Home-based EXercise and motivAtional Program Before and After Liver Transplantation: EXALT
Phase: NA
Conditions: Liver Transplant Surgery
Sponsor: University of Birmingham

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HOME-BASED EXERCISE AND MOTIVATIONAL PROGRAMME 
BEFORE AND AFTER 
LIVER TRANSPLANTATION: ExaLT Trial 
 
A PHASE IIb, RANDOMISED-CONTROLLED, TWO-CENTRE CLINICAL TRIAL ON 
THE EFFICACY OF A HOME-BASED EXERCISE AND MOTIVATIONAL 
PROGRAMME IN PATIENTS BEFORE AND AFTER LIVER TRANSPLANTATION 
 
This protocol has regard for the HRA guidance and is compliant with the SPIRIT guidelines (2013) 
 
Version Number: 5.0 
Version Date: 01 October 2024 
IRAS ID: 295426 
Sponsor reference: RG_20-065 
ISRCTN 13476586 
TRIAL PROTOCOL 

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PROTOCOL DEVELOPMENT 
Protocol amendments 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version. 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
NS-01 
21 Mar 2023 
V3.0 
Non 
substantial 
Sections 10.5 and Section 11 have been 
amended.  REDCap an online database will 
replace paper Case Report forms [CRFs].  
The BCTU will not input the CRF data, as 
originally outlined, instead Sites will enter 
data directly into the online database.  
Expedited SAE reporting will also use the 
REDCap online database. Sites will till 
email the ExaLT study Office when a SAE 
form has been entered into REDCap. 
Section 14 has been amended to bring in 
line the wording of the statistical analysis 
methods to that used in the separate 
more detailed statistical analysis plan. 
Finally 
Sponsor 
Reference 
number 
previously quoted on protocol was 
incorrect. This has now been amended. 
SA-01 
2 Jul 2023 
V4.0 
Substantial 
1. Changes to the TSC and research 
team (other than CIs or PIs). The critical 
care/transplant specialist of the TSC has 
changes from Dr Brian Hogan to Dr 
Tasneem Pirani. William Mckinnon and 
Dawn Brant from the BCTU have joined 
the trial management group.  
2. Study design: changes to study design 
a) Removal of the heart rate monitors 
(chest straps) due to not functioning as 
intended. The change does not affect 
the validity of the study and the 
adherence tools (patient diary, wrist 
watch 
monitor) 
are 
more 
than 
adequate to enable us to evaluate 
adherence to the exercise programme.

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b) The time window for visits 2 has 
changed from (+/-) 3 days to (+/-) 7 
days and for visit 5 from (+/-) 7 days to 
(+/-) 14 days. A time window of (+/-) 1 
week has also been created for 
telehealth call visits.  The changes 
allow more flexibility for sites when 
performing these visits, therefore 
avoiding a significant number of future 
protocol deviations. 
c) A section on future planning for future 
viral 
pandemics, 
industrial 
strike 
action, terrorist/war threat or severe 
mitigating 
circumstances 
(i.e. 
prolonged hospital admission unable 
to attend trial visits for prolonged 
time) has been added to the protocol.  
This allows for virtual study visits in 
these events. 
d) Mechanistic sub-study: Participants in 
the mechanistic sub-study who reach 
visit 6 without LT will be given the 
option of taking part in an additional 
sub-study assessment visit where visit 
6 has an additional 6-week window 
(i.e. week 48 + 28 days). 
e) Mechanistic sub-study: At QEUHB site 
only, participants taking part in the sub 
study will be given the option to 
consent for a small amount of urine 
(that would otherwise be wasted) to 
be 
stored 
for 
potential 
future 
research. A Urine sample (20-30ml) 
will be collected at each sub-study 
visit. 
f) Mechanistic sub-study: The order of 
the specialist biomarkers and muscle 
ultrasound will take place before the 
CPET/6MWT to ensure that their 
results 
are 
not 
impacted 
by 
acute/strenuous exertion of these 
functional tests. In addition, the CPET 
will take priority and precede the 
6MWT (with 30 minutes rest in 
between tests), since the CPET has 

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more rigorous data outputs (i.e. VO2 
peak, Anaerobic threshold, ramp 
gradient, maximal heart rate etc.) 
g) Fidelity testing: To test the fidelity of 
the 
behaviour 
therapy 
training 
throughout the entire ExaLT trial study 
period, an additional four patient 
video recordings per physio will take 
place at patient 40 (+/-3) and patient 
60 (+/-3) (i.e. a total 8 additional 
recordings per physio). Visit recordings 
will be identical to those completed at 
patient 20 (+/-3). 
h) Additional 
information 
regarding 
sample tracking and storage has been 
added to the protocol for clarity.  
i) A typographical error which recorded 
a telehealth visit post LT at week 10 
and not at the correct time of week 16 
post LT has been corrected for clarity 
in section 7.1. 
j) The time for the trial physiotherapists 
to review the participant on the post-
LT ward, prior discharge from ICU has 
been extended from 48 hours to 
within 72 hours. Also, assessments 
undertaken on the ward within 48 
hours will be extended to within 72 
hours. 
 
NS-03 
01 Oct 2024 
V5.0 
Non 
substantial 
a) The 52-week cut off for LT has been 
amended to allow 52 weeks +2 
weeks. 
b) For visit 1 to visit 6 -bloods to be 
taken on day of visit, however if some 
results are missing, results from a 
NHS visit taken within +/-4 weeks of 
study visit will be accepted. 
c) For visit 7 to visit 10 - bloods to be 
taken on day of visit, however if some 
results are missing, results from a 
NHS visit taken within +/-4 weeks of 
visit will be accepted. 
d) For L1 visit- due to the ad hoc nature 
of this visit it is recognised that it may 

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not be possible to perform these 
assessments if out of hours.  
i. 
Nutritional/physical/function
al (including LFI)  
ii. 
DASI Questionnaire  
iii. 
Blood tests  
In cases where bloods are not 
performed- sites can enter bloods 
from a previous NHS visit if performed 
within 4 weeks of this visit. Post LT 
bloods are not accepted 
 
 
Funding and support in kind 
 
Funder(s)/Supporting Organisations  
Financial and non-financial support given: 
National Institute for Health Research 
 
Birmingham’s NIHR Biomedical Research 
Centre (BRC) 
Fully funded project grant 
BRC research nurse support; Equipment (including 
muscle ultrasound machine) and laboratory support 
including -80 freezer space. 
Funding scheme (if applicable) 
NIHR EME Programme 
Funder’s reference number 
129318 
The views expressed in this publication are those of the author(s) and not necessarily those of the 
NHS, the National Institute for Health Research, Health Education England or the Department of 
Health. The funder had no role with respect to study design; collection, management, analysis, and 
interpretation of the data; writing of the report; and the decision to submit the report for publication. 

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PROTOCOL SIGN OFF 
Chief Investigator (CI) signature page 
I, the Chief Investigator, confirm that I have read and agree with the following protocol, and that I will
conduct the trial in compliance with the version of this protocol approved by the REC and any other 
responsible organisations. 
I agree to ensure that the information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor. 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as stated in this and any 
subsequent approved protocol will be explained. 
Trial name: 
ExaLT Trial 
Protocol version number: 
Version: 5.0 
Protocol version date: 
 01/OCT/2024 
 
CI (Birmingham) name: 
Dr Matthew Armstrong 
Signature and date: 
_________________________              __ __ / __ __ / __ __ __ __  
Co-CI (London) name: 
Professor Daniel Martin 
Signature and date: 
_________________________              __ __ / __ __ / __ __ __ __  
 
Sponsor statement 
By signing the IRAS form for this trial, University of Birmingham, acting as sponsor, confirm approval of 
this protocol.   
Compliance statement 
This protocol describes the ExaLT trial only. The protocol should not be used as a guide for the 
treatment of participants not taking part in the ExaLT trial.  
The trial will be conducted in compliance with the approved protocol, the UK Policy Framework for 
Health and Social Care Research, Data Protection Act 2018 and the Principles of Good Clinical Practice 
(GCP) as set out in the UK Statutory Instrument (2004/1031) and subsequent amendments thereof. 
Every care has been taken in the drafting of this protocol, but future amendments may be necessary, 
which will receive the required approvals prior to implementation. 
 
 

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Principal Investigator (PI) signature page 
As Principal Investigator, I confirm that the following protocol has been agreed and accepted, and that 
I will conduct the trial in compliance with the approved protocol where this does not compromise 
participant safety.  
 
I agree to ensure that the information contained in this document will not be used for any other purpose 
other than the evaluation or conduct of the clinical investigation without the prior written consent of 
the Sponsor. 
 
Trial name: 
ExaLT 
Protocol version number: 
Version: 5.0 
Protocol version date: 
01/OCT/2024 
 
PI name: 
 
Name of Site: 
 
Signature and date: 
_________________________              __ __ / __ __ / __ __ __ __  
 
 
 

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ADMINISTRATIVE INFORMATION 
 
 
 
Reference Numbers 
 
Sponsor number  
RG_20-065 
ISRCTN reference number 
13476586 
Clinicaltrials.gov reference number 
 
IRAS reference number 
295426 
Sponsor  
 
University of Birmingham 
Birgit Whitman 
Contact Details: 
Head of Research Governance and Integrity, 
Research Strategy and Services Central, Birmingham 
Research Park, Vincent Drive, University of Birmingham
Edgbaston B15 2TT 
Email: Researchgovernance@contacts.bham.ac.uk   
Chief Investigator 
 
Dr Matthew J Armstrong 
Consultant in Liver and Transplant Medicine  
Liver Unit. Honorary Reader at the University of 
Birmingham.                                                                         
Queen Elizabeth University  
Hospital Birmingham    
Mindelsohn Way, Birmingham  B15 2TH 
0121 371 4673 
matthew.armstrong@uhb.nhs.uk 
Co-Chief Investigator 
 
Professor Daniel Martin 
Professor of Perioperative and Intensive Care Medicine  
Peninsula Medical School 
daniel.martin@plymouth.ac.uk
Trial office contact details 
 
Birmingham Clinical Trials Unit (BCTU) 
Institute of Applied Health Research 
College of Medical and Dental Sciences 
Public Health Building 
University of Birmingham, Birmingham, B15 
2TT 
T: 0121 415 8445  
E: EXALT@trials.bham.ac.uk 
 

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Trial Management Group 
 
University Hospitals Birmingham NHS Foundation Trust 
Dr Matthew Armstrong (Chief Investigator) 
Consultant in Liver and Transplant Medicine             
University of Plymouth 
Professor Daniel Martin, OBE (Co-Chief 
Investigator)      
Professor of Perioperative and Intensive Care 
Medicine 
University of Birmingham 
Mrs Felicity Williams (Principal-Investigator; 
Birmingham) 
Lead Physiotherapist, NIHR Allied Health 
Professional Clinical Research Fellow 
Professor Joan Duda (Co-Investigator) 
Professor of Sport and Exercise Psychology 
Dr Sally Fenton (Co-Investigator) 
Senior Lecturer in Lifestyle Behaviour Change 
Royal Free London NHS Foundation Trust 
Dr Clare Melikian (Principal Investigator, 
London)                                          
Consultant Anaesthetist, Lead for Hepatobiliary 
Liver Transplant Anaesthesia 
The Royal Marsden NHS Foundation Trust 
Dr Don Milliken (Co-Investigator) 
Consultant Anaesthetist in Hepatobiliary Surgery 
University of Birmingham – Birmingham Clinical Trials Unit  
Professor Peter Brocklehurst (Co-Investigator) Professor of Women's Health, Director of 
Research and Development 
Gemma Slinn (Co-Investigator) 
William Mckinnon 
Trials Management Team Leaders 
Samir Mehta (Co-Investigator) 
Senior Medical Statistician 
Yongzhong Sun 
Trial Statistician  
Dawn Brant 
ExaLT Trial Manager  
Patient and Public Involvement 
Christian Price (Co-Investigator) 
PPI Representative 
Karen Rockell (Co-Investigator) 
PPI Representative  

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Data Monitoring Committee 
 
Dr Ian Rowe (Chair) 
Academic Fellow and Honorary Consultant 
Hepatologist  
Professor Steve Wigmore 
Professor of Transplantation Surgery  
Trish Hepburn  
Senior Medical Statistician 
 
 
Trial Steering Committee 
 
Independent Members 
Professor Denny Levett (Chair) 
Professor of Critical Care and Perioperative 
Medicine 
Dr Tasneem Pirani 
Consultant in Critical Care and Hepatology 
Dr Kate Hallsworth 
Senior Research Physiotherapist and NIHR Health 
Education England Clinical Lecturer 
Neil Corrigan 
Senior Medical Statistician 
Mark Lamond 
Patient and public involvement representative 
Non-Independent Members 
Dr Matthew Armstrong  
Consultant in Liver and Transplant Medicine             
Professor Daniel Martin 
Professor of Perioperative and Intensive Care 
Medicine 

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ABBREVIATIONS 
Abbreviation 
Term 
6MWT 
Six-minute walk test 
6MWD 
Six-minute walk distance 
A1AT 
Alpha-1 antitrypsin 
AASLD 
American Association of the Study of Liver Disease 
Ab 
Antibody 
ACSA 
Anatomical cross-sectional surface area 
AE 
Adverse Event 
AHP 
Allied healthcare professional 
AIH 
Autoimmune hepatitis 
AKI 
Acute kidney injury 
ArLD 
Alcohol-related liver disease  
ALP 
Alkaline phosphatase  
ALT 
 
Alanine transferase  
AST 
 
Aspartate transferase  
AUROC 
Area Under the Receiver Operating Characteristic Curve 
BCTU 
Birmingham Clinical Trials Unit 
BMI 
Body Mass Index 
BLTG 
British Liver Transplant Group 
BP 
Blood pressure 
BREQ-2 
Behavioural Regulation in Exercise Questionaire-2 
CCI 
Comprehensive complication index 
CI 
Chief Investigator 
CLD 
Chronic liver disease 
CMV 
Cytomegalovirus 
COPD 
Chronic obstructive pulmonary disease  
CPET 
Cardiopulmonary Exercise Test 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular accident 
CVD 
cerebrovascular disease 
DASI 
Duke Activity Status Index 
DBD 
Donation after Brainstem Death  
DCF 
Data Clarification Form 
DCD 
Donation after Circulatory Death 
DMC 
Data Monitoring Committee 
DOB 
 
Date of birth 

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ECG 
Electrocardiogram 
FBC 
 
Full blood count 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HAT 
Hepatic artery thrombosis 
HBEP 
Home-based exercise programme 
HBV 
Hepatitis B virus 
HCC 
 
 
Hepatocellular carcinoma 
HCCQ 
Health Care Climate Questionnaire 
HCV 
 
Hepatitis C virus 
HGS 
Hand grip strength 
HR 
Heart rate   
HRA 
Health Research Authority 
HRS 
Hepato-renal syndrome 
ICF 
Informed Consent Form 
ICU 
Intensive care unit 
IHD 
Ischaemic heart disease  
IL 
Interleukin 
INR 
International normalised ratio 
ISF 
Investigator Site File 
ISPACOT 
Interpersonal Support in Physical Activity Consultations Observational Tool. 
FPFV 
First patient first visit 
LFI 
Liver Frailty Index 
LFT 
Liver function tests 
LOS 
Length of stay 
LPLV 
Last patient last visit 
LRTI 
Lower respiratory tract infection 
LT 
Liver transplant 
LVP 
large volume paracentesis  
MAFLD 
Metabolic associated fatty liver disease 
MAMC 
Mid-arm muscle circumference 
MCS 
Mental component score 
MDT 
Multi-disciplinary team 
MELD 
Model for end-stage liver disease 
MELD-Na 
Model for end-stage liver disease - Sodium 
MI 
Myocardial infarction 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NHS 
National Health Service 
NHSBT 
National Health Service Blood and Transfusion 

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NICE 
National Institute for Health and Care Excellence 
NIHR 
National Institute for Health Research 
 
OGD 
Oesopho-gastro-duodenoscopy 
PBC 
Primary biliary cirrhosis 
PCS 
Physical component score 
PI 
Principal Investigator 
PPI 
Patient and Public Involvement 
PIS 
Participant Information Sheet 
PNSE 
Basic Psychological Need Satisfaction in Exercise Scale 
PSC 
Primary sclerosing cholangitis 
QoL 
Quality of Life 
QEUHB 
Queen Elizabeth Hospital, Birmingham 
R&D 
Research and Development 
RCT 
Randomised controlled trial 
REC 
Research Ethics Committee 
RIR 
Repetitions in reserve 
RGT 
Research Governance Team 
RFH 
Royal Free Hospital 
RoPE 
Rate of perceived exertion  
RR 
Respiratory rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SaO2 
Oxygen saturation 
SBP 
Spontaneous bacterial peritonitis 
SDT 
Self-determination theory 
SOP 
Standard operating procedure 
SPARC 
Secreted protein acidic and rich in cysteine 
TFTs 
Thyroid function tests 
TIA 
Transient ischaemic accident 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
U&E 
Urea, creatinine and electrolytes 
UKELD 
United Kingdom model for End-stage Liver Disease 
UK 
United Kingdom 
UoB 
University of Birmingham 
UTI 
Urinary tract infection 
 
 

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TRIAL SUMMARY 
Title 
ExaLT: Home-based EXercise and motivAtional programme before and after Liver Transplantation. 
Objectives  
The primary aim is to investigate whether a remotely monitored ‘home-based exercise and theory-
based motivation support programme’ delivered by physiotherapists before and after liver 
transplantation (LT) (intervention group) improves quality of life (QoL; physical component score of 
SF-36v2) in LT recipients compared to a control group using a patient ‘exercise’ advice leaflet (control 
group). 
The secondary aims are to investigate whether a remotely monitored ‘home-based exercise and 
theory-based motivation support programme’ delivered before and after LT (experimental arm) 
improves: 
 
Surgical complication after LT (comprehensive complication index (CCI)) 
 
Mental wellbeing/health (mental component score (MCS) of SF-36v2 health-related QoL) 
 
Clinical markers of physical frailty and fitness (liver frailty index [LFI] ; Duke activity status 
index [DASI]) 
 
Pre-LT: morbidity (United Kingdom model for end-stage liver disease (UKELD), model for end-
stage liver disease – sodium (MELD-Na), hospital admissions) and mortality  
 
Post-LT: length of intensive care unit (ICU)/hospital stay, hospital re-admissions and mortality 
(30, 90, 180 day, 1 year) 
 
Habitual physical activity levels (daily time spent in light, moderate and vigorous intensity 
physical activity) 
 
The frequency, intensity and duration of exercise (‘dose’) completed 
 
Adherence to home-based exercise programme (HBEP) (intervention arm only) 
 
Perceptions of the health care climate (how need supportive/empowering the physio is) 
 
Basic psychological need satisfaction (i.e. feelings of autonomy, relatedness, competence) 
 
Self-determined motivation to exercise 
The mechanistic objectives are to investigate: 
1. What is the dose-dependent effect of the HBEP on physical fitness, muscle biology (including 
oxidative stress and inflammation) and their association with QoL? 
2. How does the theory-based motivation support affect adherence and engagement with the 
HBEP? 
 
Trial design 
A phase 2b, open-label, two-centre randomised controlled clinical trial (RCT), with 1:1 individual 
participant randomisation. 
Participant population and sample size 
Adult patients (aged 18 years and over) who are awaiting a cadaveric, primary LT. Sample size = 266 
patients (133 patients in each arm). 

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Setting 
The ExaLT Trial will be based at the LT units of the Queen Elizabeth University Hospital, Birmingham 
(QEUHB) and the Royal Free Hospital, London (RFH). 
Eligibility criteria  
Inclusion criteria 
 
Adult patients (aged 18 years and over)  
 
Awaiting a cadaveric, primary LT at two LT centres: QEUHB and RFH.  
 
Being an out-patient at the time of baseline trial visit (consent) 
Exclusion criteria 
 
Patients awaiting super-urgent LT, multi-organ transplantation, live-related donor LT, regraft 
LT  
 
Inability to safely comply with the exercise intervention due to: 
o severe hepatic encephalopathy  
o oxygen-dependent hepato-pulmonary syndrome 
 
Patients without liver failure including:  
o liver cancer in the absence of cirrhosis 
o polycystic liver disease 
o rare metabolic/genetic conditions. 
 
Patient refuses or lacks capacity to give informed consent to participate in the trial, at the 
point of study visit 1 (baseline)1 
 
Interventions 
Eligible participants will be randomised 1:1 to receive either: 
Group 1: Intervention group. Remotely-monitored home-based exercise and theory-based motivation 
support programme whilst on the LT waiting list (max. 12 months) through to 24 weeks post-LT. 
 
Group 2: Control group. Patient exercise advice leaflet before and after LT.  
 
The interventions will be delivered to the participants in two phases: phase 1 pre-LT (maximum 
52weeks) and phase 2 post-LT (24 weeks). The study intervention will be of variable duration pre-LT, 
due to the unpredictable nature of the timing of LT (median waiting time 72 days (95% CI 64-80) 
registered between 2018-2021). All patients that are transplanted within 52 weeks (+ 2 weeks) of 
randomisation will receive a fixed 24 week intervention after LT. Group 1 and 2 will contain 
approximately the same proportion of age groups, disease severity (UKELD), gender, trial site and 
participation rates in the ‘muscle sub-study’ as a result of minimisation.  
 
1 During the course of the trial, some participants may lose capacity because of complications of their 
liver condition(s), for example hepatic encephalopathy.  

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Outcome measures 
The primary outcome measure is the physical component score (PCS) from the short form-36 version 
2.0 (SF-36v2) health-related QoL questionnaire at 24 weeks post LT. 
 
The ‘key’ secondary outcome measure is the CCI at 24 weeks post LT.  
 
