XARELTO® (rivaroxaban) Helps Protect Pediatric Patients from Blood Clots in Late-Breaking Phase 3 EINSTEIN-Jr Study

RARITAN, N.J., July 8, 2019 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today new results from the Phase 3 EINSTEIN-Jr study, showing pediatric patients (aged birth to 17 years) treated with XARELTO^® (rivaroxaban) had a similar low risk of recurrent venous thromboembolism (VTE) – or blood clots – and similar rates of bleeding when compared to current standard anticoagulation therapy. These results from the largest pediatric study ever conducted for the treatment of VTE also show that the efficacy and safety profile of XARELTO^® in a pediatric population with VTE is comparable to what has been observed in previous studies of adults with VTE. The full findings were presented during a late-breaking session at the 27th Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Melbourne, Australia.

While VTE more commonly occurs in adults, it affects approximately 58 per 10,000 hospitalized children in the United Statesⁱ. There are very limited treatment options for these young patients, and no direct oral anticoagulant is currently approved for use in this setting. Current treatment is mainly based on observational data in this group and extrapolation of data obtained in adults, even though the pathophysiology and anatomic distribution (where it occurs in the body) of VTE, along with anticoagulant responses, differ between children and adults. Until EINSTEIN-Jr, only one small randomized trial had been published evaluating the use of standard anticoagulants in pediatric patients with VTE.ⁱⁱCurrent guidelines recommend that young patients with VTE be treated with standard anticoagulation therapy. For these patients, physicians manipulate adult dosage forms of these older anticoagulants, many of which require injections and regular laboratory monitoring.

"This trial examined for the first time whether a direct oral anticoagulant could alleviate the burden of blood clots in young patients, which would allow them to focus on recovering from their other health challenges," said Christoph Male, M.D., Department of Pediatrics, Medical University of Vienna, Vienna, Austria.¹ "The EINSTEIN-Jr study with rivaroxaban represents a significant advance for pediatric VTE treatment."

The main efficacy outcome of EINSTEIN-Jr was symptomatic recurrent VTE (fatal or non-fatal), and the principal safety outcome was the composite of major and clinically relevant non-major bleeding. The study met all of its prespecified endpoints.

The following observations were made:

• Recurrent VTE was similar in both treatment groups, with a numerically lower number of events in patients treated with XARELTO^®. Specifically, 1.2 percent of the XARELTO^® group and 3.0 percent of the standard anticoagulation group experienced a recurrent event (HR: 0.40; 95% CI, 0.11 to 1.41); there were no fatal VTE events in either treatment arm.
• Clinically relevant bleeding was also similar, occurring in 3.0 percent of the XARELTO^® group and 1.9 percent of the standard anticoagulation group (HR: 1.58; 95% CI, 0.51 to 6.27). There were no major bleeding events in the XARELTO^® group, and two major bleeding events in the standard anticoagulant group.
• In addition, the composite of recurrent VTE and major bleeding (net clinical benefit²) occurred in 1.2 percent of the XARELTO^® group and 4.2 percent of the standard anticoagulation group (HR: 0.30; 95% CI, 0.08 to 0.93).

The efficacy of XARELTO^® was further demonstrated by reduction in clot burden on imaging tests that were conducted on patients both at baseline and at the end of the treatment period. Complete resolution of the initial VTE mass occurred in 38.5 percent of the XARELTO^® group compared to 26.1 percent of the standard anticoagulation group (Overall Response: 1.72; 95% CI, 1.12 to 2.69).

"VTE affects people of all ages, which is why we are committed to advancing new research and uncovering ways for XARELTO^® to help people in need," said James List, M.D., Ph.D., Global Therapeutic Area Head, Cardiovascular & Metabolism, Janssen Research & Development, LLC. "The EINSTEIN-Jr. results offer important insights on the efficacy and safety of XARELTO^® in managing blood clots in our youngest patients."

Study Background
Sponsored by Janssen and Bayer, EINSTEIN-Jr is the largest pediatric study conducted for the treatment of VTE, and the first to examine the use of a direct oral anticoagulant in this population. A Phase 3 randomized, open-label study, EINSTEIN-Jr evaluated the efficacy and safety of XARELTO^® compared to standard anticoagulation therapy in 500 children aged birth to 17 years with previously diagnosed acute VTE who had started heparin therapy. Children were enrolled from 107 sites in 28 countries. 

