Liver Biopsy In Haemophilia Gene Therapy

NCT04817462 | Recruiting DMC

• 1 other identifier: 18/0130
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

To perform a liver biopsy in haemophilia A and B patients with endogenous FVIII:C/FIX:C expression at \>1% any time after gene transfer following AAV mediated gene transfer. This is to obtain tissue for analysis, to understand if FIX/FVIII transgenic protein expression is mediated by AAV proviral DNA that is integrated into the host cell DNA or if stable expression in humans is mediated by episomal maintained AAV genome.

Conditions

Hemophilia B, Severe; Hemophilia A, Severe

Outcome Measures

Primary Outcomes (1)

• Analysis of AAV integration in hepatocytes using Target Enrichment Sequencing

  The determination of AAV integration sites will be performed for each participant using Target Enrichment Sequencing (TES) analysis of their liver biopsy sample. This will identify DNA sequences flanking the vector genome. The sequencing data will be analyzed to determine 1. Vector-Vector Concatemers and Vector-Genome Junctions Analysis 2. Integration Site,read count, genomic position and nearest gene

  Biopsy samples will be taken from participants who are between one month and up to 15 years post gene therapy

Secondary Outcomes (1)

• Histology analysis using hematoxylin and eosin staining and immunohistochemical staining to determine histopathological changes in hepatocytes

  Biopsy samples will be taken from participants who are between one month and up to 15 years post gene therapy

Study Arms (1)

Liver Biopsy

EXPERIMENTAL

All patients undergo a liver biopsy only

Procedure: Liver biopsy

Interventions

Liver biopsy PROCEDURE

The study population is patients with either haemophilia A or B who have previously been administered gene therapy treatment in one of three specific gene therapy clinical trials. In this study they will have a liver biopsy performed to take up to 3 samples for laboratory analysis.

Liver Biopsy

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and aged 18 to 80 years old
• Patients who were enrolled and treated in one of the following clinical trials at Royal Free Hospital:
• 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) \[now enrolled in long term follow up study FLT180a-04 (EudraCT No 2017-005080-40) (Sponsor: Freeline Therapeutics Ltd)
• Patients with endogenous FVIII:C/FIX:C expression at \>1% any time after gene transfer, associated with normal prothrombin (PT) and thrombin times (TT) as determined in a coagulation assay.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University College, London: lead

Study Sites (1)

Royal Free Hospital

London, NW3 2QG, United Kingdom

RECRUITING

MeSH Terms

Conditions

Hemophilia B; Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked

Study Officials

• Paul Batty, MBBS MRCP

  Royal Free Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paul Batty

CONTACT

020 7794 0500; paul.batty@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2021
• First Posted: March 26, 2021
• Study Start: August 5, 2022
• Primary Completion: July 1, 2025
• Study Completion: July 1, 2025
• Last Updated: December 20, 2024

Record last verified: 2024-12

Locations

GB (1)