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

November 13, 2023 updated by: St. Jude Children's Research Hospital

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • London, United Kingdom
        • Katharine Dormandy Haemophilia Centre and Haemostasis Unit, University College of London
  • United States
    • California
      • Stanford, California, United States, 94305
        • Stanford Medical School
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health and Science University
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • Hemophilia Center of Western Pennsylvania
    • Tennessee
      • Memphis, Tennessee, United States, 38119
        • St. Jude Children's Research Hospital
    • Texas
      • Dallas, Texas, United States, 75390-9063
        • University of Texas Southwestern
      • Temple, Texas, United States, 76508
        • Scott and White Memorial Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Group 1

All participants who meet the eligibility requirements.

Intervention: Gene Transfer and drug (scAAV2/8-LP1-hFIXco).
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.
Other Names:
  • vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time Frame: 15 years
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Collaborators

Children's Hospital of Philadelphia
National Heart, Lung, and Blood Institute (NHLBI)
University College, London
Hemophilia of Georgia, Inc.

Investigators

  • Principal Investigator: Ulrike Reiss, MD, St. Jude Children's Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 22, 2010

Primary Completion (Estimated)

June 12, 2032

Study Completion (Estimated)

December 31, 2032

Study Registration Dates

First Submitted

September 16, 2009

First Submitted That Met QC Criteria

September 16, 2009

First Posted (Estimated)

September 17, 2009

Study Record Updates

Last Update Posted (Estimated)

November 14, 2023

Last Update Submitted That Met QC Criteria

November 13, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AGT4HB
  • 5R01HL094396 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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