Phase III Study of Rivaroxaban Shows That Extending Anticoagulant Treatment by Six or 12 Months Significantly Reduced Risk of Second Symptomatic VTE
Late-Breaker Data Presented at Annual Meeting of the American Society of Hematology
NEW ORLEANS--(BUSINESS WIRE)--Dec 6, 2009 - Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD), announced today that results from the Phase III EINSTEIN-Extension (EXT) clinical trial of the novel oral anticoagulant rivaroxaban showed a significant reduction in the risk of recurrent symptomatic venous thromboembolism (VTE), compared to placebo, in patients who have been treated for a previous deep vein thrombosis (DVT) or pulmonary embolism (PE). The rate of major bleeding was low. The findings were reviewed at today's press briefing during the 51st Annual Meeting of the American Society of Hematology (ASH), and will be fully presented as part of the late-breaker session of the general meeting at 7:30 AM CST, Tuesday, December 8th.
To be eligible for enrollment in EINSTEIN-EXT, patients had to have previously completed six to 12 months of treatment with a vitamin K antagonist (VKA) for an acute episode of VTE or have participated in the ongoing Phase III EINSTEIN-DVT or EINSTEIN-PE trials, in which they were treated with either rivaroxaban or a VKA, for the same time duration. Upon enrolling in EINSTEIN-EXT, patients were randomized to receive either 20 mg of rivaroxaban dosed once-daily or placebo and were evaluated for an additional six or 12 months.
Rivaroxaban was well tolerated. Patients treated with rivaroxaban showed a highly statistically significant relative risk reduction (RRR) of 82% in the recurrence of a symptomatic VTE1 versus those treated with placebo [1.3% vs. 7.1%, (p<0.0001), respectively].
“The results from EINSTEIN-EXT highlight the potential clinical benefit of extending prophylaxis for an additional six or 12 months beyond the currently recommended treatment duration,” said Harry R. Büller, M.D., Academic Medical Center in Amsterdam. “This study could help transform the way physicians treat patients who have previously suffered a DVT or PE. Currently, up to 10% of patients who are treated adequately, according to today's recommended guidelines, still experience a recurrence within 12 months of the initial event.”
Rates of major bleeding,3 the primary safety endpoint, were low and not statistically significantly different between the two groups [0.7% vs. 0.0%, (p=0.11) for the rivaroxaban and placebo arms, respectively].
A secondary endpoint measuring the composite of major and clinically relevant non-major bleeding4 showed a statistically significant difference between the two groups [6.0% vs. 1.2%, (p<0.001) in the rivaroxaban and placebo arms, respectively]. No cases of serious liver injury were reported in either group. Liver safety results included: ALT >3x ULN + T Bili >2x ULN: 0.0%5 in both groups; ALT >3x ULN: 1.9% in the rivaroxaban arm and 0.5% of patients in the placebo arm. There were no differences in cardiovascular-related events between the two treatment groups.
The abstract (LBA-2) is available at: http://ash.confex.com/ash/2009/webprogram/Paper25669.html
About EINSTEIN Clinical Trials
Approximately two million cases of DVT and nearly 600,000 cases of PE are reported each year in the United States.6 EINSTEIN is a global program of three clinical trials in approximately 8,000 patients with acute, symptomatic deep vein thrombosis (EINSTEIN-DVT, enrollment complete) or pulmonary embolism (EINSTEIN-PE, enrollment ongoing). In these two programs, patients received oral rivaroxaban 15 mg twice-daily for three weeks, followed by oral rivaroxaban 20 mg once-daily, compared with initial enoxaparin treatment followed by a VKA.
The EINSTEIN-EXT study compared the safety and efficacy of rivaroxaban to placebo in the secondary prevention of recurrent symptomatic venous blood clots by prolonging preventive treatment by six or 12 months beyond a previously completed regimen of six or 12 months of therapy. The study enrolled approximately 1,200 patients from 28 countries around the world with symptomatic DVT or PE, which is collectively referred to as VTE.
Update on Complete Response for VTE Prevention Post Total Knee and Hip Replacement Surgery
Following discussions with the U.S. Food and Drug Administration, J&JPRD is continuing to work with its partner, Bayer HealthCare, to provide additional information from the RECORD study sites, and data from ongoing studies, to adequately address issues raised in the Complete Response letter received in May 2009. Based on those discussions, J&JPRD has decided it will not submit its complete response to the FDA seeking approval of rivaroxaban for the prevention of DVT and PE in patients undergoing hip or knee replacement surgery by the end of 2009.
Postponing the complete response until these requirements are fully addressed provides the greatest opportunity for successfully bringing rivaroxaban through the regulatory process. An updated filing strategy will be communicated following completion of these ongoing discussions.
Rivaroxaban is a novel oral anticoagulant being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. In clinical studies, the compound has shown a rapid onset of action with a predictable dose response and high bioavailability, no requirement for routine anticoagulation monitoring, and limited risk for food and drug interactions. The extensive program of clinical trials evaluating rivaroxaban makes rivaroxaban the most studied oral, direct Factor Xa inhibitor in the world today. More than 65,000 patients are expected to enroll in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., which is part of the Johnson & Johnson family of companies, and Bayer HealthCare AG.
(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from J&JPRD and/or Johnson & Johnson's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 28, 2008. Copies of this Form 10-K, as well as subsequent filings, are available online at http://www.sec.gov, http://www.jnj.com or on request from Johnson & Johnson. Neither Johnson & Johnson nor J&JPRD, undertake to update any forward-looking statements as a result of new information or future events or developments.)
1. Secondary prevention of recurrent symptomatic VTE is defined as a composite of recurrent DVT, non-fatal PE, fatal PE, and unexplained death for which PE cannot be ruled out.
2. Semin Nucl Med. 2001 Apr;31 (2):90-101.
3. Major bleeding was defined as overt bleeding associated with a fall in hemoglobin of 2 g/dL or more, or leading to a transfusion of 2 or more units of packed red blood cell or whole blood, or bleeding that occurs in a critical site or contributes to death.
4. Clinically relevant but non-major bleeding was defined as bleeding not meeting the criteria for major bleeding but is associated with medical intervention.
5. ALT >3x ULN + T Bili >2x ULN = Levels of alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN) plus Total Bilirubin greater than two times the ULN
6. Gerotziafas GT. CurrOpin PulmMed.2004; 10:356-365.
Ernie Knewitz, 908-927-2953
Todd Ringler, 917-251-8613
Johnson & Johnson
Louise Mehrotra, 732-524-6491
Lesley Fishman, 732-524-3922
Posted: December 2009