North American prophylaxis studies for persons with severe haemophilia: background, rationale and design

Abstract

Arthropathy is associated with the greatest cost and morbidity to persons with haemophilia. Clinical protocols have been developed empirically to prevent or retard the development of joint disease using routine infusions of replacement factor concentrate. However, randomized clinical trials to determine optimal therapy to prevent joint disease in persons with severe haemophilia are lacking. Two clinical trials are ongoing to answer important clinical questions about the prevention of arthropathy. The first, a US randomized clinical trial, is comparing an aggressive multiple-infusion episode-based protocol to standard alternate-day prophylaxis to determine whether prevention of joint disease requires prevention of the bleeding event, per se, or can be achieved by promoting complete resolution of each bleeding event in the joint. This study included the development and validation of sensitive new physical and imaging scales to detect the earliest signs of joint disease in young children. The second, a single-arm, open-label Canadian study, is asking whether prevention of joint disease in young children can be individualized by escalating the dose and frequency of routine replacement infusions of factor concentrate based upon the clinical course of haemophilia in the affected child. Both of these studies will contribute valuable information regarding optimal therapy and will help establish evidence-based medicine for the management of severe haemophilia.

Physicians’ perceptions of adherence to prophylactic clotting factor infusions

“…Strategies should be developed to improve adherence to prophylaxis such that physicians may be more willing to prescribe prophylaxis for potentially non-adherent. Strategies may include a graduated prophylaxis schedule [20], decreased infusion volumes, longer-acting clotting factors [21] and electronic monitoring of infusions with feedback from the HTC in real-time [22]. The goal should be to increase the prescription of prophylaxis and to convert prophylaxis from an efficacious treatment to one that effectively prevents joint disease and improves health-related quality-of-life in patients with severe haemophilia.…”

Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes

“…[1][2][3][4][5][6][7][8][9][10] Since the half-life of human FVIII is about 10 to 12 hours, 11 infusions typically need to be repeated every 2 to 3 days to maintain a FVIII level above 1% in patients treated according to the pharmacokinetic (PK) dosing model. 1,[12][13][14][15] The prevention of bleeding episodes, especially in young patients, is of vital importance, as it reduces the occurrence of hemophilic arthropathy, which usually develops secondary to repeated intraarticular bleeding episodes.…”

“…1,[12][13][14][15] The prevention of bleeding episodes, especially in young patients, is of vital importance, as it reduces the occurrence of hemophilic arthropathy, which usually develops secondary to repeated intraarticular bleeding episodes. 3,4,6,7,[16][17][18][19][20][21] Prophylactic infusions performed in order to prevent bleeding episodes can delay the time of onset of hemophilic arthropathy and reduce the severity of pain and sequelae. Patients dosed along PK parameters usually demonstrate very few bleeding episodes and low morbidity.…”

Evidence‐based treatment of haemophilia

“…While this is recommended best practice (World Federation of Hemophilia, World Health Organization, National Hemophilia Foundation of the USA, United Kingdom Haemophilia Centre Doctors' Organization), the evidence is based upon long-term studies with historical control groups, and this has been insufficient to persuade some authorities to finance treatment, particularly as there is, as yet, little information from acceptable long-term qualityof-life studies. Prospective controlled trials are underway to address some of these issues [11,12], and a supplement of Haemophilia last year was devoted to discussion of this area (May 2003, Supplement 1). In general, there are not many controlled trials; the Cochrane Collaboration has identified only 206 references to 58 trials in coagulopathies and many of these relate to short-term comparisons of treatment, particularly trials of new concentrates.…”