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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2012

Cardiovascular (CV) disease is the most common cause of morbidity and mortality among diabetic patients.The UK Prospective Diabetes Study (UKPDS) clearly showed that tight glycemic control significantly decreases diabetes-related events. Therefore, achievement of HbA1c > 7% is a major goal in the treatment of type 2 diabetes since this parameter still represents the best predictor of micro and macrovascular complications. However, it is often difficult to maintain this goal because of the progressive deterioration of pancreatic beta-cell function and insulin sensitivity. The progressive nature of type 2 diabetes generally requires a stepwise therapeutic approach starting with lifestyle intervention (diet and increased physical activity). After lifestyle changes have failed, drug therapy is initiated and progressively intensified through the combination of different classes of hypoglycemic agents. Since insulin resistance is recognized as a major factor in the pathogenesis of type 2 diabetes and associated CV risk factors, drugs that improve insulin sensitivity are advised as initial pharmacological therapy. Currently, metformin is recommended as the first-line drug for patients with type 2 diabetes. Great uncertainty exists regarding the best therapeutic option in diabetic patients inadequately controlled with metformin, due to the lack of randomized controlled trials that have directly compared the efficacy of different combination regimens in achieving glycemic goals. The paucity of sound clinical evidence in this area is highlighted in a Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes, that suggested either a sulphonylurea (SU) or a thiazolidinediones (TZD) as additional medication to metformin, in the absence of data demonstrating the superiority of one combination over the other. Addition of a SU or a TZD to concomitant metformin results in a substantial improvement in glucose control with a mean reduction in HbA1c of 1-1.5%. However, a direct evaluation of these treatment strategies, within a large clinical trial, would be most appropriate, given their different mechanisms of action, side effects and costs. Indeed, the only direct comparison between a SU and a TZD added to metformin has been obtained in a short-term study (24 weeks), which showed a greater reduction in HbA1c with the association metformin-glibenclamide (- 1.5%) compared with the association metformin-rosiglitazone (-1.1%, <0.001). More patients receiving metformin-glibenclamide reached HbA1c <7.0 % than did those receiving metformin-rosiglitazone (60% vs. 47%). In addition, a more favourable lipid profile was present in patients treated with metformin-glibenclamide, although this finding has not been confirmed in other studies. However, the short duration of the study precluded evaluation of CV endpoints.

This lack of information prevents an evidence-based choice between these two treatment options.

In this respect, several studies are underway to investigate the potential of different glucose-lowering therapies on CV outcomes. With regard to SU, retrospective cohort studies have documented a higher risk of adverse outcomes in patients treated with a SU in monotherapy or in combination with metformin as compared to metformin alone. In the UKPDS, diabetic patients treated with a combination of glibenclamide plus metformin showed an increase in CV mortality compared with other groups of treatment. However, these data derive from a post-hoc analysis and, therefore, should be interpreted with caution. In contrast, the ADOPT study has shown a lower proportion of CV events in the glibenclamide group compared with rosiglitazone and metformin. These conflicting reports underline the need to evaluate the rate of CV events induced by the combination metformin-SU in comparison with other treatment strategies. Regarding TZDs, a recent prospective study (PROACTIVE Study) has compared the efficacy of adding pioglitazone (from 15 to 45 mg/die) or placebo to the standard hypoglycaemic therapy in the secondary prevention of CV events in type 2 diabetic patients. Pioglitazone treatment did not significantly affect the primary endpoint, which included all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries and leg amputation, but significantly reduced the number of patients who experienced the secondary endpoint (all-cause mortality, nonfatal MI and stroke). However, patients treated with pioglitazone had 115 more episodes of heart failure than the placebo group. In addition, weight gain was 4 kg greater with pioglitazone than with placebo, and much greater than that expected on the basis of the improved glycemic control. These conflicting reports support the need for large-scale clinical trials that compare the efficacy of the association of metformin plus a SU vs.

metformin plus a TZD on CV outcomes. For these reasons, the Italian Diabetes Society has organized a randomized controlled clinical trial on long term cardiovascular effects of these two therapeutic strategies. At the moment, the two TZDs available are Rosiglitazone and Pioglitazone. In this study only Pioglitazone will be used because of its more favourable effects on cardiovascular risk factors than Rosiglitazone, as shown in recent meta-analyses.

