Gene Therapy for Haemophilia A. (GO-8)

This is an interventional treatment trial for Hemophilia A Read More

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