Session: 322. Disorders of Coagulation or Fibrinolysis: Poster III
Hematology Disease Topics & Pathways:
Hemophilia, Bleeding and Clotting, Diseases, Non-Biological, Therapies, coagulant drugs
Methods: We performed a single-center, randomized, controlled, open-label, crossover trial to determine if rFVIII dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on TBW in overweight and obese (body mass index ≥25 mg/m2), adult males (age ≥18) with hemophilia A (FVIII activity ≤0.40 IU/dl). Participants were randomized to 1 of 6 possible dosing sequence scenarios based on 3 different weight-based dosing regimens (TBW, LBM, and IBW). Recombinant FVIII dosing was calculated based on weight and a targeted FVIIII recovery of 2.0 IU/dl per IU/kg. Each subject administered his own rFVIII on three separate weeks following a washout period of at least 72 hrs. FVIII recovery was determined using the one-stage clotting assay obtained before and 30 min after infusion. Outcomes consisted of FVIII recovery and the proportion of participantsachieving a targeted FVIII recovery of 2.0 +/- 0.2 IU/dl per IU/kg 30 min after infusion. An intention-to-treat analysis was performed using mixed effects linear and logistic regression with random subject effect adjusted for week.
Results: Between September 2015 and March 2019, 30 eligible patients were randomized to 1 of 6 rFVIII weight-based dosing scenarios consisting of TBW, LBM, and IBW. Nineteen participants completed the study. The mean age of participants was 34.6 +/- 11.3 years. The average body mass index (BMI) of participants was 29.2 +/- 3.5 kg/m2. Twenty-six participants had severe hemophilia A and 2 participants each had moderate and mild hemophilia A. Of those receiving at least 1 dose of rFVIII, Eloctate, 66.7%, Advate, 14.3%, and Novoeight, 9.5%, were the most commonly administered products. The mean FVIII recovery for TBW, LBM, and IBW-based dosing was 2.45 (95% CI: 2.27, 2.64), 2.08 (95% CI: 1.89, 2.26), and 2.17 (95% CI: 1.99, 2.35) IU/dl per IU/kg, respectively. The mean FVIII recovery was higher in TBW vs LBW and IBW-based dosing (Table 1).The proportion of participants with a targeted FVIII recovery of 2.0 +/- 0.2 IU/dl per IU/kg was 0.25 (95% CI; 0.09, 0.52), 0.39 (95% CI: 0.18, 0.64), and 0.54 (95% CI: 0.30, 0.77) for TBW, LBM, and IBW-based dosing, respectively. There was no difference in the proportion of participants with a targeted FVIII recovery of 2.0 +/- 0.2 IU/dl per IU/kg in TBW vs LBM and IBW-based dosing (Table 1).
Discussion: In this study, rFVIII dosed according to TBW resulted in a higher FVIII recovery value than LBM and IBW-based dosing in overweight and obese, adult males with hemophilia A. There was no significant difference in the proportion of participants with a targeted FVIII recovery of 2.0 +/- 0.2 IU/dl per IU/kg in TBW vs LBM and IBW-based dosing; however, effect estimates favor alternative dosing strategies with LBM and IBW-based dosing 1.93 and 3.65 times, respectively, having greater odds of achieving targeted FVIII recovery. This may be due to limited statistical power as only 79.2% of the necessary number of participants completed the study. In addition, the rFVIII dose was erroneously calculated in 7 participants resulting in the administration of a smaller than intended amount. This primarily affected IBW and LBM-based dosing, which may have served to reduce the effect size above. In conclusion, based on these findings, overweight and obese patients with hemophilia A should undergo individualized pharmacokinetic studies using alternative descriptors of body weight to determine the most accurate, and cost-effective, method of achieving targeted FVIII recovery values.
Disclosures: Seaman: Takeda: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Bayer: Consultancy. Ragni: Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding.
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