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Gene Therapy for Chinese Hemophilia B

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04135300
Recruitment Status : Recruiting
First Posted : October 22, 2019
Last Update Posted : November 19, 2019
Sponsor:
Collaborator:
East China University of Science and Technology
Information provided by (Responsible Party):
Zhang Lei, Institute of Hematology & Blood Diseases Hospital

Brief Summary:
GT2019001 is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels. BBM-H901 is an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene and raise circulating levels of endogenous FIX.

Condition or disease Intervention/treatment Phase
Hemophilia B Genetic: Single dose intravenous injection of BBM-H901 Not Applicable

Detailed Description:
GT2019001 is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels. Three subjects will be enrolled and administered with single infusion of BBM-H901, an AAV at one dose level of 5x1012 vg/Kg.Subjects will provide informed consent and then undergo screening assessments up to 4-8weeks prior administration of BBM-H901. All subjects will undergo 52(+- 2) weeks safety observation and will be encouraged to enroll in an extension study to evaluate long- term safety of BBM-H901 for a total 5 years.The first subject will be dosed at 5x1012 vg/Kg and undergo 2 months safety observation of which the data will undergo review by an independent safety committee. The dosing to the second subject will not be performed until acquiring the approve from independent safety committee.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Hemophilia B patients
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gene Therapy for Chinese Hemophilia B With Adeno-associated Virus (AAV) Vector
Actual Study Start Date : October 16, 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm of BBM-H901
Subjects will be dosed with single dose of BBM-H901 at 5x10·12 vg/kg via intravenous infusion.
Genetic: Single dose intravenous injection of BBM-H901
Single dose intravenous infusion of BBM-H901, an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene in liver. The dose of BBM-H901 will be 5x10`12 vg/Kg.




Primary Outcome Measures :
  1. Incidence of treatment- related adverse events [ Time Frame: Infusion to the end of study, average 1 year. ]
    Number of patients experiencing treatment-related adverse events. Including inhibitor development.

  2. Change from baseline alanine aminotransferase ans aspartate amino transferase [ Time Frame: At multiple timepoints from pre-dose through up to 1 years post-dose ]
    liver function tests include ALT, AST.

  3. Antibody against AAV capsid protein [ Time Frame: from screening through up to 1 years ]
    Immune response against AAV capsid will be evaluated by measurement of the total antibody and neutralizing antibody against AAV capsid protein in plasma samples collected at multiple timepoints after dosing up to 1 year.


Secondary Outcome Measures :
  1. Vector- derived FIX:C and FIX antigen levels. [ Time Frame: At multiple timepoints from pre-dose through up to 1 years post-dose ]
    Vector- derived FIX:C and FIX antigen levels will be measured after dosing.


Other Outcome Measures:
  1. Vector shedding of BBM-H901 [ Time Frame: From date of infusion until the date of 3 consecutive documented negative results, assessed up to 1 year ]
    Serum and semen will be collected to assess clearance of vector genomes

  2. annualized bleeding rate changes from baseline [ Time Frame: through study completion, an average of 1 year ]
    annualized bleeding rate changes from baseline



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. Be able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local privacy regulations;
  2. Be male and ≥18 years of age;
  3. Have hemophilia B with ≤2 IU/dL (≤2 %) endogenous FIX activity levels as documented by a certified clinical laboratory at the time of screening. If the screening result is >2% due to insufficient washout from FIX protein product, then the severity of hemophilia B may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤2% FIX coagulant activity (FIX:C) ;
  4. Have had ≥50 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products based on historical data from the subject's record/history;
  5. a. Prophylaxis subjects: have had bleeding events and/or infusions with FIX protein products during the last 12 weeks documented in the subjects' medical records; OR b. On-demand subjects: have had ≥4 bleeding events in the last 52 weeks and/or chronic hemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints;
  6. Have no prior history of hypersensitivity or anaphylaxis associated with any FIX or IV immunoglobulin administration;
  7. Have no measurable FIX inhibitor as assessed by laboratory; or documented no prior history of FIX inhibitor after 50 EDs (family history of inhibitors will not exclude the subject) and no clinical signs or symptoms of decreased response to FIX administration;
  8. Have acceptable laboratory values:

    1. Hemoglobin ≥11 g/dL;
    2. Platelets ≥100,000 cells/μL;
    3. AST, ALT, alkaline phosphatase ≤2x upper limit of normal at the testing laboratory;
    4. Bilirubin ≤3x ULN ;
    5. Creatinine ≤2.0 mg/dL.
  9. Agree to use reliable barrier contraception until three consecutive semen samples after the administration of BBM- H901 are negative for vector sequences.

Exclusion Criteria:

  1. Have active hepatitis B or C, and HBsAg, hepatitis B core antibody, hepatitis B virus-DNA positivity or hepatitis C virus-RNA viral load positivity, respectively. Negative viral assays in two samples, collected at least six months apart, will be required to be considered negative. Both natural clearers and those who have cleared hepatitis C virus on antiviral therapy are eligible;
  2. Currently on antiviral therapy for hepatitis B or C;
  3. Have significant underlying liver disease, as defined by a preexisting diagnosis of portal hypertension, splenomegaly, encephalopathy, reduction below normal limits of serum albumin or evidence of significant liver fibrosis (fibrosis stage ≥ 3) within the past 6 months prior to or at Screening as determined by any of the following diagnostic modalities: AST-to-Platelet Ratio Index (APRI) >1;
  4. Have serological evidence of HIV-1 or HIV-2 with CD4 counts ≤200/mm3. Subjects who are HIV-positive and stable, with an adequate CD4 count (>200/mm3) and undetectable viral load (<50 gc/mL) measured twice in the six months prior to enrollment, on an antiretroviral drug regimen are eligible to enroll;
  5. Have anti-BBM-H901 neutralizing antibody titers ≥1:5;
  6. Have history of chronic infection or other chronic disease that the Investigator considers to constitute an unacceptable risk;
  7. Have participated in a previous gene therapy research trial within the last 52 weeks or in a clinical study with an investigational drug within the last 12 weeks;
  8. Any concurrent clinically significant major disease or any other condition that, in the opinion of the Investigator, makes the subject unsuitable for participation in the study;
  9. Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04135300


Contacts
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Contact: Feng XUE, MD +862223909009 xuefeng@ihcams.ac.cn
Contact: lei zhang, MD +862223909240 zhanglei1@ihcams.ac.cn

Locations
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China, Tianjin
Institute of Hematology & Blood Diseases Hospital Recruiting
Tianjin, Tianjin, China, 300020
Contact: Lei Zhang, MD       zhanglei1@ihcams.ac.cn   
Sponsors and Collaborators
Institute of Hematology & Blood Diseases Hospital
East China University of Science and Technology
Investigators
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Principal Investigator: Lei Zhang, MD Institute of Hematology & Blood Diseases Hospital
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Responsible Party: Zhang Lei, Professor/Vice director of Thrombosis &Hemostasis Center, Institute of Hematology & Blood Diseases Hospital
ClinicalTrials.gov Identifier: NCT04135300    
Other Study ID Numbers: IHBDH-GT2019001
First Posted: October 22, 2019    Key Record Dates
Last Update Posted: November 19, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Zhang Lei, Institute of Hematology & Blood Diseases Hospital:
Hemophilia B
gene therapy
ADENO-ASSOCIATED VIRUSES
Additional relevant MeSH terms:
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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