Participants were enrolled from November 2014 to September 2018 and were assigned in a 2:1 ratio to receive either an open-label, bodyweight-adjusted dose of XARELTO^® (n=335) or standard anticoagulation therapy (n=165). Various tablet strengths and weight-based oral liquid suspension doses of XARELTO^® were tested. Standard anticoagulants were given at therapeutic doses, according to international guidelines, and included unfractionated heparin, low-molecular-weight heparin (LMWH) or fondaparinux; following completion of five to nine days of standard anticoagulation, participants continued with heparin treatment or were switched to a vitamin K antagonist (VKA) at the discretion of the treating physician.

Approximately 90 percent of enrolled patients had conditions in which VTE is a known risk factor. Major surgery/trauma, major infectious diseases, major organ diseases and active cancer were among the most common conditions. For the index event, VTE was symptomatic in approximately 80 percent of participants and asymptomatic in approximately 20 percent. Of those enrolled, 23.4 percent had cerebral vein or sinus VTE, 25.4 percent had catheter-related VTE and 51.2 percent had other non-catheter-related VTE as their index event.

Participants were ineligible if they had active bleeding or were at high risk of bleeding contraindicating anticoagulant therapy, had a low platelet count, hepatic disease associated with a coagulopathy (bleeding disorder), severe renal impairment, or a life expectancy of less than three months. The main treatment period was three months (or one month in children younger than two years with catheter-related VTE).

Prior to EINSTEIN-Jr, Phase 1 and 2 studies were conducted to establish bodyweight-adjusted dose regimens of XARELTO^® for children aged birth to 17 years that matched the exposure range in adults younger than 45 years treated with XARELTO^® 20-mg once daily. In addition to a tablet form of XARELTO^®, an oral suspension formulation of XARELTO^® was developed, with similar pharmacokinetic properties as the tablet formulation, which enabled precise dosing and easier administration especially in young children.

More on the Pediatric Program with XARELTO^®  
The Phase 3 EINSTEIN-Jr study is one of five from the pediatric research program for XARELTO^® examining the use of the medicine in the management of VTE in children. A second key study, UNIVERSE, is evaluating XARELTO^® for the prevention of VTE in children aged two to eight after the Fontan procedure, the most common procedure performed for congenital heart disease after the age of two years. XARELTO^® is not currently approved by the U.S. Food and Drug Administration (FDA) for use in pediatric patients.

In adults, XARELTO^® already has five approved VTE indications, the most of any direct oral anticoagulant, including the treatment of deep vein thrombosis (DVT), treatment of pulmonary embolism (PE), reduction of the risk of recurrent DVT and PE, and primary prevention of DVT which may lead to PE in people who have just had hip or knee replacement surgery. In October 2017, the FDA approved a new dose regimen of 10-mg XARELTO^® once-daily for reducing the continued risk for recurrent VTE after completion of at least six months of initial therapy. The FDA is currently reviewing a supplemental New Drug Application (sNDA) for XARELTO^® for the prevention of VTE in medically ill patients.

About the EINSTEIN Clinical Trial Program
The pivotal EINSTEIN program is comprised of five Phase 3 studies: EINSTEIN-DVT, EINSTEIN-PE, EINSTEIN-EXT, EINSTEIN CHOICE and EINSTEIN-Jr. EINSTEIN-DVT and EINSTEIN-PE evaluated XARELTO^® versus the dual-drug regimen of LMWH and VKA for the treatment of DVT and PE, respectively, and the prevention of recurrent DVT and PE. EINSTEIN-EXT (or "Extension") compared XARELTO^® with placebo for the long-term prevention of recurrent DVT and PE in patients who previously completed six or 12 months of anticoagulation treatment with either VKA or XARELTO^®. Finally, EINSTEIN CHOICE evaluated the long-term benefit of XARELTO^® for the prevention of recurrent VTE compared to aspirin in patients who completed between six and 12 months of anticoagulant treatment for their index DVT or PE event.

About EXPLORER
A collaborative effort between Bayer and Janssen, our industry-leading EXPLORER program seeks to generate important clinical evidence on the safety and efficacy of XARELTO^® and its potential role in addressing a wide range of critical medical needs. EXPLORER is unmatched by any oral anticoagulant in the Factor Xa inhibitor class in its size, scope and ambition.