Clinical Trials

Date: 2011-07-25

Type of information: Results

phase: 3

Announcement: results

Company: Bayer HealthCare (Germany)

Product: Xarelto® (rivaroxaban)

Action mechanism: anticoagulant agent/oral direct Factor Xa inhibitor

Disease: non-valvular atrial fibrillation

Therapeutic area: Cardiovascular diseases

Country: Japan

Trial details:

• J-ROCKET AF (Japanese Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) is part of the large global clinical development program for Xarelto®, which includes the global ROCKET AF Phase III trial involving 14,264 patients randomized, the results of which were reported at AHA (Chicago, 2010). J-ROCKET AF was a smaller study (1,280 patients randomized) that was performed to evaluate the safety of Xarelto® versus warfarin in patients with non-valvular atrial fibrillation living in Japan.
• J-ROCKET AF was a prospective, randomized, double-blind Phase III study in which Japanese patients were enrolled from over 160 centres across Japan. Mean on-treatment exposure to study drugs was 499 days and 481 days for Xarelto® and warfarin, respectively. The study was led by Masatsugu Hori, M.D., President of Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan, and an academic Steering Committee of leading Japanese experts. The primary objective of the study was to evaluate the safety of Xarelto®, one tablet, once-daily versus dose-adjusted warfarin in patients with non-valvular atrial fibrillation in Japan. Non-inferiority was shown with respect to on-treatment bleeding, assessed as the composite of major and non-major clinically relevant bleeding events - the primary safety outcome. The primary efficacy endpoint was the composite of all-cause stroke and non-CNS systemic embolism.
• Patients were randomized to 15 mg Xarelto® once daily (10 mg in patients with moderate renal impairment at screening) or to warfarin with a target INR of 2.0-3.0 for patients aged <70, or 1.6-2.6 for those aged ?70. The doses of Xarelto® and warfarin were selected to reflect the prevailing Anticoagulant Guidelines in Japan - reflecting the specific characteristics of the patient population in Japan and local medical practices - and hence were lower than those evaluated in the global ROCKET AF trial (20 mg Xarelto® once daily, or 15 mg Xarelto® once daily for patients with moderate renal impairment).

Latest news:

• Conducted in Japan, the Phase III J-ROCKET AF study of Bayer’s once-daily Xarelto® (rivaroxaban) in Japanese patients with non-valvular atrial fibrillation at risk of stroke met its primary endpoint, demonstrating non-inferiority versus warfarin for the principal safety outcome - the composite of major and non-major clinically relevant bleeding. In addition, J-ROCKET AF showed a 51% reduction of stroke and non-CNS systemic embolism in the Xarelto group compared with patients receiving warfarin. This was not statistically significant, as the trial was not powered for efficacy.
• Event rates for the principal safety endpoint, the composite of major and non-major clinically relevant bleeding, were similar between the treatment groups: 18.0% and 16.4% per year for Xarelto and warfarin, respectively (hazard ratio [HR]=1.11; 95% Confidence Interval [CI] 0.87-1.42). Event rates for major bleeding were 3.0% and 3.6% per year (HR=0.85; 95% CI 0.50-1.43) and for non-major clinically relevant bleeding were 15.4% and 13.0% per year for Xarelto and warfarin, respectively (HR=1.20; 95% CI 0.92-1.56). Importantly, there was a trend toward lower rates of intracranial hemorrhages and bleeding-related death with Xarelto. These data are consistent with the results of the global ROCKET AF trial, which were reported at the Scientific Sessions of the American Heart Association (AHA) 2010 and showed similar rates of major and non-major clinically relevant bleeding in a diverse population of patients treated with once-daily Xarelto compared with dose-adjusted warfarin.
• The relative reduction in the risk of stroke and non-CNS systemic embolism observed with Xarelto® was 51% compared with warfarin (1.3% and 2.6% per year, respectively, HR=0.49; 95% CI 0.24-1.00). As the trial was powered for safety, not efficacy, this result did not reach statistical significance. This result is supported by the statistically significant reduction in stroke and non-CNS systemic embolism seen in the global ROCKET AF study in patients receiving active treatment with Xarelto®, as well as the non-inferior efficacy demonstrated in the ITT population.
• On April 14, 2011, Bayer communicated that Xarelto® had been submitted for marketing approval in the prevention of stroke in patients with atrial fibrillation to the Japanese Ministry of Health, Labor and Welfare (MHLW).

Is general: Yes