ATHN 8: Previously Untreated Patients (PUPs) Matter Study

Sponsor

American Thrombosis and Hemostasis Network (Other)

Overall Status

Recruiting

CT.gov ID

NCT03818529

Collaborator

CSL Behring (Industry), Octapharma (Industry), Takeda (Industry)

250

Enrollment

Locations

61.9

Anticipated Duration (Months)

9.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia Hemophilia A Hemophilia B Hemophilia A With Inhibitor Hemophilia B With Inhibitor Haemophilia B Without Inhibitor Haemophilia A Without Inhibitor Haemophilia

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 Design

Study Type:

Observational

Anticipated Enrollment :

250 participants

Observational Model:

Cohort

Time Perspective:

Other

Official Title:

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

Actual Study Start Date :

Oct 3, 2018

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Outcome Measures

Primary Outcome Measures

Determine percentage of patients with confirmed inhibitors [6 years]
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.

Secondary Outcome Measures

Determine risk factors including genetic variants associated with inhibitor development in PUPs [6 years]
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.
Determine percentage of eligible participants enrolled at each site [6 years]
Sites will report number of eligible participants and number of participants enrolled to determine the percentage of enrollment.
Determine mean age of diagnosis and first exposure to factor treatment product [6 years]
Sites will document the date of diagnosis and the date of first exposure to clotting factor treatment product.
Determine the number of exposure days prior to inhibitor development [6 years]
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.
Report bleeding complications that occur within the first 50 ED [6 years]
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.
Summarize factor replacement dosing regimen prescribed to this study population within the first 50 ED [6 years]
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.
Report on the number of transient inhibitor, e.g., those which resolve without change in therapy [6 years]
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.
Report on targeted post-approval safety data for events related to clotting factor replacement products used by prospectively enroll participants [6 years]
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).
Sub-study modules will be developed to evaluate and report on cohorts of study participants who initiated treatment with a specific product [6 years]
Measure the number of participants who initiate treatment with a specific treatment product

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 13 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

American Thrombosis and Hemostasis Network
CSL Behring
Octapharma
Takeda

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