ATHN 2: Factor Switching Study

• ClinicalTrials.gov Identifier: NCT02546622
• Recruitment Status: Completed
• First Posted: September 11, 2015
• Last Update Posted: December 9, 2021
• Sponsor: American Thrombosis and Hemostasis Network
• Collaborators: Shire; CSL Behring; Bioverativ Therapeutics Inc.; Bayer
• Information provided by (Responsible Party): American Thrombosis and Hemostasis Network

Study Description

Brief Summary:

This is a longitudinal, observational study of patients with Hemophilia A or B who are planning to switch to a newly approved coagulation factor replacement product, or who have recently switched factor products. The study will follow each patient for up to 1 year. Patients will be recruited at Hemophilia Treatment Centers (HTC) which are ATHN-affiliates. The primary outcome being studied is the development of inhibitor (i.e., antibodies to factor) at 1 year or 50 exposure days, whichever comes first.

The study will be conducted at approximately 30 HTCs, with a planned enrollment of 600 patients.The entire study duration is projected to be approximately 6 years.

In addition, optional substudies will be included for some products, as "Product-Specific Modules". These will be questionnaires to collect data for subjects receiving selected Factor products. For example, subjects receiving Kovaltry will be approached to participate in the 'Kovaltry Product-Specific Module'; subjects receiving Adynovate will be approached to participate in the 'Adynovate Product-Specific Module'. Questions will be related to product use, perceptions of product use, and other post-marketing consumer data.

Condition or disease	Intervention/treatment
Hemophilia	Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013; Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013

Detailed Description:

This non-interventional, minimal risk cohort study will enroll patients with Hemophilia A or B who are planning or have recently switched to a new Factor product. The study will have 2 Arms, prospective and retrospective. The Prospective Arm will enroll patients who plan to switch to a new factor. The Retrospective Arm will enroll patients who have recently switched to a new factor (within the previous 50 weeks). Patient will be seen at baseline and for up to 4 additional visits, and quarterly follow-up by phone. Required study visits will be planned to coincide with routine follow-up visits whenever possible.

Please note that Factor Replacement Products are not being provided by the study.

The primary objective is to assess and characterize the rate of inhibitor development within one (1) year or fifty (50) exposure days, whichever is first, after switching clotting factor replacement products in previously treated patients (PTPs) with hemophilia A or B.

Data collected will include eligibility, demographics, medical history, hemophilia history (clotting history, product history, genotype and family history), inhibitor history, co-morbidities at baseline (i.e., HIV, Hepatitis C.), detailed clotting factor replacement product(s) usage and switching plan, and reasons for switching factor products. Also targeted physical exams will be performed at baseline and during follow-up, and targeted concomitant medication data will be collected. Data collection will also include patient-reported outcome(s) after 1 year, bleeding events, surgeries, laboratory Inhibitor testing and details regarding testing methodology, pharmacokinetic (PK) data (if known), new diagnoses, and co-morbidities (targeted), Safety/Adverse Events using European Union Hemophilia Safety Surveillance (EUHASS) definitions.

This study will evolve to include any newly approved (since January 2013) factors as they come to market. Cohorts will be defined by the brand/type of new clotting factor replacement product approved after January 1, 2013. The current list of specific new Factor VIII replacement products include Eloctate® (Bioverativ) and NovoEight® (NovoNordisk); Factor IX replacement products include Alprolix® (Bioverativ), Rixubis® (Baxalta), and IXinity® (Emergent Biosolutions). Others are both now available and imminent and include: Adynovate®, Idelvion®, Afstyla®, Kovaltry® and Jivi®.

The over-arching rationale for this protocol is that a pragmatic study which is consistent with real world practices across a wide range of patients that is not principally tied to a particular manufacturer or product may be of great advantage to the entire hemophilia community.