The other secondary outcome measures to be assessed at 24 weeks post LT (*unless stated) include:  
 
MCS score of SF-36v2 health-related QoL questionnaire 
 
Liver Frailty Index (LFI), Duke Activity Score Index (DASI) 
 
Pre-LT morbidity (UKELD, MELD-Na, hospital admissions) and mortality (*assessed up to day 
of LT) 
 
Post-LT length of ICU/hospital stay and hospital re-admissions (frequency, duration [days]) 
 
Post-LT 30, 90, 180 and 365 day mortality 
 
Habitual physical activity levels (daily time spent in light, moderate and vigorous intensity 
physical activity) 
 
“Dose” of exercise completed (measure of the frequency, intensity and duration of exercise) 
 
Adherence to HBEP (intervention arm only) 
 
Perceptions of the health care climate (how need supportive/empowering the physiotherapist 
is) 
 
Basic psychological need satisfaction (i.e. feelings of autonomy, relatedness, competence) 
 
Self-determined motivation to exercise 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TRIAL SCHEMA 
 
 
trial: study design
A multicentre randomised controlled trial of a 
versus 
in 
patients with end-stage liver disease on the waiting list 
for liver transplantation.
Inclusion criteria:
•
Adult patients (aged 18 years and over) 
•
Awaiting a cadaveric, primary LT at two LT centres: QEUHB and RFH. 
•
Being an out-patient at the time of baseline trial visit (consent)
Exclusion criteria:
•
Patients awaiting super-urgent LT, multi-organ transplantation, live-
related donor LT, regraft LT 
•
severe hepatic encephalopathy 
•
oxygen-dependent hepato-pulmonary syndrome
•
Patients without liver failure (i.e.  liver cancer in the absence of 
cirrhosis, polycystic liver disease, rare metabolic/genetic conditions) 
PCS SF-36 (quality of life); 
Physical frailty, motivation to 
exercise (routine clinic visit)
(as per post-
transplant protocol) 
Secondary (key**): CCI**; Physical frailty; Morbidity; Mortality; Motivation to exercise
* At baseline, at 6-weeks (pre-transplant) and 24-weeks after transplant (mechanistic ‘muscle’ sub-study; n=100; optional): Cardiopulmonary exercise tests, 
muscle ultrasound and biomarkers. Key: CCI, Comprehensive complications index; PCS, Physical Component Score 
PCS SF-36 (quality of life); 
Physical frailty, motivation to 
exercise (routine clinic visit)
(as per pre-
transplant protocol) 

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TABLE OF CONTENTS 
1. BACKGROUND AND RATIONALE................................................................................................................. 21 
1.1. BACKGROUND ................................................................................................................................................ 21 
1.2. TRIAL RATIONALE ............................................................................................................................................ 21 
1.2.1. Justification for participant population .............................................................................................. 22 
1.2.2. Justification for design ....................................................................................................................... 23 
1.2.3. Justification for choice of intervention(s) ........................................................................................... 24 
1.2.4. Justification of choice of primary outcome ........................................................................................ 25 
2. AIMS AND OBJECTIVES ............................................................................................................................... 26 
2.1. PRIMARY AIM: ............................................................................................................................................... 26 
2.2. SECONDARY AIMS: ......................................................................................................................................... 26 
2.3. STUDY OBJECTIVES: ......................................................................................................................................... 26 
3. TRIAL DESIGN AND SETTING ....................................................................................................................... 27 
3.1. TRIAL DESIGN ................................................................................................................................................. 27 
3.2. TRIAL SETTING................................................................................................................................................ 28 
3.3. MECHANISTIC ‘MUSCLE’ SUB-STUDY (N=100) ...................................................................................................... 28 
3.4. ASSESSMENT OF RISK ....................................................................................................................................... 29 
4. ELIGIBILITY ................................................................................................................................................. 29 
4.1. INCLUSION CRITERIA ........................................................................................................................................ 29 
4.2. EXCLUSION CRITERIA ....................................................................................................................................... 29 
4.3. ELIGIBILITY FOR MECHANISTIC ‘MUSCLE’ SUB-STUDY (N=100) ................................................................................. 30 
4.4. CO-ENROLMENT ............................................................................................................................................. 30 
5. RECRUITMENT AND CONSENT ................................................................................................................... 30 
6. ENROLMENT, RANDOMISATION AND BLINDING ........................................................................................ 32 
6.1. PARTICIPANT IDENTIFICATION AND PRE-SCREENING: .............................................................................................. 32 
6.2. ENROLMENT (TRIAL ENTRY).............................................................................................................................. 34 
6.3. RANDOMISATION ........................................................................................................................................... 34 
6.3.1. Randomisation process ...................................................................................................................... 34 
6.3.2. Randomisation method ...................................................................................................................... 35 
6.4. BLINDING ...................................................................................................................................................... 35 
6.5. INFORMING THE PARTICIPANT’S GENERAL PRACTITIONER (GP) ................................................................................ 36 
7. TRIAL INTERVENTION ................................................................................................................................. 36 
7.1. OVERVIEW OF TRIAL INTERVENTION (GROUP 1: INTERVENTION ARM) ....................................................................... 36 
7.2. PHYSIOTHERAPY TRAINING ............................................................................................................................... 37 
7.2.1. Fidelity testing of physiotherapist-delivered intervention ................................................................. 38 
7.3. PHASE 1: GROUP 1 PRE-LT TRIAL INTERVENTION .................................................................................................. 39 
7.3.1. Visit 1 (day 0) – Group 1: Design and education of personalised HBEP ............................................. 39 
7.3.2. Aerobic exercise component of the HBEP .......................................................................................... 43 
7.3.3. Resistance exercise component of the HBEP ...................................................................................... 44 
7.3.4. Phase 1: Virtual or telephone health calls (‘Telecalls’) –Group 1 trial intervention ........................... 46 
7.3.5. Phase 1: Face-to-face clinic visits (visits 2, 3, 4, 5 and 6) –Group 1 trial intervention ....................... 46 
7.4. PHASE 2: POST-LT TRIAL INTERVENTION ............................................................................................................. 46 
7.4.6. Day 1 of ward admission (i.e. discharge from ICU) to discharge from hospital post-LT-trial 
intervention .................................................................................................................................................. 47 
7.4.7. Phase 2: Face-to-face clinic visits (visits 7, 8 and 9)- Group 1 trial intervention ................................ 48 
7.4.8. Phase 2: Virtual or telephone health calls (‘Telecalls’)- Group 1 trial intervention ............................ 48 

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7.5. GROUP 2 CONTROL (COMPARATOR) ARM ........................................................................................................... 48 
7.5.1. Phase 1 - Visit 1 (day 0) – Group 2 control arm.................................................................................. 48 
7.5.2. Phase 1 - Face-to-face clinic visits (visits 2, 3, 4, 5 and 6)- Group 2 control arm ............................... 48 
7.5.3. Phase 2 – post LT Day 1 of ward admission to discharge from hospital - Group 2 control arm ........ 49 
7.5.4. Phase 2 - Face-to-face clinic visits (visits 7, 8 and 9)- Group 2 control arm ....................................... 49 
7.6. TRIAL INTERVENTION MODIFICATION OR DISCONTINUATION .................................................................................... 49 
7.6.1. Trial intervention modification (unscheduled) ................................................................................... 49 
7.6.2. Trial intervention discontinuation (unscheduled) .............................................................................. 50 
7.6.3. Trial exercise regimen discontinued (scheduled) ............................................................................... 51 
7.7. ADHERENCE TO TRIAL INTERVENTION (HBEP) ...................................................................................................... 51 
7.8. CONTINUATION OF INTERVENTION AFTER COMPLETION OF THE TRIAL ........................................................................ 51 
8. OUTCOME MEASURES ............................................................................................................................... 52 
8.1. PRIMARY OUTCOME(S) .................................................................................................................................... 52 
8.2. SECONDARY OUTCOME(S) ................................................................................................................................ 52 
8.3. MECHANISTIC ‘MUSCLE’ SUB-STUDY OUTCOMES (N=100): ..................................................................................... 56 
9. TRIAL PROCEDURES ................................................................................................................................... 58 
9.1. STUDY TIMELINES (ESTIMATES) ......................................................................................................................... 58 
9.2. PRE-CONSENT SCREENING AT QEUHB AND RFH .................................................................................................. 58 
9.3. PHASE 1 PRE-LT TRIAL VISITS SCHEDULE .............................................................................................................. 59 
9.3.1. Pre-LT baseline Visit 1 (week 0) - maximum duration = 3-6 hours ..................................................... 59 
9.3.2. Pre-LT Visit 2 (week 6 +/- 7 days) - maximum duration = 30-60 mins* .............................................. 64 
9.3.3. Pre-LT Visits 3 (week 12 +/-7 days), 4 (week 24 +/-7 days), 5 (week 36 +/- 14 days) – max. 60min .. 65 
9.3.4. Pre-LT Visit 6 (week 48 +/- 14 days) – max. 60 min ........................................................................... 67 
9.3.5. Study intervention withdrawn (Scheduled)at 52 weeks ..................................................................... 67 
9.3.6. Pre-LT Telecalls at weeks 2, 4, 8, 10, 16 and 20 – intervention arm only........................................... 68 
9.4. DAY LT (UNPREDICTABLE TIMING) – TRIAL DATA COLLECTION [INPATIENT STAY L1] ..................................................... 68 
9.5. PHASE 2 POST-LT TRIAL SCHEDULE (INPATIENT STAY, VISITS 7-9) ............................................................................. 68 
9.5.1. LT data capture .................................................................................................................................. 69 
9.5.2. Phase 2 Post-LT inpatient surgical ward (post-ICU step-down) (Inpatient stay L2) ........................... 69 
9.5.3. Phase 2 post-LT visit 7 (6 weeks +/- 7 days) and visit 8 (12 weeks +/- 7 days) – max. 60 min ........... 71 
9.5.4. Post-LT Telecalls at weeks 4, 8 and 16, Group 1 intervention arm only ............................................. 72 
9.5.5. Post-LT (End of study intervention) Visit 9 (24 weeks +/- 14 days) .................................................... 73 
9.6. POST-LT (FOLLOW-UP) VISIT 10 (48 WEEKS +/- 14 DAYS) – MAX. 60 MINS .............................................................. 74 
9.7. FOLLOW-UP POST VISIT 10. .............................................................................................................................. 75 
9.8. WITHDRAWAL AND CHANGES IN LEVELS OF PARTICIPATION ..................................................................................... 75 
10. ADVERSE EVENT REPORTING ................................................................................................................... 77 
10.1. DEFINITIONS ................................................................................................................................................ 77 
10.2. ADVERSE EVENT RECORDING – GENERAL ........................................................................................................... 78 
10.3. ADVERSE EVENT REPORTING IN EXALT .............................................................................................................. 78 
10.4. SERIOUS ADVERSE ADVENTS (SAE) REPORTING IN EXALT..................................................................................... 78 
10.4.1. SAEs not requiring reporting to the ExaLT Trial Office ..................................................................... 79 
10.4.2. SAEs requiring non-expedited reporting to the ExaLT Trial Office ................................................... 79 
10.4.3. SAEs requiring expedited reporting to the ExaLT Trial Office ........................................................... 80 
10.5. EXPEDITED SAE REPORTING PROCESS ............................................................................................................... 80 
10.5.1. Assessment of causality of a related SAE ......................................................................................... 81 
10.5.2. Assessment of expectedness of a related SAE by the CI ................................................................... 82 
10.5.3. Provision of SAE follow-up information ........................................................................................... 83 
10.6. REPORTING SAES TO THIRD PARTIES ................................................................................................................. 83 
10.7. URGENT SAFETY MEASURES ........................................................................................................................... 83 
10.8. FOLLOW-UP OF PREGNANCY OUTCOMES FOR POTENTIAL SAES .............................................................................. 83 

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11. DATA HANDLING AND RECORD KEEPING ................................................................................................. 84 
11.1. SOURCE DATA .............................................................................................................................................. 84 
11.2. CASE REPORT FORM (CRF) COMPLETION .......................................................................................................... 85 
11.3. PARTICIPANT COMPLETED QUESTIONNAIRES ....................................................................................................... 86 
11.4. DATA MANAGEMENT ..................................................................................................................................... 86 
11.5. DATA SECURITY ............................................................................................................................................ 86 
11.6. ARCHIVING .................................................................................................................................................. 87 
12. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................................ 87 
12.1. SITE SET-UP AND INITIATION ........................................................................................................................... 87 
12.2. MONITORING .............................................................................................................................................. 88 
12.2.1. On-site monitoring ........................................................................................................................... 88 
12.2.2. Central monitoring ........................................................................................................................... 88 
12.3. AUDIT AND INSPECTION ................................................................................................................................. 88 
12.4. NOTIFICATION OF SERIOUS BREACHES .............................................................................................................. 88 
13. END OF TRIAL DEFINITION ........................................................................................................................ 89 
14. STATISTICAL CONSIDERATIONS ................................................................................................................ 89 
14.1. SAMPLE SIZE ................................................................................................................................................ 89 
14.2. ANALYSIS OF OUTCOMES ................................................................................................................................ 90 
14.2.1. Primary outcome(s) .......................................................................................................................... 90 
14.2.2. Secondary outcomes ........................................................................................................................ 91 
14.2.3. Planned subgroup analyses.............................................................................................................. 92 
14.2.4. Missing data and sensitivity analyses .............................................................................................. 92 
14.2.5. Planned final analyses ...................................................................................................................... 92 
15. SUB-STUDY: MECHANISTIC ‘MUSCLE’ SUB-STUDY (N=100) ...................................................................... 92 
15.3. BLOOD AND URINE SAMPLES FOR FUTURE RESEARCH .......................................................................................... 94 
15.4. SAMPLE TRACKING ........................................................................................................................................ 95 
15.5. SAMPLE STORAGE ......................................................................................................................................... 95 
16. TRIAL ORGANISATIONAL STRUCTURE ...................................................................................................... 95 
16.1. SPONSOR .................................................................................................................................................... 95 
16.2. COORDINATING CENTRE ................................................................................................................................. 95 
16.3. TRIAL MANAGEMENT GROUP (TMG) .............................................................................................................. 96 
16.4. TRIAL STEERING COMMITTEE (TSC) ................................................................................................................. 96 
16.5. DATA MONITORING COMMITTEE (DMC) ......................................................................................................... 96 
16.6. FINANCE ..................................................................................................................................................... 96 
17. ETHICAL CONSIDERATIONS ...................................................................................................................... 96 
18. DATA PROTECTION AND CONFIDENTIALITY ............................................................................................. 97 
19. FINANCIAL AND OTHER COMPETING INTERESTS ...................................................................................... 98 
20. INSURANCE AND INDEMNITY ................................................................................................................... 98 
21. POST-TRIAL CARE ..................................................................................................................................... 98 
22. ACCESS TO FINAL DATASET ...................................................................................................................... 99 
23. PUBLICATION PLAN .................................................................................................................................. 99 
24. ADDITIONAL PLANNING ........................................................................................................................... 99 
25. REFERENCE LIST...................................................................................................................................... 101 

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1. BACKGROUND AND RATIONALE 
1.1. Background 
Liver disease, the third commonest cause of death in the UK, predominantly kills between the ages of 
18 and 65. This leads to the loss of 62,000 years of working life each year in the UK. Liver 
transplantation (LT) remains the only curative treatment for patients with liver failure and the number 
of transplantations in the UK has risen over the past seven years by 50% to 1014/year.(1) LT is a highly 
resource intensive procedure requiring a large investment of healthcare resources. The average cost 
per procedure is estimated at over £1.1m, which includes pre-LT work-up, surgery, perioperative care, 
and an estimated seven year postoperative follow-up.(2) Complications whilst on the waiting list and 
in the perioperative period contribute substantially to this cost, and their likelihood is increased 
markedly by the presence of physical frailty.(3-5) 
 
Despite a new organ allocation system and advances in clinical management, 5-7% of patients on the 
waiting list die before LT, largely as a result of disease severity and physical frailty.(6) LT exerts a 
phenomenal physiological and psychological stress on recipients who are frail as a result of long-
standing liver failure. As a consequence, a further 5% of patients die within 6 months after LT.(6) 
Among those who survive, readmission rates are around 50% and perioperative complications can 
lead to prolonged hospital stays and long-term disability.(4, 5, 7) Ultimately, this results in a reduced 
long-term quality of life (QoL) and delayed/reduced return to productive employment after LT.(8, 9) 
End-stage liver disease triggers complex pathological changes in skeletal muscle, leading to sarcopenia 
characterised by low muscle mass and function.(10) Along with poor nutrition and physical inactivity 
and their close causative relationships, sarcopenia contributes to a high prevalence (70%) of physical 
frailty.(11) In turn, frailty is associated with poor clinical outcomes, including increased hospitalisation 
and intensive care unit (ICU) utilisation, (12-14) a 50% risk of severe postoperative complications(15) 
and a two-fold increase in pre- and post-LT mortality.(3, 16, 17) Frailty both before and after LT is 
associated with poor psychological and physical health-related QoL,(18-20) which is itself an 
independent predictor of mortality.(21) QoL post-LT significantly lags behind that of the general 
population (22) and although the majority are under 65 years old, fewer than 50% return to 
employment, which is largely attributed to prolonged disability/frailty.(9)  
 
1.2. Trial rationale 
Exercise interventions have been shown to be effective in other fields of medicine including prior to 
elective major surgery. However, due to the life-threatening, multi-systemic effects of end-stage liver 
disease, patients awaiting LT are often perceived as ‘too sick’ to exercise by healthcare professionals 
and the patient/carers themselves (PPI/Expert observations); with virtually no published data to 
support the benefits and safety of exercise in this cohort. Effective exercise interventions that reduce 
frailty pre- and post-LT have the potential to improve clinical outcomes and long-term QoL for this 
patient group, leading to cost savings for the NHS. Furthermore, a better understanding of how 
exercise works (i.e. on the muscular and cardiopulmonary systems) and how it can be effectively 
delivered (i.e. motivational approach adopted) in this unique cohort, will guide future exercise 
prescriptions (‘type’, ‘dose’, ‘duration’, ‘motivational strategies’) that are required to maximise the 
efficiency and longevity of this life-changing surgery. In an environment of substantial NHS resource 

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limitation, identifying simple, cost-effective and remotely monitored home-based interventions 
should be a priority in those patients who may benefit the most. 
 
1.2.1. Justification for participant population 
For those patients awaiting LT, the benefits of exercise are unknown as traditionally they have been 
viewed as ‘too sick’ to exercise. Healthcare professionals and research teams have therefore been 
reluctant to use exercise as a ‘medicine’ in this group. What underlies this myth is that due to their 
underlying liver disease these patients are frequently deconditioned with substantial functional 
impairment,(23) which tends to be proportional to the severity of disease.(24) End-stage liver disease 
is a multi-system disorder leading to physical frailty (muscle wasting, weakness, poor functional status, 
dependence of activities of daily living), cirrhotic cardiomyopathy, malnutrition, ascites, 
encephalopathy, anaemia and impaired pulmonary gas exchange, all of which limit a patient’s ability 
to exercise. Indeed, patients awaiting LT are some of the sickest and frailest patients in the NHS, to 
the extent that a 57 year old end-stage liver patient has the predicted physical frailty of >80 year old 
in the community.(25) Furthermore, there is an innate fear and anxiety (which has been confirmed by 
our patient feedback workshops) that exercise may actually exacerbate the complications of cirrhosis, 
thereby worsening a patient’s quality of life (QoL) and potentially even preventing them from being 
eligible for LT. These factors make patients with end-stage liver disease awaiting LT a unique cohort 
of patients in whom virtually no data exist to support the benefits and safety of exercise 
(p)rehabilitation. It cannot be assumed that because a preoperative exercise programme improves 
aerobic capacity in relatively well patients awaiting colorectal/cancer surgery that the same is true for 
patients with a life-threatening multi-system disease such as cirrhosis. When a patient with end-stage 
liver disease requires any surgery other than LT, it is highly likely that they would present ‘too’ high a 
risk (of postoperative morbidity and mortality) to be operated on. Thus, there is pressing need for 
detailed studies to answer efficacy and mechanistic questions unique to this patient population that 
cannot be addressed by simply transferring findings from other conditions. 
 
In order to optimise outcomes from LT these frail patients must survive their illness for an undefined 
period on the waiting list and then be in the best condition to survive one of the most physiologically 
and mentally challenging operations in the NHS. There is a theoretical case for the use of exercise 
therapy to improve outcomes in this cohort but this needs to be tested by rigorous clinical studies that 
are currently lacking. 
 
The physical hurdles to exercise in liver failure are apparent, however, the psycho-behavioural hurdles 
are also poorly understood.  Little is known about the motivation to engage and adhere to exercise in 
all chronic medical conditions and such knowledge is crucial in achieving benefits of exercise. Common 
psychological barriers to exercise in patients with chronic disease, include low self-efficacy 
(competence) and a lack of individualised support. Both of these factors contribute to low motivation 
to engage and adhere to exercise, and are amplified in patients awaiting LT due to patient and 
healthcare professional fear of causing harm. To promote optimal behaviour changes towards exercise 
adoption, NICE recommends that interventions target recognised determinants of behaviour (such as 
motivation) and are theoretically grounded.(26) An example of such a theoretical approach is self-
determination theory (SDT), which centres on the determinants and positive consequences linked to 

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autonomous motivation for exercise. SDT has been successfully applied by our research group in 
patients with chronic arthritis.(27) To date, the efficacy and mode of action of theory-based behaviour 
change/motivational interventions have not been tested in patients with end-stage liver disease 
awaiting and/or recovering from LT. Furthermore, training selective members of the pre-existing NHS 
workforce (i.e. surgery physiotherapists) to deliver the exercise intervention in a more motivationally 
adaptive manner can be an evolving cost-effective approach and unique to patients awaiting major 
surgery and/or with severe liver disease. 
 
