Liver Biopsy In Haemophilia Gene Therapy

Brief Title

Liver Biopsy In Haemophilia Gene Therapy

Official Title

Liver Biopsy In Haemophilia Gene Therapy

Brief Summary

      To perform a liver biopsy in haemophilia A and B patients stably expressing human FVIII/FIX
      for a period of at least 6 months 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.

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

Observational

Primary Outcome

Comprehensive analysis of AAV integration frequency in hepatocytes

Secondary Outcome

 The degree of hepatocyte damage at a morphological level

Condition

Hemophilia B, Severe

Study Arms / Comparison Groups

 Liver Biopsy

Description:  All patients undergo a liver biopsy only

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment

Start Date

April 1, 2021

Completion Date

October 1, 2021

Primary Completion Date

October 1, 2021

Eligibility Criteria

Inclusion criteria:

1. Male and aged 18 to 80 years old

2. 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)

3. 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:

1. Patients with a platelet count measured at <140 x109/L

2. 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.

3. Patients with abnormal kidney function (estimated GFR <50ml/min)

4. Patients with a known allergy to iodine-based intravenous contrast agents

5. Patients with a known allergy to local or general anaesthetic

6. Patients with a known reaction to FVIII/FIX concentrate infusions

7. Presence of FVIII or FIX inhibitor (done within 14 weeks of biopsy)

8. Evidence of any bleeding disorder not related to haemophilia A or B

9. Patients unable and unwilling to provide and sign an informed consent.

Gender

Male

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Pratima Chowdary, +44 208 016 8111, [email protected]

Administrative Informations

NCT ID

NCT04817462

Organization ID

18/0130

Responsible Party

Sponsor

Study Sponsor

University College, London

Study Sponsor

Pratima Chowdary, Principal Investigator, Royal Free Hospital NHS Foundation Trust

Verification Date

March 2021