Rosiglitazone-Metformin Combination Versus Metformin-Sulfonylurea Combination On Beta-Cell Function In Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: rosiglitazone-metformin
* Drug: Metformin
* Drug: metformin+ gliclazide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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

| Intervention/Treatment |
| --- |
|Drug: rosiglitazone-metformin|nan|
|Drug: Metformin|nan|
|Drug: metformin+ gliclazide|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change From Baseline in the Insulin Secretory Capacity After a 36-month Treatment | Change from baseline in the insulin secretory capacity was measured by the assesment of blood insulin concentrations (conc.) using the hyperglycaemic clamp (HC) technique, per intravenous glucose perfusion by a catheter. Change from baseline for insulin conc peaks (highest conc level) was calculated as the Month 36 value minus the baseline value. Insulin secretion was assessed by calculating AUC during the first 10 minutes of HC (incremental and total AUC0-10 min) and the AUC after the first 10 minutes of the HC (10-180min). | Baseline and Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change From Baseline in the Ratio M/I After a 36-month Treatment |  | Baseline and Month 36 | 
| Median Change From Baseline in the Insulin Secretion Capacity After an 18-month Treatment | Change from baseline was calculated as the Month 18 value minus the baseline value. Insulin secretion capacity is measured in blood (blood level of insulin) and is a response of the pancreatic beta-cells to hyperglycemia induced by a glucose IV bolus, then infusion. Hyperglycemic clamp (HC) is a reference technique to evaluate the initial and the secondary phases of insulin secretion. | Baseline and Month 18 | 
| Mean Change From Baseline in HbA1c at Month 36 | Change from baseline was calculated as the Month 36 value minus the baseline value. HbA1c levels were measured by blood draw. | Baseline and Month 36 | 
| Mean Change From Baseline in FBG at Month 36 | Change from baseline was calculated as the Month 36 value minus the baseline value. FBG levels were measured by blood draw. | Baseline and Month 36 | 
| Median Change From Baseline in Insulin Resistance Index (HOMA-IR) After a 36-month Treatment |  | Baseline and Month 36 | 
| Median Change From Baseline in Beta Cell Function Index (HOMA-beta) After a 36-month Treatment |  | Baseline and Month 36 | 
| Mean Change From Baseline in CPP Total and Incremental AUC T0-T30 After a 36-month Treatment |  | Baseline and Month 36 | 
| Mean Change From Baseline in CPP Concentration Peak and Incremental Concentration Peak T0-T30 After a 36-month Treatment |  | Baseline and Month 36 | 
| Mean Change From Baseline in Insulin Sensitivity Index at Months 18 and 36 | Change from baseline was calculated as the Month 18 and 36 values minus the baseline value. Insulin sensitivity is measured as the quantity of glucose metabolized per unit of plasma insulin concentration. | Baseline and Months 18 and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta cell function, Type 2 diabetes, Combination treatment