A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE)

Abstract

Introduction

High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding.

Aim

To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE^®; Baxalta US Inc., a Takeda company, Lexington, MA, USA).

Methods

SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria.

Results

Fifty-four patients aged 11–58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding.

Conclusion

These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

Keywords:

• hemophilia A
• recombinant factor VIII
• physical activity
• post-authorization study
• prophylaxis
• bleeding

Data Accessibility

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results reported in this paper, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Data requests should follow the process described in the Data Sharing section on https://clinicaltrials.takeda.com/ and https://vivli.org/ourmember/takeda/.

Additionally, Friedrich Maritsch ([email protected]) can be contacted regarding data-sharing information.

Acknowledgments

The authors acknowledge all participating patients and all study site staff, including clinical investigator Susan Lattimore. This study was funded by the sponsor, Baxalta US Inc., a Takeda company, Lexington, MA, USA. Medical writing support for this paper was provided by Rosalind Bonomally, MSc, of Excel Medical Affairs (Fairfield, CT, USA), and was funded by Baxalta US Inc., a Takeda company, Cambridge, MA, USA.

Author Contributions

All authors contributed to the study concept and design. BAK, DVQ, LR, MR, VCR, SLC, and ALD were clinical trial investigators, and were involved in the execution of the study and acquisition of data. All authors participated in interpreting the data and critically reviewing the paper. All authors read and approved all versions of the paper before submission, including the final manuscript before submission, and agreed on the journal to which the paper was submitted. All authors take responsibility and are accountable for the contents of the paper.

Disclosure

BAK has received research support from Baxalta, Pfizer, Sanofi, Sigilon, Takeda, and Uniqure; and consulting fees from BioMarin, CSL Behring, Pfizer, Sanofi, Takeda, Sigilon, Spark, and Uniqure. DVQ has received consulting fees/honoraria from Bayer, BioMarin, Genentech, Novo Nordisk, Sanofi, and Octapharma; and has been a speaker for BioMarin, Genentech, Novo Nordisk, Sanofi, and Takeda. LR has participated on advisory boards for Bayer, CSL Behring, Genentech, Roche, HemaBiologics, and XaTek. MR has received research support for Oregon Health & Science University from BioMarin, Bioverativ/Sanofi, Catalyst Biosciences, Genentech, Hema Biologics, Novo Nordisk, Shire/Takeda, Spark, and uniQure; has been a consultant for the American Thrombosis and Hemostasis Network, Bayer, Bioverativ/Sanofi, CSL Behring, Genentech, Grifols, Kedrion, LFB, Novo Nordisk, Octapharma, Pfizer, Shire/Takeda, and uniQure; has been on the board of directors of the Foundation for Women and Girls with Blood Disorders and Partners in Bleeding Disorders; and is an employee of Oregon Health & Science University. VCR has received research support from Grifols, Pfizer, and Takeda. SLC has received honoraria from CSL Behring, Genentech, Kedrion, and Novo Nordisk; has received research support from the American Thrombosis and Hemostasis Network; and has been on the board of directors for the American Thrombosis and Hemostasis Network and the Hemostasis and Thrombosis Research Society. ALD has received research support from BioMarin and Takeda; and personal fees from CSL Behring, Genentech, Medscape, and uniQure. ML is an employee of Shire US Inc., a Takeda company, and a Takeda stock owner. MW is an employee of Shire International GmbH, a Takeda company, and a Takeda stock owner. The authors report no other conflicts of interest in this work.