Gene Transfer for Subjects With Hemophilia B Factor IX Deficiency - Full Text View

Sponsors and Collaborators:	Children's Hospital of Philadelphia The Hemophilia Center of Western Pennsylvania State University of Campinas
Information provided by:	Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:	NCT00515710

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-hFIX16	Phase I

Genetics Home Reference related topics: hemophilia L1 syndrome

Drug Information available for: Factor IX

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label, Dose Comparison, Single Group Assignment, Safety/Efficacy Study
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.

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

Primary Outcome Measures:

Safety and tolerability of intra-hepatic administration of AAV2-hFIX16. Toxicity related to the administration of AAV2-hFIX16 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 2012
Estimated Primary Completion Date:	August 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental dose cohort 1	Biological: AAV2-hFIX16 Subjects will be infused with AAV2-hFIX16 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.
2: Experimental dose cohort 2	Biological: AAV2-hFIX16 Subjects will be infused with AAV2-hFIX16 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.
3: Experimental dose cohort 3	Biological: AAV2-hFIX16 Subjects will be infused with AAV2-hFIX16 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:

Willingness to adhere to protocol and companion protocol for 15 year long-term follow-up as evidenced by written informed consent.
Males with severe hemophilia B with FIX activity level ≤ 1% of normal.
Age ≥ 18 years old.
Life expectancy ≥ 1 year.
Greater than twenty exposure days of treatment with FIX protein.
No history or presence of an inhibitor to FIX protein.
Subjects must have a normal prothrombin time (PT).
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 one year 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.

Exclusion Criteria:

Platelet count < 100,000/μL.
Subjects who must remain on, or desire to remain on, a regimen of prophylactic infusion of FIX protein.
Active infections other than HCV.
Renal impairment as defined by a creatinine clearance of < 60 mL/min/1.73 m2.
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.
Subjects with known allergic history to contrast dye.
Subjects actively on anti-hepatitis C therapy.
AAV neutralizing antibody titer > 1:20.
Subjects who are HIV-positive.
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.
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

Contacts

Contact: Jennifer Wellman McDonnell, MS	215-590-7261	mcdonnellj@email.chop.edu
Contact: Junwei Sun, MS	267-426-5256	sunj@email.chop.edu

Locations

United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Amanda Wade 267-426-5586 wadea@email.chop.edu
Principal Investigator: Barbara Konkle, MD
Sub-Investigator: Valder Arruda, MD, PhD
Hemophilia Center of Western Pennsylvania	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Kristen Jaworski, RN, BSN 412-209-7284 kjaworski@itxm.org
Contact: Lauri Hahn lahahn@itxm.org
Principal Investigator: Margaret V Ragni, MD

Sponsors and Collaborators

Children's Hospital of Philadelphia

The Hemophilia Center of Western Pennsylvania

State University of Campinas

Investigators

Principal Investigator:

Margaret V Ragni, MD

The Hemophilia Center of Western Pennsylvania, University of Pittsburgh

More Information

Publications:

Mingozzi F, Hasbrouck NC, Basner-Tschkarajan E, Edmonson SA, Hui DJ, Sabatino DE, Zhou S, Wright JF, Jiang H, Pierce GF, Arruda VR, High KA. Modulation of tolerance to the transgene product in a non-human primate model of AAV-mediated gene transfer to liver. Blood. 2007 Jul 3; [Epub ahead of print]

Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, Ragni MV, Manno CS, Sommer J, Jiang H, Pierce GF, Ertl HC, High KA. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007 Apr;13(4):419-22. Epub 2007 Mar 18.

Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006 Mar;12(3):342-7. Epub 2006 Feb 12. Erratum in: Nat Med. 2006 May;12(5):592. Rasko, John [corrected to Rasko, John JE]; Rustagi, Pradip K [added].

Responsible Party:	Director, Center for Cellular and Molecular Therapeutics at CHOP ( Katherine A. High, MD )
Study ID Numbers:	AAV2-hFIX16-002, 2007-3-5212
Study First Received:	August 10, 2007
Last Updated:	December 2, 2008
ClinicalTrials.gov Identifier:	NCT00515710
Health Authority:	United States: Food and Drug Administration; United States: Institutional Review Board; 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

Study placed in the following topic categories:

Virus Diseases
Hemophilia B
Hemorrhagic Disorders
Genetic Diseases, Inborn
Hematologic Diseases

Blood Coagulation Disorders
Hemophilia A
Genetic Diseases, X-Linked
Hemostatic Disorders

Additional relevant MeSH terms:

Blood Coagulation Disorders, Inherited
Coagulation Protein Disorders

ClinicalTrials.gov processed this record on January 16, 2009