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

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.

ATHN Transcends is a cohort study to determine the safety, effectiveness, and practice of therapies used in the treatment of participants with congenital or acquired non-neoplastic blood disorders and connective tissue disorders with bleeding tendency. The study consists of 7 cohorts with additional study "arms" and "modules" branching off from the cohorts.

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.

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)

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 Investigators

Tammuella Chrisentery-Singleton, MD Ochsner Clinic Foundation American Thrombosis and Hemostasis Network

Michael Recht, MD, PhD, MBA Yale University School of Medicine National Bleeding Disorders Foundation

PUPs Arm:

Principal Investigator:

Shannon Carpenter, MD, MS University of Missouri Kansas City School of Medicine Children's Mercy Hospital

ALTUVIIO Module:

Co-Principal Investigators Shannon Carpenter, MD, MS University of Missouri Kansas City School of Medicine Children's Mercy Hospital

Co-Principal Investigator Julie Jaffray, MD University of California San Diego Rady Children's Hospital San Diego

INHIBIT Module:

Co-Principal Investigators:

Nicoletta Machin DO, MS Assistant Professor, Division of Hematology/Oncology Hemophilia Center of Western Pennsylvania University of Pittsburgh Medical Center

Hemophilia Natural History Arm:

Co-Principal Investigators:

Tyler Buckner, MD, MSc Hemophilia and Thrombosis Center University of Colorado Anschutz Medical Campus

Michael Recht, MD, PhD, MBA Yale University School of Medicine National Bleeding Disorders Foundation

Rebinyn Module

Co-Principal Investigators:

Lauren Amos, MD Children's Mercy Hospital, Kansas City

Guy Young, MD University of Southern California Children's Hospital Los Angeles

Hemophilia Gene Therapy Outcomes Arm:

Co-Principal Investigators:

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:

Co-Principal Investigators:

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

Congenital Platelet Disorders Natural History Arm:

Principal Investigator Sanjay Ahuja, MD Rainbow Babies \& Children's Hospital, Case Western Reserve University

Glanzmann Thrombasthenia Module:

Co-Principal Investigators:

Divya Citla-Sridhar, MD University of Arkansas for Medical Sciences Arkansas Children's Hospital

Meera Chitlur, MD Children's Hospital of Michigan

Hemophilia Cohort

This cohort includes three Arms and five Modules:

Previously Untreated Patients (PUPs) Arm This is a pediatric focused Arm of PUPs with hemophilia A or B.

ALTUVIIIO® Module The purpose is to investigate the safety and effectiveness of ALTUVIIIO® in PUPs with hemophilia A.

INHIBIT Module This is an observational study assessing inhibitor formation in children with severe hemophilia A.

Hemophilia Natural History Arm This Arm is investigating the safety, effectiveness, and practice of treatment for people with hemophilia.

Hemlibra® Module All participants treated with Hemlibra® are eligible to participate.

Rebinyn® Module The Rebinyn® Module is a prospective study in hemophilia B participants without inhibitors.

Hemophilia Gene Therapy Outcomes Arm This Arm is investigating the safety and effectiveness of gene therapy in people with hemophilia.

HEMGENIX® Module This is an observational study to characterize the effectiveness and safety of HEMGENIX® in participants with hemophilia B.

Congenital Platelet Disorders (CPD) Natural History Arm:

The CPD Arm is investigating the safety and efficacy of hemostatic therapies in the prevention or treatment of bleeding events in adult and pediatric participants with inherited congenital platelet disorders.

Glanzmann Thrombasthenia (GT) Module:

This Module is a study of bleeding symptoms, treatments, and treatment outcomes in patients with Glanzmann thrombasthenia.

Von Willebrand Disease Cohort No arms or modules open at this time.

Rare Disorders Cohort No arms or modules open at this time.

Bleeding NOS No arms or modules open at this time.

Thrombosis/Thrombophilia No arms or modules open at this time.

Non-Neoplastic Hematologic Conditions No arms or modules open at this time.

Eligibility Criteria:
Participants who meet the following inclusion criteria and none of the exclusion criteria are eligible for enrollment in the base study:

Inclusion Criteria:

1. Any age
2. Having a congenital or acquired non-neoplastic hematologic disorder; or
3. Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or
4. Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score.

