Prophylaxis Trumps On-Demand Dosing for Hemophilia B in RCT

Larry Hand

January 31, 2014

Once or twice weekly prophylactic dosing of recombinant factor IX nonacog alfa significantly reduced annualized bleeding rates in patients with hemophilia B in a randomized controlled trial.

Leonard A. Valentino, MD, director, Rush Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois, and colleagues reported the results in an article published online January 13 in Haemophilia.

The investigators conducted a phase 4 randomized open-label crossover study to evaluate the efficacy and safety of recombinant factor IX nonacog alfa (BeneFIX, Pfizer) as a prophylaxis compared with on-demand administration between May 2007 and October 2010. Pfizer sponsored the study.

The study represents the first such effort in more than 30 years to compare prophylaxis with on-demand treatment in patients with hemophilia, the researchers write. Of 47 males aged 6 to 65 years who had moderately severe to severe disease at the start of the study, 41 completed the trial. Incompletions were a result of 1 adverse event, 1 protocol violation, 1 patient lost to follow-up, and 3 patients lost to noncompliance. Enrollment was limited to patients with 12 or more bleeding episodes in the 12 months before enrollment.

All participants had 16 weeks of on-demand therapy at the beginning of the trial and then were randomly assigned to receive either nonacog alfa 100 IU/kg once weekly or 50 IU/kg twice weekly for 16 weeks. All patients then switched back to on-demand dosing for 8 weeks, followed by 16 weeks of prophylaxis with the dose they had not received during the first 16-week prophylaxis period. On-demand treatment was allowed during prophylaxis periods if needed.

The authors calculated the annual bleeding rate (ABR) as the number of bleeding events divided by the number of days receiving treatment divided by 365.25 days a year. Participants recorded bleeding events on electronic diaries.

The researchers found that both prophylaxis regimens significantly reduced ABR compared with on-demand treatment (mean ABR: on demand, 35.1; 100 IU/kg, 4.6; 50 IU/kg, 2.6; P < .00001). There was no significant difference between the two prophylactic regimens (P = .22).

Most joint and soft-tissue bleeding events resolved with a single infusion of nonacog alfa, whereas 5 hemarthroses episodes required more than 4 infusions of nonacog alfa. The investigators saw no evidence of 4 adverse events that were of special interest, including thrombosis, inhibitor development, allergic reactions, and red blood cell agglutination. Treatment-emergent adverse events, most of which were mild or moderate, occurred in 30 (60%) of participants, including headache, accidental injury, arthralgia, and pain.

One limitation of the study is the relatively short duration, the researchers write.

"The decreased frequency of infusions with once-weekly dosing may present a favourable option for individuals in whom venous access is a concern, potentially improving adherence and offering more convenience to patients and their caregivers compared with more frequent prophylactic dosing regimens," the authors conclude.

A Step Forward, but...

"I think the results of this study are a step forward," Val Bias, chief executive officer of the National Hemophilia Foundation in New York City, told Medscape Medical News. "I think they have to be tempered with the reality of whatever the choices the individual might need to make. The best treatment for patients in the bleeding disorders community is probably going to be individualized in some way."

Prophylaxis treatment has been available for children for a while but is still not embraced for adults by all payers, he said. "If on-demand is what you've been used to, you will adjust your lifestyle and perhaps the job that you work to the amount of activity your body can stand. What we face in this new age of a larger availability of products is the choice for a patient to lead a more active life."

Patients, along with their physicians, should make the choice between on-demand and prophylaxis treatments, he said.

This research was sponsored by Pfizer, which also funded writing and editorial support for this article. Dr. Leonard has reported receiving grant support from Baxter Bioscience (through his institution), Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, Inspiration Bioscience, Novo Nordisk and Pfizer; a coauthor has reported acting as a remunerated consultant to Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, Inspiration Bioscience, Novo Nordisk, and Pfizer; another coauthor has reported being a study investigator for Pfizer; 3 coauthors have reported being employees and stockholders of Pfizer; the remaining coauthor and Val Bias have disclosed no relevant financial relationships.

Haemophilia. Published online January 13, 2014. Abstract

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