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

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ClinicalTrials.gov Identifier: NCT04398628
Recruitment Status : Enrolling by invitation
First Posted : May 21, 2020
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
American Thrombosis and Hemostasis Network

Brief Summary:

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. 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 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. 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.


Condition or disease
Hematologic Disorder Bleeding Disorder Connective Tissue Disorder Hemophilia Thrombosis Von Willebrand Diseases Thrombophilia Rare Bleeding Disorder Platelet Disorder

Detailed Description:

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 time of enrollment, quarterly, ad hoc, and annually. Base data to be collected for all participants. Specific data will be collected for participants enrolled in cohort-specific Arms and Modules.

Each participant will be assigned in a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorder, Rare Bleeding Disorders, Bleeding not otherwise specified (NOS), Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions. The cohort for which a participant qualifies will be determined by the site Investigator.

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

ATHN Transcends Co-Investigator: Lynn Malec, MD, MSc Versiti Blood Research Institute

Arm 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

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Study Type : Observational
Estimated Enrollment : 3000 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment in People With Non-Neoplastic Hematologic Disorders
Actual Study Start Date : September 30, 2020
Estimated Primary Completion Date : June 2035
Estimated Study Completion Date : December 2035

Resource links provided by the National Library of Medicine


Group/Cohort
Hemophilia

This cohort includes three Arms:

PUPs Arm:

This Arm is for previously untreated patients (PUPs) with congenital hemophilia A or B. This is a longitudinal, observational, prospective and retrospective Arm of PUPs with moderate or severe congenital hemophilia. Participants will be followed to assess inhibitor development within 50 exposure days (ED).

Hemophilia Natural History Arm:

This Arm is investigating a natural history of the safety, effectiveness, and practice of treatment for people with hemophilia. It is a longitudinal, observational, prospective Arm for participants with acquired or congenital hemophilia A or B.

Hemophilia Gene Therapy Outcomes Arm:

This Arm is investigating the safety and effectiveness of gene therapy in people with hemophilia. It is a longitudinal, observational cohort Arm following participants prospectively and retrospective for 15 years after vector infusion.

Von Willebrand Disease
The Severe VWD Natural History Arm is investigating the natural history of the safety, effectiveness, and practice of treatment for people with severe von Willebrand disease (VWD). It is a longitudinal, observational cohort Arm following participants every 6 months for at least 2 years.
Congenital Platelet Disorders
No Arms or Modules at this time.
Rare Bleeding Disorders
No Arms or Modules at this time
Bleeding NOS
No Arms or Modules at this time
Thrombosis/Thrombophilia
No Arms or Modules at this time
Non-Neoplastic Hematologic Conditions
No Arms or Modules at this time



Primary Outcome Measures :
  1. To determine the safety of therapies used in the treatment of participants with congenital or acquired blood disorders, other non-neoplastic hematologic conditions and connective tissue disorders with bleeding tendency. [ Time Frame: 15 years ]

    Safety will be measured by those events in the European Haemophilia Safety Surveillance (EUHASS).

    1. Allergic or other acute events
    2. Treatment-emergent side effects of therapy
    3. Transfusion transmitted infections
    4. Inhibitor development
    5. Thrombosis
    6. Cardiovascular events
    7. Malignancies
    8. Neurological events
    9. Death

    In addition to the modified EUHASS endpoints, the following events will be collected as adverse events of special interest (AESI):

    A. The occurrence of thrombotic microangiopathies, injection site reactions and cases of potential drug-induced liver injury B. The development of anti-drug antibodies, to be measured and confirmed, if feasible C. Severe, unanticipated bleeding D. Hospitalizations



Secondary Outcome Measures :
  1. 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 [ Time Frame: 15 years ]
    For each Arm, a brief set of data elements of interests will be developed and reported for study participants.

  2. To describe medication dosing regimens in the above conditions [ Time Frame: 15 years ]
    1. Annualized bleeding rate (ABR), annualized spontaneous bleeding rate, annualized traumatic bleeding rate, annualized joint bleeding rate, and annualized non-joint bleeding rate
    2. Incidence of bleeding per surgical procedure describe the number and location of target joints upon study arm entry and to determine the incidence of target joint development and the proportion of target joints that resolve following Study Arm Enrollment

  3. To develop a biorepository for current and future research through the collection of biospecimens from every person enrolled on this protocol [ Time Frame: 15 years ]
    All participants will have the option of having specimens drawn (about 5mL each) at baseline to be stored in the ATHN Research Biorepository (ARB).

