The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

Abstract

Introduction: Inhibitor formation is a major complication of haemophilia for which clinical trials are planned. Despite emerging novel haemostatic agents, challenges of rare disease trials are limited subjects and lack of an organized research organization with strategic resources and partnerships.

Aim: The charge to Working Group 1 was to establish scientific priorities and innovative implementation strategies to conduct inhibitor prevention and eradication trials. To determine feasibility of trial design and strategic resources and partnerships to be leveraged, two clinical trial concepts were considered.

Results: For the Inhibitor Prevention Trial, we considered adaptive design with early stopping rules, dynamic randomization and Master Protocol models to reduce sample size; and registries to provide concurrent controls and natural history data. For the Inhibitor Eradication Trial using gene therapy, an adaptive design was considered in a small number of subjects, and, if safe and meeting regulatory requirements, enrolment would be expanded. A Haemophilia Clinical Trials Group (HCTG) infrastructure was envisioned, with uniform procedures and standardized outcomes, data collection and assays, within which trial concepts would be developed, vetted and prioritized by a Steering Committee, and submitted to NIH and other research sponsors for review and funding. Mechanistic studies would be embedded within the trials, early stage investigators trained and mentored, and the research infrastructure established within the haemophilia centre (HTC) network and supported by partnerships with foundations, community, federal partners and industry.

Conclusion: The success of inhibitor trials will depend on innovative trial design and an organized HCTG research infrastructure, leveraged through community partnerships.

Keywords: clinical trials; haemophilia; inherited bleeding disorders; inhibitor formation.

Conflict of interest statement

DISCLOSURES

M. Ragni reported institutional research funding from Alnylam (Sanofi), Biomarin, Bioverativ, CSL Behring, Pfizer, Sangamo, Shire, Spark; and advisory board service to Alnylam (Sanofi), Biomarin and Spark Therapeutics; L. George reported employment at University of Pennsylvania which holds equity in Spark Therapeutics and consultancy with Pfizer; M. Manco-Johnson reported research support from Bayer HealthCare and advisory board service with Bioverativ, CSL Behring, Genentech, Novo Nordisk and Shire; M. Carr reported Consultancy with CSL Behring and Spark Therapeutics and former employment with Novo Nordisk, Pfizer, and Spark, and Stock in Pfizer and Spark; M. Igelman reported membership on the Board of Directors, Haemophilia of North Carolina; J. de la Riva reported membership on the Board of Directors, National Haemophilia Foundation; J. Scott, A. Iorio, J. Casella, A. Long, C. Hay, I. Goldberg and J. Konduros reported no conflict of interest.

Publication 2019. This article is a U.S. Government work and is in the public domain in the USA.

Figures

FIGURE 1

Clinical Trial Concept 1: Inhibitor Prevention: Emicizumab plus FVIII vs FVIII Alone in PUPs Trial. Previously untreated patients (PUPs) with severe haemophilia A are randomized to receive weekly emizicumab plus FVIII vs weekly FVIII alone and are followed for inhibitor formation >5.0 BU at prespecified time-points for 48 wk

FIGURE 2

Master Protocol. All individuals with severe haemophilia A (HA) born in the United States are enrolled and screened for inhibitor formation at a uniform prespecified frequency. The inhibitor rate is compared between those who agree to enroll in the Inhibitor Prevention Trial, and those who agree to be followed only, thereby serving as concurrent controls and providing natural history data for inhibitor formation. Participants who develop inhibitors (HA-I), whether in the Enroll or Follow Groups may be screened to enroll in the Inhibitor Eradication Trial

FIGURE 3

Clinical Trial Concept 2: Inhibitor Eradication Gene Therapy Immune Tolerance Induction Trial. Subjects with severe haemophilia A and inhibitors receive AAV-hFVIII gene therapy and emicizumab or bypass (rFVIIa or FEIBA), and are followed for inhibitor resolution,

FIGURE 4

Haemophilia Clinical Trials Group Infrastructure. The haemophilia clinical trials group (HCTG) infrastructure was modelled after the Children's Oncology Group (COG), in which clinical trials are conducted within the organizational structure of the haemophilia treatment centre (HTC), supported by federal partners, foundations, industry, insurers, consumers and professional societies. Within HCTG, HTC MDs develop standard of care protocols and intervention trial concepts which are approved by a single IRB. Trial concepts are vetted and prioritized by the HCTG Steering Committee, and approved concepts are developed into protocols, which are submitted to NIH and other research sponsors for review and funding recommendations