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Gene Therapy for Haemophilia A. (GO-8)

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. Identifier: NCT03001830
Recruitment Status : Recruiting
First Posted : December 23, 2016
Last Update Posted : February 20, 2018
Medical Research Council
Information provided by (Responsible Party):
University College, London

Brief Summary:
The GO-8 study focuses on assessing safety and efficacy of gene therapy for patients with severe haemophilia A

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: AAV2/8-HLP-FVIII-V3 Phase 1

Detailed Description:
Haemophilia A is an x-linked, life threatening bleeding disorder arising from defects in the coagulation factor VIII (FVIII) gene. Current treatment for haemophilia A, the commonest inherited bleeding disorder (prevalence of 1 in 5000 individuals) consists of life-long, 2-3X/week, intravenous injection of clotting factor concentrates, which is demanding, exceedingly expensive not widely available nor curative. In contrast, gene therapy offers the potential of a cure for haemophilia A as illustrated by our first unequivocal success in a related condition, haemophilia B. In that study the investigators showed that a single intravenous administration of a serotype 8 based adeno-associated virus, (AAV8) vector encoding the factor IX (FIX) gene resulted in stable (>6 years) therapeutic expression of FIX without long-lasting toxicity. The investigators plan to use the same AAV8 platform to evaluate a novel FVIII expression cassette, AAV2/8-HLP-FVIII-V3, in patient with haemophilia A. Extensive preclinical studies demonstrate that AAV2/8-HLP-FVIII-V3 leads to long-term, endogenous expression of FVIII in mouse and non-human primate models without toxicity even when fifty-fold higher doses than the proposed starting clinical trial dose were used. Therefore, an open label, Phase I/II dose escalation study entailing a single systemic administration of AAV2/8-HLP-FVIII-V3 in adults (>18 years of age) with severe haemophilia A who have baseline factor FVIII levels of <1% of normal has been designed to establish safety and efficacy of our approach. Dosing will begin at 6x10^11 vector genome (vg)/kg progressing sequentially to 2x10^12vg/kg and ultimately 6x10^12vg/kg in the absence of toxicity. A minimum of 2 patients will be recruited at each dose with a possibility of expanding the dose cohort to a maximum of 6 patients based on safety and efficacy. The study duration for each patient will be 15 years after vector infusion.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: GO-8: Gene Therapy for Haemophilia A Using a Novel Serotype 8 Capsid Pseudotyped Adeno-associated Viral Vector Encoding Factor VIII-V3
Actual Study Start Date : June 14, 2017
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : January 2034

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment Arm
Treatment with AAV2/8-HLP-FVIII-V3
Biological: AAV2/8-HLP-FVIII-V3
Infusion of AAV2/8-HLP-FVIII-V3

Primary Outcome Measures :
  1. Safety - Dose Limiting Toxicity possibly attributable to the ATIMP development [ Time Frame: Up to 15 years post-infusion ]
    Toxicity will be assessed according to CTCAE, version 4.03 based on the monitoring schedule which comprises a number of clinical and laboratory evaluations

  2. Safety - Neutralising anti-hFVIII antibody development following gene therapy [ Time Frame: Up to 15 years post-infusion ]
    The presence of neutralising hFVIII antibodies will be assessed by regular laboratory tests during patient follow up post infusion

Secondary Outcome Measures :
  1. Plasma hFVIII activity [ Time Frame: Week 12 post-infusion ]
    Assessments of plasma hFVIII activity using a validated chromogenic assay

  2. Bleeding frequency [ Time Frame: Annual review for 15 years ]
    Assessment of bleeding frequency using participant diaries before and after gene transfer

  3. hFVIII concentrate usage [ Time Frame: Annual review for 15 years ]
    Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer

  4. Immune response to the AAV8 capsid. [ Time Frame: Weeks 3, 6, 9 & 12 post-infusion & Month 6 post-infusion ]
    Immune response to the AAV8 capsid will be assessed by measurement of the AAV8 antibody titre (humoral response) in plasma samples collected at various time points after gene transfer. Cellular immune response to AAV capsid will be determined using gamma interferon (IFNγ) ELIspot assay to AAV8 capsid

  5. Viral shedding [ Time Frame: Weekly from 7 days post infusion until day 42. ]
    Serum and bodily secretions will be collected to assess clearance of vector genomes

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Adult males, aged 18 years or over, with a confirmed diagnosis of severe Haemophilia A defined as baseline plasma FVIII levels of <1% of normal as assessed by a validated one-stage clotting assay or a chromogenic assay, resulting from intron 22 inversions, intron 1 inversions, splice-site mutations, small deletions/insertions and missense mutations.
  • A severe bleeding phenotype as defined by at least one of the following:

    1. On prophylaxis for a history of bleeding, or
    2. On demand therapy with a current or past history of 4 or more bleeding episodes/year, or
    3. Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion)
  • Received treatment with human FVIII concentrates with at least >50 exposure days;
  • Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up;
  • Willing to practice barrier contraception after vector administration until at least three consecutive semen samples are negative for vector sequences (may be for 2-3 months).

Exclusion Criteria:

  • Presence of neutralising anti-hFVIII antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of hFVIII inhibitor;
  • Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene.
  • Use of investigational therapy for haemophilia within 30 days before enrolment;
  • Subjects with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity, respectively or currently on antiviral therapy for hepatitis B or C. (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 HCV on antiviral therapy are eligible).
  • Serological evidence of HIV-1 who have CD4 counts ≤ 200/mm3. Subjects who are HIV-positive and stable, with an adequate CD4 count (> 200/mm3) and undetectable viral load measured twice in the six months prior to enrolment, on an antiretroviral drug regimen are eligible to enrol.
  • Evidence of liver dysfunction (persistently elevated ALT >1.5X upper limit of normal);
  • Uncontrolled glaucoma, diabetes mellitus, or hypertension (systolic BP consistently ≥140 mmHg or diastolic BP consistently ≥90 mmHg);
  • History of malignancy;
  • Suspicious Lung lesions on CT scan that raise the possibility of cancer or premalignant pathology
  • Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound
  • Patients with uncontrolled cardiac failure or unstable angina;
  • Detectable neutralising anti-AAV8 antibodies
  • Received an AAV vector, or any other gene transfer agent in the previous 6 months
  • History of active tuberculosis, fungal disease or other chronic infection
  • Subjects who are unwilling to provide the required semen samples XVI. Poor performance status (WHO score >1) XVII. Previous history or family history of venous or arterial thromboembolism

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 identifier (NCT number): NCT03001830

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Contact: Mark Phillips +442078302068 ext 33768

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United States, Tennessee
St Jude's Children's Research Hospital Not yet recruiting
Memphis, Tennessee, United States, 38105-3678
Principal Investigator: Ulrike Reiss, MD         
Sub-Investigator: Andrew Davidoff, MD         
United Kingdom
Royal Free Hospital Recruiting
London, United Kingdom, NW3 2QG
Principal Investigator: Pratima Chowdary         
Sub-Investigator: Amit Nathwani         
Sub-Investigator: Edward Tuddenham         
Sponsors and Collaborators
University College, London
Medical Research Council
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Principal Investigator: Pratima Chowdary, MD Royal Free London NHS Foundation Trust

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Responsible Party: University College, London Identifier: NCT03001830     History of Changes
Other Study ID Numbers: UCL 13/0076
2016-000925-38 ( EudraCT Number )
MR/L013185/1 ( Other Grant/Funding Number: Medical Research Council )
First Posted: December 23, 2016    Key Record Dates
Last Update Posted: February 20, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII