ATHN Transcends: A Natural History Study of Non-Neoplastic Hematologic Disorders

Study Overview
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Brief Summary
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In parallel with the growth of American Thrombosis and Hemostasis Network's (ATHN) clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing significantly. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness beyond the pivotal trials that led to their approval. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use.(1,2,3,4) In 2019 alone, the United States Food and Drug Administration (FDA) has issued approvals for twenty-four new therapies for congenital and acquired hematologic conditions.(5) In addition, almost 10,000 new studies for hematologic diseases are currently registered on www.clinicaltrials.gov.(6) With this increase in 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. As emphasized in a recently published review, accurate, uniform and quality national data collection is critical in clinical research, particularly for longitudinal cohort studies covering a lifetime of biologic risk.(7) The overarching objective of this longitudinal, observational study is to characterize the safety, effectiveness and practice of treatments for all people with congenital and acquired hematologic disorders in the US.

Detailed Description
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This is a longitudinal, natural history observational cohort study being conducted at approximately 150 ATHN-affiliated sites. Participants will be followed for a minimum of 15 years. Harmonized data elements will be collected at the time of enrollment, quarterly, annually, and ad hoc. Base data will be collected for all participants. Specific data will be collected for participants enrolled in cohort-specific Arms and Modules. Each participant will be assigned to a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorders, Rare Disorders, Bleeding Not Otherwise Specified (NOS), Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions. Study Arms and study Modules may be developed to provision disease and/or disease specific insights related to stakeholders, including but not limited to pharmaceutical companies, ATHN, and Hemophilia Treatment Centers (HTCs). Arms may branch off into product-specific data collection via Modules to be collected during the study, in conjunction with planned study assessments. ATHN Transcends Principal Investigator: Michael Recht, MD, PhD, MBA American Thrombosis and Hemostasis Network Yale University School of Medicine Arm Co-Principal Investigators: PUPs Arm: Shannon Carpenter, MD, MS University of Missouri Kansas City School of Medicine Children's Mercy Hospital Courtney Thornburg, MD, MS University of California San Diego Rady Children's Hospital San Diego Hemophilia Natural History Arm: Tyler Buckner, MD, MSc Hemophilia and Thrombosis Center University of Colorado Anschutz Medical Campus Michael Recht, MD, PhD, MBA American Thrombosis and Hemostasis Network Hemophilia Gene Therapy Outcomes Arm: Janice M. Staber, MD Iowa Hemophilia and Thrombosis Center University of Iowa Stead Family Children's Hospital Ulrike M. Reiss, MD Hemophilia Treatment Center St. Jude's Children's Research Hospital Severe VWD Natural History Arm: Robert F. Sidonio, Jr., MD, MSc Aflac Cancer and Blood Disorders Center, Hemophilia of Georgia Center for Bleeding and Clotting Disorders Angela C. Weyand, MD C.S. Mott Children's Hospital, University of Michigan Medical School, Ann Arbor

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

Conditions
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Hematologic Disorder, Bleeding Disorder, Connective Tissue Disorder, Hemophilia, Thrombosis, Von Willebrand Diseases, Thrombophilia, Rare Bleeding Disorder, Platelet Disorder

