Title: Home-based EXercise and motivAtional programme before and after Liver Transplantation: ExaLT trial
Funder: Medical Research Council

Abstract: BACKGROUND: Liver disease is the 3rd commonest cause of death in adults of working age and liver transplantation (LT) remains the only cure for liver failure. LT exerts a huge stress on the body and mind, especially in people who are already physically and mentally frail because of their liver disease. We know that physical frailty prior to surgery results in a longer hospital stay because of postoperative complications and contributes to 1 in 10 patients either dying whilst still on the waiting list or shortly after LT. _x000D_ _x000D_ Exercise has been shown to be effective in other fields of medicine (diabetes, heart disease) and elective surgery (cancer). However, due to the life-threatening, multiple health effects of liver failure patients awaiting LT have been viewed as ‘too sick’ and 'too frail' to exercise, with virtually no data to support the benefits and safety of exercise in this cohort. Exercise may have the potential to improve the lives of people with liver disease and reduce the side-effects of LT surgery. Evidence-based exercise programmes around the time of transplantation do not exist. Only a few small studies have indicated that supervised, hospital-based exercise can improve physical function and quality of life. _x000D_ _x000D_ AIMS: We aim to determine the effect of a home-based exercise and motivation-support programme in patients undergoing LT on their quality of life after surgery. We would also like to understand how and what amount ('dose') of exercise results in improvements in intricate measures of physical fitness and muscle function that account for changes in quality of life, and how the motivation-support component of the intervention enhances uptake and ongoing engagement of exercise pre and post LT._x000D_ _x000D_ CLINICAL TRIAL DESIGN: We intend to perform a clinical trial, in which patients will be randomly allocated to receive either the home-based exercise/motivation support programme (intervention group) or a patient advice leaflet (control group) whilst on the LT waiting list. The intervention will begin whilst patients are on the LT waiting list and end 6 months after LT. The intervention will consist of regular strength and endurance exercises, tailored to each patient’s level of fitness. During clinic visits and via telephone calls a physiotherapist will provide motivational support throughout the exercise programme. The trial will involve recruiting 266 patients over two years from two LT hospitals in England. We shall assess the effectiveness of the intervention by measuring quality of life before and after the study period in both groups of patients. The intervention will be deemed effective if quality of life scores are higher with the intervention than the control group._x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT (PPI): Birmingham and Royal Free London PPI groups (consisting of patients with liver disease and who have undergone LT) were directly involved in the development of the research question, the choice of quality of life as our primary measure and reviewed the whole application. Two members of the PPI group are co-applicants and the group will remain involved throughout the conduct of the study and dissemination of findings. _x000D_ _x000D_ DISSEMINATION: The findings will be presented at medical conferences, reported in the medical literature and disseminate to the public. Our PPI group will guide our public-facing outputs to maximise their impact for the people who will benefit from the findings.

Lay abstract: Background: Chronic liver disease is the 3rd commonest cause of death in the UK and liver transplantation (LT) remains the only cure, with over 1000/year performed. LT exerts a huge physiological/psychological stress on patients, who are physically and mentally frail as a consequence of liver disease. Frailty is associated with increased morbidity, mortality and poor quality of life (QoL), both before and after LT. The efficacy and safety of exercise interventions and their tolerability to patients with liver failure or those recovering from LT remains poorly understood. There are notable physical and mental barriers to exercise therapy in patients with liver disease, including the presence of ascites, encephalopathy, sarcopenia and fatigue, as well as anxiety and a lack of motivation. Evidence is lacking on how to tailor and dose exercise and behavioural techniques to this unique patient population. _x000D_ Main research question: Does a home-based exercise and theory-based motivation support programme delivered before and after LT improve QoL in LT recipients compared to a control group using patient advice leaflets? The study includes two mechanistic questions: (a) What is the mode-of action and dose-effect of the exercise intervention on physical fitness and muscle biology? (b) how does theory-based motivation affect adherence to and engagement with the exercise programme? _x000D_ Study design: A two-centre randomised controlled clinical trial. _x000D_ Primary outcome measure: Physical component summary (PCS) score from the SF-36v2 health-related QoL questionnaire at 6-months post LT. Secondary outcome measures: 1. Comprehensive Complications Index (CCI); 2. Mental component summary score of QoL; 3. Measures of frailty and physical fitness; 4. Adherence to exercise intervention (blinded accelerometer); 5. Pre-LT morbidity/mortality; 5. Post-LT length of ICU/hospital stay, morbidity/mortality (30,90,360-day). _x000D_ Intervention-arm: A remotely monitored, individualised home-based exercise and motivation-support programme undertaken pre-LT (prehabilitation) and for 6-months post-LT (rehabilitation). Control-arm: patient exercise advice leaflet._x000D_ Study population: Inclusion criteria: Adult patients awaiting a cadaveric LT at home. Exclusion criteria: super-urgent acute LT, multi-organ transplant and/or live-related donor LT; severe hepatic encephalopathy; oxygen-dependent hepato-pulmonary syndrome; patients without liver failure (e.g. polycystic disease). Sample size: 266 patients with 1:1 randomisation._x000D_ Timelines for delivery: The study duration is 54 months. This includes 6 months for trial set up/staff training, 24 months for recruitment (11/month), 18 months’ intervention, and 6 months follow-up, primary analysis and reporting. _x000D_ Anticipated impact and dissemination: An effective home-based exercise programme that improves objective measures of outcome would have a significant impact on the clinical outcomes and QoL of patients with liver failure undergoing LT. If the intervention can maintain improvements in health and wellbeing and reduce surgical complications it will deliver not only clinical, but economic benefits by reducing hospital admissions, enhancing the efficiency of LT and aiding patients to rapidly return to work. The aim is to publish the findings in high-impact, peer-reviewed medical journals, NIHR Journals Library, NHS Evidence website, present at international conferences and disseminate to patient groups so that they can drive change

Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.7 PHYSICAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.7 PHYSICAL
Health categories: ORAL AND GASTROINTESTINAL