1.2.2. Justification for design 
The ExaLT study is a phase 2b open-label two-centre randomised controlled trial (RCT) of 266 patients 
with end-stage liver disease evaluating the effectiveness of a unique remotely monitored pre- and 
post-LT programme of home-based exercise and theory-based motivation support in improving QoL 
post-LT. Delivering an effective home-based exercise programme that can be monitored and 
objectively evaluated is essential to patients with end-stage liver disease. Ensuring optimal uptake and 
adherence to such programmes is critical to realise meaningful improvements in health and wellbeing. 
The ExaLT trial intervention is designed to promote higher quality of motivation for exercise (i.e., more 
autonomously motivated), leading to sustained engagement with the home-based exercise program 
and exercise in general. 
 
To the best of our knowledge there are no other RCTs investigating the combined effect of exercise 
and targeted behavioural change/motivational strategies before or after LT. Currently an American 
team are recruiting 500 patients, either pre-LT or post-LT at baseline, to a trial of low-level resistance 
exercise via a DVD versus standard advice from their physician in clinic, on physical frailty using the 
liver frailty index (clinicaltrials.gov NCT02367092). The ExaLT study, however, is unique in that it 
follows the patient through the whole LT journey (pre-LT to post-LT) and assesses key patient-reported 
outcomes (i.e. physical and mental components of quality of life). In contrast to the American study, 
it incorporates an individualised resistance and aerobic exercise programme, physiotherapy-led 
training/monitoring, analysis of the effects of exercise on muscle physiology, and detailed assessment 
of the theory-based motivation programme and its impact on adherence and engagement with 
exercise. In addition, there are no directly competing trials regarding lifestyle/exercise/behaviour 
interventions in patients pre- and post-LT in the recruiting LT units. There are a growing number of 
interventional trials in LT, most notably donor organ optimisation with machine perfusion techniques 
(i.e. the Hope trial, NAPLES study). However, we do not feel that co-enrolment will influence the 
results of the ExaLT trial and most importantly, the use of machine perfusion will be captured in the 
trial database, as will other donor factors (age, type of organ, cold ischaemic time, intra-operative 
complications etc.).  
 
Currently in the UK, there is a lack of standardisation for exercise/physical advice across the 6 LT units; 
confirmed by a national LT audit we carried out in 2018 on behalf of British Liver Transplant Group 
(BLTG). The national audit highlighted that clinical guidance regarding physical activity can vary 
between exercise advice leaflets, verbal encouragement to keep active from clinicians and, at most 
units, no advice at all. Whilst provision of an exercise advice leaflet is not standard of care for all 
clinicians, advice about exercise is recognised as “best practice” by the NHS. Consequently, increased 

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emphasis is now being placed on the importance of communicating the benefits of exercise to patients 
(e.g., “Moving Medicine” – Public Health England and Faculty of Sport and Exercise Medicine). In order 
to standardise care for the control group across the two ExaLT trial sites (Queen Elizabeth University 
Hospitals Birmingham [QEUHB] and Royal Free Hospital London [RFH]) and minimise any potential 
variation in advice, a specifically formed ‘generic’ patient information exercise leaflet will be utilised 
for the control arm at both the QEUHB and RFH transplant centres. 
 
Eligible participants will be individually randomised in a 1:1 ratio to receive either remotely-monitored 
home-based exercise and theory-based motivation support programme (intervention arm) OR a 
standardised patient exercise advice leaflet (control arm) whilst on the LT waiting list (max.  52 weeks 
+ 2 weeks*) through to 24 weeks post-LT. Randomisation will be performed using minimisation 
method with minimisation variables age (55 years, >55 years), gender (male, female) and disease 
severity (UKELD ≤54, >54), trial site (QEUHB, RFH), as they are potential confounding factors. We will 
also include ‘consent for the muscle sub-study’ (Yes, No) as a minimisation variable in order to ensure 
equal representation of participants in the intervention arm (Group 1) and control arm (Group 2) . 
*Participants transplanted after 52 weeks can continue on study if they are transplanted within 14 
days of this date.   
 
The efficacy of the home-based exercise and theory-based motivation support programme on QoL 
(primary end-point of the trial) will be assessed at 24 weeks post-LT. At this time-point, investigators 
will also be able to assess and report the safety and effects of the exercise/motivation intervention on 
clinical measures, including physical frailty/fitness and post-LT surgical complications, length of 
ICU/hospital stay and 30, 90 and 180 day mortality.  
 
1.2.3. Justification for choice of intervention(s) 
In 2014 the American Society for Transplantation set out a research agenda for exercise interventions 
in patients awaiting solid-organ transplantation.(28) Despite the higher numbers of LT, as compared 
to heart and lung, the application of exercise training in this population is virtually non-existent.  
 
We carried out a literature review (29) to summarise the impact of physical exercise in patients with 
chronic liver disease through to LT. The majority of studies were small (1-50 patients), focused on 
supervised, hospital-based aerobic exercise interventions (but not resistance exercises) and largely 
excluded patients with significant liver failure needing LT.(30-32) Our work in this field has 
demonstrated that a supervised regimen of outpatient hospital-based exercise training sessions over 
6 weeks is both feasible and beneficial to patients awaiting LT (n=9).(33) However, this model is 
neither scalable nor cost effective because each LT unit cares for patients over a large geographic area 
and for many patients the time and cost required to travel to their LT centre several times each week 
is prohibitive.(33-35)  
 
Seven non-UK studies (4 RCTs; 3 observational studies) have demonstrated that supervised aerobic 
exercise after LT improves aerobic capacity, muscle mass/strength and in two studies, trends towards 
improved QoL.(36, 37) These small, heterogenous studies suggest that combined aerobic and 

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resistance-exercises yield the most promising improvements, but adherence is challenging. We carried 
out a proof-of-concept pilot study of a novel home-based exercise programme in patients awaiting 
LT.(38, 39) 18 patients underwent 12 weeks of resistance and aerobic exercises, with weekly 
telephone health calls. The intervention was safe and showed trends towards improved physical frailty 
and QoL in patients on the LT waiting list.  
 
There are clear advantages to home-based exercise programmes (40, 41), including increased 
flexibility and reduced travel burdens for patients, but it is essential that we focus on patients’ 
motivation to engage and psycho-behavioural barriers to exercise in order to optimise such 
interventions delivered at home. The need for behaviour change/motivational interventions has been 
repeatedly emphasised by our LT patient and public involvement (PPI) groups. Despite this, no studies 
to date have combined exercise with motivational interventions to increase intervention adherence. 
Understanding the social psychological processes through which motivational intervention influences 
patients to adopt and sustain positive changes in home-based exercise behaviour will guide larger 
studies of efficacy and cost effectiveness in this field. This is a key component to ensuring the long-
term success of home-based tailored-made exercise interventions outside of the secure, supervised 
hospital environment. 
 
1.2.4. Justification of choice of primary outcome 
The SF-36v2 (which incorporates the physical component score [PCS]), is a validated, robust, 
reproducible patient-reported outcomes tool for assessing QoL before and after medical/surgical 
interventions. It is the most widely cited QoL assessment tool in the published literature for solid-
organ transplantation and chronic liver disease.(9, 21, 36, 37, 42-44) The liver and transplant PPI 
groups (including disease support groups, National Health Service Blood and Transplant [NHSBT]) and 
the patient co-applicants strongly felt that the SF36v2 PCS QoL score captures the whole transplant 
experience from being on the transplant waiting list through to the LT and the recovery 24 weeks 
afterwards. The SF-36v2 PCS has been shown to strongly correlate with physical frailty, poor functional 
status and complications in patients undergoing LT.(9, 21) Fundamentally to the patients, their 
families and caregivers, QoL is the most important outcome to them in life (i.e. in their words ‘there 
is no point prolonging life with transplantation, if your quality of life is not worth living for afterwards’). 
The vast majority of patients undergoing LT are of working employment age with young families. If, 
however, they fail to recover their functional independence and physical activity levels post-transplant 
(only 2 out of 5 are deemed robust 1-year post liver transplant (45)), it has deleterious effects on their 
self-motivation, mental/physical health, ability to work, finances and family commitments.  
 
The SF-36 questionnaire includes 36 questions composed of 8 multi-item scales, which reflect the 
impact of health problems on both the physical and mental condition of the patient. A greater score 
reflects better QoL. Two summary sub-scores can be calculated which are weighted combinations of 
the eight scales, one to reflect the impact on physical function (PCS) and one to reflect the impact on 
psychological function mental component score (MCS).(21) A low PCS, rather than MCS, of SF-36v2 
has been associated with low survival, employment and functional status in our patient population.(9, 
21) Overall, we felt that the PCS was the best outcome measure in the evaluation of experimental 
interventions targeting physical frailty, functional status and health wellbeing in our patient 

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population. We also deemed an RCT powered to detect survival differences at 6-12 months post-LT as 
the primary end-point would not have been feasible (based on huge sample size, cost), as survival 
rates are consistently >90%. 
 
2. AIMS AND OBJECTIVES 
2.1. Primary Aim: 
The primary aim of the study is to investigate whether a remotely monitored ‘home-based exercise 
and theory-based motivation support programme’ delivered by physiotherapists before and after LT 
improves the QoL of LT recipients.  
 
2.2. Secondary Aims: 
The secondary aims are to investigate whether a remotely monitored ‘home-based exercise and 
theory-based motivation support programme’ delivered by physiotherapists before and after LT 
improves: 
 
Surgical complications (comprehensive complication index [CCI]) 
 
Mental wellbeing/health (Mental component score [MCS]) 
 
Physical frailty and fitness (Liver Frailty Index [LFI] / Duke Activity Status Index [DASI]) 
 
Pre-LT morbidity (United Kingdom model for End-stage Liver Disease [UKELD], Model for end-
stage liver disease sodium [MELD-Na], Hospital Admission) and mortality  
 
Post-LT length of ICU/hospital stay, hospital re-admissions and mortality (30,90,180 and 365 
days) 
 
Habitual physical activity levels (Daily time spent in light, moderate and vigorous intensity 
physical activity) 
 
The frequency, intensity and duration of exercise (‘dose’) undertaken 
 
Adherence to HBEP (Group 1:  intervention arm only) 
 
Perceptions of the health care climate (how need supportive/empowering the physio is) 
 
Basic psychological need satisfaction (i.e. feelings of autonomy, relatedness, competence) 
 
Self-determined motivation to exercise 
 
2.3. Study objectives: 
The main objectives are to conduct a two-centre clinical trial in which 266 patients on the LT waiting 
list will be randomised to either a) pre- and post-LT remotely monitored ‘home-based exercise and 
theory-based motivation support programme’ delivered by physiotherapists (experimental arm, 
n=133) or b) a standardised patient advice leaflet (control arm, n=133) in order: 
1. To determine the effect of the exercise/motivation programme on the QoL of LT recipients 
using the SF-36v2 health-related QoL questionnaire. 
2. To determine the effect of the exercise/motivation programme on physical frailty and fitness 
of LT recipients using LFI and DASI. 
3. To determine the effect of exercise/motivation programme on the morbidity and mortality of 
LT recipients by recording changes in: 

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a. Pre-LT:  UKELD, MELD-Na, hospital admissions, deaths. 
b. Post-LT: Post-LT length of hospital/ICU stay, re-admissions, surgical complications and 
deaths. 
4. To measure the habitual levels of physical activity both before and after LT, using a ‘blinded’ 
electronic wrist worn accelerometer and assess the impact of the exercise/motivation 
programme on levels of physical activity. 
5. To assess the ‘dose’ of exercise (frequency, intensity and duration) achieved with the 
exercise/motivation programme using ‘blinded’ electronic wrist worn accelerometer. 
6. To assess adherence to the exercise programme/advice using a self-reported exercise diary 
and ‘blinded’ electronic wrist worn accelerometer. 
7. To investigate how the theory-based motivation support provided by the physiotherapists, 
affects the patients: a) motivation to exercise; b) feelings of autonomy, relatedness, 
competence; and c) adherence to the home-based exercise programme using three 
psychological questionnaires:  
a. Health Care Climate Questionnaire (HCCQ);  
b. Basic psychological need satisfaction in exercise scale (PNSE);  
c. Behavioural Regulation in Exercise Questionaire-2 (BREQ-2)  
8. Mechanistic ‘Muscle’ Sub-study (n= 100): To investigate the dose-dependent effect of the 
exercise programme on cardiopulmonary fitness (Cardiopulmonary Exercise Test [CPET]; 6-
minute walk test (6MWT)), muscle biology (muscle ultrasound, biomarkers) and their 
association with QoL 
 
3. TRIAL DESIGN AND SETTING 
3.1. Trial design 
ExaLT is a phase 2b, open-label, two-centre RCT to assess the efficacy of a home-based exercise and 
motivational programme in patients before and after LT.  
 
The study will consist of 4 stages: 
Stage 
Time 
1 
Pre-screening/identification, enrolment, randomisation 
and baseline investigations 
1-2 weeks 
2 
Pre-LT waiting list study intervention up to the day of LT 
(from visit 1 to 6 or LT)  
1 –52weeks (variable)  
3 
Post-LT study intervention for 24 weeks (visits 7 to 9) 
24 weeks (fixed) 
End of Intervention; 
primary endpoint 
4 
Follow-up assessment (visit 10) 
24 weeks after End of 
intervention (i.e. 48 weeks 
post-LT) 

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Due to the unpredictable nature of the timing of LT, the duration of the study intervention ranges 
from a minimum of 25 weeks (1-week pre-LT; 24 weeks post-LT) to a maximum of 76 weeks (52 weeks 
pre-LT; 24 weeks post-LT). The maximum duration of the trial for an individual participant, including 
screening, intervention and the follow up visit will be approximately 2 years (100 weeks). In the event 
that a participant is not transplanted after 52 weeks, the study exercise regimen they were 
randomised to will be terminated. However, with the participant’s ongoing willingness to continue in 
the study, their data will be collected until the trial end date (see section 7.6.3 and section 9.3.5). 
 
Eligible participants will be randomly assigned to one of two groups: 
o 
Group 1: Intervention group. Remotely-monitored home-based exercise and theory-based 
motivation support programme delivered by the physiotherapists (max. 52 weeks) through to 
24 weeks post-LT. 
 
o 
Group 2: Control group. Patient ‘exercise’ advice leaflet before and after LT.  
The different levels of exercise support described above will be delivered to the participants in two 
phases: phase 1 pre-LT (maximum 52 weeks (+ 2 weeks)) and phase 2 post-LT (24 weeks).  All patients 
that are transplanted within 52 weeks (+ 2 weeks) of randomisation will receive a fixed 24 weeks (~6 
months) of the assigned exercise support after LT. Group 1 and 2 will contain approximately the same 
proportion of age groups, disease severity (UKELD), gender, trial site and ‘muscle’ sub-study as a result 
of minimisation.  
  
3.2. Trial setting 
The trial will take place across two NHS LT centres in England, namely QEUHB and RFH.  
 
3.3. Mechanistic ‘muscle’ sub-study (n=100) 
The main aim of the optional ‘muscle’ sub-study is to undertake a detailed evaluation of the biological 
and physiological mechanisms that may underlie any exercised-induced improvements in clinical 
outcomes, including QoL and physical function/frailty. A better understanding of how exercise works 
(i.e. on the muscular and cardiopulmonary systems) will guide future studies in terms of exercise dose-
response (‘frequency’, ‘intensity’, ‘duration’) that are required in patients with end-stage liver disease 
to maximise the efficiency and longevity of LT. The sub-study will aim to recruit 100 participants 
(approx. 50 in each study arm) and will take place at three time-points: pre-LT visit 1 (baseline, week 
0), pre-LT visit 2 (week 6), and at the post-LT visit 9 (24 weeks post-LT; end of intervention). In the 
event that a participant is not transplanted by visit 6 (pre-LT phase 1) of the study intervention, with 
the participant’s ongoing willingness to continue in the study, they will be given the option of a final 
sub-study visit (visit 6 [+ 6 week window]; inclusive of CPET, muscle ultrasound, 6MWT) and their data 
will be collected until the trial end date (see section 7.6.3 and section 9.3.5). See Section 15.0 for more 
information of the ‘muscle’ sub-study. 
 
 
 

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3.4. Assessment of risk 
All clinical trials can be considered to involve an element of risk and in accordance with the 
Birmingham Clinical Trials Unit (BCTU) SOPs, this trial has been risk assessed to clarify any risks relating 
uniquely to the ExaLT trial beyond that associated with usual care. A risk assessment has been 
conducted and concluded that this trial is low risk. An ongoing evaluation of risk will continue 
throughout the trial. 
 
4. ELIGIBILITY  
4.1. Inclusion criteria 
To be eligible to participate in the ExaLT Trial, patients must meet all of the following inclusion criteria: 
 
Adult patients (aged 18 years or over) 
 
Patients listed for a cadaveric, primary LT at QEUHB or the RFH 
 
Being an out-patient at the time of baseline trial visit (consent) 
 
4.2. Exclusion criteria 
If any of the following apply, the patient will not be eligible to be recruited into the ExaLT Trial:  
 
Patients listed for LT for any of the following reasons: 
o super-urgent LT (according to the Kings College criteria) 
o multi-organ transplantation (e.g. combined liver and kidney transplant) 
o live-related donor LT 
o re-graft LT 
 
Patients with an inability to safely comply with the exercise intervention due to: 
o severe hepatic encephalopathy (grade 3 or 4; or as judged by the clinical investigators) 
o oxygen-dependent hepato-pulmonary syndrome 
 
Patients without liver failure, including: 
o liver cancer in the absence of cirrhosis 
o polycystic liver disease 
o rare metabolic/genetic conditions (e.g. glycogen storage disorders) 
 
Refusal or lacks capacity to give informed consent to participate in the trial, at the point of 
study visit 1 (baseline)2 
 
 
 
 
2 During the course of the trial, some participants may lose capacity because of complications of their 
liver condition(s), for example hepatic encephalopathy.  

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4.3. Eligibility for mechanistic ‘muscle’ sub-study (n=100) 
To be eligible to participate in the ‘muscle’ sub-study, patients must meet all of the above eligibility 
criteria (section 4.1/4.2), consent for the main ExaLT trial and provide additional written consent for 
the sub-study.  
 
4.4. Co-enrolment 
The Trial Management Group (TMG) will consider requests for co-enrolment into other trials (e.g. 
donor graft machine perfusion studies) in accordance with best practice recommendations. Prior to 
co-enrolment being sanctioned, the following will be reviewed: study design and statistical 
considerations; legal and ethical considerations; biological and scientific rationale; patient 
considerations and logistical and organisational issues. For co-enrolment to occur, an agreement will 
be reached between the respective trials team prior to the patient being considered for inclusion. A 
log of all patients co-enrolled will be maintained by the ExaLT Trial Office.  
 
5. RECRUITMENT AND CONSENT 
It is the responsibility of the Principal Investigator [PI] (or designee as documented on the signature 
and delegation log) to obtain written informed consent for each participant prior to performing any 
trial related procedures. The PI can delegate this task to other members of the local research team if 
local practice allows and this responsibility has been documented in the site signature and delegation 
log. 
 
Potential participants will be identified as described in section 6.1, a member of the patient’s 
healthcare team (i.e. liver transplant coordinator) who is independent of the study/research team will 
inform them of the study to gauge interest in participation.  
 
If the potential participant is interested in taking part and agree to be approached by a member of the 
research team, a participant information sheet (PIS) will be provided to them. The PI or delegate will 
ensure that they adequately explain the aim of the trial, the trial intervention, and the anticipated 
benefits and potential hazards of taking part in the trial to the participant. They will also explain that 
participation is voluntary and that the participant is free to decide to take part and may withdraw from 
the trial at any time. The participant will be given more than 24 hours to read the PIS information and 
discuss potential participation with friends and family (in particular a personal consultee), prior to 
providing consent for the trial. The participant will be given the opportunity to ask questions before 
signing and dating the latest version of the informed consent form (ICF). If the participant then 
expresses an interest in participating in the trial, they will be asked to sign and date the latest version 
of the ICF. 
 
The PI or delegate will then sign and date the ICF. A copy of the ICF will be given to the participant, a 
copy will be filed in the medical notes and the original placed in the investigator site file (ISF). Once 
the participant is entered into the trial, the participant’s trial number will be entered on the ICF 

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maintained in the ISF. In addition, the participant understands and acknowledges that, a copy of the 
signed ICF will be transferred to the trial team at BCTU for review.  
 
Details of the informed consent discussions will be recorded in the participant’s medical notes. This 
will include date of discussion, the name of the trial, summary of discussion, version number of the 
PIS given to participant, version number of ICF signed and date consent received. Where consent is 
obtained on the same day that the trial related assessments are due to start, a note should be made 
in the medical notes as to what time the consent was obtained and what time the procedures started. 
The same process and documentation of consent will be undertaken for participation in the 
mechanistic ‘muscle’ sub-study. 
 
It is recognised that some participants may, during the course of the trial, lose capacity because of 
complications that may occur due to their pre-existing liver condition(s), for example, worsening 
hepatic encephalopathy. In this situation, the local research team will seek advice from a personal 
and/or nominated consultee (as per the Mental Capacity Act 2005) as to whether the participant 
would wish to continue participating in the trial.  
A personal consultee can be defined as someone who is: 
 
Engaged in caring for the participant (not professionally or for payment) or is interested in 
his/her welfare, and  
 
Is prepared to be consulted 
For the reason that family and/or social support (i.e. established friend) is a fundamental requirement 
during out-patient assessment for elective LT, it is extremely rare that a personal consultee cannot be 
found in this setting. To aid in this process, during the informed consent discussion with the 
participant, we will ask them to identify someone (who fulfils the above criteria), who would be willing 
to act as a ‘personal consultee.’ However, in the event a personal consultee cannot be identified, there 
will be the option to seek advice from a ‘nominated consultee.’  
A ‘nominated consultee’ is defined as someone who 
 
Has no connection with the trial 
 
Is willing to be consulted 
This can include healthcare workers (i.e. medical consultant, paid carer).  
 
If the personal consultee becomes unavailable during the study, or is no longer willing to undertake 
the role, the local research team should take steps to identify another personal consultee to take on 
the role. If no other appropriate person can be identified, a nominated consultee should be 
approached. 
 
