight loss medications (e.g. sibutramine, orlistat, rimonabant) within the last 3 months, Participation in another clinical trial within the month prior to visit 1, History of pancreatitis.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin Glargine<br>Administered once a day in the evening at dinner or at bedtime with a starting dose 0.2 U/kg. Then, the doses were to be individually adjusted, following a titration algorithm, to reach the FPG target: 70mg/dL<FPG≤100mg/dL (3.9mmol/L<FPG≤5.5mmol/L). | Drug: Insulin Glargine<br>* Subcutaneous injection. 100 Units/mL solution for injection in a pre-filled SoloStar® pen (3 mL).<br>* Other names: Lantus®;Drug: Metformin<br>* Patients continued with metformin as usual oral anti-diabetic treatment.<br>|
| Active Comparator: Sitagliptin<br>Dose of 100 mg once a day administered with or without food. | Drug: Sitagliptin<br>* Oral administration. 100 mg film-coated tablets.<br>* Other names: Januvia®;Drug: Metformin<br>* Patients continued with metformin as usual oral anti-diabetic treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c: Change From Baseline to Study Endpoint | Change in HbA1c from baseline to study endpoint defined as the last available HbA1c value measured during the 24-week treatment period. | baseline (week 0), study endpoint: visit 14 (week 24) or visit 11 (week 12) if value not available at visit 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Response Rate: Percentage of Patients Who Reach the Target of HbA1c < 7% at Study Endpoint |  | study endpoint: visit 14 (week 24) or visit 11 (week 12) if value not available at visit 14 | 
| HbA1c Response Rate: Percentage of Patients Who Reach the Target of HbA1c < 6.5% at Study Endpoint |  | study endpoint: visit 14 (week 24) or visit 11 (week 12) if value not available at visit 14 | 
| Self-monitored Fasting Plasma Glucose (SMFPG) Mean : Change From Baseline to Study Endpoint | SMFPG mean = mean of the fasting plasma glucose values recorded on the 6 consecutive days before the visit (at least 3 values needed). Study endpoint was defined as the last available SMFPG mean value collected on-treatment. Change= study endpoint - baseline | baseline (week 0), study endpoint: visit 14 (week 24) or visit 12 (week 16) or visit 11 (week 12) or visit 8 (week 6) depending on last available value | 
| 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | 7-point plasma glucose recorded before and after breakfast, before and after lunch, before and after dinner and at bedtime. Change = study endpoint - baseline. | baseline (week 0), study endpoint: visit 14 (week 24) or visit 11 (week 12) if value not available at visit 14 | 
| Insulin Dose in the Insulin Glargine Group | Daily dose at the face-to-face visits. | visit 4 (week 2), visit 8 (week 6), visit 11 (week 12), visit 12 (week 16), visit 14 (week 24), first dose received defined as first available value, study endpoint defined as last available value | 
| Lipid Profile: Change From Baseline to Study Endpoint |  | baseline (week 0), study endpoint: visit 14 (week 24) or visit 11 (week 12) if value not available at visit 14 | 
| Change in Body Weight From Baseline to Study Endpoint |  | baseline (week 0), study endpoint: visit 14 (week 24) or visit 12 (week 16) or visit 11 (week 12) or visit 8 (week 6) depending on last available value | 
| Number of Patients With at Least One Episode of Symptomatic Hypoglycemia | Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia confirmed or not by a plasma glucose measurement <= 70mg/dL [3.9 mmol/L] | During the treatment phase (24 weeks) plus 7 days after last dose | 
| Number of Patients With at Least One Episode of Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia was defined as an event with clinical symptoms which required assistance of another person and with either a Plasma Glucose level < 36 mg/dL (2 mmol/L) or with a prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration | During the treatment phase (24 weeks) plus 7 days after last dose |