Personalized Prediction of Tolerance and Immunogenicity in Hemophilia (PPTIH)

This study is not yet open for participant recruitment.
Verified July 2012 by Los Angeles Orthopaedic Hospital
Sponsor:
Collaborator:
Baxter Healthcare Corporation
Information provided by (Responsible Party):
Victor J Marder, M.D., Los Angeles Orthopaedic Hospital
ClinicalTrials.gov Identifier:
NCT01626105
First received: June 20, 2012
Last updated: July 25, 2012
Last verified: July 2012
  Purpose

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
Hemophilia A

Study Type: Observational
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Los Angeles Orthopaedic Hospital:

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

Estimated Enrollment: 55
Study Start Date: June 2012
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
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.)

  Eligibility

Ages Eligible for Study:   2 Years and older
Genders 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.

Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01626105

Contacts
Contact: Tom E. Howard, M.D., Ph.D. 404-597-8014 thoward@txbiomedgenetics.org
Contact: Victor J Marder, M.D. 310-794-1663 vmarder@mednet.ucla.edu

Locations
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    mchitlur@dmc.org   
Contact: Jeanne Lusher, M.D.    313-966-0660    jlusher@med.wayne.edu   
Principal Investigator: Meera B. Chitlur, M.D.         
Sponsors and Collaborators
Victor J Marder, M.D.
Baxter Healthcare Corporation
Investigators
Principal Investigator: Victor J. Marder, M.D. The Los Angeles Orthopaedic Hospital and The David Geffen School of Medicine at UCLA
  More Information

Additional Information:
Publications:
Responsible Party: Victor J Marder, M.D., Associate Professor, Director Hemostasis, Pathology, Veterans Affairs Greater Los Angeles, Los Angeles Orthopaedic Hospital
ClinicalTrials.gov Identifier: NCT01626105     History of Changes
Other Study ID Numbers: PPTIH No. 1
Study First Received: June 20, 2012
Last Updated: July 25, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Los Angeles Orthopaedic Hospital:
Hemophilia A
Factor VIII
Inhibitors
Immunogenicity
Pharmacogenetics
Mutation
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

ClinicalTrials.gov processed this record on April 14, 2014