Where it is necessary to seek the advice of a consultee, the PI or delegate will ensure that they 
adequately explain the aim of the trial, the trial intervention, and the anticipated benefits and 
potential hazards of taking part in the trial to them. They will also explain that participation is voluntary 
and that they may advise that the participant be withdrawn from the trial at any time. The consultee 
will be given sufficient time to read the personal consultee information sheet. The consultee will be 
given the opportunity to ask questions before signing and dating the latest version of the consultee 

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declaration form. The PI or delegate will then sign and date the consultee declaration form. A copy of 
the consultee declaration form will be given to the consultee, a copy will be filed in the medical notes 
and the original placed in the ISF. In addition, the consultee understands and acknowledges that, a 
copy of the signed consultee declaration form will be transferred to the ExaLT Trial Office at BCTU for 
review.  
 
At each visit, the participant’s willingness to continue in the trial will be ascertained and documented 
in the medical notes. Where the participant lacks capacity, advice will be sought from a consultee as 
described above. Throughout the trial, the participant (or their consultee) will have the opportunity 
to ask questions about the trial.  Should the participant regain capacity, their wishes will supersede 
those of the consultee. 
 
Any new information that may be relevant to the participant’s continued participation will be 
provided. Where new information becomes available which may affect the participants’ decision to 
continue, participants (or their consultee) will be given time to consider and if happy to continue they 
will be re-consented. Re-consent will be documented in the medical notes. The participant’s right to 
withdraw from the trial will remain.  
 
Electronic copies of the PIS and ICF will be available from the ExaLT Trial Office. The research site is 
required to present the documents on headed paper of the local institution.   
 
6. ENROLMENT, RANDOMISATION and BLINDING 
Potential trial participants will be recruited from the LT services at the supra-regional LT units in 
QEUHB and RFH. As part of the patients consent for liver transplant (which takes place before they go 
on the transplant waiting list), patients are also consented to be approached for future research 
studies. 
 
6.1. Participant Identification and pre-screening: 
Patients who are potentially eligible for the trial (Section 4.0 eligibility criteria) will be identified by 
the multidisciplinary team (MDT): a team of healthcare professionals (e.g. Hepatologist, Transplant 
Coordinator, Anaesthetist, Nurses, Allied Health Professionals [AHPs]) who are directly involved in the 
patient’s routine clinical NHS care – using the following: 
 
LT waiting list:  
o all patients ‘active’ on the UK LT waiting list are registered with NHSBT and recorded 
in a ‘live’ national database.  
o healthcare professionals (QEUHB and RFH) directly involved with the patients care on 
the LT waiting list have access to the NHSBT LT registry and their units LT waiting list 
database (on secure, password protected NHS computers).  
o in addition, both QEUHB and RFH have dedicated LT waiting MDT clinics, which are 
led by MJA (ExaLT CI) and CM (ExaLT PI RFH), respectively. In these weekly clinics, in 
which patients on the LT waiting list are under close follow-up, potential participants 

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will have the trial explained with oral and written information. At this stage the 
potential trial patient will have the opportunity to ask questions. 
o at the start of the trial, all eligible patients on the LT waiting list at QEUHB and RFH 
will receive an invite letter (in the post or in person) sent to them by the liver 
transplant coordinators who are independent of the study, which will include a brief 
overview of the trial and the contact details of the trials team if they would like to 
receive further information about the trial (i.e. PIS to be posted out). 
 
Out-patient LT assessment: 
o in total, QEUHB and RFLH undertake 500-600 LT assessments per year 
o during the out-patient LT assessment, patients and their next of kin [NoK]/friend 
(personal consultee) undergo oral, written and visual education regarding LT (i.e. 
waiting list, LT, risks, medications, aftercare, research opportunities etc.). An overview 
of the ExaLT trial will be incorporated into the assessment process. 
 
Trial information will also be available in the following formats and accessible to 
patients/public via the BCTU website: 
o ExaLT trial webpage (link to PIS, overview of study, eligibility, trial team contacts, 
frequently asked questions) 
o ExaLT trial leaflet (i.e. pamphlet) will be available in the LT waiting list and assessment 
outpatient clinics.  
o potential trial participants will then be able to approach the trial teams for further 
information (i.e. PIS), if they have not already received it via the above. 
 
All identified potential trial participants who declare an interest to learn more about the trial after 
receiving the invite letter, will either be given the PIS: 
o in person at either the liver transplant assessment or in their dedicated liver 
transplant waiting list clinic/specialist liver clinic (i.e. Primary sclerosing cholangitis 
[PSC], Hepatocellular Carcinoma [HCC]) 
and/or 
o via post, especially in light of the emergence of telephone/virtual video clinics (as a 
result of the COVID pandemic) 
o after receiving the PIS the potential participant will require greater than 24 hours to 
read the PIS information and discuss potential participation with friends and family 
(in particular a personal consultee), prior to providing consent for the trial. 
 
Details of all patients approached about the trial will be recorded on the ExaLT participant 
screening/enrolment log which will be kept in the ISF and should be available to be sent to the ExaLT 
Trial Office upon request. 
 
If the potential trial participant provisionally agrees to enrol in the trial, after reading the PIS 
information and discussing their potential participation with friends and family (in particular a 
‘personal consultee’), a baseline trial visit (visit 1) will be arranged.  
 
 
 

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6.2. Enrolment (Trial Entry) 
Enrolment to the ExaLT trial (+/- the ‘muscle’ sub-study) will take place at the baseline trial visit (Visit 
1). The study team will aim to coincide Visit 1 with the patient’s next LT waiting list clinic appointment, 
to avoid the additional burden of travelling to the LT unit. If this is not possible, the next available date 
(Monday to Friday) will be arranged. 
 
Consent (see section 5.0) 
 
NO trial specific examinations, investigations or treatments, that do not involve part of the 
patient’s routine standard healthcare, will be performed prior to obtaining written consent of 
the patient.  
 
A member of trials team (i.e. CI/PI or designee as documented on the signature and delegation 
log) will discuss with patient all the relevant information, including aims, methods, risk and 
benefits of the trial, prior to obtaining consent. 
 
At this stage the patient will also nominate a ‘personal consultee(s)’ in the event that they lack 
capacity at any stage of the trial. 
 
Once valid informed consent (i.e. ICF signed and dated by the patient) the eligibility checklist 
will be completed 
 
Confirmation of Eligibility 
The eligibility will be verified by the research nurse or another clinical member delegated by the PI via 
the delegation Log. See section 4.0 for eligibility criteria. 
 
6.3. Randomisation  
Randomisation will be provided by BCTU using a secure online system, REDCap, thereby ensuring 
allocation concealment. Unique log-in usernames and passwords will be provided to those who wish 
to use the online system and who have been delegated the role of randomising participants into the 
trial as detailed on the ExaLT site signature and delegation log. These unique log-in details must not 
be shared with other staff and in no circumstances should staff at sites access either system using 
another person’s login details. The online system will be available 24 hours a day, 7 days a week, apart 
from short periods of scheduled maintenance. In the event that the online system is not available, 
researchers should contact the ExaLT Trial Office. 
 
6.3.1. Randomisation process  
After eligibility for randomisation has been confirmed and informed consent has been given, the 
participant will be randomised using the online system. Randomisation forms will be provided to 
investigators and will be used to collate the necessary information prior to randomisation. All 
questions and data items on the online randomisation form must be answered prior to a potential 
participant being randomised into the trial and a unique trial number being issued.  
 
Following randomisation, a confirmatory e-mail will be sent to the local PI and designated members 
of the trial study team (e.g. local research nurse). The local research team should add the participant 

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to the ExaLT participant recruitment and identification log, which links participants with their unique 
trial identification number. PIs must maintain this document securely and it must not be submitted to 
the ExaLT trial office. The ExaLT participant recruitment and identification log should be held in strict 
confidence. 
 
6.3.2. Randomisation method  
Randomisation will be provided by a computer-generated programme. Participants will be individually 
randomised in a 1:1 ratio to either: 
o 
Group 1: Intervention group. Remotely-monitored home-based exercise and theory-based 
motivation support programme delivered by the physiotherapists prior LT (max. 52 weeks) 
through to 24 weeks post-LT. 
 
o 
Group 2: Control group. Patient exercise advice leaflet before and after LT.  
 
A minimisation algorithm will be used within the randomisation system to ensure balance in the 
allocation over the following variables: 
 
Gender (Male, Female) 
 
Age (≤55 years, >55 years)  
 
UKELD score (≤54, >54) 
 
Trial centre (QEBH, RFH)  
 
Enrolled in the ‘muscle’ sub-study (Yes, No) 
o this criteria will become a default “No” for all randomised patients once the target 
sample size of 100 patients enrolled in the sub-study is reached. 
 
A ‘random element’ will be included in the minimisation algorithm, so that each participant has a 
probability (unspecified here), of being randomised to the opposite treatment that they would have 
otherwise received. 
 
6.4. Blinding 
The ExaLT trial is an open-label study. Due to the nature of the study intervention (i.e. exercise and 
motivation programme) and the fact it is delivered by the study physiotherapists it is not possible to 
blind the participant or the co-investigators from the allocated study intervention. Importantly, 
however, the participants will be ‘blinded’ to the electronic wrist worn accelerometers to ensure they 
are not getting any objective positive or negative feedback from the accelerometers on their physical 
exertion or activity during the trial. In addition, data analysis of the ‘muscle’ sub-study will be blinded, 
in that the individual(s) performing the analysis of the CPET, muscle ultrasound and specialist 
biomarkers will be blinded to the study order of the investigations and allocation of the study 
intervention; thereby avoiding interpretation bias. 
 
 
 

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6.5. Informing the participant’s General Practitioner (GP) 
If the participant has agreed, the participant’s GP will be notified that they are in the ExaLT trial, using 
the approved ExaLT GP letter. 
 
7. TRIAL INTERVENTION 
7.1. Overview of Trial intervention (Group 1: Intervention arm) 
The trial intervention will be delivered to participants in two phases: 
 
Phase 1 - Pre-LT: From enrolment into the study (baseline) up to LT. Duration of phase 1 will range 
from 1 to 52 weeks (+ 2 weeks), due to the unpredictable nature of the timing of LT. 
 
Phase 2 - Post-LT: From day 1 admission to the ward (i.e. discharge from ICU) to 24 weeks post LT. 
Duration of phase 2 will be fixed at 24 weeks (minus ICU length of stay, median 2-3 days [NHSBT data 
2021]) 
 
The intervention for both phases will be delivered by study physiotherapists and will comprise of two 
core components: 
1. A remotely-monitored personalised home-based exercise programme (HBEP) and 
2. An autonomous motivation enhancement programme, known as Empowering Physio, 
delivered to physiotherapists to support them in delivering the HBEP. 
 
Home-based exercise programme (HBEP) - Following an initial assessment at Visit 1 (see section 
7.3.1), the patients will be provided with a HBEP consisting of five sessions of aerobic and resistance 
exercise per week. Thereafter, in the pre-LT phase 1, participants will attend up to four face-to-face 
visits with the physiotherapist (visit 2 - week 6; visit 3 – week 12; visit 4 – week 24; visit 5 - week 36), 
during which the participant will be assessed and the HBEP revised accordingly. If the participant has 
not had their LT by week 52 of phase 1, the participant will be withdrawn from the physiotherapist 
delivered HBEP (study intervention). After LT, the participant will initially undergo physiotherapist 
delivered walking and basic exercise programmes (supported in concordance with Empowering Physio 
principles) until discharge from hospital. The HBEP re-commences on discharge from hospital and will 
be adapted according to the patient’s LFI and DASI, performed within 24-72 hours of expected 
discharge. The PI and the consultant transplant surgeon will be consulted prior to commencing the 
HBEP if there are any ongoing surgical complications (i.e. biliary drain in-situ; wound dehiscence etc.). 
After discharge, the participant will have two face-to-face visits (visit 7 - week 6; visit 8 - week 12) with 
the physiotherapist. In addition, physiotherapist support to the participants will be provided in the 
form of virtual or telephone health calls (Telecalls) to allow revisions to their personalised HBEP and 
the continuing employment of Empowering Physio strategies techniques as required. Telecalls will 
take place in the pre-LT phase 1 at weeks 2, 4, 8, 10, 16 and 20 (pre-LT) and in the post-LT phase 2 at 
weeks 4, 8 and 16. Section 7.3 and 7.4 provide further detail of the face-to-face visits and the Telecalls. 
 

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Autonomous motivation enhancement programme - The bespoke Empowering Physio programme 
will be used to equip physiotherapists (see section 7.2) with the understanding and skills to support 
each patient’s sense of autonomy, competence and relatedness in delivering the HBEP; in order to 
help foster more autonomous motivation for uptake and adherence to the HBEP and engagement in 
exercise overall. 
 
7.2. Physiotherapy Training 
To ensure consistency across sites, the physiotherapists will receive formal training from Mrs Felicity 
Williams (Liver/LT Specialist Physiotherapist; PI) on all aspects of the assessment (including LFI and 
DASI) and HBEP intervention prior to commencement of the study at sites. Furthermore, the 
physiotherapists will be trained in the principles and strategies of Empowering Physio by Professor 
Joan Duda (Professor of sport and exercise psychology; co-investigator). The face-to-face training will 
take place over a 3-day structured course (Table 1). The overarching aim of the bespoke Empowering 
Physio training programme is to:  
 
1. Enhance physiotherapists’ understanding of: (a) what is optimal motivation for exercise and 
behaviour change; (b) the importance of the motivational ‘treatment’ climate they create; 
and (c) how that created climate (the physiotherapists’ behaviours) influences patients’ 
motivation for pursuing their physical activity goals and associated well-being.  
 
2. Provide the opportunity for the physiotherapists to: (a) learn what are the ‘building blocks’ 
of creating a more empowering motivational treatment climate when working with patients, 
and (b) develop strategies which facilitate the realisation of these ‘building blocks.’ 
 
The three day training will involve presentation content and interactive activities to highlight how 
physiotherapists interact with and provide information and feedback to patients and the implications 
of such for patients’ motivation to engage in physical activity. Physiotherapists will be asked to reflect 
on their own experiences in clinical practice in regard to optimal and questionable motivational 
stategies.  The workshop will also address the importance of communication style, and ‘how ‘ to 
exchange with patients so that they feel a greater sense of autonomy, competence and connection in 
regard to their HBEP. The persuading and directing way of communicating will be contrasted with an 
evoking, guiding and following manner of exchanging with patients. The physiotherapists will then 
have the opportunity to identify barriers to creating a more empowering treatment climate and 
develop potential strategies to overcome this. 
 
 
 

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Table 1: Study Physiotherapist Training Course 
Training Components 
Day 
1 
Day 
2 
Day 
3 
Study logistics 
 
 
 
Functional and nutritional assessments (LFI/6MWT/MAMC) 
 
 
 
Questionnaires  
(DASI/PCS-SF-36v2/MCS-SF-36v2/HCCQ/PNSE/BREQ-2) 
 
 
 
Aerobic and Resistance exercise theory 
 
 
 
Practical exercises 
 
 
 
Patient education package 
 
 
 
Muscle Ultrasound 
 
 
 
Principles and strategies of Empowering Physio 
 
 
 
Practical application of Empowering Physio 
 
 
 
Principles and strategies to delivery of face-to-face consultations, patient 
education session and Telecalls 
 
 
 
Total time (hours)
7 
7 
7 
Health Care Climate Questionnaire(HCCQ); Basic Psychological Need Satisfaction in Exercise Scale(PNSE); 
Behavioural Regulation in Exercise Questionaire-2 (BREQ) 
 
The principles and embedded strategies to more empowering physiotherapy will be revisited the 
following day and reviewed to ensure understanding and application. The physiotherapists will then 
have the opportunity to consider the face-to-face consultations they will have with their patients (with 
particular emphasis on the initial participant education session, exercise familiarisation, and provision 
of the written exercise programme) and Telecalls and develop/’bring to life’ a planned approach (i.e. 
specify motivational aims, strategies) to make these exchanges more empowering.  Role playing will 
be used to exemplify the empowering strategies that the physiotherapists will employ and address 
challenges that may arise. 
 
7.2.1. Fidelity testing of physiotherapist-delivered intervention 
The implementation fidelity of the physiotherapist delivered intervention will be assessed in regard to 
(1) expected content conveyed (e.g. explanation and demonstration of the HBEP to the patient), and 
(2) the degree to which the behaviours of the physiotherapist (when interacting with the patient) were 
motivationally empowering (and thus supportive of the patient’s autonomous motivation for 
exercise).  To test the fidelity of the behaviour therapy training throughout the entire ExaLT trial study 
period, at each site four patient video recordings per physio will take place, where recruitment 
numbers allow, at patient 20 (+/-3), patient 40 (+/-3) and patient 60 (+/-3). The four patient recordings 
include: 
 
The baseline visit 1 (week 0 pre-LT) session including exercise training/education  
 
One Telecall follow-up (either weeks 2, 4 or 8) 
 
One pre-LT face-to-face follow-up visit (either visit 2 or 3) 
 
One post-LT face-to-face follow-up visit (either visit 7 or 8) 

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The interactions between physiotherapist and patient will be examined using visual recordings for 
Telecalls and face-to-face visits. A modified (for the present exercise intervention content) of the 
Interpersonal Support in Physical Activity Consultations Observational Tool (ISPACOT) (46) will be 
employed to evaluate the degree to which the physiotherapists conveyed the expected information, 
as intended in the face-to-face consultations and Telecalls and the motivational climate manifested 
during these treatment sessions.  In regard to the latter, the ISPACOT assesses four aspects of the 
treatment climate: the degree to which the physiotherapist is autonomy supportive, demonstrated 
social support/caring, provided structure, and exhibited interpersonal control.   
 
7.3. Phase 1: Group 1 Pre-LT trial intervention  
Pre-LT Phase 1 of the HBEP will commence the day after baseline visit 1 (maximum 3 days post visit 1) 
and end on either a) the day of LT, or b) 52 weeks (+ 2 weeks) if LT has not taken place. Details of the 
intervention timeline are summarised in Table 2.  
 
7.3.1. Visit 1 (day 0) – Group 1: Design and education of personalised HBEP 
After obtaining consent and completion of baseline assessments (see section 9.0), participants will 
meet the study physiotherapist. The baseline assessments, along with Empowering Physio strategies, 
will be used to design a personalised written HBEP for the participant. Baseline LFI and DASI will be 
used to guide the entry level of difficulty for the aerobic and resistance-based exercises, respectively 
(Tables 3 and 4). In addition, the entry level of difficulty for the exercises will also be influenced by 
discussions with the participant on ways to employ strategies to support autonomous motivation for 
exercise adoption and engagement. The participants will then attend an individualised physiotherapist 
delivered training session, which will consist of: a) patient education (1 hour), b) exercise 
familiarisation (1 hour) and c) issuing of devices and written information (1 hour). Details of which are 
provided in Table 2.  
 
A) Patient education: Patient education sessions on the topics of general benefits of exercise, 
breathless management, pacing, rate of perceived exertion and nutrition pre-and post-
exercise, will be delivered in the format of power point presentation and informal discussion 
by the physiotherapist. In accordance with Empowering Physio principles, the education 
sessions will be delivered in a manner that makes it more likely that the information conveyed 
is personally meaningful and confidence enhancing. Therefore, being more likely to increase 
feelings of autonomy, competence and relatedness towards exercise by the participant. 
 
B) Exercise familiarisation: Participants will be taught a series of body-weight resistance 
exercises performed in a circuit (Table 4). The aim of this session is to familiarise the 
participant with the exercises and the use of the rate of perceived exertion tool for monitoring 
exercise intensity. This session will also provide an opportunity for the physiotherapist to 
ensure correct and safe techniques. Participants will have the opportunity to voice any 
concerns they have regarding the exercises and allow for these concerns to be resolved prior 
to completing the exercises at home. In line with Empowering Physio principles, the 
physiotherapists will also provide responsive, meaningful feedback to ensure participant’s 
individual needs are met. For example, the physiotherapist will be guided by the participant 

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and adjust exercise levels as needed to ensure participants feel competent in their exercise 
efforts. Throughout the session, physiotherapists will acknowledge effort and progress. 
 
C) Written information: Using the results of the baseline assessments of LFI and DASI (Figures 
1 and 2) and the discussions had with the participant, the physiotherapist will provide a 
personalised written aerobic and resistance HBEP. The details of which can be found below. 
Furthermore, the participant will be provided with a participant diary to record their 
completed exercise sessions.

