- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04817462
Liver Biopsy In Haemophilia Gene Therapy
Study Overview
Status
Conditions
Detailed Description
To better understand the consequences of AAV gene transfer patients will be recruited to undergo a liver biopsy. Patients will be from a unique cohort of successfully treated patients, who are at least 6 months post gene transfer (patients will be at varying timepoints post gene transfer, with the current maximum time post gene transfer being 9.5 years) and have been treated with self-complementary and over-sized AAV vectors will advance the state-of-the-art, in the following aspects:
- Provide a clearer insight into the AAV life cycle in human liver
- Define the number of human hepatocytes that are transduced
- Improve our understanding at the human hepatocyte level of long-term consequences of AAV mediated transgene expression from the liver that will include (i) changes in the pattern of gene expression in human hepatocytes following AAV mediated gene transfer, (ii) information on the epigenetic signature in the liver following AAV mediated gene transfer and how this changes with time and (iii) the consequences of transgene expression in hepatocytes including the endoplasmic reticulum stress response This study will provide new data addressing several unknowns with AAV mediated gene transfer in humans that will better inform on safety and efficacy following AAV gene transfer for patients who have already participated in gene therapy studies as well as those considering this treatment option.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Joanna Calvert
- Phone Number: 38784 020 7794 0500
- Email: joanna.calvert@nhs.net
Study Locations
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London, United Kingdom, NW3 2QG
- Recruiting
- Royal Free Hospital
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Contact:
- Joanna Calvert
- Phone Number: 38784 020 7794 0500
- Email: joanna.calvert@nhs.net
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Contact:
- Paul Batty, MBBS MRCP
- Phone Number: 020 7830 2068
- Email: paul.batty2@nhs.net
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Principal Investigator:
- Paul Batty, MBBS MRCP
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion criteria:
- Male and aged 18 to 80 years old
Patients who were enrolled and treated in one of the following clinical trials:
- AGT4HB (EudraCT No 2005-005711-17) - FIX AAV gene therapy trial (Sponsor: St Jude Children's Research Hospital)
- GO-8 (EudraCT No 2016-000925-38) - FVIII AAV gene therapy trial (Sponsor: UCL)
- FLT180a-01 (EudraCT: 2017-000852-24) - FIX AAV gene therapy trial ((Sponsor: UCL)
- Patients with endogenous FVIII:C/FIX:C expression at >1% after gene transfer that is stably maintained for >6 months and associated with normal prothrombin (PT) and thrombin times (TT) as determined in a coagulation assay
Exclusion Criteria:
- Patients with a platelet count measured at <140 x109/L
- Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study and/or would influence or interfere with evaluation and interpretation of subject safety or efficacy result.
- Patients with abnormal kidney function (estimated GFR <50ml/min)
- Patients with a known allergy to iodine-based intravenous contrast agents
- Patients with a known allergy to local or general anaesthetic
- Patients with a known reaction to FVIII/FIX concentrate infusions
- Presence of FVIII or FIX inhibitor (done within 14 weeks of biopsy)
- Evidence of any bleeding disorder not related to haemophilia A or B
- Patients unable and unwilling to provide and sign an informed consent.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
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Liver Biopsy
All patients undergo a liver biopsy only
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Comprehensive analysis of AAV integration frequency in hepatocytes
Time Frame: single time point (day of biopsy)
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Comprehensive analysis of AAV integration frequency in hepatocytes
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single time point (day of biopsy)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The degree of hepatocyte damage at a morphological level
Time Frame: single time point (day of biopsy)
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The degree of hepatocyte damage at a morphological level
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single time point (day of biopsy)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Determination of hot-spots for integration of the AAV provirus in the liver
Time Frame: single time point (day of biopsy)
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Determination of hot-spots for integration of the AAV provirus in the liver
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single time point (day of biopsy)
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Associated risk of oncogenesis at hot-spots for integration of the AAV provirus
Time Frame: single time point (day of biopsy)
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Associated risk of oncogenesis at hot-spots for integration of the AAV provirus
|
single time point (day of biopsy)
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Assessment of number of hepatocytes harbouring the AAV transgene by FISH
Time Frame: single time point (day of biopsy)
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Assessment of number of hepatocytes harbouring the AAV transgene by FISH
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single time point (day of biopsy)
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Assessment of the number of hepatocytes expressing human FVIII/FIX transcripts
Time Frame: single time point (day of biopsy)
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Assessment of the number of hepatocytes expressing human FVIII/FIX transcripts
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single time point (day of biopsy)
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Qualitative assessment of transcriptome in hepatocytes following AAV gene transfer
Time Frame: single time point (day of biopsy)
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Qualitative assessment of transcriptome in hepatocytes following AAV gene transfer
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single time point (day of biopsy)
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Quantitative assessment of transcriptome in hepatocytes following AAV gene transfer
Time Frame: single time point (day of biopsy)
|
Quantitative assessment of transcriptome in hepatocytes following AAV gene transfer
|
single time point (day of biopsy)
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Assessment of the number of hepatocytes expressing human FVIII/FIX in patients with a null mutation
Time Frame: single time point (day of biopsy)
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Assessment of the number of hepatocytes expressing human FVIII/FIX in patients with a null mutation
|
single time point (day of biopsy)
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Determination of Endoplasmic reticulum (ER) stress response following AAV gene transfer
Time Frame: single time point (day of biopsy)
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Determination of Endoplasmic reticulum (ER) stress response following AAV gene transfer
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single time point (day of biopsy)
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Assessment of the epigenetic changes within the AAV genome in the liver
Time Frame: single time point (day of biopsy)
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Assessment of the epigenetic changes within the AAV genome in the liver
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single time point (day of biopsy)
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Paul Batty, MBBS MRCP, Royal Free Hospital NHS Foundation Trust
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 18/0130
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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