Following review of interim data by the Data Safety Monitoring Board (DSMB) for two global phase III trials evaluating vorapaxar, an investigational anti-clotting medication, researchers at Brigham and Women’s Hospital and the Duke Clinical Research Institute (DCRI) reported that they are following the recommendations of the DSMB to discontinue the study drug in one study among a subset of patients and discontinue the study drug in the other trial in which the protocol target number of endpoint events had been reached.
Vorapaxar is a protease activated receptor-1 (PAR-1) inhibitor, which is a new class of antiplatelet medication that acts on a different pathway from standard therapy, which includes aspirin and a thienopyridine, such as clopidogrel. The trials were designed to evaluate vorapaxar for the treatment and prevention of cardiac events in patients with acute coronary syndromes (ACS) and those with prior heart attack, stroke or peripheral arterial disease.
Following the recommendation of a joint DSMB, the TRA 2ºP-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial will be continued among patients in the study who had experienced a previous heart attack or peripheral arterial disease and immediately discontinued for patients in the study who had a stroke. The trial is being led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham.
“We are pleased that we have gotten a green light from the DSMB to continue the trial in more than 20,000 of the patients enrolled,” said Eugene Braunwald, MD, chairman of the TIMI trial. “It is exciting to study a drug that may improve the care of patients who have had a heart attack or who have peripheral arterial disease. It does not appear to be appropriate in patients who have had a stroke.”
TRA 2ºP-TIMI 50 is a randomized, multi-national, double-blind, placebo-controlled study in approximately 26,500 patients with established atherosclerotic disease who received vorapaxar in addition to standard therapy. The trial has enrolled patients in more than 1,000 sites in approximately 30 countries. Participants are being followed for a minimum of one year.
The TRA 2ºP-TIMI 50 trial is being conducted in parallel with the DCRI’s TRA•CER (Thrombin Receptor Antagonist for Clinical Events Reduction in Acute Coronary Syndrome) trial, for which the DSMB recommended that the study drug be discontinued and also informed investigators that the protocol required number of events had been acquired.
TRA•CER is a multicenter, international, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of vorapaxar in addition to standard of care in subjects with ACS. TRA•CER operations are led by the DCRI in collaboration with a select group of global academic research organizations. The study includes 12,977 participants at more than 800 centers in more than 30 countries who were enrolled between December 2007 and November 2010.
The primary efficacy endpoint of the study was the first occurrence of any component of the composite of cardiovascular death, heart attack, stroke, recurrent ischemia with rehospitalization and urgent coronary revascularization. The secondary efficacy endpoint was the first occurrence of any one of the composite of cardiovascular death, heart attack and stroke.
“While this is an unexpected development, the requisite number of endpoints has been acquired, which provides us with enough information to definitively answer the questions posed by the TRA•CER trial,” said Robert A. Harrington, MD, director of the DCRI and TRA•CER study chairman. “We are focused on working with our colleagues to conduct a timely closeout of the trial and complete a full analysis of the findings.”
The TRA 2ºP-TIMI 50 and TRA•CER trials are funded by the Whitehouse Station, N.J.-based Merck, which is developing vorapaxar.