The aim of this study is to ascertain whether in patients with type 2 diabetes poorly controlled with metformin in monotherapy, the addition of pioglitazone reduces the rate of cardiovascular events as compared with the addition of a SU. Glucose control, major CV risk factors, safety, tolerability and economic costs with the two therapeutic regimens will also be compared.

Design: multicentre, randomised, open-label, comparative, parallel-group trial of 48 months duration (PROBE: Prospective Randomized Open Blinded End-Point) Screening and follow-up will take place at more than 20 Clinical Units which will coordinate a network of Diabetes Outpatients Clinics within the same geographical area (region/province) that will screen eligible patients and refer them to the Clinical Unit.

Each week 4-8 patients will be enrolled by each Unit in order to complete the recruitment phase in approximately one year time. Screening and follow-up visits will be performed by trained study personnel according to a standard protocol.

All eligible patients will enter a 8-week run-in period. During this time only metformin (2 gr/die) will be prescribed; patients who do not tolerate metformin will be excluded from study. All participants will receive reinforcement of lifestyle education. Glucose meters will be provided and patients will be instructed to perform home glucose monitoring and to document hypoglycaemic events. At the end of the run-in period, eligibility will be reassessed and participants will be randomised to one of two arms: - Metformin (2 gr/die) + sulphonylurea (glibenclamide, gliclazide or glimepiride, according to local practice) - Metformin (2 gr/die) + pioglitazone Patients will be seen for clinical follow up after 1, 3 and 6 months from the run-in and then every 6 months unless clinical conditions requiring more frequent medical consultations develop (according to GCP). Telephonic contacts will be established with all patients in order to take information on adverse events,on glycaemic control and to modify drugs dosage.

The metformin dose will remain constant throughout the study; the initial dose of added drug will be 5 mg glibenclamide or 30 mg gliclazide or 2 mg glimepiride for the group randomized to metformin plus SU and 15 mg pioglitazone in the group randomized to metformin plus pioglitazone. If glucose control is unsatisfactory (fasting glucose >120mg/dl or post prandial glucose >160 mg/dl in more than 50% of home readings over a 8 weeks period), study medications will be uptitrated to the maximal effective daily dose ( i.e. 15 mg glibenclamide or glipizide, 120 mg gliclazide, 6 mg glimepiride, 45 mg pioglitazone). If a HbA1c >8.0% is observed at any follow up visit, patients will receive reinforcement of lifestyle education, compliance to study protocol will be assessed and a glycated haemoglobin measurement will be repeated after three months. A confirmed value >8.0% despite adherence to maximal doses of study medications for the previous three months, will lead to addiction of a single injection of insulin Glargine bed-time. Insulin titration will be performed on the basis of fasting capillary glycaemia according to a pre-defined algorithm. If a HbA1c >8.0% is observed at two consecutive follow-up visits 3 months apart, one or more injections of analog insulin will be added. Insulin will be titrated down, according to a pre-specified algorithm, if frequent hypoglycaemic episodes occur.

Use of concomitant medications (antihypertensive, lipid-lowering and antiplatelet agents) will be permitted throughout the study, according to Good Clinical Practice Guidelines.

Patients will stop the study medications and go out the study (but continuing the follow-up) if any of the following conditions develops: - ALT increases 2.5 or more times above baseline on two consecutive occasions (one month apart) - signs and symptoms suggestive of heart failure - medical conditions requiring stable insulin treatment.

The sample size calculation is based on an estimated rate of the primary end point of 3.5% per annum. The sample size is thus estimated to detect with a statistical power of 80% a reduction in the risk of events of 20% (HR=0.80; metformin + Pioglitazone vs metformin + SU).

Given these assumptions, a total of 652 events are needed for the primary efficacy analysis.

Therefore, the total number of subjects to be enrolled is of 4.396 patients, to be followed up for at least 4 years (the study ends when the prefixed number of events has been reached).

