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

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ClinicalTrials.gov Identifier: NCT00979238
Recruitment Status : Active, not recruiting
First Posted : September 17, 2009
Last Update Posted : January 29, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Hemophilia of Georgia, Inc.
Children's Hospital of Philadelphia
University College, London
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE September 16, 2009
First Posted Date  ICMJE September 17, 2009
Last Update Posted Date January 29, 2019
Actual Study Start Date  ICMJE February 22, 2010
Estimated Primary Completion Date June 12, 2032   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2019)
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: 1 year ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 16, 2009)
To assess the safety of systemic administration of a novel self complementary AAV vector in adults with severe hemophilia B at up tp three different dosage levels. [ Time Frame: 1 year ]
Change History Complete list of historical versions of study NCT00979238 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B
Official Title  ICMJE 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
Brief 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Hemophilia B
Intervention  ICMJE
  • 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 Name: vector
Study Arms  ICMJE Group 1

All participants who meet the eligibility requirements.

Intervention: Gene Transfer and drug (scAAV2/8-LP1-hFIXco).

Interventions:
  • Genetic: Gene Transfer
  • Drug: scAAV2/8-LP1-hFIXco
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 7, 2017)
14
Original Estimated Enrollment  ICMJE
 (submitted: September 16, 2009)
18
Estimated Study Completion Date  ICMJE December 31, 2032
Estimated Primary Completion Date June 12, 2032   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00979238
Other Study ID Numbers  ICMJE AGT4HB
5R01HL094396 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Hemophilia of Georgia, Inc.
  • Children's Hospital of Philadelphia
  • University College, London
Investigators  ICMJE
Principal Investigator: Ulrike Reiss, MD St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP