ATHN Transcends: A Natural History Study of Non-Neoplastic Hematologic Disorders
Study Details
Study Description
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 | Intervention/Treatment | Phase |
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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
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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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. |
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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. |
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Congenital Platelet Disorders No Arms or Modules at this time. |
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Rare Bleeding Disorders No Arms or Modules at this time |
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Bleeding NOS No Arms or Modules at this time |
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Thrombosis/Thrombophilia No Arms or Modules at this time |
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Non-Neoplastic Hematologic Conditions No Arms or Modules at this time |
Outcome Measures
Primary Outcome Measures
- 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. [15 years]
Safety will be measured by those events in the European Haemophilia 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): 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
- 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 [15 years]
For each Arm, a brief set of data elements of interests will be developed and reported for study participants.
- To describe medication dosing regimens in the above conditions [15 years]
Annualized bleeding rate (ABR), annualized spontaneous bleeding rate, annualized traumatic bleeding rate, annualized joint bleeding rate, and annualized non-joint bleeding rate 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
- To develop a biorepository for current and future research through the collection of biospecimens from every person enrolled on this protocol [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).
- To describe real-world effectiveness of therapies used in the above conditions by evaluating [15 years]
Health care utilization as measured by number and type of visits and hospitalizations per year
- To describe bleeding events, changes in overall bleeding, and annualized bleeding rate (ABR) as measured by individual bleeding components [15 years]
Calculated per ISTH Bleeding Assessment Tool (ISTH BAT)
Other Outcome Measures
- To describe effectiveness of therapies in the above conditions [15 years]
Patient reported outcomes (PROs) as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Profile 29/25/Parent Proxy
- To describe treatment adherence in the above conditions [15 years]
Patient reported outcomes for treatment adherence as measured by Global Adherence Rating (GAR)
- To describe health related quality of life in the above conditions [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).
- To describe real-world effectiveness by evaluating [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.
- To describe bleeding events and changes in overall bleeding [15 years]
The Pictorial Bleeding Assessment Chart (PBAC), for applicable diagnoses
Eligibility Criteria
Criteria
Participants who meet the following inclusion criteria and none of the exclusion criteria are eligible for enrollment in the cohort study.
Inclusion Criteria
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Any age
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Having any congenital or acquired non-neoplastic hematologic disorder; or
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Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or
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Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score.
Exclusion Criteria
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Does not qualify for inclusion in a cohort
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Unable to give informed consent or assent
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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:
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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
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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
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Known congenital hemophilia that have a factor level >50% after receiving vector.
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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 Disorder Cohort Inclusion Criteria
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
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Abnormalities of platelet function a. Glanzmann thrombasthenia (GPIIb or GPIIIa) b. Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX)
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Abnormalities of platelet granules
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Abnormalities of platelet signal transduction
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Abnormalities of platelet secretion
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Collagen Receptor Defect
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ADP Receptor Defect
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Thromboxane Receptor Defect
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Giant Platelet Disorder
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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:
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Have an established Rare Coagulation Disorder (RCD) diagnosis of one of the following:
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PAI-1 deficiency
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Factor I, II, V, VII, X, XI, XIII deficiencies
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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:
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Have a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; OR
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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:
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Have arterial or venous thrombosis
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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:
- Having any congenital or acquired non-neoplastic hematologic disorder not included in any other cohort
Exclusion Criteria None
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Arizona Hemophilia and Thrombosis Treatment Center at Phoenix Children's Hospital | Phoenix | Arizona | United States | 85016 |
2 | Indiana Hemophilia and Thrombosis Center | Indianapolis | Indiana | United States | 46260 |
3 | Louisiana Center for Bleeding and Clotting Disorders, Tulane University | New Orleans | Louisiana | United States | 70112 |
4 | Maine Hemophilia and Thrombosis Center | Scarborough | Maine | United States | 04074 |
5 | Children's Mercy Hospital - Kansas City | Kansas City | Missouri | United States | 64108 |
6 | The John Bouhasin Center for Children with Bleeding Disorders | Saint Louis | Missouri | United States | 63104 |
7 | Hemostasis and Thrombosis Center of Nevada | Reno | Nevada | United States | 89509 |
8 | American Thrombosis and Hemostasis Network | Rochester | New York | United States | 14626 |
9 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
10 | North Texas Hemophilia and Thrombosis Program - Pediatric Program / Center for Cancer & Blood Disorders | Dallas | Texas | United States | 75235 |
Sponsors and Collaborators
- American Thrombosis and Hemostasis Network
- Pfizer
- Hemophilia of Georgia, Inc.
- Genentech, Inc.
Investigators
- Principal Investigator: Michael Recht, MD, PhD, MBA, American Thrombosis and Hemostasis Network
- Principal Investigator: Lynn Malec, MD, MSc, Versiti Blood Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
- Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a "trial effect". J Clin Epidemiol. 2001 Mar;54(3):217-24. Review.
- https://www.clinicaltrials.gov/ct2/results?cond=Hematologic+Diseases&term=&cntry=&state=&city=&dist=. Accessed 04 Jul 2019
- https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Accessed 04 Jul 2019
- Iorio A, Keepanasseril A, Foster G, Navarro-Ruan T, McEneny-King A, Edginton AN, Thabane L; WAPPS-Hemo co-investigator network. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol. JMIR Res Protoc. 2016 Dec 15;5(4):e239.
- Konkle BA, Recht M; members of Working Group 2, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national blueprint for future research. The national blueprint for 21st century data and specimen collection and observational cohort studies: NHLBI State of the Science Workshop on factor VIII inhibitors. Haemophilia. 2019 Jul;25(4):590-594. doi: 10.1111/hae.13772.
- Unger JM, Barlow WE, Martin DP, Ramsey SD, Leblanc M, Etzioni R, Hershman DL. Comparison of survival outcomes among cancer patients treated in and out of clinical trials. J Natl Cancer Inst. 2014 Mar;106(3):dju002. doi: 10.1093/jnci/dju002. Epub 2014 Mar 13.
- Weijer C, Freedman B, Fuks A, Robbins J, Shapiro S, Skrutkowska M. What difference does it make to be treated in a clinical trial? A pilot study. Clin Invest Med. 1996 Jun;19(3):179-83.
- West J, Wright J, Tuffnell D, Jankowicz D, West R. Do clinical trials improve quality of care? A comparison of clinical processes and outcomes in patients in a clinical trial and similar patients outside a trial where both groups are managed according to a strict protocol. Qual Saf Health Care. 2005 Jun;14(3):175-8.
- ATHN Transcends