Official Title: “Comparison of the Action of the Rosiglitazone-Metformin Fixed-Dose Combination and of a Metformin-Sulfonylurea Free Combination on the b-Cell Function in Type 2 Diabetic Patients Not Controlled With Metformin Alone.”

It has been shown in previous study that progressive glycemic deterioration was associated with progressive loss of b-cell function, measured by the decrease in plasma insulin levels, irrespective of the therapy used (diet, sulfonylureas or metformin).There is growing evidence that thiazolidinediones could have a positive action on the b-cell function. But it has not yet been demonstrated that they could protect from a deterioration in insulin secretion in the long term. So, it appears interesting to study the long term evolution of the b-cell function and the possible protection with rosiglitazone in patients with type 2 diabetes showing evidence of loss of b-cell function with metformin alone.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: October 2008

Intervention(s) in this Clinical Trial

• Drug: rosiglitazone-metformin
• Drug: Metformin
• Drug: metformin+ gliclazide

Primary Measures

• Beta-cell function is reflected by insulin response. Evolution of insulin secretion capacity will be assessed over 3 years, by using clamp tests and meal tests before treatment and after 18 and 36 months of treatment
• Evolution of insulin secretion capacity over 3 years measured by using clamp tests and meal tests before treatment and after 18 and 36 months of treatment (or in case of early withdrawal).
• 1st phase insulin secretion (during the 10 first minutes) : AUC, incremental AUC and peak value
• 2nd phase insulin secretion (AUC from 120 to 180 minutes and incremental AUC)
• Insulin sensitivity : M/I (M = Metabolized glucose, I = Insulin) from 120 to 180 minutes
• (The ratio M/I is a measure of the quantity of glucose metabolized per unit of plasma insulin concentration and is thus a reasonable index of tissue sensitivity to insulin).
• Arginin test (peak value, AUC and incremental AUC) from 180 to 210 minutes.
• Meal test (Sustacal): peak value of insulin and AUC over 3 hours.

Secondary Measures

• insulin secretion and sensitivity at baseline,M18 and 36. HbA1c ( glycosylated haemoglobin) at baseline ,M18 and 36. C peptide at baseline, M18 and 36
• HOMA: % insulin secretion and sensitivity, performed before each stimulatory test
• Centralised HbA1c, C-peptide at 0, 18 and 36 months or in case of early withdrawal.
• Even if clinical efficacy is not the objective of the study, the following parameters, which are essential to evaluate glycaemic control of the patients and safety
• (hypoglycemia+++) to adapt the treatment over the 3 year period, will be studied as a reference for the main evaluation and an evidence of compliance and/or of a possible therapeutic failure :
• Local FPG, HbA1c every 3 months (except when clamp test) and in case of early withdrawal Adverse events every 3 months and in case of early withdrawal.

INCLUSION CRITERIA:

• Males and females 40 to 75 years of age (inclusive at the time of screening)
• Type 2 diabetes mellitus as defined by the WHO criteria, diagnosed for at least 1 year
• Subjects receiving 1.5 to 3g of metformin alone at a constant dose for at least 8 weeks prior to visit 1
• Patients with 6.5% < HbA1c > 8% at visit 1 and visit 2
• 25 < BMI < 35

EXCLUSION CRITERIA:

• Patient with type 1 diabetes
• Treatment with other hypoglycaemic agents than metformin in the last 3 months
• FPG >200 mg/dL at visit 2
• Hypersensitivity to the studied treatments (rosiglitazone, metformin chlorhydrate, gliclazide)
• Congestive heart failure (NYHA class I to IV), unstable or severe angina, recent myocardial infarction
• Respiratory insufficiency
• Subjects who have required the use of insulin for glycaemic control in the past 6 months prior to visit 1 (except during pregnancy or acute episodes such as hospitalization, trauma or infection) or subjects with a history of metabolic acidosis including diabetic ketoacidosis
• Anemia defined by haemoglobin concentration <11.0 g/dL for males and <10.0 g/dL for females
• Renal disease or renal dysfunction, e.g. as suggested by serum creatinine levels
• ≥135.0 µmol/L in males and ≥110.0 µmol/L in females and/or creatinine clearance <40 mL/min
• Presence of clinically significant hepatic disease, with ALT, AST, total bilirubin, alkaline phosphatase >2.5 times the upper limit of the normal reference range
• Subjects with chronic diseases requiring periodic ot intermittent treatment with oral or IV corticosteroids
• Subjects receiving danazol, miconazole or phenylbutazone
• Active alcohol, drug or medication abuse within the last 6 months or any condition that would indicate the likelihood of poor subject compliance
• Women who are lactating, pregnant or planning to become pregnant
• Any clinically significant abnormality identified at screening which, in the investigator's judgement, makes the subject unsuitable for inclusion in the study
• Use of any other investigational agent within 30 days or 5 half-lives (whichever is longer) prior to visit 1
• Subjects who receive or anticipate receiving radiocontrast dye during the study

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 40 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: GlaxoSmithKline

Overall Clinical Trial Officials and Contacts

GSK Clinical Trials, MD Study Director GlaxoSmithKline  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00367055

Study ID Number: 101765

ClinicalTrials.gov Identifier: NCT00367055

Health Authority: France: National Consultative Ethics Committee for Health and Life Sciences