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

In parallel with the growth of ATHN's clinical studies, the number of new therapies for all blood disorders is increasing significantly. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have not yet demonstrated 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.2,3,4,5

In 2019 alone, the FDA has issued approvals for 24 new therapies for congenital and acquired hematologic conditions.6 In addition, almost 10,000 new studies for hematologic diseases are currently registered on www.clinicaltrials.gov.7

With this increase in potential new therapies possible, 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.8

This is a longitudinal, natural history observational cohort study being conducted at approximately 150 ATHN-affiliated sites with a target accrual of 3,000 participants. Participants will be followed for a minimum of 15 years on an assigned arm within a cohort; however, arm or module participation may last longer, and participants will continue participation in the arm or module for its duration. Harmonized data elements will be collected at the time of enrollment, semi-annually (every 6 months), annually, ad hoc, and as defined by the terms of individual arms and modules. 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 are developed to advance the exploration of blood disorders disease specific insights by ATHN and its partners. 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

Co* 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

Principal Investigator:

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

INHIBIT Module

Principal Investigator:

Nicoletta Machin DO, MS Hemophilia Center of Western Pennsylvania University of Pittsburgh Medical Center

Hemophilia Natural History Arm

Principal Investigator:

Fernando Corrales-Medina, MD, FAAP University of Miami-Comprehensive Hemophilia Treatment Center University of Miami-Miller School of Medicine

Rebinyn Module

Co-Principal Investigators:

Lauren Amos, MD University of Missouri Kansas City School of Medicine Children's Mercy Hospital

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

Distress Module

Principal Investigator:

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

Hemlibra Module

Principal Investigator:

Fernando Corrales-Medina, MD, FAAP University of Miami-Comprehensive Hemophilia Treatment Center University of Miami-Miller School of Medicine

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

HEMGENIX Module

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 Innovative Hematology, Indiana Hemophilia & Thrombosis Center

Glanzmann Thrombasthenia Module:

Co-Principal Investigators:

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

Meera Chitlur, MD Central Michigan University, Children's Hospital of Michigan

Hemophilia Cohort

This cohort includes three Arms and six Modules:

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

Efanestoctocog alfa (ALTUVIIIO®) Module The purpose is to investigate the safety, tolerability, and effectiveness of efanesoctocog alfa (ALTUVIIIO®) in PUPs with severe hemophilia A.

INHIBIT Module This is an observational study assessing the rate of inhibitor formation in young children with severe hemophilia A in the current treatment era.

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

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

Distress Module Participants with Congenital Hemophilia A or B, 18 years of age or older, will be followed longitudinally for 2 years or from time of enrollment for a total planned study duration of 3 years

Nonacog beta pegol (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.

Etranacogene dezaparvovec (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 natural history of the safety and efficacy of hemostatic therapies (such as platelet transfusions, desmopressin, antifibrinolytics, recombinant factor VIIa) in the prevention or treatment of bleeding events (on demand, surgery, prophylaxis) 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.

Participants who meet the following inclusion criteria and none of the exclusion criteria

are eligible for enrollment in one of the open disease-specific arms.

Inclusion Criteria:

1. Any age

2. Having a congenital or acquired blood 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.

5. Eligible for a currently active disease-specific arm.

6. Concurrent enrollment in the ATHNdataset or current ATHNdataset participant.

Exclusion Criteria:

1. Does not qualify for inclusion in a currently activedisease-specific arm; participants may be eligible to enroll as future cohorts and arms are activated; 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% or factor IX activity >=50% with or without a bleeding phenotype as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years OR

2. Known congenital hemophilia that have a factor level >50% after receiving vector, OR

   1. 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 a. Glanzmann thrombasthenia (GPIIb or GPIIIa) b. 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:

1. 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

7. Thrombotic Thrombocytopenia Purpura or Congenital Hemolytic Uremic Syndrome

8. Wiskott-Aldrich

9. Methylenetetrahydrofolate Reductase Deficiency

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 ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years with an unknown diagnosis, OR

2. Connective tissue disorder with bleeding tendency as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years.

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. Participants with a known congenital or acquired thrombophilia with or without 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 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 Arm/Module Participant Selection Previously Untreated Patients Arm

Inclusion Criteria:

1. Diagnosis of congenital hemophilia A (FVIII