Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial
TOSCA IT
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.
1 other identifier
interventional
3,371
1 country
61
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_4 type-2-diabetes-mellitus
Started Sep 2008
Longer than P75 for phase_4 type-2-diabetes-mellitus
61 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 18, 2008
CompletedFirst Posted
Study publicly available on registry
June 19, 2008
CompletedStudy Start
First participant enrolled
September 1, 2008
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
December 1, 2018
CompletedAugust 27, 2015
August 1, 2015
10.3 years
June 18, 2008
August 26, 2015
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
A composite endpoint including: all-causes mortality, non fatal myocardial infarction (MI) - including silent MI- , non fatal stroke, unplanned coronary revascularization
48 months
Secondary Outcomes (6)
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
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
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)
48 months
major cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference)
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)
48months
- +1 more secondary outcomes
Study Arms (2)
1
EXPERIMENTALmetformin 2000 mg + pioglitazone 15-45 mg
2
ACTIVE COMPARATORmetformin 2000 mg + glibenclamide 5-15 mg or metformin 2000 mg + gliclazide 30-120 mg or metformin 2000 mg + glimepiride 2-6 mg
Interventions
participants randomised to this arm will add pioglitazone 15 mg/die to therapy with metformin (2 gr/die)
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)
Eligibility Criteria
You may qualify if:
- 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%
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (61)
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
"Federico II"University of Naples
Naples, Naples, 80131, 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
ASL Latina
Latina, Italy
Santa Maria Goretti Hospital
Latina, Italy
"Cittadella della Salute" Hospital
Lecce, Italy
ASL 6
Livorno, Italy
San Salvatore Hospital
L’Aquila, Italy
Hospital of Massa
Massa Carrara, Italy
Matera Hospital
Matera, Italy
"Ospedali Riuniti Papardo-Piemonte" Hospital
Messina, Italy
University of Messina
Messina, Italy
Istituto Scientifico San Raffaele
Milan, Italy
Niguarda Cà Grande Hospital
Milan, Italy
"Federico II" University
Naples, Italy
Second University
Naples, Italy
Complesso Sociosanitario dei Colli
Padua, Italy
University of Padua
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
Ospedale Pertini
Roma, Italy
Policlinico di Tor Vergata
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
"G. Fracastoro" Civil Hospital
Verona, Italy
Civil Hospital
Verona, Italy
Related Publications (9)
Vaccaro O, Masulli M, Bonora E, Del Prato S, Nicolucci A, Rivellese AA, Riccardi G; TOSCA.IT Study Group. The TOSCA.IT trial: a study designed to evaluate the effect of pioglitazone versus sulfonylureas on cardiovascular disease in type 2 diabetes. Diabetes Care. 2012 Dec;35(12):e82. doi: 10.2337/dc12-0954. No abstract available.
PMID: 23173143BACKGROUNDVaccaro O, Masulli M, Bonora E, Del Prato S, Giorda CB, Maggioni AP, Mocarelli P, Nicolucci A, Rivellese AA, Squatrito S, Riccardi G; TOSCA.IT study group (Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents. Intervention Trial). Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2012 Nov;22(11):997-1006. doi: 10.1016/j.numecd.2012.09.003. Epub 2012 Oct 11.
PMID: 23063367BACKGROUNDDella Pepa G, Carli F, Sabatini S, Pezzica S, Russo M, Vitale M, Masulli M, Riccardi G, Rivellese AA, Vaccaro O, Bozzetto L, Gastaldelli A. Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control. Diabetes Metab Res Rev. 2024 May;40(4):e3798. doi: 10.1002/dmrr.3798.
PMID: 38558269DERIVEDMasulli M, Lucisano G, Bonora E, Del Prato S, Rivellese AA, Signorini S, Mocarelli P, Riccardi G, Vaccaro O, Nicolucci A; TOSCA.IT Investigators. A few clinical features improve the prediction of mortality and cardiovascular outcomes in patients with type 2 diabetes. Eur J Prev Cardiol. 2022 Feb 9;28(18):e1-e3. doi: 10.1093/eurjpc/zwaa002. No abstract available.
PMID: 33624040DERIVEDMasulli M, Della Pepa G, Cocozza S, Capasso M, Pignataro P, Vitale M, Gastaldelli A, Russo M, Dolce P, Riccardi G, Rivellese AA, Vaccaro O. The Pro12Ala polymorphism of PPARgamma2 modulates beta cell function and failure to oral glucose-lowering drugs in patients with type 2 diabetes. Diabetes Metab Res Rev. 2021 Mar;37(3):e3392. doi: 10.1002/dmrr.3392. Epub 2020 Sep 2.
PMID: 32783395DERIVEDSartore G, Chilelli NC, Seraglia R, Ragazzi E, Marin R, Roverso M, Cosma C, Vaccaro O, Burlina S, Lapolla A. Long-term effect of pioglitazone vs glimepiride on lipoprotein oxidation in patients with type 2 diabetes: a prospective randomized study. Acta Diabetol. 2019 May;56(5):505-513. doi: 10.1007/s00592-018-01278-2. Epub 2019 Feb 10.
PMID: 30740640DERIVEDVaccaro 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.
PMID: 28917544DERIVEDVitale M, Vaccaro O, Masulli M, Bonora E, Del Prato S, Giorda CB, Nicolucci A, Squatrito S, Auciello S, Babini AC, Bani L, Buzzetti R, Cannarsa E, Cignarelli M, Cigolini M, Clemente G, Cocozza S, Corsi L, D'Angelo F, Dall'Aglio E, Di Cianni G, Fontana L, Gregori G, Grioni S, Giordano C, Iannarelli R, Iovine C, Lapolla A, Lauro D, Laviola L, Mazzucchelli C, Signorini S, Tonutti L, Trevisan R, Zamboni C, Riccardi G, Rivellese AA; TOSCA.IT Study Group. Polyphenol intake and cardiovascular risk factors in a population with type 2 diabetes: The TOSCA.IT study. Clin Nutr. 2017 Dec;36(6):1686-1692. doi: 10.1016/j.clnu.2016.11.002. Epub 2016 Nov 14.
PMID: 27890487DERIVEDVitale M, Masulli M, Cocozza S, Anichini R, Babini AC, Boemi M, Bonora E, Buzzetti R, Carpinteri R, Caselli C, Ceccarelli E, Cignarelli M, Citro G, Clemente G, Consoli A, Corsi L, De Gregorio A, Di Bartolo P, Di Cianni G, Fontana L, Garofolo M, Giorda CB, Giordano C, Grioni S, Iovine C, Longhitano S, Mancastroppa G, Mazzucchelli C, Montani V, Mori M, Perriello G, Rinaldi ME, Ruffo MC, Salvi L, Sartore G, Scaranna C, Tonutti L, Zamboni C, Zogheri A, Krogh V, Cappellini F, Signorini S, Riccardi G, Vaccaro O; TOSCA.IT Study Group. Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):879-85. doi: 10.1016/j.numecd.2016.04.006. Epub 2016 Apr 16.
PMID: 27212622DERIVED
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Study Officials
- 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
Study Design
- Study Type
- interventional
- Phase
- phase 4
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 18, 2008
First Posted
June 19, 2008
Study Start
September 1, 2008
Primary Completion
December 1, 2018
Study Completion
December 1, 2018
Last Updated
August 27, 2015
Record last verified: 2015-08