Participation Criteria
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Eligibility Criteria
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Participants who meet the following inclusion criteria and none of the exclusion criteria are eligible for enrollment in the base study: Inclusion Criteria: Any age Having a congenital or acquired non-neoplastic hematologic disorder; or Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score. Exclusion Criteria: Does not qualify for inclusion in a cohort Unable to give informed consent or assent Unwilling to perform study procedures Cohort Participant Selection Each participant is to be enrolled in the cohort for which they qualify as defined below. Hemophilia Cohort Inclusion Criteria: Participants who meet any of the following inclusion criteria are eligible for enrollment into this cohort: Factor VIII or factor IX activity < 50%, without another explanation for low clotting factor other than congenital hemophilia or being a known carrier for congenital hemophilia; OR Being a known carrier for congenital hemophilia with a factor VIII or factor IX activity greater than or equal to 50% with or without a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score; OR Known congenital hemophilia that have a factor level >50% after receiving vector; OR Acquired hemophilia Exclusion Criteria: None Von Willebrand Disease Cohort Inclusion Criteria: Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: Meeting the definition of VWD or low VWF per most recent international guidelines Exclusion Criteria: None Congenital Platelet DisorderS Cohort Inclusion Criteria: Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: Abnormalities of platelet function Glanzmann thrombasthenia (GPIIb or GPIIIa) Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX) Abnormalities of platelet granules Abnormalities of platelet signal transduction Abnormalities of platelet secretion Collagen Receptor Defect ADP Receptor Defect Thromboxane Receptor Defect Giant Platelet Disorder Abnormalities in platelet aggregation testing due to another or unknown cause (not drug related) Exclusion Criteria: Platelet disorders secondary to medications or other substances Rare Disorders Cohort Inclusion Criteria: Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: 1. Have an established Rare Coagulation Disorder (RCD) diagnosis of one of the following: PAI-1 deficiency Factor I, II, V, VII, X, XI, XIII deficiencies Combined FV and FVIII deficiency Plasminogen deficiency Decreased tissue plasminogen activator Afibrinogenemia/hypofibrinogenemia/dysfibrinogenemia Exclusion Criteria: None Bleeding NOS Cohort Inclusion Criteria: Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: Have a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; OR Connective tissue disorder with bleeding tendency as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score Exclusion Criteria: None Thrombosis/Thrombophilia Cohort Inclusion Criteria Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: Have a prior history of arterial or venous thrombosis Patients with a known congenital or acquired thrombophilia with or without a thrombosis a. Common congenital thrombophilias:: i. Protein C deficiency ii. Protein S deficiency iii. Antithrombin deficiency iv. Factor V Leiden v. Prothrombin gene mutation b. Rare genetic factors i. Hyperhomocysteinemia c. Indeterminate genetic factors i. Elevated factor VIII ii. Elevated factor IX iii. Elevated factor XI iv. Elevated lipoprotein (a) d. Acquired thrombophilias i. Lupus anticoagulant ii. Anti-cardiolipin antibodies/Beta2 glycoprotein antibodies iii. Antiphospholipid syndrome Exclusion Criteria 1. Acquired thrombophilia secondary to medications (birth control pills or hormone replacement therapy, overweight or obesity, smoking, cancer, pregnancy, surgery, injury, prolonged inactivity/bedrest, heart failure, inflammatory bowel disease, or kidney disease Non-Neoplastic Hematologic Conditions Cohort Inclusion Criteria Participants who meet the following inclusion criteria are eligible for enrollment into this cohort: 1. Having any congenital or acquired non-neoplastic hematologic disorder not included in any other cohort Exclusion Criteria None
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hemophilia<br>This cohort includes three Arms and two Modules: PUPs Arm: This is a longitudinal, observational Arm of previously untreated patients (PUPs) with moderate or severe congenital hemophilia. Efanesoctocog alfa® Module: The purpose of this study is to investigate the safety and effectiveness of efanesoctocog alfa in PUPs. Hemophilia Natural History Arm: This Arm is investigating the safety, effectiveness, and practice of treatment for people with hemophilia. Hemophilia Gene Therapy Outcomes Arm: This Arm is investigating the safety and effectiveness of gene therapy in people with hemophilia. It is a longitudinal Arm following participants for 15 years after vector infusion. HEMGENIXTM® Module: The HEMGENIX Module is an observational post-authorization long-term follow up study to characterize the effectiveness and safety of HEMGENIX (etranacogene dezaparvovec) in patients with hemophilia B. | |
| Von Willebrand Disease<br>The Severe Von Willebrand Disease (VWD) Natural History Arm is investigating the natural history of the safety, effectiveness, and practice of treatment for people with severe VWD. It is a longitudinal, observational cohort Arm following participants every 6 months for at least 2 years. | |
| Congenital Platelet Disorders<br>This cohort includes one Arm and Module: Congenital Platelet Disorders Natural History Arm: The Congenital Platelet Disorders Natural History Arm is investigating the natural history of the safety and efficacy of hemostatic therapies (platelet transfusions, desmopressin, antifibrinolytics, recombinant factor VIIa) in the prevention or treatment of bleeding events (on demand, surgery, prophylaxis) in adult and pediatric patients with inherited congenital platelet disorders. Glanzmann Thrombasthenia (GT) Module: The Glanzmann thrombasthenia Module thrombasthenia Module is a cohort study of bleeding symptoms, treatments, and treatment outcomes in patients with Glanzmann thrombasthenia. | |
| Rare Disorders<br>No Arms or Modules at this time | |
| Bleeding NOS<br>No Arms or Modules at this time | |
| Thrombosis/Thrombophilia<br>No Arms or Modules at this time | |
| Non-Neoplastic Hematologic Conditions<br>No Arms or Modules at this time | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of therapies used in the treatment of participants with congenital or acquired non-neoplastic blood disorders and connective tissue disorders with bleeding tendency. | Safety will be measured by those events in the European Safety Surveillance (EUHASS). Allergic or other acute events Treatment-emergent side effects of therapy Transfusion transmitted infections Inhibitor development Thrombosis Cardiovascular events Malignancies Neurological events Death In addition to the modified EUHASS endpoints, the following events will be collected as adverse events of special interest (AESI): The occurrence of thrombotic microangiopathies, injection site reactions and cases of potential drug-induced liver injury The development of anti-drug antibodies, to be measured and confirmed, if feasible Severe, unanticipated bleeding Hospitalizations Glomerulonephritis Additional safety events of interest (TBD) may be collected. These may be chosen from drug development profiles based on investigational studies, package inserts, and emerging clinical and scientific observations. | 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish a platform to support study Arms and Modules for participants with bleeding, clotting, other non-neoplastic blood disorders, and connective tissue disorders with bleeding tendency. | For each Arm, a brief set of data elements of interests will be developed and reported for study participants. | 15 years | 
| To describe medication dosing regimens in the above conditions. | This objective will be evaluated by: Determining the number of participants who initiate and/or switch treatment with non-factor products and participants' reasons for initiating and/or switching treatment with non-factor products Determining the number of participants who do not initiate treatment with non-factor products Determining the number of participants who switch between different non-factor products and the participants' reasons for switching non-factor products Determining the number of participants who discontinue treatment with non-factor products and participants' reasons for discontinuing treatment with non-factor products | 15 years | 
| To grow and evolve a biorepository for current and future research through the collection of biospecimens from every person enrolled on this protocol. | All participants will have the option of having specimens drawn (about 5mL each) at baseline to be stored in the ATHN Research Biorepository (ARB). | 15 years | 
| To describe real-world effectiveness of therapies by evaluating for Health care utilization | Measured by number and type of visits and hospitalizations per year. | 15 years | 
| To describe bleeding events, changes in overall bleeding, and annualized bleeding rate (ABR) as measured by individual bleeding components. | This objective will be calculated per ISTH Bleeding Assessment Tool (ISTH BAT), and if applicable, a Pictorial Bleeding Assessment Chart (PBAC), for applicable diagnoses. | 15 years |