  4. To describe real-world effectiveness of therapies used in the above conditions by evaluating [ Time Frame: 15 years ]
    Health care utilization as measured by number and type of visits and hospitalizations per year

  5. To describe bleeding events, changes in overall bleeding, and annualized bleeding rate (ABR) as measured by individual bleeding components [ Time Frame: 15 years ]
    Calculated per ISTH Bleeding Assessment Tool (ISTH BAT)


Other Outcome Measures:
  1. To describe effectiveness of therapies in the above conditions [ Time Frame: 15 years ]
    Patient reported outcomes (PROs) as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Profile 29/25/Parent Proxy

  2. To describe treatment adherence in the above conditions [ Time Frame: 15 years ]
    Patient reported outcomes for treatment adherence as measured by Global Adherence Rating (GAR)

  3. To describe health related quality of life in the above conditions [ Time Frame: 15 years ]
    Patient reported outcomes including health related quality of life as measured by EQ-5D-5L. EQ-5D-5L is the correct term to use in print; it is a standardized measure of health developed by the EuroQol Group as a generic measure of health. There are five levels of perceived problems (Level 1 = no problem; Level 5 = unable to/extreme problems).

  4. To describe real-world effectiveness by evaluating [ Time Frame: 15 years ]
    Goal attainment as measured by GOAL-Hem for those participants that opt into this measurement. GOAL-HEM is the Goal Attainment Scaling for Life-Hemophilia scale. The scores are the sum of goal attainment x the relative goal weights transformed into a standard measure.

  5. To describe bleeding events and changes in overall bleeding [ Time Frame: 15 years ]
    The Pictorial Bleeding Assessment Chart (PBAC), for applicable diagnoses


Biospecimen Retention:   Samples With DNA

All participants will have specimens drawn (about 5mL each) at baseline to be stored in the ATHN Research Biorepository (ARB).

Inhibitor testing is required for this study as follows:

  • Baseline Visit (not required if no product has ever been given)
  • At each Annual Visit (optional if no product given in interval from last test)
  • At time of product switch
  • At time of suspected inhibitor development
  • At time of confirmatory test for previously elevated result
  • At Study Exit
  • Additional as per any modules

Genetic testing will be optional and provided by central labs, as funding allows, across all cohorts. Genetic testing will be performed once, for applicable participants.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
This is a real-world study in which participants with congenital or acquired blood disorders will be enrolled.
Criteria

Participants who meet the following inclusion criteria and none of the exclusion criteria are eligible for enrollment in the cohort study.

Inclusion Criteria

  1. Any age
  2. Having any 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 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 >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.
  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 Disorder 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 Congenital platelet disorders secondary to medications or other substances

Rare Bleeding 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

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 arterial or venous thrombosis
  2. Patients with a known congenital or acquired thrombophilia with or without a thrombosis a. Established genetic factors: i. Protein C deficiency ii. Protein S deficiency iii. Antithrombin deficiency iv. Factor V Leiden v. Prothrombin gene mutation b. Rare genetic factors i. Dysfibrinogenemias ii. Hyperhomocysteinemia c. Indeterminate genetic factors i. Elevated factor VIII ii. Elevated factor IX iii. Elevated factor XI iv. Plasminogen deficiency v. Decreased tissue plasminogen activator vi. Elevated lipoprotein (a) d. Acquired thrombophilias i. Lupus anticoagulant ii. Anti-cardiolipin 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04398628


Locations
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United States, New York
American Thrombosis and Hemostasis Network
Rochester, New York, United States, 14626
Sponsors and Collaborators
American Thrombosis and Hemostasis Network
Investigators
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Principal Investigator: Michael Recht, MD, PhD, MBA American Thrombosis and Hemostasis Network
Principal Investigator: Lynn Malec, MD, MSc Versiti Blood Research Institute
Publications:
https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Accessed 04 Jul 2019
https://www.clinicaltrials.gov/ct2/results?cond=Hematologic+Diseases&term=&cntry=&state=&city=&dist=. Accessed 04 Jul 2019

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Responsible Party: American Thrombosis and Hemostasis Network
ClinicalTrials.gov Identifier: NCT04398628    
Other Study ID Numbers: ATHN Transcends
First Posted: May 21, 2020    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thrombosis
Hemostatic Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Von Willebrand Diseases
Hematologic Diseases
Thrombophilia
Blood Platelet Disorders
Connective Tissue Diseases
Disease
Hemorrhage
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Blood Coagulation Disorders, Inherited
Coagulation Protein Disorders
Genetic Diseases, Inborn