Reduced Volume and Faster Infusion Rate of Activated Prothrombin Complex Concentrate: A Phase 3b/4 Trial in Adults with Hemophilia A with Inhibitors

Abstract

Background Activated prothrombin complex concentrate (aPCC) is indicated for bleed treatment and prevention in patients with hemophilia with inhibitors. The safety and tolerability of intravenous aPCC at a reduced volume and faster infusion rates were evaluated. Methods This multicenter, open-label trial (NCT02764489) enrolled adults with hemophilia A with inhibitors. In part 1, patients were randomized to receive three infusions of aPCC (85 ± 15 U/kg) at 2 U/kg/min (the approved standard rate at the time of the study), in a regular or 50% reduced volume, and were then crossed over to receive three infusions in the alternative volume. In part 2, patients received three sequential infusions of aPCC in a 50% reduced volume at 4 U/kg/min and then at 10 U/kg/min. Primary outcome measures included the incidence of adverse events (AEs), allergic-type hypersensitivity reactions (AHRs), infusion-site reactions (ISRs), and thromboembolic events. Results Of the 45 patients enrolled, 33 received aPCC in part 1 and 30 in part 2. In part 1, 24.2 and 23.3% of patients with regular and reduced volumes experienced AEs, respectively; 11 AEs in eight patients were treatment related. AHRs and ISRs occurred in four (12.1%) and two (6.1%) patients, respectively. In part 2, 3.3 and 14.3% of patients with infusion rates of 4 and 10 U/kg/min experienced AEs, respectively; only one AE in one patient was treatment related; no AHRs or ISRs were reported. Most AEs were mild/moderate in severity. Overall, no thromboembolic events were reported. Conclusions aPCC was well tolerated at a reduced volume and faster infusion rates, with safety profiles comparable to the approved regimen.

Keywords: aPCC; hemophilia with inhibitors; safety; treatment burden.

Fig. 1

Study design. Patients were required to have received at least two of the three infusions in each sequence in part 1 to be eligible for part 2. aPCC was supplied at 85 ± 15 U/kg and reconstituted in sterile water for infusion. aPCC, activated prothrombin complex concentrate.

Fig. 2

Summary of ( A ) global satisfaction and ( B ) convenience scores on the TSQM-9 (safety analysis set). Data are shown as the mean (SD) change from baseline in the score. Baseline is defined as the last nonmissing result before the first administration of aPCC. TSQM-9 scores were graded on a scale from 0 to 100, with higher scores indicating greater satisfaction. In part 1, patients in sequence A received aPCC in the regular volume first (infusions 1–3), then in the 50% reduced volume (infusions 4–6). Patients in sequence B received aPCC in the 50% reduced volume first (infusions 1–3), then in the regular volume (infusions 4–6). aPCC, activated prothrombin complex concentrate; n , number of patients; SD, standard deviation; TSQM-9, 9-item Treatment Satisfaction Questionnaire for Medication.