Initial Results of a Randomized, Prospective Trial of Prophylaxis To Prevent Joint Disease in Young Children with Factor VIII (FVIII) Deficiency.

Background: Retrospective reviews of hemophilia therapy correlate normal joint X-ray (XR) and physical exam (PE) with early institution of routine infusions of FVIII dosed to prevent bleeding. Although the National Hemophilia Foundation recommended prophylaxis for all persons with severe hemophilia in 1995, fewer than half of affected persons in the US have adopted prophylaxis due to cost, effort, lack of perceived need and complications. Objective: The “Joint Outcome Study” was constructed as a multi-center, open-label, two-arm, prospective, randomized clinical trial to compare full prophylaxis with an intensive treatment regimen for joint hemorrhage. Methods: A regimen of every other day infusions of FVIII at 25 U/kg to prevent hemorrhage (prophylaxis, P) was compared with intensive therapy using ≥ 3 infusions totaling ≥ 80 U/kg FVIII at the time of each joint hemorrhage to minimize joint damage (enhanced episodic, EE). Primary outcome was the proportion of boys in each arm with bone or cartilage damage on XR or magnetic resonance imaging (MR) of index joints (elbows, knees, and ankles). Outcomes were judged independently by two research radiologists who were blinded to treatment arm and bleed history, with a third for discrepant readings. Other outcomes included joint function on a physical exam scale validated for young children (PE), # of joint hemorrhages and factor utilization. Boys were followed from entry between 12 and 30 months until age 6 years. At entry all children had normal joints on XR and MR and had no more than two hemorrhages into any one joint. Results: Sixty-five boys were randomized to P (32) or EE (33). The study has been completed. While adjudication of XR and MR outcomes is still ongoing, clinical study results show the following: Children on P consumed more FVIII (mean 163 vs 47 infusions/year, P < 0.001) and had fewer joint hemorrhages per year (0.47 vs 4.9, p < 0.001) than boys on EE. PE scores for the six index joints were lower on the P arm compared with EE (mean score 4.7 vs. 8.6, p< 0.01). Conclusion: This first randomized clinical trial of prophylaxis in young children with FVIII deficiency showed improved joint function by age 6 years in children on early every other day prophylaxis in comparison to an aggressive program of multiple infusions administered promptly at the time of joint hemorrhage. Joint structural outcome confirmation will be based on MR and XR.