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Trial Visits
Trial Intervention 
V1 
W0 
THC 
W2 & 4
Devices 
W4-6 
V2 
W6 
THC  
W8,10
Devices 
W10-12 
V3 
W12 
THC  
W16& 
20
Devices 
W22-24 
V4 
W24 
V5 
W36
V6 
W48 
LT  
 
IP 
stay 
THC  
W4 
Dev
W
Education 
Patient education session 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Devices and Handouts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accelerometer 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X
HR monitor (during 
structured exercise session 
only) 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X
Participant Diary issued 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Exercise instruction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-LT A/R exercise plan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review and adaptation of 
A/R exercises 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
Review of participant diary 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
Post-LT A/R exercise plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Empowering Physio 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identify knowledge about 
benefits of exercise 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Link exercise to personally 
meaningful goals/events 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decisional balance patient 
centred goal setting 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
Supports attempts to 
change behaviour 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
Normalise failed attempts 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
Problem solving 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
X 
Table 2: Group 1 Study Intervention timelines. Key: A/R = aerobic/resistance;  HR = heart rate; LT = liver transplant; V = visit; THC =

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Level of 
difficulty 
Exercise 
Intensity 
Duration 
(mins) 
1 
Walking/cycling/swimming/cross-
trainer/running 
1x5mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x5mins @ RoPE 12-14 
 
13 
2 
Walking/cycling/swimming/cross-
trainer/running 
1x7mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x7mins @ RoPE 12-14 
 
17 
3 
Walking/cycling/swimming/cross-
trainer/running 
1x10mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x10mins @ RoPE 12-14 
 
23 
4 
Walking/cycling/swimming/cross-
trainer/running 
1x12mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x12mins @ RoPE 12-14 
 
27 
5 
Walking/cycling/swimming/cross-
trainer/running 
1x10mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x10mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x10mins @ RoPE 12-14 
 
33 
6 
Walking/cycling/swimming/cross-
trainer/running 
1x15mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x15mins @ RoPE 12-14 
 
33 
7 
Walking/cycling/swimming/cross-
trainer/running 
1x20mins @ RoPE 12-14 
1x3mins recovery @ RoPE 9-11 
1x10mins @ RoPE 12-14 
 
33 
8 
Walking/cycling/swimming/cross-
trainer/running 
 
1x30mins @ RoPE 12-14 
30 
9 
Walking/cycling/swimming/cross-
trainer/running 
 
1x35mins @ RoPE 12-14 
35 
10 
Walking/cycling/swimming/cross-
trainer/running 
1x40mins @ RoPE 12-14 
40 
Table 3: Aerobic exercise programme 

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7.3.2. Aerobic exercise component of the HBEP 
 The initial level (duration, recovery period, intensity) of aerobic exercise sessions will be determined 
from the baseline DASI (Figure 1), while accounting for any exercise limiting comorbidities, such as 
ascites, peripheral oedema and/or hepatic encephalopathy. It will be recommended to the 
participants that they aim to complete two sessions of aerobic exercise per week. In line with 
Empowering Physio theory, a rationale for this recommendation will be provided. The participants will 
also be asked to select their exercise modality of choice from the following options; walking, cycling, 
swimming, cross-trainer, rowing ergo or running. In collaboration with the physiotherapist, the 
participant will be able to change their choice of modality week by week or continue with the same 
choice depending on their preferences. Furthermore, the physiotherapist will involve the participant 
in discussions about previous positive exercise experiences to facilitate personal goal setting. The level 
set will be appropriate to the participant’s current level of function but also ensure the participant 
feels competent in their exercise effort. Each aerobic session will consist of alternating “work” and 
“active rest” periods: 
 
During the work periods, participants will be asked to exercise at a moderate intensity (rate 
of perceived exertion (RoPE) score of 12-14 (6-20 scale)).  
 
During their active rest periods, participants will be asked to work to a RoPE of 9-11. Details 
of the aerobic exercise intervention and levels of difficulty are detailed in Table 3. 
 
Exercise intensity will be progressed depending on the feedback from regular Telecalls to the 
participant (weeks 2, 4, 8, 10, 16 and 20) pre-LT.  
 
 
 
 
 
 
 
Duke Activity Status Index (DASI) 
DASI <20 
DASI=20-34 
DASI = 35-47 
DASI = 48-58 
Level 1 
Level 2-3 
Level 3-4 
Level 4-5 
Figure 1 - Flow diagram for use of DASI when prescribing the ‘entry level’ aerobic exercise programme 

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7.3.3. Resistance exercise component of the HBEP 
Participants will be asked to participate in a 20-minute circuit of bodyweight resistance exercises twice 
weekly on alternate days to the aerobic sessions. The circuit will consist of four cycles of 8-12 
repetitions of five exercises, chosen by the patient (Table 4 and 5) with two minutes of “active rest” 
(walking slowly on the spot) between each exercise and each cycle. The programme and entry level 
will be developed according to baseline LFI (Figure 2), and a trial of 8-12 repetitions exercises within 
the designated entry level. Furthermore, the entry level will be discussed collaboratively with the 
participant to support feelings of competence and autonomy.  
 
The participant will be instructed to terminate each set of an exercise when they reach a “repetitions 
in reserve” (RIR) of 1-2; that is, they feel they could complete 1 or 2 additional repetitions, but no 
more. The participant will be advised to progress to each level of difficulty once they can achieve 12 
repetitions with 1-2 RIR and depending on feedback from the Telecalls at weeks 2, 4, 8, 10, 16 and 20 
pre-LT. Details of the resistance exercise circuits and levels of difficulty are detailed in Table 4 and 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Frailty Index (LFI) 
LFI = ≥75% 
LFI = 51-75% 
LFI = 26-50% 
LFI = ≤25% 
Level 1 
Level 2-3 
Level 3-4 
Level 4-5 
Figure 2 - Flow diagram for use of LFI when prescribing the ‘entry level’ resistance exercise programme 

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Muscle 
Group 
Exercise 
1 
2 
3 
4 
5 
Upper 
Limb 
Press 
Horizontal press 
Wall press-up 
Press-up on knees 
Hands-elevated press-
up 
Progressively lower 
hands-elevated press-
up 
 
Press-
Vertical press 
Overhead press, 
arms only  
Overhead press 
with light weight 
(e.g. soup cans)  
 
Overhead press with 
heavier weight (e.g. 
water bottles)  
 
Pike push-up, hands on 
raised surface 
Pike p
Upper 
Limb Pull 
Horizontal pull 
Two-arm row with 
light weight (e.g. 
soup can) 
 
One-arm row with 
light weight (e.g. 
soup cans) 
Two-arm row with 
heavier weight (e.g. 
water bottles)  
One-arm row with 
heavier weight (e.g. 
water bottles)  
 
Two-a
progre
resista
 
Lateral/Vertical 
pull 
Lateral rotation 
with yellow TB 
Bilateral abduction 
with TB 
Diagonal TB pull 
Vertical pull down with 
yellow TB 
Vertic
red TB
 
Lower 
Limb 
Squat 
Raised surface 
chair stands 
Wall squat 
Chair stands 
Full squat 
Squat
(e.g. s
 
 
Lunge 
Static lunge with 
support 
 
Static lunge without 
support 
Dynamic half lunge 
Dynamic full lunge 
Walki
 
Step ups 
Low step-up (e.g. 1 
stair) 
Low step-up with 
knee raise 
Low step-up with knee 
raise and light weight 
(e.g. soup cans) 
High step-up with high 
knee 
High s
knee a
(e.g. s
Core 
Stability 
Anti-anterior 
flexion 
Four-point 
kneeling holds 
 
Four-point kneeling 
with leg raises 
 
Four point kneeling 
alternate arm and leg 
raises 
 
Kneeling plank  
Plank
 
Glute med/anti-
lateral flexion 
 
Clams 
Clams heels raised 
Straight leg clam 
Elbows-elevated side 
plank  
Elevat
 
 
Extension 
Pelvic tilt in crook 
lying 
Bridges 
Bridges with yellow TB 
Bridges with red TB 
Bridge
heel r
Table 4 – Resistance Exercise Programme 

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7.3.4. Phase 1: Virtual or telephone health calls (‘Telecalls’) –Group 1 trial intervention 
At weeks 2 (+/- 1 week), 4 (+/- 1 week), 8(+/- 1 week), 10(+/- 1 week), 16(+/- 1 week) and 20 (+/- 1 
week) pre-LT, the participant will receive either a virtual or telephone health call by the 
physiotherapist, known as a ‘Telecall’. The purpose of these calls (duration 15-30 minutes) will be to: 
 
Identify any adverse events or areas of concern. 
 
Gain feedback from the participant regarding the HBEP. 
 
Provide motivational support for engagement with the HBEP through the implementation of 
Empowering Physio strategies. For example, to empower patients in their attempts to be 
active, the physiotherapists will support attempts to change behaviour, problem solve and to 
develop strategies to overcome personally reported barriers and enhance self-efficacy for 
exercise. It is also an opportunity to revisit goals to ensure they are aligned with participant’s 
perceptions of their exercise competencies (Table 3).  
 
Guide weekly progression of exercises and goal setting. 
An interview guide underpinned by Empowering Physio principles and related motivation-based 
theories of behaviour change, will be used to provide a standardised framework of the Telecalls at 
both sites.  
 
7.3.5. Phase 1: Face-to-face clinic visits (visits 2, 3, 4, 5 and 6) –Group 1 trial intervention 
Participants will attend the hospital (QEUHB or RFH), in line with their routine waiting list clinic 
appointment (where possible), at weeks 6 (+/- 7 days), 12 (+/- 7 days), 24 (+/- 7 days), 36 (+/- 14 days) 
and 48 (+/- 14 days). At these visits, a repeat of the baseline assessment, including LFI and DASI, will 
be undertaken (see Procedure section 9.0). The results of these assessments, review of the participant 
exercise diary and discussions with the participant themselves will be used to progress exercises and 
revise goals of their HBEP. As per Empowering Physio principles strategies, the active role of the 
participant in the decision-making process, regarding progression and goal revision, will continue to 
support more autonomous reasons for engagement in the HBEP. Revisions will be based upon physical 
frailty/function scores (LFI, DASI) and the participant’s owned perceived progress with the training 
HBEP. The end of the study intervention (HBEP, motivation programme) will be at 52 weeks (+ 2 
weeks) if the participant has not undergone LT. At this stage, they will be asked if they wish to continue 
in the study (data collection only) as outlined in section 7.6.3.   
 
7.4. Phase 2: Post-LT trial intervention  
Post-LT Phase 2 of the HBEP will commence on day 1 of admission to the post-LT ward (i.e. within 24 
hours of discharge from ICU) and end 24 weeks after the date of the LT surgery (visit 9). Details of the 
intervention timeline are summarised in Table 2. 
No of exercises 
 
No of 
circuits 
Repetitions 
Rest period between circuits 
(mins) 
Total time 
(mins) 
1x upper limb push 
1x upper limb pull 
2x lower limb 
1x core/balance
4 
8-12 
2 
26 
Table 5 – Resistance Exercise Session Template 

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7.4.6. Day 1 of ward admission (i.e. discharge from ICU) to discharge from hospital post-LT-trial 
intervention 
The trial physiotherapists will review the participant on the post-LT ward, within 72 hours of discharge 
from ICU. The participants will start a supervised progressive walking programme, based upon the 
participant’s current level of physical frailty/function, in keeping with post-surgical care. If able, the 
participant will be asked to complete a walk (distance determined by physiotherapist, based upon 
participant’s current level of function) twice daily working to a RoPE of 12-14 throughout the walk. 
Distance walked should be increased on a daily basis provided the participant is medically safe to 
achieve this and feels competent in doing so. In addition, the participant will also be asked to complete 
twice daily a basic exercise programme consisting of upper limb, lower limb, balance, coordination 
and core-strengthening exercises (Table 6). This post-LT exercise ‘inpatient’ programme will also be 
supported in concordance with Empowering Physio principles. If there are concerns by the 
physiotherapist about the patient’s safety to exercise (i.e. walk, chair stand etc.), the patient’s 
consultant (i.e. surgeon, hepatologist) and clinical team (i.e. nurse) will be consulted, as per routine 
NHS care. 
 
Within 72 hours prior discharge from hospital (or day 10 post-LT (+/- 3 days) if not discharged by this 
point; main exception that patient is still on ITU receiving organ support), a repeat of the baseline 
assessments, including LFI and DASI, will be undertaken on the ward (see Trial Procedures section 9.0). 
The results of these assessments, along with Empowering Physio strategies, will be used to prescribe 
a personalised written HBEP for the participant post-LT. The participant will also be given participant 
exercise diary. 
 
 
Level
Exercise 
Sets/Reps 
1 
Marching on the spot 
Pelvic tilts 
Wall squat 
Wall press 
 
3x8-12reps
2 
Step-ups 
Bridge holds (5 seconds) 
Chair stands 
Arm raises 
 
3x8-12reps
3 
Step-up high knees 
Single leg bridge holds (5 seconds)
Squats 
Arm raise with Theraband© 
3x8-12reps
 
Table 6: Post-Liver Transplant Basic Exercise Programme 

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7.4.7. Phase 2: Face-to-face clinic visits (visits 7, 8 and 9)- Group 1 trial intervention 
Participants will attend the hospital (QEUHB or RFH), in line with their routine post-LT follow-up clinic 
appointment (where possible), at weeks 6 (visit 7; +/- 7 days) and 12 (visit 8; +/- 7 days). At these visits, 
a repeat of the baseline assessment, including LFI and DASI, will be undertaken (see Trial Procedures 
section 9.0). As per phase one, the physiotherapist will use these assessments along with Empowering 
Physio techniques and the participant’s owned perceived progress to revise their personalised HBEP. 
Of note, visit 9 (24 weeks post-LT +/- 7 days) will mark the end of the study intervention (HBEP, 
motivation programme). 
 
7.4.8. Phase 2: Virtual or telephone health calls (‘Telecalls’)- Group 1 trial intervention 
Participants will receive a ‘Telecall’ (duration 15-30 minutes) by the physiotherapist at weeks 4 (+/- 1 
week), 8 (+/- 1 week), and 16 (+/- 1 week) post-LT. The Telecalls will follow the same format as phase 
one with the purpose to highlight any participant concerns or adverse events, as well as to gain 
feedback on the exercise intervention. However, the Empowering Physio delivery will now shift to 
employ strategies for the participant to foster long-term autonomous motivation and maintenance of 
exercise behaviour. 
 
7.5. Group 2 Control (comparator) arm  
The control arm will be delivered during the pre-LT (phase 1) and post-LT (phase 2) phases of the trial. 
Participants will receive a standardised patient information ‘exercise’ leaflet, which includes standard 
written advice on physical activity and exercise before and after LT.  
 
7.5.1. Phase 1 - Visit 1 (day 0) – Group 2 control arm 
Following baseline assessment (see procedures 9.0) participants will receive a 20-minute face-to-face 
consultation with the physiotherapist, during which they will receive verbal and written (patient 
leaflet) advice on the generic benefits of exercise pre-LT. This will include information on how to 
maintain physical activity and exercise levels whilst on the LT waiting list, as well as four basic 
resistance exercises for participants to complete (as described in the leaflet). As part of this 
consultation, the physiotherapist will demonstrate these exercises and practice them with the 
participant to ensure they are safe to complete at home. The participants in the control group will not 
be required complete a participant exercise diary.  
 
7.5.2. Phase 1 - Face-to-face clinic visits (visits 2, 3, 4, 5 and 6)- Group 2 control arm 
Participants will attend the hospital (QEUHB or RFH), in line with their routine waiting list clinic 
appointment (where possible), at weeks 6 (+/- 7 days), 12 (+/- 7 days), 24 (+/- 7 days), 36 (+/- 14 days) 
and 48 (+/-14 days). At each visit, the participant will have an opportunity to discuss any concerns 
regarding physical activity or exercise they have with the physiotherapist (15 minutes). However, the 
physiotherapist will only provide information in line with established generic physical activity and 
exercise guidelines on the patient exercise leaflet. Furthermore, the participant will not receive any 
Telecalls during phase 1 of the study. Of note, 52 weeks (+ 2 weeks) will mark the end of control arm 

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(standardised patient advice leaflet) if the participant has not undergone LT. At this stage, they will be 
asked if they wish to continue in the study (data collection) as outlined in section 7.6.3.   
 
7.5.3. Phase 2 – post LT Day 1 of ward admission to discharge from hospital - Group 2 control arm 
As per the intervention, phase 2 of the control arm will commence on day 1 of admission to the post-
LT ward (i.e. within 24 hours of discharge from ICU) and end 24 weeks after the date of the LT surgery 
(visit 9). The trial physiotherapists will review the participant on the post-LT ward, within 48-72 hours 
of discharge from ICU. The participants will start a supervised progressive walking programme, based 
upon the participant’s current level of physical frailty/function, in keeping with routine post-surgical 
care. If able, the participant will be asked to complete a walk (distance determined by physiotherapist, 
based upon participant’s current level of function) twice daily working to a RoPE of 12-14 throughout 
the walk. Distance walked should be increased on a daily basis provided the participant is medically 
safe to achieve this and feels competent in doing so. However, unlike the intervention group, no other 
formal exercises will be provided for the participant. If there are concerns by the physiotherapist about 
the patient’s safety to exercise (i.e. walk etc), the patient’s consultant (i.e. surgeon, hepatologist) and 
clinical team (i.e. nurse) will be consulted, as per routine NHS care. 
 
Within 72 hours prior to discharge from hospital (or day 10 post-LT +/- 3 days; main exception that 
patient is still on ITU receiving organ support), a repeat of the baseline assessments, including LFI and 
DASI, will be undertaken on the ward (see Trial Procedures section 9.0).  The participant will receive 
a 30-minute inpatient consultation with the physiotherapist where they will be advised to gradually 
increase their exercise post-LT. This information will be supported with the phase 2 post-LT patient 
‘exercise’ advice leaflet; which will include four basic resistance exercises.  
 
7.5.4. Phase 2 - Face-to-face clinic visits (visits 7, 8 and 9)- Group 2 control arm 
Participants will attend the hospital (QEUHB or RFH), in line with their routine post-LT follow-up clinic 
appointment (where possible), at weeks 6 (visit 7; +/- 7 days) and week 12 (visit 8; +/- 7 days). As per 
phase 1 of the control arm, the physiotherapist will continue providing the advice highlighted in the 
patient ‘exercise’ advice leaflet. Of note, visit 9 (24 weeks post-LT +/- 7 days) will mark the end of the 
study of the control arm advice (standardised patient advice leaflet). Furthermore, no Telecalls will be 
made to the comparator group throughout phase 2 of the control arm. 
 
7.6. Trial intervention modification or discontinuation 
7.6.1. Trial intervention modification (unscheduled) 
Throughout phases 1 and 2 of the trial intervention the level of HBEP will be modified (scheduled) at 
the face-face trial visits or via the Telecalls, based upon the participants physical frailty/function 
assessments (LFI, DASI) or the participant’s own perceived progress with the HBEP respectively. In 
addition, in the event that the participant (or personal consultee), clinician (including GP, local hospital 
clinical team) and/or a clinical member of the study team highlight that there is: 
 
A significant deterioration in the participants liver disease severity (i.e. severe hepatic 
encephalopathy, new onset moderate/severe ascites, worsening anaemia, Spontaneous 
bacterial peritonitis [SBP]  

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 
An acute deterioration in the participant’s health status that does not require hospitalisation, 
but will impact on the participant’s ability to comply with the HBEP. 
o musculoskeletal injury 
o systemic illness (i.e. viral illness, urinary tract infection (UTI), pneumonia) 
 
An acute deterioration post-LT (specifically) in the participant’s health status that does not 
require hospitalisation, but will impact on the participant’s ability to comply with the HBEP 
e.g. 
o post-LT surgical complication (e.g. incisional hernia) 
o complications 
of 
immunosuppression 
(e.g. 
mycophenolate 
induced 
diarrhoea/gastrointestinal upset; tacrolimus induced neuropathy/headaches) 
o opportunistic infection (e.g. cytomegalovirus [CMV]) 
It will be the responsibility of the PI/CI or nominated clinical co-investigator on the delegation Log to 
determine if the participant has had a significant deterioration in their liver disease and instruct the 
physiotherapist to modify the HBEP appropriately. These ad-hoc (unscheduled) modifications to the 
HBEP will take place via an unscheduled Telecall/face-to-face clinic visit or the next scheduled 
Telecall/Face-to-face trial visit. 
 
7.6.2. Trial intervention discontinuation (unscheduled) 
The trial intervention (HBEP and motivation programme) will be paused (scheduled) on the day of LT 
and will restart once the participant is discharged from ICU to the post-LT surgical ward. The trial 
intervention will be discontinued (unscheduled) if the participant is re-admitted to ICU during the 
post-LT period of the trial. The HBEP and motivation program will be restarted as discussed in section 
7.4. NOTE day 1 of discharge to ICU post LT will continue to be recorded as the start of the trial 
intervention (irrespective of re-admissions and complications). The trial intervention (HBEP) will be 
discontinued immediately in the event of any of the following: 
 
Serious adverse events (SAE; refer to section 10.0 for definitions). Examples include: 
o fall/musculoskeletal injury (i.e. fracture, head injury) 
o cardiac event or cerebrovascular accident [CVA] (i.e. myocardial infarction/angina, 
arrhythmia, stroke, transient ischaemic attack, Cerebral haemorrhage) 
o other surgical or medical emergencies (e.g. diabetic ketoacidosis, bowel obstruction, 
severe anaemia etc.) 
o pre-LT (on LT waiting list): 
 
severe hepato-renal syndrome (HRS)/acute kidney injury (AKI) 
 
severe hepatic encephalopathy 
 
variceal haemorrhage requiring oesopho-gastro-duodenoscopy (OGD) +/- 
therapy 
 
sepsis secondary to spontaneous bacterial peritonitis (SBP) or cholangitis 
 
severe jaundice at the discretion of PI/CI. 
o post-LT: 
 
post-LT surgical complication (e.g. bile leak, peritonitis, hepatic artery 
thrombosis (HAT), wound dehiscence) 
 
post-LT medical complications (e.g. organ rejection, severe opportunistic 
infections e.g. CMV, graft dysfunction, AKI) 

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In the event that an SAE has resolved, the participant will only resume the trial intervention (HBEP) on 
the advice of clinical members of the trial team (including the PI/CI or nominated member of the 
research team as per the delegation log) after a clinical review of their health status and physical 
function. This clinic review will either take place via an unscheduled Telecall/face-to-face clinic visit or 
at the next scheduled Telecall/face-to-face trial visit. If there are concerns by the physiotherapist 
about the patient’s safety to perform the HBEP, the patient’s consultant (i.e. surgeon, hepatologist) 
will be consulted as per routine NHS care and the PI (or CI) for the trial site will be informed. 
 
7.6.3. Trial exercise regimen discontinued (scheduled) 
In the event a participant has not received a LT after 52 weeks, the physiotherapy-led exercise regimen 
the participant was randomised to will be terminated.  However, with the participant’s ongoing 
willingness to continue in the trial, routine data will be collected every 3 months for first year, and 
then 6-monthly until end of the study (see section 9.3.5). Note in addition to routine data (routine 
bloods, weight/BMI, LFI, DASI), the SP36 v2 questionnaire will be completed by the participant every 
3 months for the first year. 
 
