Gene Therapy for Haemophilia A.

Hemophilia A Clinical Trial

— GO-8  

Official title:

GO-8: Gene Therapy for Haemophilia A Using a Novel Serotype 8 Capsid Pseudotyped Adeno-associated Viral Vector Encoding Factor VIII-V3

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03001830
• Other study ID #: UCL 13/0076
• Secondary ID: 2016-000925-38MR
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 14, 2017
• Est. completion date: December 2029

Study information

• Verified date: October 2023
• Source: University College, London
• Contact: Joanna Calvert
• Phone: 020 7794 0500
• Email: joanna.calvert[@]nhs.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: December 2029
• Est. primary completion date: January 2029
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• AAV2/8-HLP-FVIII-V3
Infusion of AAV2/8-HLP-FVIII-V3

Locations

Country	Name	City	State
United Kingdom	Royal Free Hospital	London
United States	St. Luke'S Regional Medical Center, Ltd	Boise	Idaho
United States	University of Kentucky	Lexington	Kentucky
United States	St Jude's Children's Research Hospital	Memphis	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Medical Research Council

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety - Dose Limiting Toxicity possibly attributable to the gene therapy	Toxicity will be assessed according to CTCAE, version 4.03 based on the monitoring schedule which comprises a number of clinical and laboratory evaluations	Up to 5 years post-infusion
Primary	Safety - Neutralising anti-hFVIII antibody development following gene therapy	The presence of neutralising hFVIII antibodies will be assessed by regular laboratory tests during patient follow up post infusion	Up to 5 years post-infusion
Secondary	Plasma hFVIII activity	Assessments of plasma hFVIII activity	Regularly up to 5 years post-infusion
Secondary	Bleeding frequency	Assessment of bleeding frequency using participant diaries before and after gene transfer	Annual review for 5 years
Secondary	hFVIII concentrate usage	Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer	Annual review for 5 years
Secondary	Immune response to the AAV8 capsid.	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 (IFN?) ELIspot assay to AAV8 capsid	Weeks 3, 6, 9 & 12, month 6 and annually post-infusion to Year 5
Secondary	Viral shedding	Serum and bodily secretions will be collected to assess clearance of vector genomes	Weekly from 7 days post infusion until sample clearance.