Abstract: Introduction: The benefits of primary prophylaxis with a factor VIII (FVIII) product in pediatric patients with severe hemophilia A are well established. Fewer data are available on the benefits of secondary prophylaxis (started after ≥2 joint bleeds but before the onset of documented joint disease). The 3-year SPINART study compared the efficacy and safety of routine prophylaxis vs on-demand treatment in adolescents and adults with severe hemophilia A, all of whom were treated with Bayer's sucrose-formulated recombinant FVIII (rFVIII-FS). Primary 3-year data on magnetic resonance imaging (MRI) joint assessments in SPINART have been recently reported. Here we present additional analyses of the SPINART 3-year MRI data. Methods: SPINART was a 3-year, randomized, controlled, parallel-group, open-label study conducted at 31 centers in the United States, Bulgaria, Romania, and Argentina. Male patients aged 12–50 years were eligible for SPINART if they had severe hemophilia A (FVIII:C 〈 1%), ≥150 exposure days to any FVIII product, no current evidence or history of FVIII inhibitors, no prophylaxis for 〉 12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. Eligible patients were randomly assigned 1:1 to on-demand treatment or prophylaxis. Patients assigned to prophylaxis received rFVIII-FS 25 IU/kg 3 times weekly; in patients with ≥12 bleeding episodes per year, dose increases of 5 IU/kg were permitted at years 1 and 2. All patients underwent MRI assessments at baseline and year 3 to evaluate the structure of 6 index joints (knees, ankles, elbows). Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the Extended MRI (eMRI) scale. The eMRI scale has 2 domains (soft tissue, osteochondral), and total eMRI scores range from 0 to 45 based on soft-tissue domain scores of 0 to 9 and osteochondral domain scores of 0 to 36; higher eMRI scores indicate greater joint structural damage. Change from baseline to year 3 in eMRI total score based on all 6 index joints was analyzed for the following baseline characteristics: region (US vs non-US), age (≤29 vs 〉 29 years), and number of bleeding episodes in the previous 6 months ( 〈 8 vs ≥8). For patients with target joints, change from baseline to year 3 in eMRI scores in the worst target joint was analyzed using analysis of covariance adjusted for bleeding frequency during the prior 6 months. Results: Eighty-four patients (42 per treatment group) were enrolled in the SPINART study. Target joint analysis data for patients with target joints who completed the study were available for 28 on-demand and 20 prophylaxis patients. Least squares (LS) mean change from baseline to year 3 in eMRI total score in the analyzed target joint was 0.91 (95% CI, –0.06 to 1.88) and 1.09 (95% CI, 0.12–2.07) for the on-demand and prophylaxis groups, respectively; the difference was not statistically significant (LS mean difference, 0.18; 95% CI, –1.05 to 0.70; P=0.68). Results for the subgroup analyses are shown in the Table. Table.eMRI Total Score (Mean ± SD Change From Baseline to Year 3)Region Age, y Number of Bleeds in Past 6 MonthsUSNon-US≤29 〉 29 〈 8≥8On demand0.56±0.77 (n=14)1.24±1.35 (n=16)1.34±1.21 (n=18)0.29±0.70 (n=12)0.88±0.83 (n=4)0.93±1.20 (n=26)Prophylaxis1.05±1.36 (n=10)0.61±1.70 (n=22)0.46±1.88 (n=17)1.08±1.15 (n=15)0.91±0.69 (n=11)0.67±1.91 (n=21) Conclusions: Over 3 years of treatment, change in eMRI total score for target joints was similar for the on-demand and prophylaxis groups in SPINART. In the prophylaxis group, progression of joint structural damage after 3 years of treatment, as indicated by changes in eMRI total scores based on all 6 index joints, did not differ by number of bleeding episodes in the preceding 6 months but appeared to be less pronounced among younger patients compared with older patients and among those in the non-US group compared with the US group; results by age and region in the on-demand group were opposite of those seen in the prophylaxis group. These results must be interpreted with caution given the small patient numbers, the possibility that the study duration was not sufficient to show changes on MRI, and the fact that target joints were assessed. These results may underscore the importance of preventing target joint development and show that once a target joint has developed, MRI may not show reversal of pre-existing damage despite prophylaxis. Disclosures Lundin: Bayer: Received reimbursement from Bayer for symposium attendance, Received reimbursement from Bayer for symposium attendance Other; Bayer HealthCare : Employed by the Center for Medical Imaging and Physiology at Skåne University Hospital and is under contract to Bayer HealthCare for work performed for SPINART Other. Hong:Bayer HealthCare: Employment. Raunig:Employed by ICON Medical Imaging and is under contract to Bayer HealthCare for work performed for SPINART on the validation of the eMRI scale and Colorado Adult Joint Assessment Scale.: Consultancy. Engelen:Bayer HealthCare: Employment. Peterfy:Spire Sciences, Inc.: Owner of Spire Sciences, Inc., which provides central image analysis services to pharmaceutical and medical device companies. Other. Werk:Bayer HealthCare: Under contract to Bayer HealthCare for work performed for SPINART. Other. Manco-Johnson:Bayer: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: In patients with hemophilia, magnetic resonance imaging (MRI) can be used to identify target joints and guide prophylaxis to prevent progressive arthropathy. Current MRI scales developed to assess joint changes, such as the 17-point International Prophylaxis Study Group (IPSG) MRI scale, have limited sensitivity for detecting change in severely damaged joints or for detecting greater joint involvement at lower levels of damage. The Extended MRI (eMRI) scale was developed to provide a means of evaluating the range of joint damage seen in adults with hemophilia. Results from an eMRI validation analysis using baseline data from the 3-year SPINART study, a randomized trial comparing prophylaxis vs on-demand treatment with sucrose-formulated recombinant factor VIII, have been reported. Here, we present eMRI validation results using 3-year data from SPINART. Methods: The eMRI scale consists of 2 domains: soft tissue and osteochondral, each of which has 3 items (effusion hemarthrosis, synovial hypertrophy, and hemosiderin for soft tissue; erosion, subchondral cysts, and cartilage loss for osteochondral). Each osteochondral item is scored for each of the 3 bones that articulate the joint (ankles, elbows, knees). The total eMRI joint score (soft-tissue and osteochondral domains combined) ranges from 0 to 45, with higher scores indicating greater joint structure damage. Analyses of change over time evaluated baseline and 3-year data using linear mixed-effects models to estimate the minimum detectable difference (MDD) for each joint. The effect of scoring individual joint bones was determined for the ankle by evaluating the addition of at least 1 additional bone that had no damage (eMRI score = 0) for each item that had damage in the other bone(s) at baseline, which would not necessarily be detected using the IPSG MRI scale. eMRI scores were also evaluated for monotonicity and ideally linearity through comparisons with age as a measure of lifetime hemarthroses, Colorado Adult Joint Assessment Scale (CAJAS) scores as a measure of joint function, and IPSG MRI scale scores as a reference measure. Reproducibility (through measurements of interreader variability and site variance) and repeatability (through inter- and intrareader analyses) were evaluated to assess scale reliability. Results: Of the 84 patients enrolled in SPINART, 74 had evaluable MRI data. Interrater variability was excellent for all joints, with intraclass correlation coefficients (ICCs) of 0.92 (ankle), 0.96 (elbow), and 0.97 (knee); corresponding intrareader variability values were similar (ICC, 0.98 [ankle], 0.95 [elbow] , and 0.94 [knee]). The MDD for each joint was approximately 1.4 (ankle), 4.2 (elbow), and 2.4 (knee). Nine patients had increased eMRI ankle scores in 13 joints resulting from the addition of at least 1 additional bone in the assessment of eMRI osteochondral items; increased eMRI scores resulted from erosion in 2 patients (4 joints), subchondral cysts in 2 patients (4 joints), and cartilage loss in 5 patients (5 joints). At baseline, eMRI scores demonstrated a high linear association with the entirely independent CAJAS joint function scores. Spearman rank correlation between the eMRI scale and CAJAS was 0.80; the correlation at year 3 was 0.75 for the on-demand group and 0.64 for the prophylaxis group, with the change from baseline correlation being 0.07 and 0.03, respectively. Conclusions: The moderate correlation between the eMRI scale and CAJAS observed at baseline was maintained at year 3; therefore, after 3 years of hemarthroses, deteriorating joint conditions in the population did not substantially disrupt the correlation. The increased range of eMRI scores resulting from evaluation of additional bones indicates that the eMRI scale is a more sensitive measure of joint structure changes in adults with severe hemophilia A compared with the IPSG MRI scale. Disclosures Raunig: Dr Raunig is employed by ICON Medical Imaging and is under contract to Bayer HealthCare for work performed for SPINART on the validation of the eMRI scale and Colorado Adult Joint Assessment Scale. : Consultancy. Peterfy:Spire Sciences, Inc.: Owner of Spire Sciences, Inc., which provides central image analysis services to pharmaceutical and medical device companies. Other. Werk:Bayer HealthCare: Under contract to Bayer HealthCare for work performed for SPINART. Other. Hong:Bayer HealthCare: Employment.