7.7. Adherence to trial intervention (HBEP) 
Adherence to the HBEP will be assessed using: 
 
Self-reported participant ‘exercise’ diary: The participants will be asked to fill in their diary 
every time they complete a session of structured exercise (maximum 5 sessions of HBEP per 
week). The study physiotherapists will be able to monitor adherence to the HBEP by reviewing 
the diaries at each face-to-face visit and during the scheduled telecalls with the participant. 
 
Wrist-worn accelerometers (Actigraph GT9X): The accelerometers will be worn 24 hours/day 
for set 14 day periods, ensuring they are still worn during their scheduled exercise (see 
sections 8.2 and 9.0). Accelerometers will be initialised to ensure participants will not receive 
any feedback on their activity levels during their participation in the trial. i.e. accelerometers 
are being employed as secondary outcome measures, not as part of the intervention. The 
devices are waterproof and do not need to be removed for bathing, showering or swimming; 
thereby not affecting the adherence analysis. In the event of skin irritation from the wrist 
watch, the participant should inform the study investigators and advice will be given 
accordingly. The physical activity raw data (i.e. frequency, intensity, and duration) will be 
collected by the physiotherapist at pre-LT visits 2-4 and post-LT visits 7-9 and safely stored for 
data analysis. 
The patient can remain in the trial throughout the duration of the study, irrespective of the degree of 
adherence, but reasons for poor adherence will be documented (i.e. encephalopathy and loss of 
capacity). 
 
7.8. Continuation of intervention after completion of the trial 
The participant will officially complete the remotely monitored ‘home-based exercise and theory-
based motivation support programme’ delivered by physiotherapists at visit 9 (24 weeks after LT). The 
hypothesis is that the participant will then have the physical functional status, knowledge, 

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competence, confidence and self-determined motivation to continue to engage with unsupervised 
exercise in the future. This hypothesis will be assessed at follow-up visit 10 (48 weeks post-LT; 24 
weeks after stopping physiotherapy delivered intervention) with measures of physical and mental 
well-being (PCS and MCS SF-36v2 QoL questionnaire) and behaviours/motivation towards exercise 
(behavioural/psychological based questionnaires) (see sections 8.0 and 9.0). After the participants 
have completed the trial at visit 10, they will be followed up in their routine NHS post-LT clinic and will 
receive the standard of healthcare in place at that time. There will be no possibility of the prescribed 
physiotherapist delivered ‘home-based exercise and theory-based motivation support programme’ 
until the results of the trial are analysed and published.  
 
8. OUTCOME MEASURES 
All primary and secondary outcomes measures will be completed at the following time-points (unless 
stated): 
 
Pre-LT (phase 1): baseline visit 1 (0 weeks; pre-intervention), visit 2 (6 weeks; +/- 7 days), visit 
3 (12 weeks; +/- 7 days), visit 4 (24 weeks; +/- 7 days), visit 5 (36 weeks; +/- 14 days) and visit 
6 (48 weeks; +/- 14 days). Of note, as the timing of LT is unpredictable, the participant will 
enter the post-LT phase 2 of the trial on the day of LT, irrespective of how many study visits 
they completed in pre-LT phase 1. 
 
 
Post-LT (phase 2): visit 7 (6 weeks post-LT; +/- 7 days), visit 8 (12 weeks; +/- 7 days), visit 9 (24 
weeks; +/- 7 days; end of intervention) and visit 10 follow-up (48 weeks; +/- 14 days). 
 
NOTE in addition to visits listed above, on the day of admission for LT (immediately pre-LT) LFI, UKELD 
and MELD-Na will be completed. Post LT and within 72 hours prior discharge from hospital (or day 10 
post-LT +/- 3 days) LFI, UKELD, MELD-Na and DASI will be completed.  
 
8.1. Primary outcome(s)  
The primary outcome measure for this trial is the PCS from the SF-36v2 health-related QoL 
questionnaire at 24 weeks post LT. The SF-36v2 questionnaire includes 36 questions composed of 
eight multi-item scales, which reflect the impact of health problems on both the physical and mental 
condition of the patient.(47, 48) A higher score reflects better quality of life. Two summary sub-scores 
can be calculated which are weighted combinations of the 8 scales, one to reflect the impact on 
physical function (PCS) and one to reflect the impact on psychological function, known as the mental 
component score (MCS).(21) Justification for the primary outcome measure is summarised in Section 
1.2.4. Scoring of the SF-36v2 questionnaire will based on the instructions provided in the SF-36v2 
user’s manual.(49)  
 
8.2. Secondary outcome(s)  
The ‘Key’ secondary outcome measure to be assessed at 24 weeks post-LT is: 
 

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 
Comprehensive Complication Index (CCI): The CCI is a well validated, reproducible tool in 
surgery and LT, which provides a 0-100 index (0=no complications, 100=death) using the 
frequency and grade (CTCAE grade) of surgical-related complications (i.e. wound dehiscence, 
bile leak, abdominal collections, bleeding, hepatic artery thrombosis etc).(15, 50) The sample 
size will enable an accurate, representative comparison of the intervention and control arms 
24 weeks post-LT to investigate if the HBEP significantly reduces surgical complications post-
LT. 
 
The other secondary outcome measure to be assessed at 24 weeks post LT are: 
 
Mental component score (MCS) of SF-36v2 health-related QoL: The SF-36v2 questionnaire is 
a practical, reliable, and valid measure of physical and mental health that can be completed 
in 5 to 10 minutes. Scoring of the (MCS) SF-36v2 questionnaire is as described above for PCS 
SF-36v2 questionnaire. 
 
Liver frailty index (LFI): The LFI is a composite metric of three performance-based measures: 
hand grip strength (HGS), time to do 5 chair stands (seconds) and time holding 3 balance 
positions (feet side by side, semi-tandem and tandem) to objectively assess physical frailty in 
ambulatory patients with end-stage liver disease.(51) The LFI score can be calculated using an 
on-line calculator (available at: http://liverfrailtyindex.ucsf.edu) with patient physical frailty 
categorised as robust, pre-frail and frail according to their index (index ≤ 3.2 (robust), 3.2-4.5 
(pre-frail), >4.5 (frail)). In addition to the time-points listed above, LFI will be completed on 
the day admission for LT (immediately pre-LT) and prior to discharge (within 72 hours) from 
hospital post-LT or day 10 post-LT +/- 3 days. 
 
Duke activity status index (DASI): The DASI is a 12 item self-reported assessment of functional 
capacity that requires minimal time to complete.(52) It provides prognostic information in a 
variety of chronic diseases and can be used as an index of disease progression over time (53-
55). In addition to the time-points listed above, DASI will be completed prior to discharge 
(within 72 hours) from hospital post-LT or day 10 post-LT +/- 3 days. 
 
Pre-LT morbidity (UKELD, MELD-Na, Hospital Admissions) and mortality: 
o UKELD: is a scoring system (using a patient’s international normalized ratio (INR), 
serum bilirubin, creatinine and sodium) which is used to predict the prognosis of 
patients with end-stage liver disease.(56) 
 
UKELD = [(5.395Xln(INR)) + (1.485Xln(creatinine)) + (3.13Xln(bilirubin)) - 
(81.565Xln(Na))] + 435 
o MELD-Na Score: is a scoring system (INR, serum bilirubin, creatinine and sodium) 
created in 2008, based on the original MELD score, but with the addition of serum 
sodium.(57) The MELD-Na, largely used for prioritisation in the United States, is a 
better predictor of mortality than the MELD score.  
 
MELD-Na = MELD Score - Na – [0.025 x MELD x (140-Na)] + 140 
Patients on oral anti-coagulants (including warfarin and the new oral anti-coagulants; 
predicted to be <2%) will be excluded from the analysis, as their UKELD/MELD-Na will 
be artificially high. In addition to the pre-LT time-points listed above, UKELD and 

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MELD-Na will be completed on the day admission for LT (immediately pre-LT) and 
prior to discharge (within 72 hours) from hospital post-LT or day 10 post-LT +/- 3 days). 
o unscheduled hospital admissions: The frequency and duration (days) of non-elective 
hospital admissions will be recorded between study baseline (visit 1, week 0) and LT 
or the 48 week visit. The reason for admission will be categorised based on the SAE 
recording. 
o mortality: The date and cause (based on death certificate) of death pre-LT will be 
recorded.  
 
Post-LT morbidity and mortality: The post-LT morbidity will be assessed by length of ICU stay 
(hours), length of hospital stay (days; immediately post-LT), and frequency and duration of 
hospital re-admission (LT to 24 week visit 9). Of note, the post-LT complications will be 
captured by the CCI as described above and in addition re-listing for transplant will be 
recorded (date, reason). 
o ICU length of stay (hours): This will be calculated by a member of the site team (i.e. 
research nurse; research fellow) using the electronic patient records of the date/time 
(24hr) of admission to ICU immediately after LT to the date/time (24hr) of discharge 
from ICU (either through death or transfer to post-LT ward). Re-admission to ICU on 
the same hospital admission for LT will be included recorded and added to the total 
ICU length of stay (hours).  
o Length of Hospital stay (LOS; days): This will be calculated using the date of LT and 
the date of discharge from hospital to home (either through death or discharge 
home). In the rare event that a patient is transferred to their local non-LT hospital or 
an inpatient rehabilitation unit, these bed days will be included in the hospital LOS. 
o Unscheduled Hospital re-admission (frequency, days): The frequency and duration 
(days) of non-elective hospital admissions will be recorded between LT and visit 9 (24 
weeks). The reason for admission will be categorised based on the SAE recording. 
o Mortality (30 day, 90 day, 180 day and 1 year): The date and cause of death will be 
documented using the death certificate for reference.  
 
Habitual (daily) physical activity times: Habitual (daily) levels of physical activity engagement 
(light, moderate and vigorous intensity) which may occur during the course of the trial will be 
measured using a ‘blinded’ wrist worn accelerometer (Actigraph GT9X). These will be worn 
for 14 days (24 hours/day): 
o Baseline (visit 1, week 0) to 14 days 
o 14 days before visit 2 (6 weeks), visit 3 (12 weeks) and visit 4 (24 weeks) pre-LT 
o 14 days before visit 7 (6 weeks post-LT), visit 8 (12 weeks post-LT) and visit 9 (24 weeks 
post-LT, end of intervention) 
Data captured during the 14-day periods will be analysed to quantify daily time (min/day) 
spent in; (1) light physical activity (1.6 – 2.9 metabolic equivalents (METS), (2) moderate 
physical activity (≥ 3 – 5.9 METS), (3) vigorous physical activity (≥6 METS), and sedentary time 
(≤1.5 METS). 
 
“Dose” of exercise completed (measure of the frequency, intensity and duration of 
exercise): Data will be analysed from the ‘blinded’ wrist worn accelerometer (Actigraph GT9X) 

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to understand the intensity and duration of the exercises completed during the 14 day 
periods. 
 
Adherence to HBEP (Group 1: intervention arm only): As discussed in section 7.7, adherence 
to the HBEP will be measured using the ‘blinded’ wrist-worn accelerometer worn in the 14 
day periods (described above). In addition, the participant will fill a self-reported exercise 
diary throughout the trial, which will be reviewed by the physiotherapist at each face-to-face 
trial visit until visit 9 (24 weeks post-LT, end of intervention). Using the diary, the 
physiotherapist will document how many structured HBEP sessions the participant has 
completed per week (maximum 5 per week). 
 
3**Perceptions of the health care climate (how need supportive/empowering the 
physiotherapist is): This will be measured using the Health Care Climate Questionnaire 
(HCCQ).(58) The HCCQ comprises 15 items/statements which represent the patient’s 
perceptions of the degree to which they feel their interactions with their physiotherapist 
(health care climate) empower them to engage in exercise (e.g. “I feel that my physiotherapist 
has provided me choices and options”). Patients are asked to respond to each item, indicating 
the extent to which they agree with each statement, on a Likert scale ranging from 1 (strongly 
disagree) to 7 (strongly agree). For each participant, an average of the 15 items will be 
calculated for use in analysis. Note: Item 13 is negatively coded, and the score provided will 
be subtracted from a score of 8 to compute the participant’s response to this item. 
 
3**Basic psychological need satisfaction (i.e. feelings of autonomy, relatedness, 
competence): This will be measured using the Basic Psychological Need Satisfaction in 
Exercise Scale (PNSE): The PNSE will be used to examine participants basic psychological need 
satisfaction, in relation to their exercise engagement.(59) The PNSE comprises 18 items, 
capturing the three basic psychological needs of autonomy (6 items, e.g. “I feel free to exercise 
in my own way”), competence (6 items, e.g. “feel that I am able to complete exercises that 
are personally challenging”) and relatedness (6 items, e.g. I feel connected to the people who 
I interact with while I exercise”). Participants are asked to respond to each item, indicating the 
degree with which they agree with each statement, on a Likert scale from 1 (false) to 6 (true). 
Average scores for each of the three sub-scale will be computed (e.g. 6 items for autonomy 
are added and divided by 6 to give the average for autonomy need support), to determine 
participants degree of autonomy, competence and relatedness need support. These individual 
variables will be used in analysis. In addition, an overall average will also be calculated using 
responses to all 18 items, to provide and overall PNSE score for use in analysis. 
 
3**Self-determined motivation to exercise: This will be measured using the Behavioural 
Regulation in Exercise Questionaire-2 (BREQ-2).(60) The BREQ-2 will measure participant’s 
degree of self-determined motivation to engage in exercise, by assessing their external, 
introjected, identified and intrinsic regulations, as well as motivation. Following the stem, “I 
take part in exercise” participants will be asked to respond to 19 items assessing intrinsic 
regulation (4 items; e.g., “because I enjoy doing this”), identified regulation (4 items; e.g., 
“because I value the benefits of doing this”), introjected regulation (3 items; e.g., “because I 
feel guilty when I am not doing this”), external regulation (4 items; e.g., “because my friends 
and family say I should”) and motivation (4 items; e.g., “but I think doing this is a waste of 
time”). Participants were asked to rate their agreement with each statement on a 5-point 
Likert scale from 0 (not true for me) to 4 (very true for me).  For this study, average scores for 

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each subscale will be computed, and used to produce composite scores for autonomous 
motivation (identified regulation + intrinsic regulation) and controlled motivation (external 
regulation + introjected regulation). 
 
3**Theory-based motivation support programme will be assessed with (i) HCCQ, (ii) Basic 
PNSE and (iii) BREQ-2 Questionnaires, as discussed above. To test the theoretically-expected 
psychological mechanisms underlying behaviour change, a theoretical process model of 
behaviour change will be tested.  
Specifically, we will examine whether the intervention (i.e. perceived support for patient autonomy, 
competence, relatedness by the physiotherapist) predicts change in the targeted psychological 
determinants (i.e. psychological need support, motivation for exercise), and subsequently, the 
targeted behaviour including physical activity and QoL. By testing the process model grounded in SDT 
in this way, we can begin to understand how the experiment intervention has worked. For example: 
which SDT constructs/determinants did the intervention successfully target/change, in order to 
encourage behavioural change. This will enable the home-based exercise with motivation support 
intervention to be subsequently refined and optimised. We will conduct this evaluation using 
structural equation modelling and path analysis, as previously described.(27, 61) 
________________________ 
3 ** denotes where analysis will be conducted outside of the BCTU SAP by Prof Joan Duda and Dr Sally Fenton. 
 
8.3. Mechanistic ‘muscle’ sub-study outcomes (n=100): 
In addition to the primary/secondary outcome measures (listed above), the mechanistic ‘muscle’ sub-
study outcomes measures will be completed at the pre-LT baseline visit 1 (0 weeks; within 3 days of 
visit 1), pre-LT visit 2 (6 weeks; +/- 7 days) and post-LT visit 9 (24 weeks post-LT; +/- 7 days) or visit 6 
(48 weeks + 28 days) if no LT. 
In the event that a participant is not transplanted by visit 6 (pre-LT phase 1), with the participant’s 
ongoing willingness to continue in the study, they will be given the option of a final sub-study visit 
(visit 6, with an additional 6-week window; inclusive of CPET, muscle ultrasound, 6MWT, serology 
biomarkers) and their data will be collected until the trial end date (see section 7.6.3 and section 
9.3.5). 
 
The outcome measures include: 
1. 6 minute walk test (6MWT): The 6MWT is a self-paced field walking test conducted under 
controlled conditions and is a reliable and valid measure of exercise tolerance in various 
patient populations.(62) The test is inexpensive and simple to administer. It requires a 30 
metre level indoor walking course and the course layout and degree of patient 
encouragement will be standardised, as they significantly affect the distance walked.(63) The 
learning effect (i.e. patient becomes more familiar with the test) will be reduced by 
performing two tests and recording the best result at each study time point. The 6 minute 
walk distance (6MWD) will be recorded in metres. 
2. Cardiopulmonary exercise testing (CPET): Cardiopulmonary exercise testing (CPET), using a 
cyclo-ergometer, is the gold standard assessment tool of aerobic exercise capacity. It directly 
assesses gas exchange, work, heart rate and rhythm, and blood pressure during intense 

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exercise (64). With the exception of safety reports (i.e. new cardiac arrhythmia), the trial 
management group, physiotherapists and the patients clinicians will be blinded to the CPET 
outcome measures until the end of the trial – in order to avoid the results altering the patients 
clinical course (i.e. as not routine NHS care in QEUHB and RFH). All CPETs will be analysed by 
an independent assessor at the end of the trial, who will be blinded to the intervention and 
order of the CPETs. The key CPET outcomes to be measured, include: 
 
Oxygen consumption at anaerobic threshold (AT; ml/kg/min) 
 
Peak oxygen consumption (VO2peak; ml/kg/min) 
 
Other measures include: ramp rate (W/min; peak power output (W); maximum heart 
rate (bpm); maximum oxygen pulse (ml/beat); reason for test termination (participant 
symptoms/request; operators request); exercised to volitional fatigue (YES/NO); 
ventilatory equivalents for carbo dioxide (VE/CO2); respiratory exchange ratio at peak 
exercise. 
It is important to acknowledge that CPET is not part of routine care for liver transplant 
assessment or monitoring in the two liver transplant units in the ExaLT trial. In addition, 
patients on the transplant waiting list have already been through a standardised 
cardiorespiratory risk assessment and have been deemed physically fit to proceed to liver 
transplant by a multi-disciplinary team. Therefore, in keeping with other CPET studies, it is 
deemed safe and methodologically robust to blind the clinical and research teams from the 
key CPET outcomes listed above. However, the research team and the local clinical liver 
transplant team will be immediately alerted by the trained operator of the CPET, in the event 
of rare, life-threatening heart arrhythmia – as this could have significant implications for the 
safety of the future liver transplant and their health. 
3. Right Quadricep muscle size, architecture and quality (ultrasound): A Two-dimensional B-
mode ultrasonography Esoate MyLabTM Alpha point of care ultrasound, 4.6cm probe (SL1543, 
13-4Mhz scanning frequency)) will be performed by a member of the clinical trials team 
(research fellow, physiotherapist, or nominated co-investigator on delegation log). The 
following will be measured: vastus lateralis [VL) muscle thickness, fascicle pennation angle, 
fascicle length and total quadricep muscle anatomical cross-sectional surface area [ACSA]). All 
variables will be obtained offline via imageJ imaging software and will be presented as a mean. 
For assessment of all quadricep muscles, two extended field of view ultrasound images will be 
taken at 50% femur length; this will allow for the quantification of quadriceps ACSA. 
Echogenicity can be determined using a computer-assisted grey-scale analysis offered by 
ImageJ. (65)  
4. Specialist biomarkers: Blood will be centrifuged, processed and then stored at -80oC at the 
study sites before being transferred to the UoB (NIHR BRC Immunology and infection 
laboratory) for analysis of the following: 
 
Common measures of oxidative stress: Total redox status, malonyldialdehyde, 
Myeloperoxidase, 4-Hydroxynonenal.  
 
Serum antioxidant capacity: catalase, glutathione peroxidase and superoxide 
dismutase.  
 
A profile of key myokines: IL-6, IL-10, IL-15, Irisin, leukaemia inhibitory factor, and 
secreted protein acidic and rich in cysteine (SPARC) 

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 
Tumour necrosis factor alpha (not a myokine, but an inflammatory marker).  
 
In addition, at QEUHB site only, with participant consent, 20-30ml of urine will be 
stored for future research providing ethical approval for these additional studies has 
first been obtained (see Section 15). 
 
A full standard operating procedure (SOP) has been produced for the ‘muscle’ sub-study that details 
the methodology of all the measures outlined above. Data from this sub-study will be combine with 
data collected from the main study in order to fully evaluate the effect of the exercise intervention on 
muscle physiology. The specialist biomarkers and muscle ultrasound will take place before the 
CPET/6MWT to ensure that their results are not impacted by acute/strenuous exertion of these 
functional tests. In addition, the CPET will take priority and precede the 6MWT (with 30 minutes rest 
in between tests), due to the fact that the CPET has more rigorous data outputs (i.e. VO2 peak, 
Anaerobic threshold, ramp gradient, maximal heart rate etc.) (see section 15). 
 
9. TRIAL PROCEDURES 
9.1. Study Timelines (estimates) 
The total trial length is 55 months and comprises 6 months for trial set-up and contract execution, 24 
months for recruitment (estimated 12 patients/month), maximum 76 weeks intervention (note: 
minimum = 1 day pre-LT + 24 weeks post-LT), and 24 weeks follow-up, primary analysis and reporting. 
 
