ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness and Practice of Treatment in People with Non-Neoplastic Hematologic Disorders

Background: Clinical researchers affiliated with the American Thrombosis and Hemostasis Network (ATHN) conduct multi-institutional, observational cohort studies assessing the safety and effectiveness of various interventions for people affected by bleeding and clotting disorders. In parallel with the growth of ATHN's clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use. With this explosion of potential new therapies on the horizon, it is imperative that clinicians and clinical researchers in the field of non-neoplastic hematology have a uniform, secure, unbiased, and enduring method to collect long-term safety and efficacy data. The overarching objective of ATHN Transcends (NCT04398628) is to characterize the safety, effectiveness, and practice of treatments for all people with congenital and acquired hematologic disorders in the United States.

Study Design and Methods: ATHN Transcends is a longitudinal, natural history, observational cohort study being conducted at approximately 150 ATHN-affiliated sites (ATHN Affiliate Network). Participants will be followed for a minimum of 15 years. Specific data will be collected for participants enrolled in cohort-specific arms. Each participant will be assigned in a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorder, Rare Bleeding Disorders, Bleeding Not Otherwise Specified, Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions (see Figure 1).

Inclusion criteria include: any age, any congenital or acquired non-neoplastic hematologic disorder, having a bleeding phenotype with an unknown diagnosis, or having a connective tissue disorder with a bleeding tendency. Exclusion criteria include not qualifying for a cohort and the unwillingness or inability to give informed consent or assent.

Data will be collected at baseline, every three months, annually and at study exit (Figure 2). Participant biologic samples will be collected at enrollment and yearly thereafter. Safety endpoints mirror those collected by the European Haemophilia Safety Surveillance and include allergic and other acute events, treatment-emergent side effects of therapy, transfusion-transmitted infections, inhibitor development, thrombosis and cardiovascular events, malignancies, neurologic events, and deaths. Adverse events of special interest including thrombotic microangiopathies, anti-drug antibodies, unanticipated bleeding, and hospitalizations will be collected. A panel of patient-reported outcomes (Table 1) will be collected at baseline and annually.

Descriptive statistics will be calculated to analyze the primary and secondary outcomes. If there are questions involving multiple cohorts, given there is adequate power to make comparisons between cohorts, for a discrete outcome, we will report estimated difference in percentage between cohorts as well as the 95% confidence interval (CI) of such a difference. If the outcome measurement is a continuous variable, we will report the mean difference and its associated 95% CI.

Discussion: The key advantages of an independent study conducted by the ATHN Affiliate Network include the ability to observe participants on a variety of treatment regimens regardless of regimen dosing, frequency, or time of initiation; the ability to observe participants on recently FDA-approved therapies as well as continued monitoring of well-established therapies; the ability to enrich the ATHNdataset; and the ability to be the initial cohort study involving potentially all ATHN-affiliated sites to provide the infrastructure for all congenital and acquired hematologic disorders-related sub-studies in cooperation with other funders, including federal, foundation, academic and industry sources. ATHN Transcends received central institutional review board approval in April 2020. The protocol is currently being rolled out throughout the ATHN Affiliate Network.

Figure 1

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Figure 1

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