Source of Factor VIII Replacement (PLASMATIC OR RECOMBINANT) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia a: The Multicenter Randomized Sippet Study

摘要: Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects rate inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites 14 countries from Africa, Americas, Asia Europe. The original aim was screen 300 patients, randomize 270 (10% screening failure) follow them for 50 exposure days (ED) 3 years. Once intended numbers included, follow-up terminated due logistic budgetary reasons. Screening criteria age 5 BU/ml) a secondary outcome. Patients censored end (50 EDs, years end), inhibitor development drop-out. Kaplan-Meier Cox regression survival analyses took into account as putative confounders FVIII gene mutations, ethnicity, family history, previous blood component exposure, therapeutic regimen, first treatment country site. Results Of 39 failures, 13 excluded because had received >5 treatments components 10 not infused after randomization. remaining 251 analysed 35 truncated (25 dropout, termination). aged 0-81 months randomization (median months) between 1 infusions concentrates 22). those did develop inhibitor, over 70% >20 ED. 76 developed which high-titred. cumulative incidence 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% inhibitors within 20 both all high-titre inhibitors. After 125 pdFVIII 126 rFVIII. equally divided two product class arms. There 29 (20 high-titred) group treated 47 (30 26.7% (CI95 18.3-35.1%) 44.5% 34.7-54.3%) rFVIII (Figure). For 18.5% 12.1-26.9%) 28.4% 19.6-37.2%) By univariate analysis associated 87% higher than (hazard ratio (HR) 1.87, CI95 1.18-2.97). increased (HR 1.70, 0.96-2.99). associations materially change adjustment confounders: adjusted models remained 70-90% elevated vs pdFVIII. When restricted that second generation full length (n=131 25 inhibitors), risk other still twofold 1.99, 1.00-3.99). Conclusions 1.87-fold class. This difference even when concentrate analyses. results this have implications choice management PUPs, remains major challenge haemophilia (Funded by Angelo Bianchi Bonomi Foundation, Italian Ministry Health, Grifols, Kedrion LFB - Registed EudraCT 2009-001186-88). Disclosures Peyvandi:Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Biotest, Baxalta: Membership on entity9s Board Directors advisory committees, Speakers Bureau. Karimi:Octapharma: Investigator. Young:Baxter, Grifols: Honoraria. Santagostino:Roche: Bureau; Bayer: Baxter/Baxalta: Octapharma: Biotest: Novo Nordisk: Kedrion: Biogen/Sobi: Behring: Pfizer: Funding, Mancuso:Baxter, Pfizer, Behring, Baxter, Sobi/Biotest: Consultancy; Nordisk, Mahlangu:Biogen: Funding; Roche: committees; NovoNordisk: committees. Bonanad:Baxalta: Ewing:Baxter, Owaidah:King abdulaziz city science, Kobrinsky:Octapharma: Sanofi: Biopharma: Kavakli:Baxter: board member educational investigational support; Bio Products Laboratory: support. Manco-Johnson:Baxter, bayer, biogen, NovoNordish: Neme:Novo Nordisk fees speaking. Wicklund:NovoNordisk, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Zulfikar:Eczacýbaþý-Baxter,