Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial (TOSCA IT)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Associazione Medici Diabetologi (AMD)
Associazione Nazionale Medici Cardiologi Ospedalieri
Information provided by (Responsible Party):
Italian Society of Diabetology
ClinicalTrials.gov Identifier:
NCT00700856
First received: June 18, 2008
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Cardiovascular Disease
Drug: add-on pioglitazone
Drug: add-on sulphonylurea
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
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.

Resource links provided by NLM:


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: No ]
  • 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 ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 3371
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)
Arms Assigned Interventions
Experimental: 1
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)

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Males and females, age 50-75 years
  • Type 2 diabetes of at least 2 years duration
  • BMI 20-45 Kg/m2
  • Stable treatment for the last two months with metformin in monotherapy (at least 2 gr/die)
  • HbA1c >=7.0% and <=9.0%

Exclusion Criteria:

  • Type 1 diabetes
  • Previous treatment with thiazolidinediones in the last six months
  • Contraindication/intolerance to metformin or SUs or TZDs
  • Documented coronary or cerebrovascular events in the previous 3 months
  • Serum creatinine > 1.5 mg/dl
  • History of congestive heart failure, NYHA I or higher
  • Chronic use of glucocorticoids
  • Ischemic ulcer or gangrene
  • Liver cirrhosis or severe hepatic dysfunction (ALT increase of 2.5 times the upper normal limit)
  • Pregnancy or breast feeding
  • Cancer, substance abuse, or any health problem that may interfere with the compliance to the study protocol or limit life expectancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

  Hide Study Locations
Locations
Italy
Ospedale Locatelli di Piario
Seriate, Bergamo, Italy
Hospitaal of Treviglio
Treviglio, Bergamo, Italy
Hospital of Lanciano
Lanciano, Chieti, Italy
Ospedale Casa Sollievo della Sofferenza
San Giovanni Rotondo, Foggia, Italy
ASL 4 - Chiavarese
Chiavari, Genova, Italy
ASL 64
Eboli, Salerno, Italy
Presidio Ospedaliero Atri
Atri, Teramo, Italy
"Maggiore" Hospital
Chieri, Turin, Italy
Inrca - Irccs
Ancona, Italy
San Donato Hospital
Arezzo, Italy
University of Bari
Bari, Italy
Ospedali Riuniti di Bergamo
Bergamo, Italy
Policlinico S. Orsola Malpigli
Bologna, Italy
Presidio Ospedaliero A.S.RE.Molise
Campobasso, Italy
"Garibaldi di Nesima" Hospital
Catania, Italy
"Mater Domini" University
Catanzaro, Italy
M. Bufalini Hospital
Cesena, Italy
ASP
Cosenza, Italy
Arcispedale "S.Anna"
Ferrara, Italy
University of Ferrara
Ferrara, Italy
University of Florence
Florence, Italy
Ospedali Riuniti
Foggia, Italy
University of Genova
Genova, Italy
San Salvatore Hospital
L'Aquila, Italy
Santa Maria Goretti Hospital
Latina, Italy
ASL Latina
Latina, Italy
"Cittadella della Salute" Hospital
Lecce, Italy
ASL 6
Livorno, Italy
Hospital of Massa
Massa Carrara, Italy
Matera Hospital
Matera, Italy
University of Messina
Messina, Italy
"Ospedali Riuniti Papardo-Piemonte" Hospital
Messina, Italy
Niguarda Cà Grande Hospital
Milan, Italy
Istituto Scientifico San Raffaele
Milan, Italy
"Federico II"University of Naples
Naples, Italy, 80131
"Federico II" University
Naples, Italy
Second University
Naples, Italy
University of Padua
Padua, Italy
Complesso Sociosanitario dei Colli
Padua, Italy
University of Palermo
Palermo, Italy
University of Parma
Parma, Italy
University of Perugia
Perugia, Italy
Civil Hospital
Pescara, Italy
Ospedale Gugliemo da Saliceto
Piacenza, Italy
University of Pisa
Pisa, Italy
Spedali Riuniti di Pistoia
Pistoia, Italy
ASP
Potenza, Italy
Praia a Mare Hospital
Praia a Mare, Italy
Operative Unit of Diabetologia - ASL 4
Prato, Italy
University of Ravenna
Ravenna, Italy
Ospedale Infermi
Rimini, Italy
Policlinico di Tor Vergata
Roma, Italy
Ospedale Pertini
Roma, Italy
Sant'Andrea Hospital
Rome, Italy
University of Siena
Siena, Italy
"San Matteo degli Infermi" Hospital
Spoleto, Italy
"Molinette" Hospital
Turin, Italy
Azienda Ospedaliero Universitaria " S.Maria della Misericordia "
Udine, Italy
Hopital of Gallarate
Varese, Italy
Civil Hospital
Verona, Italy
"G. Fracastoro" Civil Hospital
Verona, Italy
Sponsors and Collaborators
Italian Society of Diabetology
Associazione Medici Diabetologi (AMD)
Associazione Nazionale Medici Cardiologi Ospedalieri
Investigators
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
  More Information

Publications:
Responsible Party: Italian Society of Diabetology
ClinicalTrials.gov Identifier: NCT00700856     History of Changes
Other Study ID Numbers: FARM6T9CET
Study First Received: June 18, 2008
Last Updated: June 19, 2014
Health Authority: Italy: The Italian Medicines Agency

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

Additional relevant MeSH terms:
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pioglitazone
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 23, 2014