REpurposing SirolimUS in Compensated Advanced Chronic Liver Disease. the RESUS Proof of Concept Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- proportion of deactivation of activated HSCs from baseline to 6 months
研究概览
简要总结
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.
详细描述
TRIAL DESIGN This is a phase II, randomised, patient-blinded, placebo-controlled, proof of concept, parallel group single centre trial. Phase I information is not required since sirolimus has been in use for other therapeutic indications.
STUDY SETTING This is a single centre study and will be undertaken at Nottingham University Hospitals NHS Trust.
TRIAL PROCEDURES Recruitment Recruitment will be over 15 months from hepatology clinics. Based on previous experience, recruiting 3 patients per month will achieve the recruitment of 45 participants over 15 months. Progression criteria around recruitment, retention and treatment compliance will be defined as assessed at three monthly intervals.
Patient identification The chief investigator who is part of the clinical team will identify potential participants by reviewing patient records (e.g., previous clinic letters) of patients attending hepatology clinics. Information packs (patient information sheet and trial team contact details) will be sent to all patients who appear to meet the eligibility criteria. A delegated research professional (e.g., research nurse) will then gauge the interest of the patient through a telephone call 1 - 2 weeks after sending the information pack via post.
Screening Screening will include a baseline clinic which will involve eligibility check, medical history and general physical examination, informed consent, routine bloods and liver biopsy, followed by an MRI scan 2 weeks after the baseline clinic visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo
15 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
干预措施: 1st MRI scan (Diagnostic Test)
Placebo
15 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
干预措施: 1st Percutaneous or Endoscopic Ultrasound guided liver biopsy (Procedure)
Placebo
15 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
干预措施: Placebo 0.5mg capsule (Drug)
Placebo
15 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
干预措施: Baseline Blood Tests (Diagnostic Test)
Placebo
15 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
干预措施: Baseline Clinical Examination (Diagnostic Test)
Placebo
15 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
干预措施: Week 1 - 5 Titration Blood Tests (Diagnostic Test)
Placebo
15 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
干预措施: Month 2 Clinical Examination (Other)
Placebo
15 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
干预措施: Month 2 Blood Tests (Diagnostic Test)
Placebo
15 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
干预措施: Month 4 Clinical Examination (Other)
Placebo
15 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
干预措施: Month 4 Blood Tests (Diagnostic Test)
Placebo
15 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
干预措施: Month 6 Clinical Examination (Other)
Placebo
15 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
干预措施: Month 6 Blood Tests (Diagnostic Test)
Placebo
15 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
干预措施: 2nd Percutaneous or Endoscopic Ultrasound guided liver biopsy (Procedure)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Sirolimus 0.5Mg Tab (Drug)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: 1st MRI scan (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: 1st Percutaneous or Endoscopic Ultrasound guided liver biopsy (Procedure)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Baseline Blood Tests (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Baseline Clinical Examination (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Week 1 - 5 Titration Blood Tests (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 2 Clinical Examination (Other)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 2 Blood Tests (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 4 Clinical Examination (Other)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 4 Blood Tests (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 6 Clinical Examination (Other)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: Month 6 Blood Tests (Diagnostic Test)
Sirolimus
30 participants will be randomised to the study drug.
干预措施: 2nd Percutaneous or Endoscopic Ultrasound guided liver biopsy (Procedure)
结局指标
主要结局
proportion of deactivation of activated HSCs from baseline to 6 months
时间窗: 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.
次要结局
- the safety and tolerability of sirolimus in patients with advanced chronic liver disease(6 months)
- change in histological fibrosis stage from baseline to 6 months(6 months)
- change in multiparametric MRI measures from baseline to 6 months(6 months)