Study Duration

• Subjects on prophylaxis will be followed on study for up to 1 year. Each subject will be seen during a study visit or contacted by telephone at least once every 3 months (i.e., quarterly). Patients may participate for multiple 'cycles', if they switch factor products more than once while the study is actively recruiting.

Treatment regimen will be at the discretion of the subject's hemophilia caregivers. No treatment is being provided by the study.

• Substudies A number of substudies are planned with pharmaceutical sponsors to collect information from patients about their products' use. Participation in these optional substudies (product-specific modules) will be planned to coincide with study visits. These modules will collect information from subjects about their perception and use of factor use/treatment, physical activity levels and other general health questions. These data will be collected via questionnaire, primarily via phone.

Concomitant and Excluded Therapies

• Immune tolerance therapy is excluded on study. This includes immunosuppressive treatments used to eradicate inhibitors. Steroid treatments for allergic disorders and asthma, are allowed.

Data Collection System

• All data collected will be entered into electronic case report forms (eCRFs) within the secure ATHN Study Manager system. Subject Identifiers (IDs) will be generated in Clinical Manager.
• Reimbursement will be managed by each participating HTC. Most study centers will reimburse study subjects for travel and parking, but this varies by center.

Study Design

• Study Type: Observational
• Actual Enrollment: 310 participants
• Observational Model: Cohort
• Time Perspective: Other
• Official Title: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Factor Replacement Products
• Study Start Date: September 2015
• Actual Primary Completion Date: June 30, 2020
• Actual Study Completion Date: June 30, 2020

Groups and Cohorts

Group/Cohort	Intervention/treatment
Arm A Prospective; Patients who are switching to a new Factor VIII and Factor IX Replacement Product for Hemophilia A and B which was FDA approved after January 1, 2013. These patients will be followed prospectively for up to 1 year.	Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013; Prophylaxis for prevention of bleeding, various regimens.; Other Names: Eloctate®; NovoEight®; Adynovate®; Nuwiq®; Afstyla®; Kovaltry®; Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013; Prophylaxis for prevention of bleeding, various regimens.; Other Names: Alprolix®; Rixubis®; IXinity®; Idelvion®; Rebinyn®
Arm B Retrospective; Patients who have recently switched to a new Factor VIII and Factor IX Replacement Product for Hemophilia A and B which was FDA approved after January 1, 2013. Patients must have switched products within the past 50 weeks at the time of enrollment. These patients will be assessed retrospectively and/or followed prospectively for up to 1 year.	Biological: Factor VIII Replacement Products for Hemophilia which were FDA approved after January 1, 2013; Prophylaxis for prevention of bleeding, various regimens.; Other Names: Eloctate®; NovoEight®; Adynovate®; Nuwiq®; Afstyla®; Kovaltry®; Biological: Factor IX Replacement Products for Hemophilia which were FDA approved after January 1, 2013; Prophylaxis for prevention of bleeding, various regimens.; Other Names: Alprolix®; Rixubis®; IXinity®; Idelvion®; Rebinyn®

Outcome Measures

Primary Outcome Measures :

1. Inhibitor Development [ Time Frame: After 50 Exposure Days or 1 Year, whichever comes first ]
   Inhibitor development is the primary outcome. Subjects will be followed closely and tested at baseline, after 10 Exposure Days and 50 Exposure Days, and/or at 1 year. Specimens will be submitted to local laboratories and evaluated for inhibitor titers, and inhibitors will be confirmed by local laboratories and CDC.

Secondary Outcome Measures :

1. Inhibitor Development [ Time Frame: 10 days ]
   To determine the prospective incidence of inhibitor development after 10 exposure days to a new, novel recombinant factor following a switch from another clotting factor replacement product.
2. Prevalence of risk factors for inhibitor development [ Time Frame: 1 year ]
   To compare the prevalence of selected risk factors in patients with hemophilia who develop inhibitors following switching to a new product, to those found in subjects who do not develop inhibitors.
3. Targeted post-marketing approval safety and efficacy data [ Time Frame: 1 year ]

   To collect and summarize targeted post-marketing approval safety and efficacy data for events related to clotting factor replacement products, specifically

   • To collect data on bleeding events following switching factor.
   • To summarize replacement factor product dosing regimens prescribed to the study population.
4. Platform for additional substudies [ Time Frame: 1 year ]
   To serve as a platform for product-specific questionnaires in cohorts of patients who switch to a particular product.

