ALBERT

Description: 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.

Description: The Joint Outcome Study (JOS) was a randomized controlled clinical trial in boys with severe factor VIII deficiency comparing prophylaxis consisting of 25 IU/kg factor VIII every other day begun prior to age 30 months with an enhanced episodic regimen given only in response to bleeding. At JOS exit at age 6 years, joint outcome by sensitive magnetic resonance image (MRI) and joint physical examination (PE) of 6 index joints (both ankles, knees and elbows) determined superiority of prophylaxis over episodic therapy (p 〈 0.05). At JOS end, all parents were informed of the study results and boys in the episodic arm were counseled to initiate prophylaxis therapy; all but 1 JOS participant on episodic therapy switched to prophylaxis. The JOS Continuation Study is being performed to determine the results of early prophylaxis on joint development until the age of 18 years and to determine the impact of delaying prophylaxis initiation until age 6 years. All boys in the original JOS were eligible to enroll in the continuation study. Study data collected includes cumulative number of index joint and total hemorrhages, joint PE score of 6 index joints using the Colorado Pediatric Joint Assessment Scale as previously described (Haemophilia 6:649) and MRI soft tissue, osteochondral and total scores of 6 index joints using the expanded MRI 45 Scale as recently presented (ISTH OP Mon 7/1/13, 9 am). Additional data are collected on prophylaxis adherence, activities, surgeries, quality of life and replacement factor utilization. To date, results of 26 (40%) of the original 65 boys (16 on early and 10 on delayed prophylaxis) including 156 index joints are available for analysis. Results, expressed as a cumulative score for all 6 index joints, are shown in Table 1. While still enrolling, the JOS Continuation Study is documenting an ongoing disparity in joint outcome in children with initiation of prophylaxis delayed until age 6 years, compared with prophylaxis started before 30 months of age. Following delayed initiation of prophylaxis, adolescents manifest increased numbers of hemarthroses and increased MRI damage particularly affecting bone and cartilage. Joint PE is less sensitive than MRI in determination of joint outcome in hemophilia. Disclosures: Manco-Johnson: Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; NovoNordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding. Manco-Johnson:Bayer HealthCare: Research Funding. Lane:Bayer HealthCare: Honoraria; Baxter BioScience: Paid travel to attend a meeting, Paid travel to attend a meeting Other. Shapiro:Bayer HealthCare: Research Funding; Baxter BioScience: Research Funding; Biogen Idec: Research Funding; Cangene: Research Funding. Valentino:Baxter BioScience: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GTC Biotherapeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration Bioscience: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; NovoNordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Brown:Baxter BioScience: Research Funding; Biogen Idec: Research Funding; CSL Behring: Research Funding.