Exclusion Criteria:

1. Does not qualify for inclusion in a cohort 2. Unable to give informed consent or assent 3. 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:

1. 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
2. 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
3. Known congenital hemophilia that have a factor level \>50% after receiving vector; OR
4. 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:

1. 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:

1. Abnormalities of platelet function

   1. Glanzmann thrombasthenia (GPIIb or GPIIIa)
   2. Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX)
2. Abnormalities of platelet granules
3. Abnormalities of platelet signal transduction
4. Abnormalities of platelet secretion
5. Collagen Receptor Defect
6. ADP Receptor Defect
7. Thromboxane Receptor Defect
8. Giant Platelet Disorder
9. 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:

1. PAI-1 deficiency
2. Factor I, II, V, VII, X, XI, XIII deficiencies
3. Combined FV and FVIII deficiency
4. Plasminogen deficiency
5. Decreased tissue plasminogen activator
6. 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:

1. Have a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; OR
2. 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:

1. Have a prior history of arterial or venous thrombosis
2. 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

Previously Untreated Patients Arm Eligibility Criteria

Inclusion Criteria Diagnosis of congenital hemophilia A (FVIII \<40%) or hemophilia B (FIX \<40% or below lower limit for age)

1. Age \<18 years at time of enrollment
2. Parent or authorized guardian or legally authorized representative (LAR) can provide informed consent
3. Care established at one of the participating HTCs

Exclusion Criteria

1. CFC exposure, fresh frozen plasma (FFP), cryoprecipitate, and single donor platelets \>3 EDs
2. Concomitant diagnosis with another bleeding disorder
3. History of confirmed inhibitor

INHIBIT Module Eligibility Criteria:

Inclusion Criteria

1. Diagnosis of severe factor VIII deficiency with baseline factor VIII level \<1%
2. Initiating or plan to initiate prophylaxis with emicizumab or factor replacement
3. Factor exposure, plasma/FFP, cryo, and single donor platelets ≤3 EDs
4. ≤5 years of age

Exclusion Criteria

1. Concomitant diagnosis with bleeding disorder other than hemophilia A
2. Immune disorder
3. Factor exposure, plasma/FFP, cryo, and single donor platelets \>3 EDs
4. Previous history or presence of factor VIII inhibitor

ALTUVIIIO® Module Eligibility Criteria:

Inclusion criteria:

* People with severe HA with a baseline FVIII activity of less than 1%. (While inclusion for participation in ATHN Transcends lists \<5% FVIII activity, this proposed module will limit enrollment to people with FVIII activity levels of \<1%)
* \<18 years of age
* No history of FVIII inhibitor
* Sex at birth of male, female, or intersex
* Participants may be exposed to unfractionated blood components, no more than one dose of FVIII concentrate other than efanesoctocog alfa and up to three doses of efanesoctocog alfa prior to enrollment
* Potential participants who have a history of bleeding will be eligible for participation if they meet all other inclusion criteria

Exclusion criteria:

* Not meeting all the inclusion criteria
* Any exposure to blood components or FVIII replacement products except as described in the inclusion criteria
* History of positive inhibitor testing
* History of hypersensitivity reactions associated with efanesoctocog alfa administration
* Any concurrent clinically significant major disease that, in the investigator's opinion, would make the participant unsuitable for enrollment.
* The presence of any additional inherited bleeding disorder diagnosis
* Enrollment in a concurrent clinical interventional drug study
* Intake of an Investigational Medicinal Product within three months prior to inclusion in this study
* Inability to comply with study requirements
* Other, unspecified reasons that, in the investigator's opinion, make the participant unsuitable for enrollment.

Hemophilia Natural History Arm Eligibility Criteria:

Inclusion Criteria

1. Congenital hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility.

Exclusion Criteria

1. Presence of any known bleeding disorder other than congenital hemophilia A or B
2. Presence of concurrent hemophilia and a second hemostatic defect (low Von Willebrand Factor (VWF) without VWD diagnosis is not excluded)
3. Unable or unwilling to comply with the study arm protocol.

Rebinyn® Module Eligibility Criteria

Inclusion Criteria:

Participants who meet the following inclusion criteria at the time of screening are eligible to enroll in the study module.

Rebinyn® Cohort

1. Has provided signed written consent for the Rebinyn® Module before any study-related activities.
2. Male participants, at any age with hemophilia B, naïve or minimally exposed (up to 3 EDs) to nonacog beta pegol treatment at time of study enrollment.
3. Decision to initiate treatment with commercially available nonacog beta pegol has been made by the participant(s)/Legally Authorized Representative(s) (LAR(s)) and the treating physician before and independently from the decision to include the participant in this study.

