Press Release - Mar 28, 2008

New size of up to 18,000 subjects will ensure timely completion to evaluate the effect of ezetimibe on clinical events

Boston MA and Durham NC: The academic leadership of the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) announced today that the number of subjects enrolled into the trial now exceeds 11,000 and will be increased to up to 18,000 subjects. Trial chairman Dr. Eugene Braunwald of the Thrombolysis in Myocardial Infarction (TIMI) Study group at Brigham and Women’s Hospital and co-chairman Dr. Robert Califf of the Duke Clinical Research Institute (DCRI) noted that the sample size reassessment was based on ongoing evaluation of blinded, aggregate cardiovascular event rates in the trial, in conjunction with review of data on the relationship between the lowering of low-density lipoprotein cholesterol (LDL-C) and clinical benefit that has emerged since the original protocol was prepared. "This expansion will allow the trial to test definitively whether the additional lowering of LDL cholesterol with ezetimibe, when added to a statin, will translate into further clinical benefit", noted Dr. Braunwald.

The IMPROVE IT trial, sponsored by the Merck/Schering Plough joint venture, is a multicenter, international, randomized, controlled trial which compares the combination of ezetimibe/simvastatin versus simvastatin alone on cardiovascular outcomes in patients recovering from an acute coronary syndrome. The original protocol called for enrollment of 10,000 subjects and was designed to detect a reduction in the primary endpoint of cardiovascular death, non-fatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days following randomization) or stroke. A total of 2955 primary endpoints were initially projected to meet this goal.

The publication of the Cholesterol Treatment Trialists (CTT) meta-analysis (Baigent C, et al. Lancet 2005;366:1267-1278) and a meta-analysis of the four intensive vs. standard-dose statin trials (Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445) prompted further review of the statistical assumptions surrounding the relationship between LDL-C lowering and the expected reduction in clinical events. After this review, it was determined that a total of approximately 5,250 primary endpoint events would be required to have appropriate power to detect a significant reduction in risk. This led to a

protocol amendment in September, 2007 in which the targeted number of events was increased to 5,250 and the study sample size to 12,500 subjects. It was anticipated that the sample size would be updated as the trial progressed.

More recently, the availability of better estimates of aggregate, blinded event rates in IMPROVE-IT has led to the decision to increase the sample size further (up to 18,000 subjects) in order to ensure the accrual of the needed number of clinical events in the most timely manner. The protocol is being discussed with regulatory authorities and is being amended accordingly. At the present time, over 11,000 patients have been enrolled in the trial.

The first patient was enrolled into IMPROVE IT in October, 2005. At that time, with a projected enrollment of 10,000 subjects, with a minimum of 2 ½ year follow-up, the trial was projected to end in 2011. IMPROVE IT is an "event driven" trial, and therefore the end of the study is declared when the target number of events is reached and the last subject enrolled will have been followed for a minimum of 2 1/2 years. With the increase in enrollment, the current estimate for the completion of the trial is 2012. However, the actual date of completion is highly dependent on the observed event rates during the follow-up phase of the trial and the rate of enrollment. Therefore, it is not possible to determine with precision an exact date that the trial will end. It is planned to adjust both the trial timeline and the number of subjects needed to be enrolled based on review of the aggregate, blinded event rate at six month intervals.

All trial participants and leaders are blinded to which treatment the patients are receiving. An independent Data Monitoring Committee is evaluating the trial results periodically in an unblinded fashion and could recommend earlier cessation if a definitive excess of benefit or harm were found. At their last evaluation, held on February 18, 2008, the Data Monitoring Committee advised that it found no indication in the data of adverse safety signals that would warrant a change in the protocol, and recommended that the study be continued.

Dr. Califf noted, "We are pleased that this large randomized trial will have adequate sample size and statistical power to determine the clinical effects of the combination of ezetimibe and simvastatin vs. simvastatin alone. This will answer an important question that many patients and doctors are asking about the secondary prevention of coronary artery disease and to the balance between benefit and risk of reducing LDL-cholesterol to very low levels in high-risk patients."

For more information please contact BWH Media Relations at BWHMediaRelations@partners.org or (617) 534-1600.

Brigham and Women's Hospital is a 747-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery.  BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 860 physician-investigators and renowned biomedical scientists and faculty supported by more than $416 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative.