Objectives:
PAIR is an ongoing, global, non-interventional, post-authorization safety surveillance designed to collect information on ADVATE safety and effectiveness in immune tolerance induction (ITI) therapy in routine practice.
Methods:
From July, 2007 to April, 2011, individuals with hemophilia A and inhibitors were enrolled in 10 countries. The primary objective is to assess the incidence of adverse events (AEs) related to ADVATE during ITI therapy. Secondary objectives are incidence of central venous access device (CVAD)-related complications, and success rates of ITI therapy. Maximum observation period for ITI is 33 months plus a 12 month follow-up.
Summary:
As of April 1, 2014, 36 of 44 subjects (81.8%) completed ITI therapy, 28 (63.6%) of which completed the 12 month follow-up. Six subjects withdrew prior to completing ITI therapy. Dosing regimens were: ≥200 IU/kg/day (n=4, 9.1%); 131-199 IU/kg/day (n=3, 6.8%); 90-130 IU/kg/day (n=26, 59.1%) and <90 IU/kg/day (n= 11, 25.0%). During the observation period, 337 bleeding episodes and 273 AEs were reported for all enrolled subjects (N=44). Of these AEs, 52 (19.0%) were serious and none were considered related, while 15 (5.5%) were non-serious and related. CVAD complications were common; 32 subjects experienced one or more CVAD-related AE such as hospitalization, line infection, line malfunction, line removal, and pain following port-a-cath bleed. Of the subjects that completed ITI, 21 achieved negative titer levels, two experienced a high to low titer conversion, seven failed to achieve negative titer, and six were un-assessable per protocol. After 18 months therapy, Kaplan Meier estimates of success for achievement of first negative titer was 65.4% (asymptotic 95% CI: 48.7-81.5%, n=36) for the completer group. Rates were higher for the per protocol analysis set (72.2%, CI: 54.6-87.5%, n=30), and slightly lower for the full analysis set (63.5%, CI: 48.0- 78.7%, n=44).
Conclusions:
These interim outcome results are consistent with previous reports from PAIR and other published data on ADVATE in ITI. No new ADVATE related safety issues have been seen. The last two participating subjects will end observation within the next year.