Prior to the study opening to recruitment, the following will take place: 
 
3-day physiotherapist training days (home-based exercises; ‘Empowering the Physio’)  
 
Application and approval by REC, Sponsor (UoB), local confirmation of capacity and capability 
(QEUHB, RFH) 
 
9.2. Pre-consent screening at QEUHB and RFH 
Pre-consent screening will take place before the participant invite letters by the transplant 
coordinators, hepatologists (anaesthetists) and AHPs directly involved in the patients LT waiting list 
care (Section 6.1.). It is important to note that as part of the patients consent for LT (which takes place 
before they go on the LT waiting list), patients are also consented to be approached for future research 
studies. Review of the NHSBT ‘active’ adult liver transplant waiting list will be undertaken and all 
potentially eligible patients will either be given the participant invite letter and then the PIS (at a later 
date if they express an interest after reading the invite letter): 
 
In person at either their liver transplant assessment or in their dedicated liver transplant 
waiting list clinic/specialist liver clinic (i.e. PSC, HCC) 
OR 
 
Via post, especially in light of the emergence of telephone/virtual video clinics (as a result of 
the COVID-19 pandemic) 
 

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If a patient expresses an interest to participate in the trial after reading the PIS (either via phone, email 
or in person) they will be invited to attend visit 1 (baseline) of the trial. Where possible the study team 
will schedule visit 1 (baseline) to be on the same day as their next routine waiting list clinic 
appointment, during which the patient +/- relative or ‘personal consultee’ will be able to ask questions 
about the trial before providing consent. 
 
9.3. Phase 1 Pre-LT trial visits schedule 
The phase 1 Pre-LT trials visits schedule will consist of a baseline visit 1 (week 0), visit 2 (6 weeks +/- 7 
days), visit 3 (12 weeks +/- 7 days), visit 4 (24 weeks +/- 7 days), visit 5 (36 weeks +/- 14 days) and visit 
6 (48 weeks +/- 14 days). These are summarised in Table 7. 
 
9.3.1. Pre-LT baseline Visit 1 (week 0) - maximum duration = 3-6 hours 
At the beginning of the trial visit 1, written consent will be obtained by PI or designee as documented 
on the site signature and delegation log and the eligibility criteria checklist will be completed by a 
designated member of the clinical trials team (on delegation log). See section 5 and 6.2: 
 
NO trial specific examinations, investigations or treatments, that do not involve part of the 
patient’s routine standard healthcare, will be performed prior to obtaining written consent of 
the patient.  
 
A member of the site research team (e.g. PI or designee as documented on the signature and 
delegation log) will discuss with patient, all of the relevant study information including aims, 
methods, risk and benefits of the trial, prior to obtaining consent. 
 
At this stage the patient will also be asked nominate a potential ‘personal consultee(s)’ in the 
event that they lack capacity at any stage of the trial. A contact list of the participant’s 
nominated personal consultee(s) will be securely stored at the trial site. 
 
Eligibility and confirmation of consent (including version of ICF, date, time) will be 
documented in the participants clinical noting.  
 
After eligibility has been confirmed and informed consent given, the patient will be randomised in a 
(1:1) ratio to either the study intervention (Group 1) or control (Group 2) (section 6.3) and provided 
with a unique Trial Identification Number (ID). The Trial ID number will be used on all future trial 
documentation, alongside the patient’s initials, date and visit number. 
The following data collection will take place at Baseline visit 1 (week 0): 
 
Patient demographics: Patient’s name, DOB, gender, ethnicity; post code, local hospital (non-
LT centre). 
 
Hospital trial site (QEUHB, RFH) 
 
Information on Covid-19: Full course of COVID vaccination; Previous positive PCR test for 
COVID 
 
Current medical history and clinical examination, including: hepatic encephalopathy, ascites 
(defined as - mild (imaging only), moderate (on examination), severe (tense, requiring large 
volume paracentesis [LVP]), diuretic-resistant or diuretic-intolerant ascites, LVP (frequency), 
peripheral oedema, jaundice, haematemesis/melaena (< 4 weeks), pruritis, fever, right upper 
quadrant abdominal pain, fatigue, tiredness. 

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 
Past medical history: 
o primary chronic liver disease 
 
type (NAFLD/MAFLD, ArLD, Cryptogenic, PSC, AIH, PBC, A1AT, HBV, HCV, 
other) 
 
HCC 
 
largest Size 
 
number of active lesions 
 
previous treatment (TACE, RFA, SABR) 
 
portal Hypertension 
 
ascites  
 
hepatic encephalopathy  
 
spontaneous bacterial peritonitis (SBP)  
 
hepatopulmonary syndrome  
 
main portal vein thrombosis  
o listing for LT (at the time) 
 
date of listing with NHSBT  
 
indication (UKELD ≥ 49, HCC, Variant Syndrome i.e. recurrent cholangitis, 
refractory ascites) 
 
UKELD score, MELD-NA 
 
blood group 
 
listing graft choice (DBD, DCD, or both) 
 
Current/recent illnesses (<6 weeks) specifically: SBP, variceal haemorrhage (melaena, 
haematemesis), hepatorenal syndrome/Acute Kidney Injury (AKI), sepsis, severe hepatic 
encephalopathy (admission to hospital), chest pain, shortness of breath, palpitations, 
dizziness/collapse, significant fall 
 
Significant co-morbidities: diabetes (Type 2 or Type 1; duration; insulin; retinopathy; 
neuropathy; proteinuria), hypertension; atrial fibrillation/atrial flutter, ischaemic heart 
disease (IHD), cerebrovascular disease (CVD), pulmonary disease (asthma, COPD, interstitial 
lung disease); musculoskeletal disease, mental health illness. 
 
Drug History (key), including: diuretics, beta-blockers, anti-encephalopathy medication, SBP 
prophylaxis, anti-depressants/anti-anxiolytic, sleeping adjuncts, analgesia, anti-diabetic 
drugs, long-term antibiotics, anti-pruritus, anti-coagulants. 
 
Nutritional supplements (prescribed amount): 
o oral  
o enteral  
o additional supplements 
 
Creon/nutrizyme/pancrex 
 
vitamin D 
 
Social history: 
o smoking status 
o alcohol intake 
o employment status  
o living situation  
 

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The following assessments (nurses checklists, CRFs) will take place at visit 1: 
 
Full clinical examination (including general, cardiovascular, respiratory, abdominal, 
neurological)  
 
Clinical Observations, including: 
o blood pressure (mm/Hg) – patient sitting 2 minutes prior. 
o resting pulse (beats/min)  
o oxygen Saturations on room air (%) – sitting 
o temperature (oC) 
 
Nutrition/Physical/functional status: 
o wet weight (kg) 
o height (cm) 
o wet BMI (kg/m2) 
o estimated 
dry 
weight 
(kg) 
[using 
the 
5/10/15% 
reduction 
rule 
for 
mild/moderate/severe ascites; 5% for peripheral oedema] 
o estimated dry BMI (kg/m2) 
o handgrip strength (HGS; dominant hand) 
o Mid-arm muscle circumference [MAMC] (cm) 
 
LFI (range 1.5 to 7.5; record in 2dp) 
o HGS: mean = ……. Kg (as above – autofill from above) 
o time to do 5 chair stands = …… seconds (NB if can’t do record as ‘0’) 
o balance (feet); total = ……… (maximum 30 secs) 
 
side = XX/10 secs 
 
semi-tandem = XX/10 secs 
 
tandem = XX/10 secs 
The following questionnaires will take place at visit 1: 
 
DASI: 
o DASI Points =…………. (range  0-58.2) 
o VO2 peak (ml/kg) = 0.43 x DASI points + 9.6 = …….ml/kg (range 9.6-34.6 automated) 
o Metabolic equivalents (METs) = VO2 peak/3.5 = ……………(range 2.74-9.89) 
 
SF-36v2 Health Survey (Quality of Life Questionnaire) [  ]: 
o Total score =    [range 0-100] 
o PCS=     [range 0-100; PRIMARY OUTCOME MEASURE] 
o MCS=     [range 0-100] 
o these will be batch calculated using the Quality Metric software as described above. 
 
HCCQ 
 
Basic PNSE 
 
BREQ-2 
 
 
 

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The following investigations will be completed at visit 1: 
 
Urine Albumin-to-creatinine ratio [ACR] (white top urine bottle to biochemistry) – visit 1 only 
 
12-lead ECG (if not within previous 6 weeks) – visit 1 only 
o rate (beats per minute) 
o rhythm  
 
Blood samples* (non-fasted):  
(*Bloods to be taken on day of visit. If some blood results are not available results from a NHS visit 
within +/-4 weeks of this visit will be accepted) 
o haematology: FBC, reticulocytes, Prothrombin Time (PT), INR  
o biochemistry: Ferritin, Trans Sats (%), B12, Folate, Vitamin D, Calcium (Adjusted Ca) 
o biochemistry: Urea & Electrolytes (including magnesium, phosphate), liver function 
tests (LFTs) including AST, GGT 
o biochemistry: HbA1c, TFTs (TSH, T4), lipid profile (Total cholesterol, HDL, triglyceride) 
o biochemistry: AFP, CRP, Alcohol (if listed for ArLD) 
o biochemistry: Ammonia (on ice to laboratory within 15 minutes of collection) 
 
The following with be calculated (study automated by eCRF): 
o UKELD**      **if on oral anticoagulant – result will be void. 
o MELD-Na** 
o Childs-Pugh score** (5-15) 
 
The following additional mechanistic ‘muscle’ sub-study’ investigations will take place at visit 1 (if 
consented for sub-study) in the following order: 
1. Specialist biomarkers: Blood (non-fasted) will be collected in 2 x purple top tubes (3ml each) 
and 3 x red top tubes (5ml each). Blood will be centrifuged, processed, and stored at -80oC at 
the study site (if site outside Birmingham) before being transferred in batches to our specialist 
laboratory at the University of Birmingham where they will be stored at 80oC and then batch 
analysed. All plasma and serum samples will be labelled with unique Trial ID, site, date, visit 
number and patient initials. Batch analysis will take place for measures of oxidative stress, 
anti-oxidant capacity, myokines and inflammatory markers as listed in section 8.0. Any 
samples remaining at the end of the study will either be destroyed in accordance with 
laboratory procedures or if patient has given consent for samples to be used in future 
research, remaining samples will be transferred to another ethically approved study. 
2. Right Quadricep Muscle size, architecture and quality (Ultrasound): A Two-dimensional B-
mode ultrasonography Esoate MyLabTM Alpha point of care ultrasound, 4.6cm probe (SL1543, 
13-4Mhz scanning frequency)) will be performed by a member of the clinical trials team 
(research fellow, physiotherapist, or nominated co-investigator on delegation log) prior to any 
significant functional tests (i.e. 6MWT, CPET). The following will be measured: VL muscle 
thickness, fascicle pennation angle, fascicle length and total quadricep muscle ACSA. For 
assessment of all quadricep muscles, two extended field of view ultrasound images will be 
taken at 50% femur length; this will allow for the quantification of quadriceps ACSA.  
3. Cardiopulmonary exercise testing (CPET): CPET, using a cyclo-ergometer, will be performed 
to directly assess gas exchange, work, heart rate and rhythm, and blood pressure during 
intense exercise. With the exception of safety reports (i.e. new cardiac arrhythmia), the trial 

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management group, physiotherapists and the patients clinicians will be blinded to the CPET 
outcome measures until the end of the trial. A SOP for CPET will be used at both trial sites to 
ensure standardised methodology for collaborating equipment, preparing the patient (mask 
fitting, seat height), software set-up, safety rules (i.e. contraindications, stopping rules), 
cycling/resting protocol and data storage. Participants will be encouraged to maintain a 
cycling speed of 60-65 rpm for as long as they can, whereby it will start easy and become more 
difficult as the resistance increases. The key CPET outcomes to be measured are summarised 
in section 8.0 and will be determined by an independent, trained ‘blinded’ physiologist at a 
later date using the methods described in the POETTS guidelines.(66) 
4. 6MWT (supervised by the study AHPs or Clinical Research Fellow/PIs): 30 metre level indoor 
walking course and the course layout and degree of patient encouragement will be 
standardised. ‘The learning effect’ (i.e. patient becomes more familiar with the test) will be 
reduced by performing two tests and recording the best result. 6-minute walk distance 
(6MWD) will be recorded in metres (range 50 to 2000 metres). In addition, participants will 
wear a pulse oximeter throughout the 6MWT and the starting SaO2 on room air (% ) and 
lowest SaO2 on room air (%) will be recorded. There will be a minimum of 30 minutes rest time 
after the CPET. 
 
Study Intervention: 
After completion of the baseline assessments, participants will have a face-to-face consultation with 
the study physiotherapist. HBEP will commence a maximum of 3 days after visit 1: 
 
Intervention Group 1 (see section 7.3): A 60-minute consultation with the physiotherapist, 
during which the entry level of difficulty for the HBEP (aerobic and resistance) will be 
determined. The participant will be provided with a personalised written HBEP. The 
physiotherapist will record and save personalised written HBEP in the site file and patients 
clinical noting. The participants will then attend a physiotherapist delivered training session 
(group session; maximum 4 participants/day), which will consist of: a) patient education (1 
hour), b) exercise familiarisation (1 hour) and c) issuing of devices and written information (1 
hour). 
 
Control Group 2 (see section 7.5): A 20-minute consultation with the physiotherapist, during 
which they will receive verbal and written (patient leaflet) advice on the generic benefits of 
exercise pre-LT. 
 
Exercise Monitoring (section 7.7): 
The physiotherapist will issue participants in the intervention and control groups with: 
 
A participant ‘exercise’ diary (paper booklet), intervention group only: for them to self-
record all structured exercise undertaken during the trial. 
 
A ‘blinded’ wrist worn accelerometer (Actigraph GT9X): for them to wear for the next 14 days 
(Days 1-14; 24 hours/day). Participants will be given a free post envelope and asked to return 
accelerometer and/or HR monitor as soon as possible after 14 days. A member of research 
team will then download the data from the devices, and securely store it at the trial site.  

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 
Participant will be informed that the devices will be sent out again in the post and they will 
be asked to wear the accelerometer for 14 days prior to visit 2 (week 6). They will be asked to 
bring devices in with them to visit 2*. 
 
Participants will be asked to contact the research team should they have any queries regarding 
accelerometer wear. 
 
*The blinded’ wrist worn accelerometer (Actigraph GT9X) will be sent in post to participants at least 
14 days prior to visit 2 (week 6).  
 
9.3.2. Pre-LT Visit 2 (week 6 +/- 7 days) - maximum duration = 30-60 mins* 
Visit 2 will take place alongside the participant’s routine LT waiting list clinic (where possible). At visit 
2 the following will take place: 
 
Record ‘new’ clinical events since last visit: Current/recent illnesses (<6 weeks), specifically: 
hepatic encephalopathy (I-IV), ascites (moderate to severe), number of LVP, peripheral 
oedema, variceal haemorrhage (requiring endoscopy), hepatorenal syndrome/AKI, 
sepsis/fever, significant fall. 
 
Record Serious Adverse Events (SAEs): non-elective hospitalisation (Days in hospitals; if ‘0’ = 
no 
hospitalisation); 
requirement 
for 
organ 
support/intensive 
care, 
hepatorenal 
syndrome/AKI, 
severe 
hepatic 
encephalopathy, 
variceal 
haemorrhage, 
serious 
fall/musculoskeletal injury, cardiac or cerebrovascular event, sepsis/infection requiring 
admission (esp. SBP, pneumonia). 
 
Record 
‘new’ medications: 
diuretics, 
beta-blockers, anti-hepatic encephalopathy 
medications, SBP prophylaxis, antibiotics (not SBP prophylaxis), anti-depressants/anti-
anxiolytics, sleeping adjuncts. 
 
Record Nutritional supplements (prescribed amount) – as per visit 1 
 
Full examination, clinical observations and nutritional/physical/functional (including LFI) – 
as per visit 1 
 
Questionnaires (DASI, SF-36v2, HCCQ, Basic PNSE, BREQ-2) – as per visit 1 
 
Blood tests (including calculation of UKELD, MELD-Na, Childs-Pugh) – as per visit 1 
 
Mechanistic ‘muscle’ sub-study’ investigations (if consented for ‘sub-study’; biomarkers, 
muscle ultrasound, CPET, 6MWT  in that order) – as per visit 1 
 
Study Intervention: 
o Intervention Group 1: The study physiotherapist will progress exercises and revise the 
level/goals of the HBEP after review of the LFI/DASI assessments, participant 
‘exercise’ diary and discussions with the participant themselves will be used to 
progress exercises and revise goals of their HBEP. As per ‘Empowering Physio’ 
principles strategies, the active role of the participant in the decision-making process, 
regarding progression and goal revision, will continue to support more autonomous 
reasons for engagement in the HBEP. The updated written HBEP will be saved in the 
trial site file and recorded in clinical notes. 
o Control Group 2: The participant will have an opportunity to discuss any concerns 
regarding physical activity or exercise they have with the physiotherapist (15 
minutes). However, the physiotherapist will only provide information in line with 

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established generic physical activity and exercise guidelines on the patient exercise 
leaflet. 
 
Exercise monitoring: The participant will return the wrist-worn accelerometer and the 
participant ‘exercise’ diary (intervention group only). A member of research team will then 
download the data from the devices, and securely store it at the trial site. 
 
Preparation for next trial visit (3): 
o at the end of the trial visit, the participant will be given a time/date for their next 
appointment  
o Issued with the participant ‘exercise’ diary (intervention group only) for them to self-
record all structured exercise undertaken during the trial. 
o prior to the next trial visit the research team will post the accelerometer out to the 
participant for them to wear for the 14 days prior to the next trial visit (i.e. visit 3; 12 
weeks).  
 
9.3.3. Pre-LT Visits 3 (week 12 +/-7 days), 4 (week 24 +/-7 days), 5 (week 36 +/- 14 days) – max. 
60min  
Visits 3-5 will take place alongside the participant’s routine LT waiting list clinic (where possible). All 
procedures, data collection, and study intervention will be the same as visit 2, without the mechanistic 
‘muscle’ sub-study investigations.  
Similarly to visit 2, at the end of the trial visit, the participant will be given a time/date for their next 
appointment and the participant ‘exercise’ diary (intervention group only). Prior to the trial visits 3 
and 4 the research team will post the accelerometer to the participant for them to wear for the 14 
days prior to the next trial visit. 
 

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Table 7: ExaLT trial visit schedule 
*52-week cut-off: study intervention will stop if participant hasn’t had their LT by 52 weeks (+2 weeks). (X) optional sub-study consent if haven’t undergone 
LT within the 1-year time-frame 
 
  
BASELINE
End-of-Intervention FOLLOW-UP
TRANSPLANT
Study visits
VISIT 1
VISIT 2
VISIT 3
VISIT 4
VISIT 5
VISIT 6
VISIT 7
VISIT 8
VISIT 9
VISIT 10
Time points
0 weeks
6 weeks
12 weeks
24 weeks
36 weeks
48 weeks
*52 week cut-off
Inpatient stay
6-weeks post 12 weeks post 24 weeks post
48 weeks post
(+/- 7 days)
(+/- 7 days) (+/- 7 days) (+/- 14 days (+/- 14 days)
day 10 +/- 3 days
(+/- 7 days)
(+/- 7 days)
(+/- 14 days)
(+/- 14 days)
Consent
X
Randomisation (Intervention vs. control))
X
Clinical examination and review (routine clinic)
X
X
X
X
X
X
X
X
X
X
X
X
Standard bloods pre-LT (FBC, U+E, LFTs, AST, GGT, INR, CRP, nutrition, ammonia)
X
X
X
X
X
X
X
Standard bloods post-LT (FBC, U+E, LFTs, AST, GGT, INR, CRP, nutrition, tacrolimus)
X
X
X
X
X
Standard clinic observations (BP, dry BMI, weight, hand grip strength, MAMC)
X
X
X
X
X
X
X
X
X
X
X
X
Frailty/Functionality assessment (LFI, DASI)
X
X
X
X
X
X
X
X
X
X
X
X
Primary outcome SF-36v2 questionnaire
X
X
X
X
X
X
X
X
X
X
X
Behavioural/psychological questionnaires (HCCQ, PNES, BREQ-2)
X
X
X
X
X
X
X
X
X
X
X
Serious adverse events (complications/morbidity)
X
X
X
X
X
X
X
X
X
X
X
X
Liver Transplant data (date, donor details, organ support, ICU stay)
X
Exercise Adherence: review participant 'exercise' diary
X
X
X
X
X
X
X
X
X
X
Exercise Adherence: Acceleromter
week 0-2
4-6
10-12
22-24
week 4-6
10-12
22-24
Mechanistic 'muscle' sub-study (n=100, optional):
CPET, muscle USS, 6MWT, specialist biomarkers
X
X
(X)
X
Interventions:
Intervention: home-based exercise and theory-based motivation support programme
X
X
X
X
X
X
X
X
X
X
Intervention: Telecall (15-30 minutes)
week 2,4
8, 10
16,20
4
8
16
Control: standard of care patient 'exercise' advice leaflet
X
X
Pre-Liver Transplant (variable time-line)
Post-Liver Transplant (fixed time-line)

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9.3.4. Pre-LT Visit 6 (week 48 +/- 14 days) – max. 60 min 
Visits 6 will take place alongside the participant’s routine LT waiting list clinic (where possible). At visit 
6 (week 48 +/- 14 days), the following will be undertaken: 
 
Record ‘new’ clinical events since last visit: Current/recent illnesses (<6 weeks) – as 
described for visit 2 
 
Record Serious Adverse Events (SAEs only) – as described for visit 2 
 
Record ‘new’ medications – as described for visit 2 
 
Record Nutritional supplements (prescribed amount) – as described for visit 1 
 
Full examination, clinical observations and nutritional/physical/functional (including LFI) – 
as described for visit 1 
 
Questionnaires (DASI, SF-36v2, HCCQ, Basic PNSE, BREQ-2) – as described for visit 1 
 
Blood tests (including UKELD, MELD-Na, Childs-Pugh) – as described for visit 1 
 
The participant will return the participant ‘exercise’ diary (intervention group only). 
 
Participant at trial visit 6 (48 weeks +/- 14 days within randomisation) will have the option of asking 
questions and discussing their current HBEP with the study physiotherapist (maximum 20 minutes). 
They will be informed that they will be withdrawn from study intervention if they do not receive a LT 
by 52 weeks. However, they will be asked to continue with their study intervention up to 52 weeks 
post randomisation. They will have an ‘optional’ opportunity to consent to have the ‘muscle’ sub-
study investigations repeated (CPET, 6MWT, muscle USS, biomarkers), as they will no longer be having 
the sub-study investigations 6-months post-LT (i.e. LT has not taken place). 
 
