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Inhibitor Development in Patients With Hemophilia A Undergoing Surgery (PASs)

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ClinicalTrials.gov Identifier: NCT01571934
Recruitment Status : Completed
First Posted : April 5, 2012
Last Update Posted : April 26, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
Hemophilia A is a genetic deficiency of factor VIII that causes blood to clot too slowly. The disease is classified based on how much factor VIII is in the blood. People with mild or moderate hemophilia A have low, but detectable, blood levels of factor VIII and bleed with trauma or surgery. At the time of surgery, they need to receive factor VIII replacement by infusion into the vein so that blood can clot normally and abnormal bleeding can be avoided. A complication of hemophilia A is the development of an antibody that binds factor VIII and makes the factor VIII infused for treatment not work properly. This antibody is called an inhibitor. In mild and moderate hemophilia A, inhibitors are not common, but have been reported to occur after intensive factor VIII infusions, as may occur at the time of surgery. This study is designed to observe people with mild and moderate hemophilia A who are having surgery. Information on the surgery, treatments given, bleeding, and infection will be gathered. Also, blood will be drawn to determine how the immune system is reacting to the factor VIII. No specific treatments will be given as part of this study. We will use the information to determine what influences inhibitor development. A better understanding of inhibitor development will help medical providers do things to avoid inhibitor development in this population or researchers to design new treatments.

Condition or disease
Hemophilia A

Detailed Description:

The development of neutralizing anti-factor VIII (fVIII) antibodies, fVIII inhibitor, is the most significant complication affecting patients with hemophilia A (HA). Once an inhibitor develops, treatment is less effective and costly. Although inhibitors occur most commonly in those with severe HA, 25% of new inhibitors occur in those with non-severe HA. In patients with non-severe HA, the development of a fVIII inhibitor can change the course of disease from one that is easily managed to one with the potential for spontaneous life-threatening difficult to treat bleeding. Although significant advances have been made in understanding risk factors for fVIII inhibitor development in patients with severe HA, studies that seek to understand the risk for fVIII inhibitor development in those with non-severe disease have been limited to retrospective analyses. In these retrospective analyses, intensive fVIII treatment and surgery have been identified as risk factors for fVIII inhibitor development in non-severe HA. Additionally, receiving fVIII by continuous infusion has been associated with fVIII inhibitor development in non-severe HA in some but not all studies and may be due in part to a more robust proinflammatory response during continuous infusion. Accordingly, the next logical step to evaluate the risk of inhibitor development associated with continuous fVIII infusion is a prospective observational cohort study. Additionally, knowledge of the immune response to fVIII in the surgical setting is essential for identification of patients at high risk for inhibitor development and development of strategies to prevent inhibitor development and is best evaluated in the setting of an prospective cohort study.

This multicenter prospective observational cohort study will enroll a total of 140 subjects at 10 centers who have mild or moderate hemophilia a (fVIII activity 1-40%) who are scheduled to undergo surgery for which at least 5 consecutive days of fVIII replacement therapy is required. The study will gather clinical data and collect blood specimens on 4 occasions over a 3 month period. Outcomes include: inhibitor development, total fVIII usage, bleeding, and markers of T cell activation.

Study Design

Study Type : Observational
Actual Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Inhibitor Development in Patients With Hemophilia A Undergoing Surgery
Study Start Date : November 2011
Primary Completion Date : February 2016
Study Completion Date : March 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia
U.S. FDA Resources

Groups and Cohorts

Mild or moderate hemophilia A
Subjects with mild or moderate hemophilia A (fVIII activity 1-40%) who are scheduled to undergo surgery for which at least 5 consecutive days of fVIII replacement therapy is required.

Outcome Measures

Primary Outcome Measures :
  1. Inhibitor development (inhibitor titer > 0.4 BU/ml) [ Time Frame: postopereratvie date 90 ]
    Primary Study Endpoint: Inhibitor development (inhibitor titer > 0.4 BU/ml) by post-operative (POD) day 90. Three months or 90 days was selected as the primary end point based on data collected in the case-control study where 17/18 cases had developed their inhibitor within 12 weeks of their intensive fVIII treatment and only 1 case developed the inhibitor >16 weeks after the intensive fVIII treatment.

Biospecimen Retention:   Samples With DNA

Blood drawn during study includes 15 ml within 7 days prior to surgery and 15 ml drawn on post-operative days 1, 14 and 90.

Samples for DNA storage will be generated from blood draw study samples.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
In addition to Emory University, subjects will be recruited at one of 8 following sites: University of Pittsburgh, University of North Carolina, Oregon Health and Science University, University of Colorado, University of Texas Health Science Center at Houston, University of Minnesota, and Indiana Hemophilia Treatment Center.

Inclusion Criteria:

  • Males with mild/moderate hemophilia A (fVIII activity 1-40%)
  • Planned surgical intervention which is anticipated to require 5 consecutive days of fVIII replacement therapy (These can be outpatient or inpatient treatment days.)
  • Weight >22.5 kg (To assure that volumes of blood to be drawn for study purposes are safe.)

Exclusion Criteria:

  • Past history of an inhibitor (inhibitor titer >0.4 BU/ml)
  • HIV infection with CD4 count <400/ul
  • Currently receiving immunosuppressive medication(s)
  • Unable to tolerate quantity of blood to be drawn
  • Current or past diagnosis autoimmune disorder
  • Current or past diagnosis of immune deficiency disorder other than HIV
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01571934

United States, Colorado
University of Colorado, Hemophilia and Thrombosis Center
Aurora, Colorado, United States, 80045
United States, Georgia
Emory University Comprehensive Hemophilia Treatment Center
Atlanta, Georgia, United States, 30322
United States, Indiana
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, United States, 46260
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599-7035
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pittsburgh and Hemophilia Center of Pennsylvania
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
The University of Texas Health Science Center at Houston
Houston, Texas, United States, 77030
Sponsors and Collaborators
Emory University
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Christine Kempton, MD, MSc Emory University
More Information

Responsible Party: Christine Kempton, MD, MSc, Emory University
ClinicalTrials.gov Identifier: NCT01571934     History of Changes
Other Study ID Numbers: IRB00046800
5K23HL105785 ( U.S. NIH Grant/Contract )
PASs ( Other Identifier: Other )
First Posted: April 5, 2012    Key Record Dates
Last Update Posted: April 26, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Christine Kempton, MD, MSc, Emory University:
Hemophilia A

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