ATHN 8: Previously Untreated Patients (PUPs) Matter Study

US Cohort Study of Previously Untreated Patients (PUPs) With Congenital Hemophilia

This is a multi-center cohort study of approximately 250 previously untreated patients (PUPs) with congenital moderate to severe hemophilia A or B in a network of up to 50 US Hemophilia Treatment Centers (HTCs). Participants will be followed as they receive their first 50 exposure days (ED) to clotting factor replacement product, both prospectively and retrospectively. The data collected on evolving treatment practices will define the incidence and risk factors for inhibitor development during the high risk period of first 50 ED and improve the outcomes of this vulnerable population.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Hemophilia B; Hemophilia; Hemophilia A With Inhibitor; Haemophilia; Hemophilia B With Inhibitor; Haemophilia A Without Inhibitor; Haemophilia B Without Inhibitor

Detailed Description

This multi-center, longitudinal, observational, prospective and retrospective study of previously untreated patients (PUPs) with moderate to severe hemophilia A or B during the initial 50 exposure days (ED) to clotting factor replacement product or until the development of a confirmed inhibitor. The Primary Investigators have designed the study to utilize the American Thrombosis and Hemostasis Network (ATHN) electronic infrastructure to leverage existing data and enable the collection of more in-depth clinical and laboratory data on PUPs. The study aligns with the National Hemophilia Foundation Medical and Scientific Advisory Council (MASAC) recently issued Recommendation #243 which includes: "Regardless of which option is chosen, all PUPs should be enrolled in the ATHN data collection system or a clinical trial to assess outcomes." Co-enrollment in the ATHNdataset by participants is required. The total study duration is planned for 6 years.

The primary objective is to determine the percentage of patients with confirmed inhibitors within the first 50 ED. Confirmed inhibitors are defined as two consecutive positive inhibitor titers (per CDC laboratory criteria; >0.5 Nijmegen Bethesda Units for hemophilia A and >0.3 Nijmegen Bethesda Units for hemophilia B) on different blood samples which result in change in treatment recommendations.

Please note - the treatment regimen will be at the discretion of the participants' hemophilia caregivers. No treatment products are being provided by the study nor will the participants be paid. However, inhibitor titer testing will be provided at no cost to participants by the Centers for Disease Control and Prevention (CDC).

All study procedures and follow-up will be timed to coincide with scheduled hemophilia care whenever possible. Ad hoc, quarterly follow-up, annual and final visits are for participants who have not met study endpoints (50 ED or inhibitor development) prior to enrollment.

Data collected will include eligibility, demographics, medical history (co-morbidities, surgery/procedures, immunizations and allergies), hemophilia history (severity, genotype and family history), birth history, inhibitor testing results, detailed treatment product(s) usage, bleeding events, bleeding disorder related medical visits during the study, and EUHASS adverse events.

Sub-studies

A number of sub-studies are planned with pharmaceutical sponsors to collect information from patients about their specific product use. Participation in these product specific sub-studies is optional and sub-study visits will be planned to coincide with HTC visits. The sub-study will collect information from patients about their perception and use of treatment products, physical activity levels and other general health questions. This data will be collected via questionnaire.

Data Collection System

All data collected will be entered into electronic case report forms (eCRFs) within the secure ATHN System by HTC site personnel. All participating study sites will have in place a current, executed Data Use and Business Associate Agreement (DUBAA) with ATHN.

• Study Type: Observational
• Enrollment (Actual): 237

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Arizona Hemophilia and Thrombosis Center at Phoenix Children's Hospital
  • California
    • Madera, California, United States, 93636
      • Valley Children's Hospital
    • San Diego, California, United States, 92123
      • Rady Children's Hospital San Diego
    • San Francisco, California, United States, 94158
      • UCSF Pediatric Hemophilia Treatment Center at Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver Hemophilia and Thrombosis Center
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • Connecticut Bleeding and Clotting Disorders Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta/Emory
    • Augusta, Georgia, United States, 30912
      • Augusta University Hemophilia Treatment Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center (IHTC)
  • Kansas
    • Kansas City, Kansas, United States, 64108
      • Kansas City Regional Hemophilia Center
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Hemophilia and Thrombosis Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Hemophilia Center at Children's Hospital of Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hemophilia and Coagulation Disorders
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Comprehensive Hemophilia Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center, Hemophilia & Thrombosis Center
    • Cleveland, Ohio, United States, 44106
      • UHHS Cleveland
    • Toledo, Ohio, United States, 43606
      • Northwest Ohio Hemophilia Treatment Center at the Toledo Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Center for Bleeding and Clotting Disorders
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Utah Center for Bleeding & Clotting Disorders at Primary Children's Hospital
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54311
      • Hemophilia Outreach Center
    • Milwaukee, Wisconsin, United States, 53201
      • Blood Center of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 13 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll a cohort of 250 participants born with hemophilia on or after January 1, 2010 who meet the eligibility criteria and are receiving care from one of the participating HTCs.

