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

• ClinicalTrials.gov Identifier: NCT00979238
• Recruitment Status: Active, not recruiting
• First Posted: September 17, 2009
• Last Update Posted: May 15, 2023
• Sponsor: St. Jude Children's Research Hospital
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Genetic: Gene Transfer; Drug: scAAV2/8-LP1-hFIXco	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: February 22, 2010
• Estimated Primary Completion Date: June 12, 2032
• Estimated Study Completion Date: December 31, 2032

Arms and Interventions

Arm	Intervention/treatment
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 Name: vector

Outcome Measures

Primary Outcome Measures :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford Medical School

Stanford, California, United States, 94305

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40536

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Hemophilia Center of Western Pennsylvania

Pittsburgh, Pennsylvania, United States, 15213

United States, Tennessee

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38119

United States, Texas

University of Texas Southwestern

Dallas, Texas, United States, 75390-9063

Scott and White Memorial Hospital

Temple, Texas, United States, 76508

United Kingdom

Katharine Dormandy Haemophilia Centre and Haemostasis Unit, University College of London

London, United Kingdom

Sponsors and Collaborators

St. Jude Children's Research Hospital

National Heart, Lung, and Blood Institute (NHLBI)

Hemophilia of Georgia, Inc.

Children's Hospital of Philadelphia

University College, London

Investigators

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

More Information

Additional Information:

St. Jude Children's Research Hospital 

Clinical Trials Open at St. Jude 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20;371(21):1994-2004. doi: 10.1056/NEJMoa1407309.

Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O'Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357-65. doi: 10.1056/NEJMoa1108046. Epub 2011 Dec 10.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00979238
• Other Study ID Numbers: AGT4HB; 5R01HL094396 ( U.S. NIH Grant/Contract )
• First Posted: September 17, 2009
• Last Update Posted: May 15, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:

Hemophilia B; Factor IX Gene; Factor IX Protein; Vector

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked