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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.
 
ClinicalTrials.gov Identifier: NCT03001830
Recruitment Status : Recruiting
First Posted : December 23, 2016
Last Update Posted : March 13, 2020
Sponsor:
Collaborator:
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
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 : December 2020
Estimated Study Completion Date : June 2025

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
Criteria

Inclusion criteria:

I. Adult males, ≥ 18 years of age; confirmed diagnosis of severe HA (baseline plasma hFVIII levels of <1% of normal; assessed by a one-stage clotting or chromogenic assay) resulting from gene mutations that have a low risk for inhibitor development, such as intron 22 inversions, intron 1 inversions, splice-site mutations, small deletions/insertions, duplications and missense mutations; 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; VII. Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene.

VIII. Use of investigational therapy for haemophilia within 30 days before enrolment; IX. 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).

X. Serological evidence of HIV; XI. Evidence of liver dysfunction (persistently elevated ALT >1.5X upper limit of normal); XII. Uncontrolled glaucoma, diabetes mellitus, or hypertension (systolic BP consistently ≥140 mmHg or diastolic BP consistently ≥90 mmHg); XIII. 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.; XIV. 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) XV. Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound XVI. Patients with uncontrolled cardiac failure or unstable angina; XVII. Detectable neutralising anti-AAV8 antibodies XVIII. Received an AAV vector, or any other gene transfer agent in the previous 6 months XIX. History of active tuberculosis, fungal disease or other chronic infection XX. Subjects who are unwilling to provide the required semen samples XXI. Poor performance status (WHO score >1) XXII. 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).

XXIII. 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 ClinicalTrials.gov identifier (NCT number): NCT03001830


Contacts
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Contact: Mark Phillips +442078302068 ext 38784 mark.phillips@ucl.ac.uk

Locations
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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
Investigators
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Principal Investigator: Pratima Chowdary, MD Royal Free London NHS Foundation Trust
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Responsible Party: University College, London
ClinicalTrials.gov 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: March 13, 2020
Last Verified: March 2020
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