ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    Thiazolidinediones Or Sulphonylureas Cardiovascular Accidents Intervention Trial
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00700856
Recruitment Status : Active, not recruiting
First Posted : June 19, 2008
Last Update Posted : August 27, 2015
Sponsor:
Collaborators:
Associazione Medici Diabetologi (AMD)
Associazione Nazionale Medici Cardiologi Ospedalieri
Information provided by (Responsible Party):
Italian Society of Diabetology

Brief Summary:

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 or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Cardiovascular Disease Drug: add-on pioglitazone Drug: add-on sulphonylurea Phase 4

  Show Detailed Description

Study Type : Interventional
Estimated Enrollment : 3371 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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.
Study Start Date : September 2008
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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)




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. major cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference) [ Time Frame: 48 months ]
  5. 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 ]
  6. 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 ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00700856


  Show 61 Study Locations
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

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Vaccaro O, Masulli M, Nicolucci A, Bonora E, Del Prato S, Maggioni AP, Rivellese AA, Squatrito S, Giorda CB, Sesti G, Mocarelli P, Lucisano G, Sacco M, Signorini S, Cappellini F, Perriello G, Babini AC, Lapolla A, Gregori G, Giordano C, Corsi L, Buzzetti R, Clemente G, Di Cianni G, Iannarelli R, Cordera R, La Macchia O, Zamboni C, Scaranna C, Boemi M, Iovine C, Lauro D, Leotta S, Dall'Aglio E, Cannarsa E, Tonutti L, Pugliese G, Bossi AC, Anichini R, Dotta F, Di Benedetto A, Citro G, Antenucci D, Ricci L, Giorgino F, Santini C, Gnasso A, De Cosmo S, Zavaroni D, Vedovato M, Consoli A, Calabrese M, di Bartolo P, Fornengo P, Riccardi G; Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):887-897. doi: 10.1016/S2213-8587(17)30317-0. Epub 2017 Sep 13. Erratum in: Lancet Diabetes Endocrinol. 2017 Nov;5(11):e7.

Responsible Party: Italian Society of Diabetology
ClinicalTrials.gov Identifier: NCT00700856     History of Changes
Other Study ID Numbers: FARM6T9CET
First Posted: June 19, 2008    Key Record Dates
Last Update Posted: August 27, 2015
Last Verified: August 2015

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

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