A clinical trial to study reduction of cardiovascular mortality and morbidity in Type 2 diabetes mellitus patients with a recent Acutecoronarysyndrome event
Scientific Title of Study
Cardiovascular outcomes study to evaluate the potential of aleglitazar to reduce cardiovascular risk in patients with a recent acute coronary syndrome (ACS) event and type 2 diabetes mellitus (T2D)
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
BC22140ROW
Protocol Number
NCT01042769
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr.Bipin Kumar Sethi
Designation
Affiliation
Address
Care Hospitals Road No:1, Banjara Hills Hyderabad ANDHRA PRADESH 500034 India
Phone
+914030418123
Fax
+914066258792
Email
bipinkumarsethi@yahoo.co.uk
Details of Contact Person Scientific Query
Name
Dr.Bipin Kumar Sethi
Designation
Affiliation
Care hospitals
Address
Care Hospitals Road No:1, Banjara Hills Hyderabad ANDHRA PRADESH 500034 India
Phone
+914030418123
Fax
+914066258792
Email
bipinkumarsethi@yahoo.co.uk
Details of Contact Person Public Query
Name
Dr. Vinodvenkatesh Patil
Designation
Affiliation
Address
George Institute for international Health-India 839C, Road No:44A, Jubilee Hills Hyderabad ANDHRA PRADESH 500033 India
Phone
+914023558091
Fax
+914023541980
Email
vpatil@george.org.in
Source of Monetary or Material Support
F.Hoffmann-La Roche Ltd
Primary Sponsor
Name
The George Institute for international Health-India
839C, Road No:44A, Jubilee Hills,
Hyderabad-500033
Andhra Pradesh- India
St.Johns medical college Institutional Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Type 2 Diabetes Mellitus and a Recent Acute Caronary Syndrome event,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Aleglitazar
150µg once daily
Comparator Agent
NIL
NIL
Inclusion Criteria
Age From
Age To
Gender
Details
1.Males or females aged > 18 years
2. Known Type 2 Diabetes or newly diagnosed Type2Diabetes (confirmed prior to randomization according to the American Diabetes Association diagnostic criteria
3. Hospitalization for an ACS event and randomization within 2 to 6 weeks after the ACS index event (day of hospitalization). In case of any subsequent ACS event, procedure related MI or coronary bypass surgery occurring during the run-in period, randomization should occur between 2 and 6 weeks from this event. In these patients, the allowed maximum duration from index event to randomization is 12 weeks.
4. Ability and willingness to give written informed consent and to comply with the requirements of the study
ExclusionCriteria
Details
1.Concomitant treatment with a thiazolidinedione and/or fibrate
2. Prior intolerance to a thiazolidinedione and/or fibrate
3. Triglycerides (fasting) > 400 mg/dL (> 4.5 mmol/L)
4. Patients with clinically apparent liver disease, eg, jaundice, choleastasis, hepatic impairment, active hepatitis or asymptomatic ALT > 3x ULN
5.Anemia defined as hemoglobin< 10 g/dL (< 100 g/L, 6.21 mmol/L) or hematocrit<30 %
6. eGFRMDRD < 45 ml/min/1.73m2
7. Symptomatic congestive heart failure classified as NYHA class II-IV
8. Hospitalization in the 12-month period preceding the index event for a primary diagnosis of heart failure
9. Peripheral edema which in the judgment of the investigator is believed to be clinically severe
10. Systemic corticosteroid therapy for > 2 weeks, within 3 months prior to screening examination
11. Any serious medical condition that according to the investigator could interfere with the conduct of the study
12. Serious comorbid disease in which the life expectancy of the patient is shorter than the duration of the trial (e.g.acute systemic infection, cancer or other serious illnesses).Treated basal-cell carcinoma occurring > 2 years beforerandomization is not excluded
13. Unwillingness or inability to comply with study requirements (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)
14. Positive pregnancy test, breast feeding women or women of childbearing potential not using highly effective methods of contraception
15. Participation in any clinical trial with an investigational drug or device within one month prior to the screening
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
The primary endpoint of this study is the time to first occurrence of any component of the composite endpoint as adjudicated by the clinical events Committee. Components of the primary endpoint are cardiovasculardeath, nin-fatal myocardial infarction and non-fatal stroke.
The study is an event-driven trial and will last until 950
adjudicated events occur but at least until all patients are
treated for 2.5 years.
Secondary Outcome
Outcome
TimePoints
A composite with the following components: cardiovascular mortality, non-fatal MI, hospitalization for biomarker-negative ACS and non-fatal stroke
A composite with the following components: all-cause mortality, non-fatal MI and non-fatal stroke
Individual components of the composite endpoints
Unanticipated, ie, excluding planned before randomization, coronary revascularization
The study is an event-driven trial and will last until 950
adjudicated events occur but at least until all patients are
treated for 2.5 years.
