Natural History Study of Factor IX Treatment and Complications (B-Natural)

This study will examine two groups of subjects with factor IX (FIX) deficiency: 1) those with a current or history of inhibitors to FIX, and; 2) groups of two or more affected brothers, with or without inhibitors. The overall goal is to characterize the study groups in terms of their medical history, their patterns of bleeding, their care, quality of life, and complications including the development of joint disease, inhibitory antibodies to FIX, use of immune tolerance induction (ITI) and outcome.

Study Overview

• Status: Active, not recruiting
• Conditions: Factor IX Deficiency
• Intervention / Treatment: Other: Standard care with blood and urine sample collection

Detailed Description

Hemophilia B, FIX deficiency, is the second most common type of hemophilia, occurring in about one in 25,000 male births. This disease is in some ways more complex than hemophilia A, and is less well understood. Differences include a lower incidence and a greater risk of side effects to treatment, for example, allergic reactions and kidney disease. This study will examine two groups of subjects with FIX deficiency - those with a current or history of inhibitors to FIX, and groups of two or more affected brothers, with or without inhibitors. The overall goal is to characterize the study group in terms of their medical history, their patterns of bleeding, their care, quality of life, and complications including the development of inhibitory antibodies to FIX, allergies, kidney, and joint disease.

• Study Type: Observational
• Enrollment (Anticipated): 550

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia & Thrombosis Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The population includes groups of two or more affected brothers, with or without a history of inhibitors, who share(d) one or both biological parents; and individuals with a history of an inhibitor. Most affected brother pairs will be concordant for no inhibitor and will serve as a control group for those with inhibitors. The study is open to subjects with mild (0.05-0.40 IU/mL), moderate (0.01-<0.05 IU/mL), or severe (<0.01 IU/mL) FIX deficiency. Females meeting the eligibility criteria may participate. There are no lower or upper age limits. Type of treatment, regimen, dosing and product(s) used are at the discretion of the investigator.

Description

Inclusion Criteria:

1. A consent approved by the appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC) has been obtained from the subject or his legally acceptable representative

2. Subject has FIX deficiency AND

   • Is part of an affected brother pair/group that will also enroll; AND/OR
   • Has a current or history of inhibitor, defined as >0.6 Bethesda units (BU)

Exclusion Criteria:

1. Subject has another congenital bleeding disorder
2. Subject is a carrier of hemophilia B with factor level >0.40 IU/mL

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inhibitory antibodies	Current or history of inhibitors	Baseline
Annualized bleeding rate	Overall and by bleeding site	6 months
Joint assessment	Range of motion	Baseline
Renal disorders	Reported subject and family history of renal disease	6 months
Hemophilia treatment adherence	Validated Hemophilia Regimen Treatment Adherence Scale--Prophylaxis (VERITAS-Pro), Validated Hemophilia Regimen Treatment Adherence Scale - PRN (VERITAS-PRN)	Baseline
Health related quality of life	European Quality of Life - 5 Dimensions (EQ5D)	Baseline
Non-inhibitory antibodies	Measured at central laboratory	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Factor IX usage	Treatment history with FIX replacement	6 months
Number of hospitalizations	Hospitalizations reported during 6 month follow up period	6 months
Number of surgical procedures	Surgical procedures reported during 6 month follow up period	6 months
number of days missed from school or work	Days missed from school or work during 6 month follow up period	6 months

Collaborators and Investigators

• Sponsor: Skane University Hospital
• Collaborators: Indiana Hemophilia &Thrombosis Center, Inc.; Bioverativ Therapeutics Inc.; Swedish Orphan Biovitrum
• Investigators: Study Director: Erik Berntorp, MD, PhD, Skåne University Hospital, Malmö; Study Director: Amy D Shapiro, MD, Indiana Hemophilia &Thrombosis Center, Inc.; Study Director: Jan Astermark, MD, PhD, Skåne University Hospital, Malmö; Principal Investigator: Christine Knoll, MD, Phoenix Children's Hospital, Phoenix, AZ; Principal Investigator: Yasmina Abajas, MD, University of North Carolina Hemophilia Treatment Center, Chapel Hill, NC; Principal Investigator: Catherine McGuinn, MD, Weill Cornell Medical College, New York, NY; Principal Investigator: Munira Borhany, MD, National Institute of Blood Disease and Bone Marrow Transplantation, Karachi, Pakistan; Principal Investigator: Philip Kuriakose, MD, Henry Ford Health System, Detroit, MI; Principal Investigator: Eva Funding, MD, National University Hospital Copenhagen, Copenhagen, Denmark; Principal Investigator: Stacy Croteau, MD, Boston Hemophilia Center, Boston, MA; Principal Investigator: Christine Kempton, MD, Emory University, Atlanta, Georgia; Principal Investigator: Susan Kearney, MD, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN; Principal Investigator: Suchitra Acharya, MD, Cohen Children's Medical Center, New Hyde Park, NY; Principal Investigator: Roshni Kulkarni, MD, Michigan State University, East Lansing, MI; Principal Investigator: Raina Liesner, MD, Great Ormond Street Hospital for Children, London, UK; Principal Investigator: Christoph Bidlingmaier, MD, Dr. v Hauner Children's University Hospital, Munich, Germany; Principal Investigator: Alice J. Cohen, MD, Newark Beth Israel Medical Center, Newark, NJ; Principal Investigator: Manuela Carvalho, MD, Centro Hospitalar de São João, Porto, Portugal; Principal Investigator: Margaret Ragni, MD, University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittburgh, PA US; Principal Investigator: Ulrike Reiss, MD, St. Jude Children's Research Hospital, Memphis, TN US; Principal Investigator: Michelle Witkop, DNP, FNP-BC, Munson Medical Center, Traverse City, MI, US; Principal Investigator: Katharina Holstein, MD, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Principal Investigator: Cristina Tarango, MD, Cincinnati Children's Hospital Medical Center, Cincinnati, OH US; Principal Investigator: Michael D Tarantino, MD, Bleeding and Clotting Disorders Institute, Peoria, IL US; Principal Investigator: Johannes Oldenburg, MD, Ph.D, University Clinic, Bonn

Publications and helpful links

General Publications

• Shapiro AD, Ragni MV, Borhany M, Abajas YL, Tarantino MD, Holstein K, Croteau SE, Liesner R, Tarango C, Carvalho M, McGuinn C, Funding E, Kempton CL, Bidlingmaier C, Cohen A, Oldenburg J, Kearney S, Knoll C, Kuriakose P, Acharya S, Reiss UM, Kulkarni R, Witkop M, Lethagen S, Donfield S, LeBeau P, Berntorp E, Astermark J. Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural). Haemophilia. 2021 Jan;27(1):49-59. doi: 10.1111/hae.14139. Epub 2020 Dec 5.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: July 13, 2015
• First Submitted That Met QC Criteria: July 16, 2015
• First Posted (Estimate): July 20, 2015

Study Record Updates

• Last Update Posted (Actual): May 25, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Hemophilia B; Hemophilia B with Inhibitors
• 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 B
• Other Study ID Numbers: B-Natural