Personalized Prediction of Tolerance and Immunogenicity in Hemophilia (PPTIH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01626105
Recruitment Status : Unknown
Verified July 2012 by Victor J Marder, M.D., Los Angeles Orthopaedic Hospital.
Recruitment status was:  Not yet recruiting
First Posted : June 22, 2012
Last Update Posted : July 26, 2012
Baxter Healthcare Corporation
Information provided by (Responsible Party):
Victor J Marder, M.D., Los Angeles Orthopaedic Hospital

Brief Summary:
This study is designed to accurately identify the pharmacogenetic determinants of risk of Factor VIII (FVIII) inhibitor development by focusing on only a select group of Hemophilia A (HA) patients who have: (i) received a recombinant FVIII therapeutic product containing the same primary amino acid sequence since their original diagnosis; (ii) verifiable FVIII infusion histories; and (iii) been tested regularly for FVIII inhibitor development.

Condition or disease
Hemophilia A

Detailed Description:

We are developing a novel, personalized strategy for assessing immunogenicity of protein therapeutics using, as our model, the infusion of Factor VIII (FVIII) into hemophilia A (HA) patients. About 20% of all treated HA patients develop neutralizing FVIII alloantibodies ("inhibitors") that make disease management difficult and expensive. Nowadays, HA is usually treated with highly purified human recombinant (r)-proteins, an advance in safety from pathogens not accompanied by a decrease in inhibitor incidence. Current strategies for upcoming FVIII formulations focus largely on engineering the most immunogenic epitopes in the hope of forming a universally less immunogenic protein. In contrast, we are pioneering a pharmacogenetic approach to immunogenicity that takes into account the underlying variability of the patient population.

This project focuses on defining the role of individual genetic differences on FVIII immunogenicity. The principles, however, have broader application for protein therapeutics in general. We have studied non-HA-causing variants in the FVIII gene (F8) and have shown that (i) nonsynonymous (ns)-single-nucleotide polymorphisms (SNPs) encode several structurally distinct wild-type FVIII proteins in the human population and (ii) a sequence mismatch between patients' endogenous FVIII and infused FVIII due to ns-SNPs is a risk factor for inhibitor development that may explain the high inhibitor incidence in HA patients with black African ancestry.

The most well established risk factor for inhibitor development is the type of HA-causing F8 gene mutation. As a rule, large alterations in F8 and absence of antigenically cross-reactive material (CRM) in plasma are associated with inhibitor development. The most common F8 mutation causing severe HA, an intron-22-inversion (I22I), fits that description but is not associated with a high inhibitor risk. Similarly, while most HA patients with missense mutations do not develop inhibitors, this alloimmune complication occurs frequently in patients with one of a few highly recurrent missense mutations.

While not definitively established, population heterogeneity in the repertoires of HLA-class-II (HLA-II) molecules expressed on the surfaces of the antigen-presenting cells in individual patients is likely another genetic contributor to inhibitor risk.

This project is a comprehensive assessment of the pharmacogenetics of the immune response to FVIII leveraging a unique resource comprised of a group of 55 subjects with severe or moderately-severe HA who were (i) enrolled as previously-untreated patients (PUPs) in the recently concluded clinical trial known as the Advate PUP study and (ii) have received the same r-FVIII protein (i.e., Advate) since birth. Prior PUP-study data as well as new blood samples and data will be obtained from these subjects upon their enrollment into the current study. In addition to having been treated with only a single FVIII product, this exceptional patient cohort was (and continues to be) closely monitored for both FVIII infusion history and inhibitor development, the latter of which by undergoing frequent Bethesda testing. (HA patients who have been treated with several FVIII products are not ideal for testing the hypotheses we have proposed.)

Study Type : Observational
Estimated Enrollment : 55 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Study of Severe Hemophilia A Patients Who Have Only Received a Single Recombinant FVIII Therapeutic for the Purpose of Identifying the Pharmacogenetic Determinants of Tolerance and Immunogenicity
Study Start Date : June 2012
Estimated Primary Completion Date : April 2013
Estimated Study Completion Date : June 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia
U.S. FDA Resources

Biospecimen Retention:   Samples With DNA

A core laboratory exists for this study and will house a Biorepository containing the following:

  1. White blood cells
  2. Blood plasma

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Fifty five patients with severe or moderately severe hemophilia A who have received replacement therapy with a Factor VIII product representing only a single primary amino acid sequence.

Inclusion Criteria:

  • Patients with severe or moderately severe hemophilia A (HA) who have since birth been treated with only a single Factor VIII product (i.e., FVIII protein molecules containing only one primary amino acid sequence).

Exclusion Criteria:

  • HA patients with severities other than severe or moderately severe.
  • Hemophilia B patients.
  • HA patients who have been treated with more than one FVIII product.
  • HA patients who have been treated with more than one FVIII product.
  • HA patients who do not have verifiable infusion histories.
  • HA patients who lack documentable inhibitor testing & infusion histories.

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 identifier (NCT number): NCT01626105

Contact: Tom E. Howard, M.D., Ph.D. 404-597-8014
Contact: Victor J Marder, M.D. 310-794-1663

United States, Michigan
Children's Hospital of Michigan Not yet recruiting
Detroit, Michigan, United States, 48201-2196
Contact: Meera B. Chitlur, M.D.    313-966-0660   
Contact: Jeanne Lusher, M.D.    313-966-0660   
Principal Investigator: Meera B. Chitlur, M.D.         
Sponsors and Collaborators
Victor J Marder, M.D.
Baxter Healthcare Corporation
Principal Investigator: Victor J. Marder, M.D. The Los Angeles Orthopaedic Hospital and The David Geffen School of Medicine at UCLA

Additional Information:
Responsible Party: Victor J Marder, M.D., Associate Professor, Director Hemostasis, Pathology, Veterans Affairs Greater Los Angeles, Los Angeles Orthopaedic Hospital Identifier: NCT01626105     History of Changes
Other Study ID Numbers: PPTIH No. 1
First Posted: June 22, 2012    Key Record Dates
Last Update Posted: July 26, 2012
Last Verified: July 2012

Keywords provided by Victor J Marder, M.D., Los Angeles Orthopaedic Hospital:
Hemophilia A
Factor VIII
Nonsynonymous Single Nucleotide Polymorphisms
Class II Human Leukocyte Antigens

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn