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Gene Transfer for Subjects With Hemophilia B Factor IX Deficiency

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
The Hemophilia Center of Western Pennsylvania
Royal Prince Alfred Hospital, Sydney, Australia
University of Campinas, Brazil
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT00515710
First received: August 10, 2007
Last updated: April 5, 2013
Last verified: April 2013
History of Changes
  Purpose

Hemophilia B is caused by a defect in the gene that produces the factor IX protein. Factor IX protein is important in blood clotting. Patients with severe hemophilia B, have less than 1% of the normal factor IX. Such low levels can result in spontaneous bleeding episodes that cause destruction of bone and tissue. The purpose of this research study is to determine the safety of a new type of approach called gene transfer for the treatment of hemophilia B. Since the factor IX gene was discovered, scientists have been working on ways to transfer the normal factor IX gene into hemophilia B patients' cells to cause their cells to produce normal factor IX protein. This type of approach is called gene transfer. The agents used to bring a gene inside cells are called "vectors". Many vectors are derived from viruses. In nature, viruses must get inside cells in order to reproduce. Adeno-associated virus (AAV) will be used to transfer a normal gene for human clotting factor IX into subjects with severe hemophilia B (AAV human Factor IX vector). In this study, AAV human Factor IX vector will be injected into the liver using a catheter inserted into a large blood vessel (called the proper hepatic artery or the right hepatic artery).


Condition Intervention Phase
Hemophilia B
 Biological: AAV2-hFIX
 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Safety Study in Subjects With Severe Hemophilia B (Factor IX Deficiency) Using Adeno-Associated Viral Vector to Deliver the Gene for Human Factor IX Into the Liver Coupled With Transient Immunomodulation.

Resource links provided by NLM:

Drug Information available for: Factor IX
U.S. FDA Resources

Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Safety and tolerability of intra-hepatic administration of AAV2-hFIX. Toxicity related to the administration of AAV2-hFIX will be evaluated locally and systemically. [ Time Frame: 12 month study with long-term follow-up to 15 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The study will evaluate potential efficacy in each dose group by measuring biological and physiological activity of the transgene product. [ Time Frame: 12 month study with long-term follow-up to 15 years ] [ Designated as safety issue: No ]
  • To assess the humoral and cellular immune responses to the AAV vector and transgene product FIX. [ Time Frame: 12 month study with long-term follow-up to 15 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 9
Study Start Date: August 2007
Estimated Study Completion Date: August 2024
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
dose cohort 1
 Biological: AAV2-hFIX
Subjects will be infused with AAV2-hFIX as they are enrolled into the clinical study. Subjects within a dose cohort will be staggered by at least six weeks. Escalation to a higher dose cohort will be based on interim safety assessments; the data from all subjects enrolled in a cohort, out to at least 4 weeks following the vector infusion, will be reviewed by the DSMB prior to dose escalation. Progression to a higher dose cohort will not occur until at least one subject in the previous cohort has completed the immunosuppressive regimen with no dose limiting toxicity.
Experimental: 2
dose cohort 2
 Biological: AAV2-hFIX
Subjects will be infused with AAV2-hFIX as they are enrolled into the clinical study. Subjects within a dose cohort will be staggered by at least six weeks. Escalation to a higher dose cohort will be based on interim safety assessments; the data from all subjects enrolled in a cohort, out to at least 4 weeks following the vector infusion, will be reviewed by the DSMB prior to dose escalation. Progression to a higher dose cohort will not occur until at least one subject in the previous cohort has completed the immunosuppressive regimen with no dose limiting toxicity.
Experimental: 3
dose cohort 3
 Biological: AAV2-hFIX
Subjects will be infused with AAV2-hFIX as they are enrolled into the clinical study. Subjects within a dose cohort will be staggered by at least six weeks. Escalation to a higher dose cohort will be based on interim safety assessments; the data from all subjects enrolled in a cohort, out to at least 4 weeks following the vector infusion, will be reviewed by the DSMB prior to dose escalation. Progression to a higher dose cohort will not occur until at least one subject in the previous cohort has completed the immunosuppressive regimen with no dose limiting toxicity.

