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

"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."

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.

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

"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."

"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"

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.

"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."

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.

"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"

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.

"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"

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.

"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"

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.

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.