Gene Therapy for Haemophilia A

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Not specified

Target Recruitment: 18

Inclusion Criteria

i.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 for example 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 destruction, and loss of range of motion);
iii.Received treatment with human FVIII 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 after vector administration until at least three consecutive semen samples are below the sensitivity of the assay for vector sequences (may be for 2-3 months);

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

I.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;
II.Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene.
III.Use of investigational therapy for haemophilia within 30 days before enrolment;
IV.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).
V.Serological evidence of HIV.
VI.Evidence of liver dysfunction (persistently elevated ALT >1.5X upper limit of normal);
VII.Uncontrolled glaucoma, diabetes mellitus, or hypertension;
VIII.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;
IX.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);
X.Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound
XI.Patients with uncontrolled cardiac failure or unstable angina;
XII.Detectable neutralising anti-AAV8 antibodies
XIII.Received an AAV vector, or any other gene transfer agent in the previous 6 months
XIV.History of active tuberculosis, fungal disease or other chronic infection
XV.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
XXIII.Patients with a CHA2DS2-VASc score of 2 and above

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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