Detailed Description:

The purpose of this research study is to determine the safety of gene transfer for the treatment of hemophilia B. Adeno-associated virus (AAV) will be used to transfer a normal gene for human clotting factor IX into subjects with severe hemophilia B (AAV human Factor IX vector). In this study, AAV human Factor IX vector will be injected into the liver using a catheter inserted into the proper hepatic artery or the right hepatic artery.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willingness to adhere to protocol and companion protocol for 15 year long-term follow-up as evidenced by written informed consent.
  2. Males with severe hemophilia B with FIX activity level ≤ 1% of normal.
  3. Age ≥ 18 years old.
  4. Life expectancy ≥ 1 year.
  5. Greater than twenty exposure days of treatment with FIX protein.
  6. No history or presence of an inhibitor to FIX protein.
  7. Subjects must have a normal prothrombin time (PT).
  8. Hepatitis C infected subjects will be evaluated for liver fibrosis based on liver biopsy data graded on a scale of 0-4 (Poynard et al., 1997). Subjects who are Hepatitis C antibody and RNA positive and have not had a liver biopsy within the last 36 months will be required to undergo one. The subject is eligible if he meets the following liver fibrosis criteria:

8.1. The subject has had a liver biopsy within the 36 months prior to enrollment and has a liver fibrosis stage of 0-2.

8.2. The liver biopsy may be waived for those subjects who are hepatitis C antibody positive but RNA viral load negative by PCR analysis on two separate occasions (at least six months apart), and do not have a history of receiving anti-hepatitis C therapy. These subjects are considered to have spontaneously cleared their hepatitis C infection.

8.3. Treatment for Hepatitis C infection is acceptable for enrollment in the study if the treatment concluded more than one year prior to vector administration; subjects who are RNA viral load negative as a result of anti-hepatitis C therapy will require a liver biopsy within the last 36 months.

Exclusion Criteria:

  1. Platelet count < 100,000/μL.
  2. Subjects who must remain on, or desire to remain on, a regimen of prophylactic infusion of FIX protein.
  3. Active infections other than HCV.
  4. Renal impairment as defined by a creatinine clearance of < 60 mL/min/1.73 m2.

  5. Moderate liver disease defined as any of the following:

    5.1. Bilirubin: > 2.5 X upper limits of normal. 5.2. Transaminases: > 2 X upper limits of normal. 5.3. Alkaline phosphatase: > 2 X upper limits of normal.

  6. Subjects with known allergic history to contrast dye.
  7. Subjects actively on anti-hepatitis C therapy.
  8. AAV neutralizing antibody titer > 1:20.
  9. Subjects who are HIV-positive.
  10. Subjects with a history of active cancer in the past 6 months. Subjects with any history of skin cancer will be seen by a dermatologist before entering the trial.
  11. Participation in a clinical study with an investigational drug in the past 6 months.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00515710

Locations
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Hemophilia Center of Western Pennsylvania
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Children's Hospital of Philadelphia
The Hemophilia Center of Western Pennsylvania
Royal Prince Alfred Hospital, Sydney, Australia
University of Campinas, Brazil
Investigators
Principal Investigator: Margaret V Ragni, MD The Hemophilia Center of Western Pennsylvania, University of Pittsburgh
  More Information

Publications:

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT00515710     History of Changes
Other Study ID Numbers: AAV2-hFIX-002, 10-007630
Study First Received: August 10, 2007
Last Updated: April 5, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: Human Research Ethics Committee
Brazil: National Committee of Ethics in Research
Brazil: Ministry of Health

Keywords provided by Children's Hospital of Philadelphia:
Hemophilia B
Gene Transfer
Adeno-Associated Virus (AAV)
Coagulation Factor IX

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

ClinicalTrials.gov processed this record on May 19, 2013