REpurposing SirolimUS in Compensated Advanced Chronic Liver Disease. the RESUS Proof of Concept Study

Summary

Background: Advanced liver scarring leads to liver failure, liver cancer and premature death. It mainly affects people in the working age group (18-65 years) and is the only major cause of death that is still increasing every year in the UK. It costs the NHS £2.1 billion a year. This will continue to rise due to increasing alcohol misuse and the obesity crisis.

Advanced liver scarring remains incurable as there is no treatment to slow progression of scarring. Sirolimus is a medication that has been used to prevent rejection after organ transplantation for over 20 years. It reduces liver scarring, improves liver functioning and prolongs life in animals. It has also been shown to reduce liver scarring in patients after liver transplantation. Sirolimus, therefore offers a potential treatment option for liver scarring.

Question and Objectives: If used in patients with advanced liver scarring, can sirolimus slow the progression of scarring? The main objective is to undertake a small-scale study (proof of concept) to investigate if sirolimus could slow the progression of scarring in patients with advanced liver scarring using clinically relevant biomarkers, which will see if the liver responds to treatment. How it will be done: The study will be conducted in Nottingham University Hospitals NHS Trust. 45 patients with advanced liver scarring will be randomly given either sirolimus or placebo tablets daily for 6 months. Participants will have a liver biopsy and a MRI scan at the start and end of the study to measure the change in the biomarkers of liver scarring. A reduction in these markers will indicate successful treatment. Participants will be monitored for safety of the drug. Potential Impact: If found efficacious, sirolimus would provide an acceptable treatment for patients with advanced liver scarring and would also save a substantial sum of money for the NHS.

Conditions

• Advanced Chronic Liver Disease

Interventions

DRUG

Sirolimus 0.5Mg Tab

Once randomised, participants will receive either sirolimus or placebo daily for 6 months. Participants will start on a dose of 1mg daily (2 x 0.5mg tablets) and will have weekly routine bloods including full blood count, renal function and electrolytes and liver function test along with sirolimus trough levels measured to determine the next dose. The aim will be to achieve a steady state blood trough level of 3-7 ng/ml, which is usually achieved in 3-5 weeks. Placebo will also be started at 2 capsules daily. All participants will undergo weekly blood tests for the first 3-5 weeks and placebo doses will be adjusted randomly to maintain blinding. All participants will be reviewed by a research clinician at 2, 4 and 6 months.

DIAGNOSTIC_TEST

1st MRI scan

If participants opt in for MRI scans, a non-contrast MRI scan will be undertaken at Sir Peter Mansfield Imaging Centre, University of Nottingham at the start of the trial, and at the end, after 6 months of taking trial medication. This is to see whether any radiological features of fibrosis change can be detected to correlate with histological findings.

PROCEDURE

1st Percutaneous or Endoscopic Ultrasound guided liver biopsy

After informed consent, participants will undertake up to a 8-week screening period to provide baseline data to ensure eligibility. During this period, participants will undergo blood tests, percutaneous or endoscopic ultrasound-guided liver biopsy, unless the participant has undergone a liver biopsy within the past 3 months, in which case the previous liver biopsy sample will be utilised for this study. They will undergo a second liver biopsy at the end of the study, after taking 6 months of the study drug, to look for any histological change in fibrosis progression rate with sirolimus when compared to placebo

DRUG

Placebo 0.5mg capsule

Once randomised, participants will receive either sirolimus or placebo daily for 6 months. The placebo is unmatched. Participants will start on a dose of 1mg daily (2 x 0.5mg capsules) and will have weekly routine bloods including full blood count, renal function and electrolytes and liver function test along with sirolimus trough levels, to maintain blinding of the research team members carrying out blood tests. Placebo doses will be adjusted randomly, in a pattern that mirrors the adjustments made to participants on sirolimus. All participants will be reviewed by a research clinician at 2, 4 and 6 months.

