REpurposing SirolimUS in Compensated Advanced Chronic Liver Disease. the RESUS Proof of Concept Study
RESUS
1 other identifier
interventional
41
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Jul 2022
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
July 25, 2022
CompletedFirst Submitted
Initial submission to the registry
October 19, 2022
CompletedFirst Posted
Study publicly available on registry
December 23, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 25, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
June 25, 2024
CompletedOctober 1, 2024
September 1, 2024
1.9 years
October 19, 2022
September 27, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
proportion of deactivation of activated HSCs from baseline to 6 months
The primary objective is to determine proportion of deactivation of activated HSCs by sirolimus compared to placebo, in patients with advanced chronic liver disease from baseline to 6 months. This will be measured by the change in the proportion in alpha smooth muscle actin (αSMA) expression in the liver biopsies at baseline and at 6 months in the sirolimus and placebo groups. Alpha smooth muscle actin is a protein present in fibrotic tissue. It is stained for during histological analysis. The presence of alpha smooth muscle actin is reported as a proportion of the tissue sample e.g., 60% of this tissue sample stained positively for alpha smooth muscle actin. Response to treatment is defined as a reduction in αSMA of at least 50% from baseline to 6 months e.g., now only 30% stains positive. It is impossible to say what the average starting proportion would be as this varies significantly from patient to patient. What is important is the proportionate change.
6 months
Secondary Outcomes (3)
change in histological fibrosis stage from baseline to 6 months
6 months
change in multiparametric MRI measures from baseline to 6 months
6 months
the safety and tolerability of sirolimus in patients with advanced chronic liver disease
6 months
Study Arms (2)
Placebo
PLACEBO COMPARATOR15 participants will receive a non-identical placebo tablet. They will be asked to take the placebo daily, exactly as instructed for the intervention arm, be subject to monitoring and random titration to mirror the study drug
Sirolimus
EXPERIMENTAL30 participants will be randomised to the study drug.
Interventions
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.
Eligibility Criteria
You may qualify if:
- capable of giving informed consent
- aged 18-75 years
- compensated advanced chronic liver disease (Child Pugh class A) due to excess alcohol consumption or fatty liver disease
- willing to and able to undergo percutaneous or endoscopic ultrasound-guided liver biopsy at baseline and at 6 months
You may not qualify if:
- inability to provide informed consent
- inability to comply with the study protocol
- subjects who may be unavailable for the duration of the treatment course, likely to be noncompliant, or who are felt to be unsuitable by the Investigator for any other reason
- previous history of decompensation of liver disease or liver cancer
- women who are pregnant or breastfeeding
- unable or unwilling to use highly effective contraception during and 12 weeks after the trial participation
- history of allergy or adverse event to sirolimus
- previous or current use of sirolimus
- concurrent use of experimental agents
- an unstable or uncontrolled medical disorder which in the investigator's opinion precludes recruitment within the trial
- major medical comorbidities (e.g., end-stage organ disease, cancer or immunodeficiency)
- increased risk of infectious complications (e.g., immunodeficiency, recent live vaccination)
- surgery within the past 6 months or an anticipated requirement for surgery during the study period
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Queen's Medical Centre, Nottingham University Hospitals NHS Trust
Nottingham, Nottinghamshire, NG7 2UH, United Kingdom
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
- Masking Details
- Participants will be randomised to sirolimus or placebo. To ensure reasonable costs at this early stage of study, the placebo will not be identically matched. The participants and their clinical care providers will be blinded. In this proof of concept study, sirolimus is not expected to have a recognisable health benefit to the participants and therefore unlikely to lead to unblinding of allocated treatment. Further, blinding will be maintained throughout the trial by having random titration schedules in the placebo arm. The Investigating team and pharmacy representative will not be blinded at this early stage of study. The final unblinding of all trial participants will be undertaken after the creation of a locked analysis data set.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 19, 2022
First Posted
December 23, 2022
Study Start
July 25, 2022
Primary Completion
June 25, 2024
Study Completion
June 25, 2024
Last Updated
October 1, 2024
Record last verified: 2024-09