Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial (TOSCA IT)
Background: In patients with type 2 diabetes inadequately controlled with metformin, two main therapeutic options are equally plausible: add-on a sulfonylurea (SU) or a thiazolidinedione (TZD). Since the two classes of drugs clearly differ in terms of mechanisms of action, side effects, economic costs and cardiovascular risk factors profile, a direct comparison of the two therapeutic strategies would be most appropriate.
Aims: 1) To evaluate the effects of add-on pioglitazone as compared with add-on a SU on the incidence of cardiovascular events in type 2 diabetic patients inadequately controlled with metformin; 2) To compare the two treatments in terms of glycemic control, safety, and economic costs.
Methods: multicentre, randomised, open label, parallel group trial of 48 months duration. Eligible participants (type 2 diabetic males and females, aged 50-75 years, BMI 20-45 Kg/m2, in treatment for the last two months with metformin 2 gr/die in monotherapy and with HbA1c > =7.0% and <= 9.0%) will be randomized to add-on: a SU - glibenclamide (5-15 mg/die), gliclazide (30-120 mg/die), glimepiride (2-6 mg/die), chosen according to local practice - or pioglitazone (15-45 mg/die). A HbA1c value > 8.0 % on two consecutive occasions will lead to addition of insulin to ongoing oral therapy.
Primary efficacy outcome: a composite endpoint of all-cause mortality, non fatal MI (including silent MI), non fatal stroke, and unplanned coronary revascularization.
Secondary outcomes. Principal secondary outcome: a composite ischemic endpoint of sudden death, fatal and non fatal acute MI (including silent MI), fatal and non fatal stroke, major amputations (above ankle), endovascular or surgical intervention on the coronary, leg or carotid arteries.
Other secondary outcomes
- a composite cardiovascular end point including the primary end point plus hospitalization for heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries, silent MI, angina - by WHO criteria and confirmed by a new electrocardiogram abnormality - intermittent claudication with an ankle/brachial index lower than 090; events of heart failure; a microvascular endpoint including: plasma creatinine increase of 2 times above the baseline value or creatinine clearance reduction of 20ml/min/1. 73m2 or development of overt nephropathy (dialysis or plasma creatinine >3,3 mg/dl) or macroalbuminuria; glycemic control (changes from baseline in HBA1c, time to failure of glycemic control, i.e., HBA1c >8.0% on two consecutive occasions three months apart); major CV risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference); safety and side effects; direct and indirect costs.
Data regarding CV endpoints, safety, tolerability, and study conduct will be monitored and analyzed by an independent committee, and will be not available to the study investigators until the closing of data collection. Efficacy end points will be analyzed on an intention-to-treat basis.
|Type 2 Diabetes Mellitus Cardiovascular Disease||Drug: add-on pioglitazone Drug: add-on sulphonylurea||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Effects on Incidence of Cardiovascular Events of the Addition of Pioglitazone as Compared With a Sulphonylurea in Type 2 Diabetic Patients Inadequately Controlled With Metformin.|
- A composite endpoint including: all-causes mortality, non fatal myocardial infarction (MI) - including silent MI- , non fatal stroke, unplanned coronary revascularization [ Time Frame: 48 months ]
- A composite ischemic end point of: sudden death, fatal and non fatal MI (including silent MI), fatal and non fatal stroke, major leg amputation (above the ankle), endovascular or surgical interventions on the coronary, leg or carotid arteries [ Time Frame: 48 months ]
- a composite CV endpoint including the primary endpoint plus heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries, angina, intermittent claudication with an ankle/brachial index < 0.85 [ Time Frame: 48 months ]
- glycemic control (changes from baseline in HbA1c, time to failure of oral hypoglycaemic therapy, i.e., HBA1c >8.0% on two consecutive occasions three months apart) [ Time Frame: 48 months ]
- major cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference) [ Time Frame: 48 months ]
- development of nephropathy: plasma creatinine increase of 2 times above the baseline value or creatinine clearance reduction of 20ml/min/1. 73m2 or development of microalbuminuria or overt nephropathy (dialysis o plasma creatinine >3,3 mg/dl) [ Time Frame: 48months ]
- events of heart failure evaluated according to the American Heart Association and the American Diabetes Association consensus on glitazones and heart failure [ Time Frame: 48 months ]
|Study Start Date:||September 2008|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
metformin 2000 mg + pioglitazone 15-45 mg
Drug: add-on pioglitazone
participants randomised to this arm will add pioglitazone 15 mg/die to therapy with metformin (2 gr/die)
Active Comparator: 2
metformin 2000 mg + glibenclamide 5-15 mg or metformin 2000 mg + gliclazide 30-120 mg or metformin 2000 mg + glimepiride 2-6 mg
Drug: add-on sulphonylurea
participants randomized to this arm will add a sulphonylurea (glibenclamide 5 mg/die; gliclazide 30 mg/die or glimepiride 2 mg/die)to monotherapy with metformin (2 gr/die)
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00700856
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|Study Chair:||Gabriele Riccardi, Professor||Italian Diabetes Society|
|Study Director:||Olga Vaccaro, professor||"FedericoII" University of Naples|
|Study Director:||Maria Masulli, PhD||"Federico II" University of Naples|