Gene Therapy for Haemophilia A.
- Registration Number
- NCT03001830
- Lead Sponsor
- University College, London
- Brief Summary
The GO-8 study focuses on assessing safety and efficacy of gene therapy for patients with severe haemophilia A
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 14
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment Arm AAV2/8-HLP-FVIII-V3 Treatment with AAV2/8-HLP-FVIII-V3
- Primary Outcome Measures
Name Time Method Safety - Neutralising anti-hFVIII antibody development following gene therapy 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
Safety - Dose Limiting Toxicity possibly attributable to the gene therapy 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
- Secondary Outcome Measures
Name Time Method Plasma hFVIII activity Regularly up to 5 years post-infusion Assessments of plasma hFVIII activity
Bleeding frequency Annual review for 5 years Assessment of bleeding frequency using participant diaries before and after gene transfer
hFVIII concentrate usage Annual review for 5 years Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer
Viral shedding Weekly from 7 days post infusion until sample clearance. Serum and bodily secretions will be collected to assess clearance of vector genomes
Immune response to the AAV8 capsid. 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
Trial Locations
- Locations (4)
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, United States
Royal Free Hospital
🇬🇧London, United Kingdom