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
The proposed phase 3 cardiovascular outcomes trial, described in this protocol, will be in patients with T2D following a recent acute coronary syndrome.
The available data for aleglitazar, showing clinically meaningful effects on dyslipidemia, glycemic control, peripheral insulin sensitivity as well as on cardiovascular and inflammatory markers (hsCRP, PAI-1, fibrinogen), and moderately favorable effects on blood pressure, does support the potential benefit for aleglitazar for reducing the risk of cardiovascular morbidity and mortality. In the phase 2 dose-ranging study BM17864, 150 μg aleglitazar showed notably greater beneficial effects on the lipid profile than 45 mg pioglitazone, and comparable effects on glycemic control. The changes in hsCRP and PAI-1 for the 150 μg dose of aleglitazar were in the range of those seen with 45 mg pioglitazone, and the decrease in fibrinogen was greater than observed with pioglitazone.
Taken together, these data indicate greater beneficial effects on key markers of cardiovascular risk than the comparator pioglitazone at its top dose suggesting the potential for greater benefit on cardiovascular outcomes.
Notably, the main lipid benefit of aleglitazar treatment appears to be the marked increase in HDL-C and the marked decrease of TGs. Numerous prospective epidemiological studies have shown a strong inverse relationship between HDL-C levels and the major protein apolipoprotein A-I (apoA-I) and CHD suggesting that a 2-3% reduction in CHD risk could be achieved for each 1 mg/dL rise in HDL-C. The current National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recognize low HDL-C (< 40 mg/dL/ or < 1 mmol/L) as an independent major risk factor for CHD, a component of metabolic syndrome, and a potential target for therapeutic intervention.
Lipid-modifying drugs which are most widely used, such as statins and fibrates, generally increase HDL-C levels by up to 5-15% (statins) and 10-15% (fibrates). Niacin has been shown to increase HDL-C (15-35%) but its use is limited by poor tolerability, and in addition it should be used with caution in patients with T2D because it may increase glucose intolerance. The value of raising HDL-C levels in combination with LDL-C lowering was demonstrated by the HDL-Atherosclerosis Treatment Study (HATS). In this trial, combined treatment of simvastatin with niacin in patients with clinical coronary artery disease and low HDL over a 3-year period was associated with decreased progression of atherosclerosis and a 90% reduction in major cardiovascular events .
Elevated levels of TGs have also been reported to be associated with an increased risk of recurrent cardiovascular events in patients following an ACS event. PPARα activation decreases TGs levels and shifts the size of LDL-C particles from small, dense particles to larger particles. Thus, the beneficial effects of aleglitazar seen in the phase 2 studies in lowering TGs would be anticipated to further reduce the high residual cardiovascular risk in patients with an ACS event on top of therapy with statins.
Importantly, the available data for pioglitazone also suggest beneficial effects of PPARγ agonism on cardiovascular outcomes. The PRO active study compared pioglitazone to placebo on top of standard of care in CHD patients with T2D. While statistical significance was not achieved in the study for the primary composite endpoint of all cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or revascularization of the leg, pioglitazone was shown to reduce the risk of the main secondary composite endpoint of all cause mortality, myocardial infarction, or stroke. The relative risk reduction in PRO active was 16% for the composite endpoint of all-cause death, non-fatal MI excluding silent MI and non-fatal stroke, and 18% for the composite endpoint of cardiovascular mortality, non-fatal MI excluding silent MI and stroke. In addition to PRO active, several other lines of evidence suggest a beneficial effect on cardiovascular outcomes for pioglitazone, including a post-hoc meta-analysis of randomized controlled trials with pioglitazone, and carotid intima-media thickness (cIMT) and intravascular ultra sonography (IVUS) imaging studies. In the post-hoc meta-analysis, there was an 18% relative risk reduction in the composite endpoint of all-cause death, non-fatal MI and stroke, consistent with the above reported results for PRO active. The observed reduction of cardiovascular risk in the PRO active outcome study and the meta analysis of randomized clinical trials with pioglitazone are also in line with the significantly lower rate of progression of atherosclerosis in two imaging studies with pioglitazone, the PERISCOPE randomized controlled trial (by IVUS) and the CHICAGO randomized controlled trial(by high resolution B-mode carotid artery ultra sonography) In summary, in view of the available data for aleglitazar showing beneficial effects on multiple cardiovascular risk factors, and the available cardiovascular outcomes data for pioglitazone, aleglitazar is viewed to have strong potential to provide benefit in improving cardiovascular morbidity and mortality over current standard of care in patients with T2D following a recent ACS. Thus, aleglitazar potentially meets an important unmet medical need in these patients, who are at particularly high risk for there current cardiovascular events despite the currently available treatments.