Assuming a trial discontinuation rate of 15%, a total of 5.172 patients will be enrolled (2.586 in each treatment arm). Primary efficacy analysis will be event driven.

A Clinical Endpoints Committee (CEC) composed of Cardiologists and Specialists in Internal Medicine with vascular expertise will review and adjudicate all potential end points, according to pre-specified criteria. This committee will be blind to the study medication assignment group and independent of the Steering Committee. Side effects (i.e. weight gain, peripheral oedema, hypoglycaemic episodes, etc.) will be monitored. All adverse events, whether or not attributed to study drugs, will be collected and recorded on the appropriate, ad hoc page(s) of the Case Report Form (CRF). The Data Safety Monitoring Board, composed of clinical trials expertises, will monitor events and side effects and will decide the study discontinuation in the case of a significant difference between the two arms in the rate of the primary endpoint or serious adverse events.

At baseline and at each follow-up visit (ever six months) the following parameters will be assessed: - vital signs, anthropometry, check for any new signs/symptoms - home glucose readings - frequency of hypoglycaemic episodes graded by severity. - intercurrent illnesses/events, change(s) in use or dose of drugs - history of hospitalization for myocardial infarction, stroke, major leg amputation (above ankle), acute coronary syndrome, heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries) - angina or intermittent claudication At baseline and every months safety parameters (ALT, AST) and HbA1c will be evaluated.

At baseline and every 12 months serum lipids (total cholesterol, HDL cholesterol and triglycerides), microalbuminuria and C Reactive Protein (CRP) will be evaluated.

At baseline and every 12 months a standard resting ECG (Minnesota coding) will be performed.

All study investigations will be performed according to a standard protocol described in detail in the operating manual which will be produced by the Coordinating Center in collaboration with the Steering Committee. Prior to study start-up, the investigators will attend training and standardization sessions to reduce inter-observer variability; these sessions will be organized and supervised by the Coordinating Centre. Ad hoc CRFs will be developed to collect information which will be transmitted to the Epidemiology Unit.

The CRFs will be reviewed and data queries will be produced to correct missing or incorrect data on the CRFs. Periodically a Quality Team (appointed by the Steering Committee) will check the amount of CRFs per centre and produce recalls for centres not sending CRFs. An electronic data base will be created using a standardized procedure of data input.

The study conduct (i.e. timing, adherence to protocol etc..) at each participating centre will be monitored by regular visits of professional monitors (at the start-up, at the end of the study and twice a year). A Steering Committee will meet to review the study progress every 6 months, and an independent Data and Safety Monitoring Committee (DSMC) will monitor safety outcomes throughout the course of the study. This Committee will assess at given intervals the safety data, the critical efficacy endpoints and will recommend whether to continue, modify, or stop the trial. Stringent statistical criteria will be set for early study termination in the event of a clear-cut difference between the treatment groups with respect to all-cause mortality. The DSMC should also recommend termination of the study for other serious safety reasons. The DSMC will meet independently of the Steering Committee.

The study will be conducted according to Good Clinical Practice (GCP)Guidelines. The protocol must be approved by Ethics Committees or Institutional Review Boards of each centre. Written informed consent will be obtained from all participants before beginning the study.

Intervention(s) in this Clinical Trial

• Drug: add-on pioglitazone
  • participants randomised to this arm will add pioglitazone 15 mg/die to therapy with metformin (2 gr/die)
• 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)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • metformin 2000 mg + pioglitazone 15-45 mg
• 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

Primary 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
    Safety Issue?: No

Secondary 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
    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
    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
    Safety Issue?: No
• major cardiovascular risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference)
  • Time Frame: 48 months
    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
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 50 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Italian Society of Diabetology

Overall Clinical Trial Officials and Contacts

Gabriele Riccardi, Professor Study Chair Italian Society of Diabetologia  

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

Information obtained from ClinicalTrials.gov on August 21, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00700856

Study ID Number: FARM6T9CET

ClinicalTrials.gov Identifier: NCT00700856

Health Authority: Italy: The Italian Medicines Agency