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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 : October 25, 2023
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 Phase 2

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, 2-3 times/week, intravenous injection of clotting factor concentrates, which is demanding and expensive. In contrast, gene therapy offers the potential of a cure for haemophilia A. In a previous gene therapy study in haemophilia B 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 twenty-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 5 years after vector infusion.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
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 : January 2029
Estimated Study Completion Date : December 2029

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 gene therapy [ Time Frame: Up to 5 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 5 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: Regularly up to 5 years post-infusion ]
    Assessments of plasma hFVIII activity

  2. Bleeding frequency [ Time Frame: Annual review for 5 years ]
    Assessment of bleeding frequency using participant diaries before and after gene transfer

  3. hFVIII concentrate usage [ Time Frame: Annual review for 5 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, month 6 and annually post-infusion to Year 5 ]
    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 sample clearance. ]
    Serum and bodily secretions will be collected to assess clearance of vector genomes

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

Inclusion criteria:

I. Adult males, ≥ 18 years of age; confirmed diagnosis of severe haemophilia A (baseline plasma hFVIII levels of <1% of normal; assessed by a one-stage clotting or chromogenic assay) II. A severe bleeding phenotype as defined by at least one of the following: (a) On prophylaxis for a history of bleeding or (b) On demand therapy with a current or past history of 4 or more bleeding episodes/year or (c) evidence of chronic haemophilic arthropathy (pain, joint damage, and loss of range of motion) III. Received treatment with hFVIII concentrates with at least >50 exposure days; IV. Able to give full informed consent and able to comply with all requirements of the trial including 5-year long-term follow-up; V. Willing to practice barrier contraception until at least three consecutive semen samples after vector administration are below the sensitivity of the assay for vector sequences.

Exclusion criteria:

VI. 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 on at least two occasions that required clinical management ; VII. Use of investigational therapy for haemophilia within 30 days before enrolment; VIII. Subjects with active hepatitis B or C, and HBsAg or hepatitis C 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 hepatitis C on antiviral therapy are eligible).

IX. Serological evidence of HIV; X. Evidence of liver dysfunction (persistently elevated alanine transaminase >1.5 times upper limit of normal); XI. Uncontrolled glaucoma, diabetes mellitus, or hypertension (systolic BP consistently ≥140 mmHg or diastolic BP consistently ≥90 mmHg); XII. Any disease or condition (including cancer) at the physician's discretion that would prevent the patient from fully complying with the requirements of the study.; XIII. Suspicious lung lesions on CT scan that raise the possibility of cancer or premalignant pathology (based on chest CT scan done at screening or within 6 months prior to the screening visit) XIV. Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound XV. Patients with uncontrolled cardiac failure or unstable angina; XVI. Detectable neutralising anti-AAV8 antibodies XVII. Received an AAV vector, or any other gene transfer agent in the previous 6 months except for vaccines XVIII. History of active tuberculosis, fungal disease or other chronic infection XIX. Subjects who are unwilling to provide the required semen samples XX. Poor performance status (WHO score >1) XXI. Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrillation).

XXII. Patients with a CHA2DS2-VASc score of 2 and above

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: Joanna Calvert 020 7794 0500 ext 38784

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United States, Idaho
St. Luke'S Regional Medical Center, Ltd Active, not recruiting
Boise, Idaho, United States, 83712
United States, Kentucky
University of Kentucky Recruiting
Lexington, Kentucky, United States, 40506
Contact: Vlad Radulescu, MD         
United States, Tennessee
St Jude's Children's Research Hospital 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    
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: October 25, 2023
Last Verified: October 2023
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