Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B

Hemophilia B Clinical Trial

Official title:

An Open Label Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector (scAAV 2/8-LP1-hFIXco) For Gene Transfer in Hemophilia B

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00979238
• Other study ID #: AGT4HB
• Secondary ID: 5R01HL094396
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: February 22, 2010
• Est. completion date: December 31, 2032

Study information

• Verified date: May 2024
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety of giving a normal factor IX gene to treat individuals who have an abnormal or no factor IX gene. Recruitment will be limited to adults (≥ 18 years) with a confirmed diagnosis of hemophilia B (HB), resulting from a missense mutation in the coagulation factor IX (FIX) gene or a nonsense mutation that has not been associated with an inhibitor. Only subjects who have no evidence of active hepatitis or anti-hFIX antibodies, and who have been treated/exposed to Factor IX concentrates for at least ten years and have had an average of 3 bleeding episodes per year requiring FIX administration will be enrolled. Patients will be recruited within the United States for treatment at St. Jude Children's Research Hospital, and patients will be recruited in England and other countries for treatment in London by our British collaborators.

Description:

Hemophilia B is caused by an absence or abnormality in the gene that produces the factor IX protein. Affected individuals cannot make a blood clot effectively and suffer from severe bleeding episodes. Repeated bleeding episodes, specifically into joints, can cause chronic joint disease and lead to disability. This research study will test the safety of giving an affected individual a normal factor IX gene which can produce factor IX protein in his body. We will give the normal gene for factor IX by using an inactivated (not able to function) virus called "the vector." The vector used in this study was developed from an adeno-associated virus that has been changed so that it is unable to cause a viral infection in humans. This inactivated virus was further altered to carry the factor IX gene and to locate within liver cells where factor IX protein is normally made.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 14
• Est. completion date: December 31, 2032
• Est. primary completion date: June 12, 2032
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males = 18 years of age with established severe HB (FIX:C<1u/dl),

• Treated/exposed to FIX products (e.g., concentrates or fresh frozen plasma) for at least 10 years or 50 exposure days.

• A minimum of an average of 3 bleeding episodes per year requiring FIX infusions or prophylactic FIX infusions because of frequent prior bleeding episodes

• Able to give informed consent and comply with requirements of the trial

• Currently free of inhibitor and have no history of inhibitors to FIX protein

• A negative family history for the development of an inhibitor,

• Willing to practice a reliable barrier method of contraception until 3 sequential samples are negative for vector genomes using our PCR assay.

Exclusion Criteria:

• Evidence of active infection with Hepatitis B or C virus as reflected by HBsAg or NCV RNA positivity, respectively. To be considered negative for active infection, two negative assays at a minimum of a six month interval are required.

• Exposure to Hepatitis B or C who are currently on antiviral therapy.

• Serological evidence of HTLV or active HIV infection. Individuals who are effectively being treated with antiretroviral therapy are eligible. Specific criteria for effectiveness of treatment include the following:

• Documented CD4+ T-cell count of > 350 cells/mm^3.

• HIV-1 RNA viral load < 400 copy/ml for at least the past 12 months, including at least 2 viral load test results of < 400 copy/ml during the immediate 12 month interval prior to screening.

• Screening HIV-RNA viral load < 400 copies/ml.

• Stable HAART regimen (drugs of at least 2 different classes) for at least 12 months prior to study entry. Treatment regimen changes for dosing convenience and in response to toxicity are permitted.

• Documented and confirmed (repeated) viral loads of = 400 copies/ml during the 12 month time interval prior to screening are bases for exclusion although a single, unconfirmed, "glimpse" of = 400 copies/ml are permitted.

• Significant liver dysfunction as defined by an abnormal ALT (alanine transaminase), bilirubin, alkaline phosphatase or INR. Potential participants who have had a liver biopsy in the past 3 years will be excluded if they have significant fibrosis of 3 or 4 as rated on a scale of 0-4.

• Coronary artery disease as a co-morbid condition

• Platelet count of <50 x 10^9/l

• Creatinine = 1.5 mg/dl

• Hypertension with systolic blood pressure (BP) = 140 mmHg or diastolic BP = 90 mmHg

• History of active tuberculosis, fungal disease or other chronic infection

• History of chronic disease that would adversely affect performance other than hemophilic arthropathy

• Detectable antibodies reactive with AAV8

• Subjects who are unwilling to provide the required semen samples

• Poor performance status (WHO performance status score >1) or

• Received an AAV vector or any other gene transfer agent in the previous 6 months

• Presence of lung nodule(s) suspicious of malignancy on screening chest tomography

• Presence of liver abnormalities suspicious of malignancy on screening liver ultrasound

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia B

Intervention

Genetic:
• Gene Transfer
Peripheral vein infusion of scAAV2/8-LP1-hFIXco vector once per participant

Drug:
• scAAV2/8-LP1-hFIXco
Peripheral vein infusion of scAAV2/8-LP1-hFIXco vector once per participant.

Locations

Country	Name	City	State
United Kingdom	Katharine Dormandy Haemophilia Centre and Haemostasis Unit, University College of London	London
United States	University of Texas Southwestern	Dallas	Texas
United States	University of Kentucky	Lexington	Kentucky
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Hemophilia Center of Western Pennsylvania	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Stanford Medical School	Stanford	California
United States	Scott and White Memorial Hospital	Temple	Texas

Sponsors (5)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Children's Hospital of Philadelphia, Hemophilia of Georgia, Inc., National Heart, Lung, and Blood Institute (NHLBI), University College, London

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To assess the safety of systemic administration of a novel self-complementary AAV vector in adults with severe hemophilia B at up to four different dosage levels.	Outcome measures are descriptive in nature but data collected in a longitudinal manner will also be analyzed (as and when appropriate) using longitudinal methods such as mixed effect model which takes into account the correlation among the observation taken at various time points within a participant.	15 years

External Links

•   Clinical Trials Open at St. Jude
•   St. Jude Children's Research Hospital