Biospecimen Retention:   None Retained

Plasma drawn at baseline, after 10 Exposure Days, after 50 Exposure Days, and at study end (1 year). If inhibitor suspected, sample will be drawn and tested locally, and within 2 weeks of first positive inhibitor, a confirmatory sample will be drawn and sent to CDC. Patients may be co-enrolled in other ATHN studies such as My Life Our Future, will performs genotype Samples may be linked in patient who have authorized

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

The study will enroll approximately 600 patients with hemophilia who meet the eligibility criteria and are receiving care from one of the ATHN-affiliated Hemophilia Treatment Centers (HTC). There will be 2 arms:

Arm A (Prospective) will include patients who are switching factor replacement products and will be followed prospectively for up to 1 year.

Arm B (Retrospective) will include patients who have switched factor replacement products previously (within the past 50 weeks at the time of enrollment). These patients will be assessed retrospectively and/or followed prospectively for up to 1 year.

Criteria

Inclusion Criteria

• Moderate or Severe Congenital Hemophilia A or B (FVIII or FIX clotting activity less than or equal to 5% of normal).
• Able to give informed consent (by patient or parent/authorized guardian).
• Previously treated with plasma-derived or recombinant clotting factor replacement products with at least 50 exposure days (as assessed either from direct clinical records in children under age 5, or by clinical history of dosing in older patients). For Arm B being enrolled retrospectively, this previous treatment must be prior to product switch under study.
• Planning to switch, or recently switched within the previous 50 weeks, to a new brand or type of replacement factor VIII or IX, FDA approved after January 1, 2013.
• Arm B only: Negative inhibitor screen within the last 6 months prior to switching.

Note: History of prior transient inhibitor or inhibitor eradicated by immune tolerance induction (ITI) are eligible.

Exclusion Criteria

• Presence of any known bleeding disorder other than hemophilia A or B (i.e., patients with concurrent hemophilia and a second hemostatic defect are NOT eligible). Low Von Willebrand Factor (VWF) without VWF diagnosis are not excluded.
• Presence of an active inhibitor >0.6 BU for factor VIII, > 0.4 BU for factor IX at the time of eligibility assessment. Detection of such an inhibitor at the baseline visit prior to dosing with the new product (Arm A), or after dosing with new factor dosing (Arm B), would result in early termination without other study assessments.
• Currently undergoing ITI.
• Immunosuppressive therapy (cyclophosphamide, mycophenolate, IVIG) within 90 days and Rituximab within 6 months; topical steroid treatments and short course steroids for asthma or allergy allowed.
• Previous participation in Phase I, II or III interventional trials of the factor product being switched to.

Contacts and Locations

Locations

United States, California

University of California San Diego (UCSD)

San Diego, California, United States, 92122

United States, Colorado

University of Colorado Denver Hemophilia and Thrombosis Center

Aurora, Colorado, United States, 80045

United States, Connecticut

Yale Hemophilia Treatment Center

New Haven, Connecticut, United States, 06520

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Florida

Johns Hopkins All Children's Hospital

Saint Petersburg, Florida, United States, 33701

St. Joseph's Children's Hospital

Tampa, Florida, United States, 33607

United States, Georgia

Children's Healthcare of Atlanta/Emory

Atlanta, Georgia, United States, 30322

United States, Illinois

Bleeding and Clotting Disorders Institute

Peoria, Illinois, United States, 61615

United States, Indiana

Indiana Hemophilia and Thrombosis Center (IHTC)