DIAGNOSTIC_TEST

Baseline Blood Tests

During the initial clinical visit, venous blood samples will be taken to ensure that participants have no significant organ dysfunction: * Full blood count * Urea and electrolytes * Liver function tests * Clotting screen Research bloods will also be taken: \- 5ml EDTA blood for storage and subsequent fibrosis marker analysis once all participants have complete study

DIAGNOSTIC_TEST

Baseline Clinical Examination

A thorough medical examination will be undertaken at the first clinical visit (cardiovascular, respiratory, abdominal, neurological, musculoskeletal, skin), to ensure participants are clinical stable. This will also serve as a comparator for future clinical examinations once participants have commenced the study drug.

DIAGNOSTIC_TEST

Week 1 - 5 Titration Blood Tests

Participants will start on a dose of 1mg daily (2 x 0.5mg tablets) and will have weekly bloods: * full blood count, * urea and electrolytes and * liver function tests to check the study drug is not causing any significant organ damage. * Sirolimus trough levels will be measured to determine the next dose. The aim will be to achieve a steady state blood trough level of 3-7 ng/ml, which is usually achieved in 3-5 weeks. Therefore, participants will have a minimum of 3 weeks of blood tests during this period, The need for week 4 and 5 blood tests will be decided by the trial pharmacist who will be monitoring results. Placebo will also be started at 2 capsules daily. All participants will undergo weekly blood tests for the first 3-5 weeks and placebo doses will be adjusted randomly to maintain blinding.

OTHER

Month 2 Clinical Examination

A thorough medical examination will be undertaken at Month 2 (cardiovascular, respiratory, abdominal, neurological, musculoskeletal, skin), to ensure participants remain clinically stable whilst on the study drug. They will also be asked about potential side effects in detail.

DIAGNOSTIC_TEST

Month 2 Blood Tests

During the Month 2 clinical visit, venous blood samples will be taken to ensure that participants have no significant organ dysfunction: * Full blood count * Urea and electrolytes * Liver function tests * Clotting screen * Sirolimus trough level will also be repeated to ensure that the previously titrated study drug has remained in steady state Research bloods will also be taken: \- 5ml EDTA blood for storage and subsequent fibrosis marker analysis once all participants have complete study

OTHER

Month 4 Clinical Examination

A thorough medical examination will be undertaken at Month 4 (cardiovascular, respiratory, abdominal, neurological, musculoskeletal, skin), to ensure participants remain clinically stable whilst on the study drug. They will also be asked about potential side effects in detail.

DIAGNOSTIC_TEST

Month 4 Blood Tests

During the Month 4 clinical visit, venous blood samples will be taken to ensure that participants have no significant organ dysfunction: * Full blood count * Urea and electrolytes * Liver function tests * Clotting screen * Sirolimus trough level will also be repeated to ensure that the previously titrated study drug has remained in steady state Research bloods will also be taken: \- 5ml EDTA blood for storage and subsequent fibrosis marker analysis once all participants have complete study

OTHER

Month 6 Clinical Examination

A thorough medical examination will be undertaken at Month 6 (cardiovascular, respiratory, abdominal, neurological, musculoskeletal, skin), to ensure participants have remained clinically stable whilst on the study drug. At this visit, they will be asked to finish taking the study drug. They will also be asked about potential side effects in detail.

DIAGNOSTIC_TEST

Month 6 Blood Tests

During the Month 6 clinical visit, venous blood samples will be taken to ensure that participants have no significant organ dysfunction: * Full blood count * Urea and electrolytes * Liver function tests * Clotting screen * Sirolimus trough level will also be repeated to ensure that the previously titrated study drug has remained in steady state Research bloods will also be taken: \- 5ml EDTA blood for storage and subsequent fibrosis marker analysis once all participants have complete study

PROCEDURE

2nd Percutaneous or Endoscopic Ultrasound guided liver biopsy

All participants will undergo a second liver biopsy at the end of the study, after taking 6 months of the study drug, to look for any histological change in fibrosis progression rate when compared to their first biopsy.

DIAGNOSTIC_TEST

1st MRI scan

If participants opt in for MRI scans, a non-contrast MRI scan will be repeated at the end of the trial, after 6 months of taking trial medication. This is to see whether any radiological features of fibrosis change can be detected to correlate with histological findings.

Sponsors & Collaborators

• Nottingham University Hospitals NHS Trust

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-07-25

Primary Completion

2024-06-25

Completion

2024-06-25

Countries

• United Kingdom

Study Locations