Clinical trial NCT02546622: ATHN 2: Factor Switching Study
Official title: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Factor Replacement Products
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hemophilia
Keywords: Factor
Coagulation
Inhibitor
HTC
Bleeding
Lead sponsor: American Thrombosis and Hemostasis Network
Sponsor class: NETWORK
Collaborators: name: Shire
name: CSL Behring
name: Bioverativ Therapeutics Inc.
name: Bayer
First posted: 2015-09-11
Enrollment: 310
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
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.

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.

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.

Eligibility 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.

Primary outcomes:
measure: Inhibitor Development
timeFrame: After 50 Exposure Days or 1 Year, whichever comes first
Secondary outcomes:
measure: Inhibitor Development
timeFrame: 10 days
measure: Prevalence of risk factors for inhibitor development
timeFrame: 1 year
measure: Targeted post-marketing approval safety and efficacy data
timeFrame: 1 year
measure: Platform for additional substudies
timeFrame: 1 year
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California San Diego (UCSD)
state: California
city: Aurora
country: United States
facility: University of Colorado Denver Hemophilia and Thrombosis Center
state: Colorado
city: New Haven
country: United States
facility: Yale Hemophilia Treatment Center
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta/Emory
state: Georgia
city: Peoria
country: United States
facility: Bleeding and Clotting Disorders Institute
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center (IHTC)
state: Indiana
city: New Orleans
country: United States
facility: Louisiana Center for Bleeding and Clotting Disorders
state: Louisiana
city: Scarborough
country: United States
facility: Maine Hemophilia and Thrombosis Center
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins University Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston Hemophilia Center at Children's Hospital of Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hemophilia and Coagulation Disorders Program
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University Center for Bleeding and Clotting Disorders
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Comprehensive Hemophilia and Thrombosis Center
state: New Hampshire
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Rochester
country: United States
facility: Mary M. Gooley Hemophilia Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Comprehensive Hemophilia and Thrombophilia Program / Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: The Hemophilia Center of Western Pennsylvania
state: Pennsylvania
city: Memphis
country: United States
facility: St Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: UTSW Medical Center at Dallas/Children's Medical Center
state: Texas
city: Seattle
country: United States
facility: Washington Center for Bleeding Disorders Bloodworks Northwest d/b/a Puget Sound Blood Center
state: Washington
city: Milwaukee
country: United States
facility: Blood Center of Wisconsin
state: Wisconsin
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Ellis J Neufeld, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oklahoma Center for Bleeding and Clotting Disorders
name: Janna Journeycake, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.