Description

Inclusion Criteria:

• Congenital hemophilia A; FVIII </=5% or congenital hemophilia B; FIX </=5%;
• Birth date on or after January 1, 2010;
• Care established at one of the participating HTCs;
• Co-enrollment in the ATHNdataset; and
• Parent or authorized guardian can provide informed consent

Exclusion Criteria:

• Patients who are referred to the HTC with no record of bleed and factor utilization data

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine percentage of patients with confirmed inhibitors	Participants will be followed to assess inhibitor development (per CDC laboratory criteria; >0.5 Nijmegen Bethesda Units for hemophilia A and >0.3 Nijmegen Bethesda Units for hemophilia B) within 50 exposure days. Blood specimens will be submitted to the CDC for inhibitor testing at various time points outlined in the protocol.	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine risk factors including genetic variants associated with inhibitor development in PUPs	The study will provide a systematic approach to data collection by using the ATHN System to provide database infrastructure and data collection methods to evaluate determinants of inhibitor formation.	6 years
Determine percentage of eligible participants enrolled at each site	Sites will report number of eligible participants and number of participants enrolled to determine the percentage of enrollment.	6 years
Determine mean age of diagnosis and first exposure to factor treatment product	Sites will document the date of diagnosis and the date of first exposure to clotting factor treatment product.	6 years
Determine the number of exposure days prior to inhibitor development	Sites and participants will work together to provide detailed records of exposure days to clotting factor replacement products. The CDC will act as the central laboratory for the study and provide inhibitor testing.	6 years
Report bleeding complications that occur within the first 50 ED	The documentation of bleeding events in the study records will be based on the review of bleeding and infusion records provided by the participant or the from medical chart review during the first 50 exposure days to clotting factor replacement product.	6 years
Summarize factor replacement dosing regimen prescribed to this study population within the first 50 ED	A summary of the prescribed clotting factor replacement regimen will provide data on evolving treatment practices, including specific clotting factor replacement and non-factor products.	6 years
Report on the number of transient inhibitor, e.g., those which resolve without change in therapy	The CDC is acting as the central laboratory for inhibitor testing. The CDC will report results to the participating HTC. If a blood specimen from a participant has an elevated result; potentially indicating the development of an inhibitor, a new blood specimen from the participant will be tested within 10 days of the first elevated result to determine if an inhibitor has developed. A transient inhibitor is defined as a positive inhibitor which is not confirmed on a consecutive repeat testing. Inhibitor testing results on all participants will be documented and reported by the HTC.	6 years
Report on targeted post-approval safety data for events related to clotting factor replacement products used by prospectively enroll participants	Documentation of adverse events experienced by prospectively enrolled participants during the study period of first 50 exposure days to clotting factor replacement product will be reported. The types of adverse events to be reported are limited to Serious Adverse Events as defined by the European Union Haemophilia Safety Surveillance System (EUHASS).	6 years
Sub-study modules will be developed to evaluate and report on cohorts of study participants who initiated treatment with a specific product	Measure the number of participants who initiate treatment with a specific treatment product	6 years

Collaborators and Investigators

• Sponsor: American Thrombosis and Hemostasis Network
• Collaborators: Takeda; CSL Behring; Octapharma
• Investigators: Principal Investigator: Shannon Carpenter, MD, MS, Children's Mercy Hospital Kansas City; Principal Investigator: Courtney Thornburg, MD, MS, University of California San Diego, Rady Children's Hospital San Diego; Principal Investigator: Marijke van den Berg, MD, PhD, Versiti

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 3, 2018
• Primary Completion (ACTUAL): January 26, 2022
• Study Completion (ACTUAL): December 31, 2022

Study Registration Dates

• First Submitted: January 23, 2019
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (ACTUAL): January 28, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 1, 2023
• Last Update Submitted That Met QC Criteria: January 30, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Haemophilia; Hemophilia; Clotting Factor Replacement Products; Previously Untreated Patients (PUPs)
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: ATHN 8

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No