Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents (TOSCA IT)

/Home/Complications of Diabetes/Diabetes and Stroke/Clinical Trials for Diabetic Stroke

Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents (TOSCA IT)
This study is not yet open for participant recruitment.
Verified by Italian Society of Diabetology, June 2008
Sponsored by: Italian Society of Diabetology

Information provided by: Italian Society of Diabetology
ClinicalTrials.gov Identifier: NCT00700856

Purpose
In patients with type 2 diabetes inadequately controlled with metformin, two main therapeutic options are equally plausible: addition of a sulphonylurea (SU) or addition of a thiazolidinedione (TZD). Since the two classes of drugs clearly differ in mechanisms of action, side effects, economic costs and cardiovascular (CV) risk factors profile, a direct comparison of the two strategies would be most appropriate. Aims: 1) To evaluate the effects of addition of pioglitazone as compared with a SU on the incidence of CV 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: Randomised, open label, parallel group trial of 48 months duration involving more than 20 Clinical Units throughout Italy and 1 Epidemiology/Statistics Unit. After a 8-week run-in period, participants will be randomized to add-on either 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), to metformin (2 gr/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 plus 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 CV end point of the primary end point above plus heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries, silent MI, angina, intermittent claudication with an ankle/brachial index lower than 0.90; 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 microalbuminuria or overt nephropathy (dialysis or plasma creatinine >3,3 mg/dl); 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 cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference). 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 analysed on an intention-to-treat basis.

Condition Intervention Phase
Type 2 Diabetes Mellitus
Cardiovascular Disease
Drug: add-on pioglitazone
Drug: add-on sulhonylurea
Phase IV

MedlinePlus related topics: Diabetes Heart Failure
Drug Information available for: Pioglitazone Pioglitazone hydrochloride Glyburide Metformin Metformin hydrochloride Glimepiride Gliclazide
U.S. FDA Resources
Study Type:Interventional
Study Design:Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
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

Further study details as provided by Italian Society of Diabetology:

Primary Outcome Measures:
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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
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 ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: Yes ]

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 ] [ Designated as safety issue: No ]

major cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference) [ Time Frame: 48 months ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: No ]

Estimated Enrollment:5172
Study Start Date:September 2008
Estimated Primary Completion Date:December 2012 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
1: Experimental
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)
2: Active Comparator
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 sulhonylurea
participants randomized to this arm will add a sulphonylurea (glibenclamide 5 mg/die; gliclazide 30 mg/die or glimepiride 2 mg/die)to monjotherapy with metformin (2 gr/die)

Eligibility
Ages Eligible for Study:50 Years to 75 Years
Genders Eligible for Study:Both
Accepts Healthy Volunteers:No
Criteria
Inclusion Criteria:

Patients with type 2 diabetes (WHO criteria) of at least 2 years duration
Males and females
Age 50-75 years
BMI 20-40 Kg/m2
Stable treatment for the last three months with metformin in monotherapy
Glycated haemoglobin (HbA1c) >7.0% and <9.0%
Potentially childbearing women must use a reliable contraceptive method
Exclusion Criteria:

Type 1 diabetes
Previous or current use of insulin (if not on pregnancy or for surgery or for intercurrent acute illness).
Current use of glucose lowering therapies other than metformin
Contraindication/intolerance to metformin or sulphonylureas or thiazolidinediones
Chronic use of glucocorticoids
Documented coronary or cerebrovascular events in the previous 6 months
Serum creatinine >1.5 mg/dl
Proliferative retinopathy
Ischemic ulcer or gangrene
History of congestive heart failure, NYHA (New York Heart Association ) class I or higher
Liver cirrhosis or severe hepatic dysfunction (2.5 times the upper limit of normal concentration of alanine aminotransferase)
Pregnancy or breast feeding
Cancer, substance abuse, any health problem that may interfere with the compliance to study protocol or limit life expectancy
Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00700856

Contacts
Contact: Gabriele Riccardi, Professor +390817462117 riccardi@unina.it

Locations
Italy
University of Pisa
Pisa, Italy
"Maggiore" Hospital
Verona, Italy
"Molinette" Hospital
Turin, Italy
University of Palermo
Palermo, Italy
University of Bari
Bari, Italy
"San Paolo" Hospital
Milan, Italy
Complesso Sociosanitario dei Colli
Padua, Italy
University of Perugia
Perugia, Italy
"Garibaldi di Nesima" Hospital
Catania, Italy
University of Genova
Genova, Italy
University of Padua
Padua, Italy
"Mater Domini" University
Catanzaro, Italy
"La Sapienza" University of Rome
Rome, Italy
Operative Unit of Diabetologia - ASL 4
Prato, Italy
University of Siena
Siena, Italy
University of Florence
Florence, Italy
Inrca - Irccs
Ancona, Italy
University of Ravenna
Ravenna, Italy
University of Ferrara
Ferrara, Italy
University of Messina
Messina, Italy
University of Chieti
Chieti, Italy
"Federico II"University of Naples
Naples, Italy, 80131
Italy, Chieti
Hospital of Lanciano
Lanciano, Chieti, Italy
Consorzio Mario Negri Sud
Santa Maria Imbaro, Chieti, Italy
Italy, Turin
"Maggiore" Hospital
Chieri, Turin, Italy

Sponsors and Collaborators
Italian Society of Diabetology
Investigators
Study Chair: Gabriele Riccardi, Professor Italian Society of Diabetologia

Responsible Party:Italian Society of Diabetology, Via Pisa, 21 00162 Roma ( Italian Society of Diabetology )
Study ID Numbers:FARM6T9CET
First Received:June 18, 2008
Last Updated:July 17, 2008
ClinicalTrials.gov Identifier:NCT00700856 [history]
Health Authority:Italy: The Italian Medicines Agency

Keywords provided by Italian Society of Diabetology:
diabetes
cardiovascular disease
pioglitazone
sulphonylurea
metformin monotherapy

Study placed in the following topic categories:
Glyburide
Metabolic Diseases
Pioglitazone
Gliclazide
Metformin
Diabetes Mellitus
Endocrine System Diseases
2,4-thiazolidinedione
Glimepiride
Diabetes Mellitus, Type 2
Endocrinopathy
Glucose Metabolism Disorders
Metabolic disorder

Additional relevant MeSH terms:
Hypoglycemic Agents
Physiological Effects of Drugs
Cardiovascular Diseases
Pharmacologic Actions