Award Title: Palliative Long-term Abdominal Drains Versus Repeated Drainage in Untreatable Ascites Due to Advanced Cirrhosis: A Randomised Controlled Trial (REDUCe 2 Study)
Funder: Department of Health and Social Care

Abstract: Our aim is to see if long-term abdominal drains (LTADs) result in better quality of life in patients with fluid in the belly (abdomen) due to liver scarring, compared with current standard of care. _x000D_
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The liver can be damaged (scarred), by excessive alcohol and viral infections. If liver damage continues, this scarring leads to permanent damage (cirrhosis). As cirrhosis progresses, it causes a painful buildup of fluid (ascites) in the abdomen. Initially, drugs can treat ascites, but these may stop working, leading to untreatable ascites. A liver transplant is then the best option. Most people, however, do not receive a transplant due to concerns about their alcohol use or lack of donors._x000D_
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People with cirrhosis and untreatable ascites who do not receive a liver transplant live on average for about six months. Medical care then focuses on controlling symptoms and having the best possible quality of life. This is known as palliative care. Current standard palliative care for untreatable ascites involves coming into hospital for 1-2 days, putting a thin tube into the abdomen for a few hours and draining 5-15 litres of fluid. This reduces the pain from ascites. However, as the ascites builds up quickly, hospital visits are needed every 10-14 days. Our patients describe repeated hospital drainage as ”devastating” and “unbearably painful”. _x000D_
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For people with untreatable ascites due to cancer (rather than cirrhosis), palliative care involves placing another tube, an LTAD, into their abdomen. This tube is fitted in hospital but stays in place for months. Nurses/carers then drain smaller amounts of fluid (1-2 litres) up to three times a week in the community. LTADs avoid frequent hospital visits and can improve quality of life._x000D_
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LTADs are not routinely offered to people with cirrhosis as they can have complicated social issues like addiction, making community care difficult. Secondly, people with cirrhosis are at increased risk of ascitic fluid infection. The concern is that LTADs might further increase this risk. It remains uncertain, therefore, if LTADs could improve quality of life for people with cirrhosis._x000D_
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We ran a small study (2015-18) with 36 patients with cirrhosis and untreatable ascites. Half received LTADs and half continued with standard hospital drainage. LTAD insertion went well with no major complications. Almost all with LTAD were managed in the community with lower overall costs compared with hospital drainage. Participants were willing to fill in study questionnaires and take part in interviews. Patients and clinical staff told us that LTADs were acceptable to them. _x000D_
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We now need a larger study to understand the risks/benefits of palliative LTADs in people with cirrhosis. In this study, people who agree to take part will have ascites drained through either LTAD or repeated hospital visits. Community nurses will visit LTAD patients at home up to three times a week for ascites drainage. Researchers will visit ALL participants at home every 2 weeks for 3 months for safety monitoring and also record quality of life, symptoms, carer workload and use of NHS services (using questionnaires). We will record all infections that occur. We will talk with patients/carers/clinical staff to ask their views about the research. The most important measure chosen to see if LTAD is a good option for people with cirrhosis is quality of life. The study has been designed with help of the patients/caregivers who are part of the research team.

Lay Abstract: RESEARCH QUESTION: Do palliative long-term abdominal drains (LTADs) result in better health related quality of life (HRQoL) in patients with refractory ascites due to end-stage liver disease (ESLD) compared with standard of care (large volume paracentesis, LVP)?                                                                                                                      _x000D_
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BACKGROUND: Refractory ascites confers a median transplant-free survival of six mths and needs repeated hospitalisation for drainage (LVP). LTADs allow home drainage but are not routinely used in ESLD. Our REDUCe study (LVP vs. LTADs in ESLD) demonstrated feasibility to proceed with a definitive trial.                                                                                                         _x000D_
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AIM: To assess whether LTADs result in better HRQoL vs. LVP in patients with refractory ascites due to ESLD.                                                                                                                                    _x000D_
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METHODS: We will recruit patients with ESLD and refractory ascites, randomised 1:1 to either LTADs or LVP. Community nurses will visit LTAD patients at home, 2-3 times a week to perform drainage (1-2 L per visit). LVP patients will attend hospital every 10-14 days with 5-15 L of ascites drainage. Research staff will visit ALL participants at home fortnightly for 3-mths for safety monitoring and questionnaire-based assessments (Ascites Q, SFLDQoL, EQ-5D-5L, CRRS). The primary outcome will be HRQoL assessed by the SFLDQoL questionnaire. An embedded qualitative study will explore perspectives on LTADs and LVP by patients (n=30), caregivers (n=20) and health care professionals (n=20). The minimal clinically important difference (MCID) is the mean change in HRQoL score for patients reporting a minimal yet perceptible change in HRQoL between baseline and follow-up assessments. We have selected an MCID of 8 points. REDUCe study data showed the pooled baseline mean across SFLDQoL domains (excluding sexual function) was 56.4 (SD=26.1). With 93 participants in each group, we will have 90% power for 5% significance to detect a difference in adjusted mean SFLDQoL scores of 8 points between the LTAD and LVP groups at the end of 3-mths (effect size 0.31). We will assume a correlation between baseline and follow-up measurements of 0.48 (lower bound of 95% CI, REDUCe study data). With an expected 40% attrition, we will recruit 310 patients in total for the trial. Statistical analysis will follow intention-to-treat principles, performing for the primary outcome, a longitudinal analysis of covariance by fitting a mixed effects linear regression model. Qualitative data will be analysed using thematic analysis and triangulation. A probabilistic cost effectiveness analysis will be conducted, service use being assessed by the AHCR and an in house designed hospital use questionnaire.                                                                                                                                     _x000D_
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DELIVERY TIMELINES: Study duration 57-mths: 6-mths set up; 18-mths internal pilot with STOP/GO criteria; 29-mths main trial and 4-mths data analysis/dissemination. The pilot will recruit 84 patients from 24 sites. Assuming a successful pilot, 11 more sites will be opened over 5-mths, recruiting the remaining 226 patients from 35 sites.                                                                                                                      _x000D_
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IMPACT: This large UK trial will improve end of life care for an underserved group.

Research Activity Codes: 6.3 MEDICAL DEVICES
Health Categories: ORAL AND GASTROINTESTINAL