Rebinyn® RWE Cohort

1. Has provided signed written consent for ATHN Transcends Study before any study-related activities.
2. Currently treated with nonacog beta pegol
3. Any age

Exclusion Criteria:

Participants who fall into any of the following exclusion criteria at the time of screening are not eligible for enrollment into the study module:

Rebinyn® Cohort

1. Previous participation in this study. Participation is defined as having given informed consent in this study.
2. Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation, including a diagnosis or suspicion of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) per the discretion of the Principal Investigator.
3. Known or suspected hypersensitivity to nonacog beta pegol or related products.
4. Clinical suspicion or presence of FIX inhibitor at time of inclusion.
5. Inability or unwillingness to undergo the neurological assessment/ structured developmental history.

Rebinyn® RWE Cohort 1. None

Hemophilia Gene Therapy Outcomes Arm Eligibility Criteria:

Inclusion Criteria

1. Hemophilia A or B of any severity with or without inhibitors having received or will receive a hemophilia gene transfer product in the next 6 months.
2. Age 18 years and older
3. Able to give informed consent.

   Exclusion Criteria None

   HEMGENIX® Module Eligibility Criteria

   Inclusion Criteria:

   HEMGENIX Cohort • Age 18 years of age or older

   • Treatment with commercial HEMGENIX

   • Have provided signed written informed consent within 3 months before or within 6 months after HEMGENIX treatment, or within 6 months of when the study is initiated at the treating site.

   Exclusion Criteria, both cohorts:

   • Have been treated with etranacogene dezaparvovec in a clinical trial.

   Congenital Platelet Disorders Arm Eligibility Criteria:

   Inclusion Criteria

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1. Platelet adhesion defect

   1. Bernard Soulier syndrome (Defective GPIb-IX-V receptor, impaired adhesion to VWF)
   2. Velocardio-facial syndrome/DiGeorge syndrome (Defective GPIb-IX-V receptor)
   3. Platelet type vWD (Defective GPIb-IX-V, gain of function interaction between VWF-GP1bα)
2. Platelet aggregation defect

   1. Glanzmann thrombasthenia (Defective integrin αIIbβ3 (GPIIb/IIIa)
   2. Platelet aggregation defect, NOS
3. Agonist receptor defects

   1. Epinephrine
   2. ADP
   3. Collagen
   4. Thromboxane A2
4. Platelet signaling defects

   1. Cyclooxygenase deficiency (PTGS1 mutation)
   2. Phospholipase A2 deficiency
   3. Thromboxane synthase deficiency (TBXAS1 mutation)
   4. G protein activation defect (GNAS mutation)
   5. Scott syndrome (defect in phosphatidyl serine translocation)
5. Platelet Granule disorders

   1. Dense granule storage pool disorder • Hermansky Pudlak syndrome

      * Chediak Higashi syndrome
      * Griscelli syndrome
   2. Alpha granule storage pool disorder

      • Grey platelet syndrome
      * Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) syndrome
      * Quebec platelet disorder
      * Paris-Trousseau syndrome
   3. Combined alpha delta granule deficiency
6. Platelet cytoskeletal structure defects

   1. Wiskott Aldrich syndrome
   2. MYH9 associated disorders (myosin heavy chain)

      • May Hegglin syndrome

      • Fechtner syndrome
      * Sebastian syndrome
      * Epstein syndrome
   3. Other mutations • FLNA mutations (Filamin) • DIAPH1 (Actin and microtubules) • ACTN1 (alpha actinin) • TPM4 (tropomyosin)

      * TUBB1 (beta tubulin)
7. Other Congenital thrombocytopenias

   1. Familial platelet disorders and predisposition to AML (RUNX1)
   2. X linked thrombocytopenia with dyserythropoiesis (GATA1)
   3. Congenital amegakaryocytic thrombocytopenia (MPL)

Exclusion Criteria

1. Diagnosis of von Willebrand disease (Meeting the definition of VWD or low VWF per most recent international guidelines)
2. Diagnosis of Hemophilia A or Hemophilia B (Factor VIII or IX ≤ 40%)

   FIX Prophylaxis Cohort

   • Age 18 years of age or older

   • Treatment with FIX prophylaxis therapy

   • Has provided signed written consent at any time for ATHN Transcends Study

   Glanzmann Thrombasthenia (GT) Module Eligibility Criteria:

   Inclusion Criteria

1. Participant has signed the informed consent/assent form 2. Participant has flow cytometry or aggregometry or genetics confirmed GT 3. Participant is willing to perform study procedures, including daily bleed tracking for 3 months

Exclusion Criteria None