Indianapolis, Indiana, United States, 46260

United States, Louisiana

Louisiana Center for Bleeding and Clotting Disorders

New Orleans, Louisiana, United States, 70112

United States, Maine

Maine Hemophilia and Thrombosis Center

Scarborough, Maine, United States, 04074

United States, Maryland

Johns Hopkins University Medical Center

Baltimore, Maryland, United States, 21205

United States, Massachusetts

Boston Hemophilia Center at Children's Hospital of Boston

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan Hemophilia and Coagulation Disorders Program

Ann Arbor, Michigan, United States, 48109

Michigan State University Center for Bleeding and Clotting Disorders

East Lansing, Michigan, United States, 48823

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New Hampshire

Dartmouth-Hitchcock Comprehensive Hemophilia and Thrombosis Center

Lebanon, New Hampshire, United States, 03756

United States, New York

Weill Cornell Medicine

New York, New York, United States, 10065

Mary M. Gooley Hemophilia Center

Rochester, New York, United States, 14621

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, United States, 19104

Pennsylvania Comprehensive Hemophilia and Thrombophilia Program / Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

The Hemophilia Center of Western Pennsylvania

Pittsburgh, Pennsylvania, United States, 15213

United States, Tennessee

St Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

UTSW Medical Center at Dallas/Children's Medical Center

Dallas, Texas, United States, 75235

United States, Washington

Washington Center for Bleeding Disorders Bloodworks Northwest d/b/a Puget Sound Blood Center

Seattle, Washington, United States, 98104

United States, Wisconsin

Blood Center of Wisconsin

Milwaukee, Wisconsin, United States, 53201

Sponsors and Collaborators

American Thrombosis and Hemostasis Network

Shire

CSL Behring

Bioverativ Therapeutics Inc.

Bayer

Investigators

• Principal Investigator: Ellis J Neufeld, MD, PhD; St. Jude Children's Research Hospital
• Principal Investigator: Janna Journeycake, MD; Oklahoma Center for Bleeding and Clotting Disorders

More Information

Additional Information:

Hemophilia Treatment Center Directory 

American Thrombosis and Hemostasis Network (ATHN) 

Publications:

Josephson CD, Abshire T. The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement? Clin Adv Hematol Oncol. 2004 Jul;2(7):441-6.

Powell JS. Lasting power of new clotting proteins. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):355-63. doi: 10.1182/asheducation-2014.1.355. Epub 2014 Nov 18.

Ragni, MV, Kessler, CM, and Lozier, JN (2009). Clinical aspects and therapy for hemophilia, in Hoffman R, Benz EJ, Shattil, SJ et al eds, Hematology, Basic Principles and Practice, 5th Edition, Churchill Livingstone, Philadelphia, pp 1911-1930.

Abshire TC, Brackmann HH, Scharrer I, Hoots K, Gazengel C, Powell JS, Gorina E, Kellermann E, Vosburgh E. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS Study Group. Thromb Haemost. 2000 Jun;83(6):811-6.

Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, Hanabusa H, Gupta N, Kulkarni R, Fogarty P, Perry D, Shapiro A, Pasi KJ, Apte S, Nestorov I, Jiang H, Li S, Neelakantan S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Dodd N, Nugent K, Vigliani G, Luk A, Brennan A, Pierce GF; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16;123(3):317-25. doi: 10.1182/blood-2013-10-529974. Epub 2013 Nov 13.

• Responsible Party: American Thrombosis and Hemostasis Network
• ClinicalTrials.gov Identifier: NCT02546622
• Other Study ID Numbers: ATHN 2
• First Posted: September 11, 2015
• Last Update Posted: December 9, 2021
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Product-Specific Module data for subjects enrolled in each module will be shared with each sponsor, as appropriate.

Keywords provided by American Thrombosis and Hemostasis Network:

Factor; Coagulation; Inhibitor; HTC; Bleeding

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Factor VIII; Coagulants