Abstract
Background and Rationale
Switching from standard-half-life (SHL) to extended-half-life (EHL) recombinant factor VIII (rFVIII) products allows patients to maintain hemostasis with less frequent dosing and improves the treatment burden for people with hemophilia A (PWHA), leading to an overall improvement in quality of life. Currently, the most common approach is to rely on assumptions informed by patient characteristics and clinical history with or without PK analysis. This 'trial and error' approach can lead to suboptimal protection and can cause harmful bleeds, or an excessive use of rFVIII products leading to an economic impact without easing treatment burden. Currently, there is no defined consensus for determining the most therapeutically and economically appropriate prophylaxis (PPX) regimen for PWHA switching from a SHL to EHL product. While the literature contains documented phenotypic and biologic variables with a high predictive potential for determining the optimal regimen for PWHA who may wish to switch to an EHL product, these criteria have not yet been studied prospectively, neither individually nor in combination. The PREDICT study aims to assess a new scoring system based on the best known phenotypic and biologic variables to select the optimal (individualized and most appropriate) regimen, for a favorable outcome when switching from a SHL rFVIII product to the EHL rFVIII product damoctocog alfa pegol.
Study Design and Methods
PREDICT is a multi-center, prospective, open-label, phase 4 clinical study in the US. It aims to enroll 65-70 previously treated patients including women (≥150 exposure days), aged ≥12 years old with congenital hemophilia A, regardless of disease severity, who have received prior PPX treatment with a SHL rFVIII product for ≥1 year prior to study participation, with no history or current evidence of inhibitors (≥0.6 BU/ml). Key exclusion criteria include patients with any other inherited or acquired bleeding disorder, a platelet count <100,000/mm 3 based on last medical record, or a planned major surgery.
Each patient will receive a score at baseline, which is expected to aid in selecting the most appropriate damoctocog alfa pegol regimen for the individual. The scoring system consists of five, individually weighted phenotypic and biologic variables.
In the first 4 weeks of the study, all patients will start treatment with twice weekly (2×W) damoctocog alfa pegol PPX (Figure 1), as per the US product information. Patients with a high-risk total score, will continue with 2×W PPX for the remainder of the study, while patients with a medium risk score will switch to every 5 days (E5D) PPX after the first 4 weeks for the remainder of the study. Patients with a low-risk score will switch to E5D PPX for a further 4 weeks, then switch to a less frequent dosing (e.g., every 7 days).
The primary endpoint is the occurrence of favorable outcomes on the score-selected dosing regimen, analyzed by the proportion of patients with a favorable outcome. A favorable outcome is defined as no change of the risk-score-assigned dosing regimen during the study with one of the following: (1) an improved ABR vs prestudy ABR with either decreased or similar frequency of administration versus prestudy frequency, (2) a decreased dosing frequency and similar ABR versus prestudy. Secondary endpoints include the occurrence of patients with 0 and ≤1 spontaneous bleeds, change from baseline in ABRs, change from baseline in frequency of damoctocog alfa pegol administration and patient-reported outcomes. Descriptive statistical analyses will be performed.
An interim analysis may be performed for publication purposes. The patient score is expected to predict the most appropriate damoctocog alfa pegol regimen leading to a favorable outcome for at least 70% of the patients enrolled in the study. A post-hoc analysis of the PROTECT VIII study data was done to evaluate the potential of the scoring system. Considering that not all variables were available in the PROTECT VIII study, it was determined that it was feasible to proceed with the study. The proposed patient scoring system is expected to be an effective tool for determining the optimal PPX regimen for PWHA switching from SHL rFVIII products to damoctocog alfa pegol and could potentially improve quality of life.
Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Reding: Bayer, Biomarin (institutional research funding): Research Funding; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda: Honoraria; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda (advisory committees): Membership on an entity's Board of Directors or advisory committees; Bayer, CSL Behring, Sanofi Genzyme, Takeda: Speakers Bureau. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Quon: Orthopaedic Institute for Children: Current Employment. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Leissinger: Tulane University: Current Employment; BioMarin: Research Funding; Advisory boards: Bayer, Catalyst, CSL Behring, Dova, Enova, Forma, GBT, Genentech, Sanofi, Takeda, UniQure: Honoraria, Membership on an entity's Board of Directors or advisory committees. Charlet: Bayer: Current Employment. Boukerrou: Bayer: Current Employment.