9.3.5. Study intervention withdrawn (Scheduled)at 52 weeks  
If at 52 weeks (+ 2 weeks) participant has not received a LT, they will be withdrawn from the study 
intervention. Those patients still willing to continue with routine data collection will be followed (at 
their routine clinic visits) up every 3 months for first year then 6-monthly until the end of the study. 
Data will be collected from patient notes and captured by NHSBT and existing transplant databases at 
participating sites. In addition, patients still willing to continue completing the SP36 v2 questionnaire 
will be asked to complete the questionnaire at 3 monthly intervals for the first year. Data collection 
(every 3 months for 1st year after study intervention termination and every 6 months until the study 
ends) will include: 
 
Routine bloods [FBC, U+E, CRP, LFTs inc AST, INR, Ammonia; including UKELD, MELD-Na, 
Childs-Pugh]  
 
LFI, DASI 
 
SP36 v2 questionnaire. 
 
Death pre-LT (including cause) 
 
LT data (if undergoes LT before study end date), as listed in section 9.4, 9.5.1 and severe 
surgical complications/SAE, re-admission to ITU, death (including cause) and re-
transplantation.  
This data collection will continue until the study ends/closes. 
 

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9.3.6. Pre-LT Telecalls at weeks 2, 4, 8, 10, 16 and 20 – intervention arm only 
For the intervention arm only (Group 1) Telecalls will be performed by the study physiotherapist at 
week 2 (+/- 1 week), week 4 (+/- 1 week), week 8 (+/- 1 week), week 10(+/- 1 week), week 16(+/- 1 
week) and week 20 (+/- 1 week) (Table 7). The purpose of these calls (duration 15-30 minutes) will be 
to: identify any adverse events or areas of concern; gain feedback from the participant regarding the 
HBEP; and provide motivational support for engagement with the HBEP through the implementation 
of Empowering Physio strategies (Table 2).  
 
9.4. Day LT (unpredictable timing) – trial data collection [Inpatient stay L1] 
The following (below) investigations and data collection will take place on the admission for LT (i.e. 
prior to the LT).  This is called the L1 inpatient assessment visit. If the participant is admitted overnight, 
the data (where possible) will be collected in the morning prior to the LT: 
 
Record ‘new’ clinical events since last visit: Current/recent illnesses (<6 weeks), specifically: 
hepatic encephalopathy (I-IV), ascites (moderate to severe), number of LVP, peripheral 
oedema, variceal haemorrhage (requiring endoscopy), hepatorenal syndrome/AKI, 
sepsis/fever, significant fall. 
 
Record SAEs: non-elective Hospitalisation (Days in hospitals; if ‘0’ = no hospitalisation); 
requirement for organ support/intensive care [yes/no]; hepatorenal syndrome/AKI, severe 
hepatic encephalopathy, variceal haemorrhage, serious fall/musculoskeletal injury, cardiac or 
cerebrovascular event, sepsis/infection requiring admission (esp. SBP, pneumonia). 
 
Record ‘new’ medications: diuretics, beta-blocker, anti-hepatic encephalopathy medications, 
SBP prophylaxis, antibiotics (not SBP prophylaxis], anti-depressants/anti-anxiolytics, sleeping 
adjuncts. 
 
Record Nutritional supplements (prescribed amount) – as per visit 1-6 
 
Full examination, clinical observations and nutritional/physical/functional (including LFI) (if 
possible) *– as per visit 1-6 
 
DASI Questionnaire (if possible)* – NB no other questionnaires will be performed immediately 
prior to LT, as high risk of inaccuracy due to the emotional stress associated with waiting for 
high risk surgery (LT). 
 
Blood tests (if possible) * (including UKELD, MELD-Na, Childs-Pugh) – as per visit 1-6 
*Due to the ad hoc nature of this visit it may not be possible to perform these assessments.   
In cases where bloods are not performed- sites can enter bloods from a previous NHS visit if performed 
within 4 weeks of this visit. Post LT bloods are not acceptable for this visit. 
 
9.5. Phase 2 Post-LT trial schedule (inpatient stay, visits 7-9) 
The phase 2 Post-LT trials schedule will consist of the inpatient stay visit (within 72 hours prior to 
discharge from hospital post-LT or 10 days (+/- 3 days) post LT), visit 7 (week 6 weeks +/- 7 days), visit 
8 (12 weeks +/- 7 days), visit 9 (24 weeks +/- 14 days), visit 10 (48 weeks +/-14 days) post LT. This is 
called the L2 inpatient assessment visit. 
 
 
 

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9.5.1. LT data capture 
The following data will be obtained by a member of the research team from the LT operation note, 
anaesthetic chart, ICU charts, clinical noting and the NHSBT database (if required) (Table 7): 
 
Date of LT 
 
Donor and operation details: 
o type of donor 
o type of graft 
o ABO match 
o donor age 
o cytomegalovirus (CMV) donor status 
o graft steatosis 
o normothermic machine perfusion 
 
duration on the machine  
o cold ischaemic time 
o operation time  
o renal replacement therapy intra-operative; continuous veno-venous hemofiltration 
(CVVH) 
o recipient cardiac arrest in theatre  
o blood products in theatre 
 
ICU stay (time of admission to ICU to time of discharge to post-LT ward): 
o length of ICU stay (hours)* includes re-admission to ICU on the index post-LT hospital 
admission 
o duration of invasive ventilation (hours) = time of admission to ICU to time of 
extubation. 
o post-LT lactate (1st lactate on return to ICU after LT) 
o duration of inotropes  
o CVVH (including duration) 
 
Immunosuppression regimen (including renal-sparing regimen if required) 
9.5.2. Phase 2 Post-LT inpatient surgical ward (post-ICU step-down) (Inpatient stay L2) 
The following (below) investigations and data collection will take place post-LT on the inpatient 
surgical ward (post ICU step-down): 
 
Record LT Surgical complications/SAEs (frequency, CTCAE grade), including: biliary 
stricture/anastomosis, bile leak, wound dehiscence, abdominal collection (requiring 
drainage/intravenous antibiotics), haematoma/bleeding (requiring surgical/radiological 
intervention), anaemia requiring blood transfusion, AKI (requiring renal replacement 
therapy), Ileus/bowel obstruction, re-laparotomy, portal vein thrombosis, hepatic artery (or 
conduit) thrombosis, bacteraemia requiring intravenous antibiotics, hyperglycaemia requiring 
insulin infusion, infection (pneumonia; cholangitis; urinary tract; wound; peritonitis; central 
nervous system; CMV), acute rejection (biopsy proven) 
 
Record any of the following: 
o re-admission to ICU 
o death (including cause) 
o re-transplantation 

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 
Record new medications (specific; prior to discharge): anti-depressants/anti-anxiolytics, 
prescribed sleeping adjuncts, analgesics.  
 
Blood (non-fasted) tests on post-LT day 1,3 and 7 (+/-1 day): 
o FBC (full blood count; inc. neutrophils, lymphocytes, eosinophils, prothrombin time 
(PT) and INR 
o urea and electrolytes (inc. magnesium and phosphate). Document if on renal 
replacement support. 
o LFTs including AST 
o peak ALT (IU/L) 
o C-reactive protein (CRP) 
o tacrolimus trough level (if applicable) 
 
Day prior to discharge or day 10 post-LT +/- 3 days record nutrition/Physical/functional 
status: 
o wet weight (kg) 
o height (cm) 
o wet BMI (kg/m2) 
o estimated 
dry 
weight 
(kg) 
[using 
the 
5/10/15% 
reduction 
rule 
for 
mild/moderate/severe ascites; 5% for peripheral oedema] 
o estimated dry BMI (kg/m2) 
o nutrition management: 
 
route (inc. protein intake) 
 
oral supplements (inc. protein intake) 
 
normal diet  
o Handgrip strength (HGS; dominant hand) 
 
1st ………..2nd………..3rd…………Mean =……….Kg 
o MAMC (cm; if possible) 
o LFI (range 1.5 to 7.5; record in 2dp) by member of the research team (nurse, 
physiotherapist, Clinical Research Fellow) 
o DASI questionnaire 
o SF-36v2 Health Survey (Quality of Life Questionnaire) 
 
Record the length (days) of index hospital stay post-LT (inc. transfer to other hospitals) 
 
Record discharge destination (home, rehabilitation unit, other hospital, care facility)  
 
Study Intervention post-LT: 
The trial physiotherapists will review all participants on the post-LT ward, within 48-72 hours of 
discharge from ICU and will start a supervised (basic) exercise programme, based upon the 
participant’s current level of physical frailty/function, in keeping with post-surgical care (see section 
7.4.1). If there are concerns by the physiotherapist about the participant’s safety to exercise (i.e. walk, 
chair stand etc.), the participant’s consultant (i.e. Transplant surgeon, hepatologist) and clinical team 
(i.e. nurse) will be consulted – as per routine NHS care. 
 
The post-LT baseline assessments (LFI and DASI) undertaken 72 hours prior to discharge (or day 10 
post-LT +/- 3 days), along with “Empowering Physio” strategies, will be used to prescribe a 
personalised written HBEP for the participant post-LT (intervention group 1 only). The control group 

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will be given the post-LT patient ‘exercise’ advice leaflet within 72 hours prior to discharge. 
Participants in the intervention group will also be given a participant ‘exercise’ diary to self-report 
exercises undertaken between discharge and visit 7. 
 
Preparation for next trial visit 7 (6-weeks post-LT): 
Prior to discharge, the participant will be given a time/date for their next trial visit appointment, which 
where possible will be on the same day as their routine post-LT clinic. Prior to the next trial visit (visit 
7) the research team will post the accelerometer out to the participant for them to wear for the 14 
days prior to the next trial post-LT visit 7. 
 
9.5.3. Phase 2 post-LT visit 7 (6 weeks +/- 7 days) and visit 8 (12 weeks +/- 7 days) – max. 60 min 
These visits will take place alongside the participant’s routine post-LT clinic (where possible). The 
following investigations and data collection will take place at each visit (Table 7): 
 
Record ‘new’ clinical events (since discharge/last visit): ascites, peripheral oedema, jaundice, 
confusion/delirium, fever/night sweats, severe gastrointestinal symptoms, significant 
fall/injury. 
 
Record LT surgical complications/SAEs (frequency, CTCAE grade), including: biliary 
stricture/anastomosis, bile leak, wound dehiscence, new onset ascites (requiring LVP, 
admission), 
abdominal 
collection 
(requiring 
drainage/intravenous 
antibiotics), 
haematoma/bleeding (requiring surgical/radiological intervention), anaemia requiring blood 
transfusion, AKI (requiring renal replacement therapy), ileus/bowel obstruction, re-
laparotomy, portal vein thrombosis, hepatic artery (or conduit) thrombosis, bacteraemia 
requiring intravenous antibiotics, hyperglycaemia requiring insulin infusion, infection 
(pneumonia; cholangitis; urinary tract; wound; peritonitis; CNS; CMV), acute rejection (biopsy 
proven*), other (e.g. seizure, cardiac event (i.e. MI)/CVA): 
 
Record any of the following: 
o re-admission to ICU  
o death (including cause) 
o re-transplantation 
 
Record new medications (specific; prior to discharge): anti-depressants/anti-anxiolytics, 
prescribed sleeping adjuncts, analgesics. 
 
Immunosuppression regimen (including renal-sparing regimen if required) 
 
The following assessments/investigations (nurses checklists, CRFs) will take place at visits 7 and 8: 
 
Full clinical examination (including general, cardiovascular, respiratory, abdominal, 
neurological) 
 
Clinical Observations – as per visit 1-6 
 
Nutrition/Physical/functional status – as per visit 1-6 
 
LFI – as per visit 1-6 
 
Questionnaires (DASI, SF-36v2, HCCQ, Basic PNSE, BREQ-2) – as per visit 1-6 
 
Blood tests (non-fasted)*: 
o FBC (inc. neutrophils; lymphocytes; eosinophils), Prothrombin Time (PT), INR 

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o ferritin, trans sats (%), B12, folate, vitamin D, calcium (adjusted) 
o urea and electrolytes (inc. magnesium, phosphate) 
o LFTs including AST 
o CRP 
o HbA1c 
o tacrolimus – trough level (if applicable) 
(*Bloods to be taken on day of visit. If some blood results are missing, results from NHS visit within 
+/-4 weeks of visit will be accepted) 
 
Study Intervention: 
After completion of the assessments/investigations, participants will have a face-to-face consultation 
with the study physiotherapist: 
 
Intervention Group 1 (see section 7): A 30-60-minute consultation with the physiotherapist. 
As per phase one, the physiotherapist will use the assessments (LFI, DASI) along with 
“Empowering Physio” techniques and the participant’s owned perceived progress to revise 
their personalised HBEP. The participant will be provided with a personalised written HBEP. 
The physiotherapist will record and save personalised written HBEP in the site file and patients 
clinical notes. 
 
Control Group 2 (see section 7): As per phase 1 of the control arm, the physiotherapist will 
continue providing the advice highlighted in the patient ‘exercise’ advice leaflet.  
 
Exercise Monitoring (section 7.7): 
The physiotherapist will issue participants in both the intervention and control groups with: 
 
A participant ‘exercise’ diary (paper booklet), intervention group only: for them to self-
record all structured exercise undertaken during the trial. 
 
An ‘blinded’ wrist worn accelerometer (Actigraph GT9X): for them to wear for 14 days before 
visits 8 and 9. Participants will be asked to bring it to the next visit. Participants will be asked 
to contact the research team should they have any queries regarding accelerometer wear.  
 
Preparation for next trial visit 9 (24-weeks post-LT): 
The participant will be given a time/date for their next trial visit appointment, which where possible 
will be on the same day as their routine post-LT clinic. 
 
9.5.4. Post-LT Telecalls at weeks 4, 8 and 16, Group 1 intervention arm only 
Telecalls will be performed by the study physiotherapist at week 4 (+/- 1 week), week 8(+/- 1 week), 
and week 16 (+/- 1 week) post-LT (Table 7). The purpose of these calls (duration 15-30 minutes) will 
be to: identify any adverse events or areas of concern; gain feedback from the participant regarding 
the HBEP; and provide motivational support for engagement with the HBEP through the 
implementation of Empowering Physio strategies (Table 2).  
 
 
 

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9.5.5. Post-LT (End of study intervention) Visit 9 (24 weeks +/- 14 days) 
The end of intervention visit (visit 9) will take place alongside the participant’s routine post-LT clinic 
(where possible). The following investigations and data collection will take place at this visit: 
 
Record ‘new’ clinical events (since last visit): ascites [mild, moderate or severe], peripheral 
oedema, jaundice, confusion/delirium, fever/night sweats, severe gastrointestinal symptoms 
(Vomiting/diarrhoea/nausea/loss of appetite); significant Fall/injury or NONE. 
 
Record LT Surgical complications/SAEs (frequency, CTCAE grade), including: biliary 
stricture/anastomosis, bile leak, wound dehiscence, new onset ascites (requiring LVP, 
admission), 
abdominal 
collection 
(requiring 
drainage/intravenous 
antibiotics), 
haematoma/bleeding (requiring surgical/radiological intervention), anaemia requiring blood 
transfusion, AKI (requiring renal replacement therapy), Ileus/bowel obstruction, re-
laparotomy, portal vein thrombosis, hepatic artery (or conduit) thrombosis, bacteraemia 
requiring intravenous antibiotics, hyperglycaemia requiring insulin infusion, infection 
(Pneumonia; Cholangitis; Urinary tract; Wound; Peritonitis; CNS; CMV), other (record), acute 
rejection (biopsy proven), other (i.e. seizure, cardiac/CVA event). 
 
Record any of the following: 
o re-admission to ICU  
o death (including cause) 
o re-transplantation 
 
Record new medications (specific; since last visit: anti-depressants/anti-anxiolytics, 
prescribed sleeping adjuncts, analgesics.  
 
Immunosuppression regimen (including renal-sparing regimen if required) 
 
The following assessments/investigations (nurses checklists, CRFs) will take place at visit 9: 
 
Full clinical examination (including general, cardiovascular, respiratory, abdominal, 
neurological)  
 
Clinical Observations – as per visit 1-6 
 
Nutrition/Physical/functional status – as per visit 1-6 
 
LFI – as per visit 1-6 
 
Questionnaires (DASI, SF-36v2, HCCQ, Basic PNSE, BREQ-2) – as per visit 1-6 
 
Blood tests (non-fasted) – as per visits 8 and 9 
 
The following additional mechanistic ‘muscle’ sub-study’ investigations (nurses checklists, 
CRFs) will take place at visit 1 (if consented for sub-study) in the following order: 
o specialist biomarkers – as per visits 1 and 2  
o right Quadricep Muscle size, architecture and quality (Ultrasound) – as per visits 1 
and 2. 
o CPET – as per visits 1 and 2 
o 6MWT (supervised by the study AHPs or Clinical Research Fellow/PI) – as per visits 
1 and 2. 
 
 
 

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End of study Intervention: 
After completion of the assessments/investigations, participants will have a face-to-face consultation 
with the study physiotherapist: 
 
Intervention Group 1 (see section 7): This visit will mark the end of the study intervention 
delivered by the physiotherapists. No further personalised written HBEP will be provided. The 
participant will have a face-to-face consultation with the study physiotherapist. “Empowering 
Physio” techniques will be finalised and the participant will be given advice on the following 
domains to promote long-term motivation/engagement with exercise after the study 
intervention: 
o decisional balance patient-centred goal setting 
o supports attempts to change behaviour 
o normalised failed attempts 
o problem-solving 
 
Control Group 2 (see section 7): No further patient ‘exercise’ advice leaflets will be provided. 
 
Exercise Monitoring (section 7.7): 
The physiotherapist will collect, store and download (if electronic) the participants: 
 
Participant ‘exercise’ diary (paper booklet) (intervention group only) 
 
‘Blinded’ wrist worn accelerometer (Actigraph GT9X) 
Preparation for next trial visit 10 (48-weeks post-LT): 
The participant will be given a time/date for their next trial visit appointment, which where possible 
will be on the same day as their routine post-LT clinic. The participant will be provided with a 
participant ‘exercise’ diary (intervention group only) and encouraged to continue to record any 
exercises undertaken between visits 9 and 10. 
 
9.6. Post-LT (follow-up) Visit 10 (48 weeks +/- 14 days) – max. 60 mins 
The end of study follow-up visit 10 (post-LT +/- 14 days) will take place alongside the participants 
routine post-LT clinic (where possible). The following investigations and data collection will take place 
at this visit: 
 
Record LT Surgical complications/SAEs (frequency, CTCAE grade), including: biliary 
stricture/anastomosis, bile leak, wound dehiscence, new onset ascites (requiring LVP, 
admission), 
abdominal 
collection 
(requiring 
drainage/intravenous 
Antibiotics), 
haematoma/bleeding (requiring surgical/radiological intervention), anaemia requiring blood 
transfusion, AKI (requiring renal replacement therapy), Ileus/bowel obstruction, re-
laparotomy, portal vein thrombosis, hepatic artery (or conduit) thrombosis, bacteraemia 
requiring intravenous antibiotics, hyperglycaemia requiring insulin infusion, infection 
(Pneumonia; Cholangitis; Urinary tract; Wound; Peritonitis; CNS; CMV), other (record), acute 
rejection (biopsy proven*) 
 
*mild [   ] moderate [  ] severe [   ] 
 
pulsed steroids [   ] 
 
T-cell [   ] AMR (+DSA) [   ] 
Other (i.e. Seizure, cardiac/cva event; reason for re-admission to hospital): 

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 
Record any of the following: 
o re-admission to ICU  
o death: (including cause)  
o re-transplantation 
The following assessments/investigations (nurses checklists, CRFs) will take place at visit 10: 
 
Full clinical examination (including general, cardiovascular, respiratory, abdominal, 
neurological) 
 
Clinical Observations – as per visit 1-6 
 
Nutrition/Physical/functional status – as per visit 1-6 
 
LFI – as per visit 1-6 
 
Questionnaires (DASI, SF-36v2, HCCQ, Basic PNSE, BREQ-2) – as per visit 1-6 
 
Blood tests (non-fasted) – as per visit 9 
At the end of trial visit 10 (end of study), a member of the research team will: 
 
Collect/store the participant ‘exercise’ diary (intervention group only). 
 
Ensure the patient has a date for their next routine NHS post-LT clinic appointment. 
 
Research team will inform in writing the GP, LT units clinician and the local hospitals 
hepatologist that the patient has completed the trial. 
 
The patient will be thanked for their participation and will be informed of any future trial 
results, conclusions and publications in writing (or via the PPI and patient support groups). 
 
9.7. Follow-up post visit 10. 
If participants are still willing to continue with data collection after 48 weeks post LT, the following 
data will be collected until the end of study:  
 
Death (and cause) 
 
Re-transplantation 
Data will be collected from patient notes and captured by NHSBT and existing transplant databases at 
participating sites.  
 
9.8. Withdrawal and changes in levels of participation 
Informed consent is defined as the process of learning the key facts about a clinical trial before 
deciding whether or not to participate. It is a continuous and dynamic process and participants will be 
asked about their ongoing willingness to continue participation at all visits. Participants will be made 
aware from the beginning of the trial that they can freely withdraw (cease to participate) from the 
trial at any time. A participant may wish to cease to participate in a particular aspect of the trial (i.e. 
study intervention, sub-study), but give consent to participate in the remaining trial visits and outcome 
measure data collection. The date and reason the patient withdraws consent for a particular aspect 
of the trial (state ‘reason unknown’ if no reason provided) will be clearly documented in the patient’s 
medical notes. 
 
To enable enrolment into the ExaLT trial, all patients must give consent to participate in the pre-LT 
and post-LT treatment period, follow-up appointments and compliance with investigations required 

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for treatment efficacy and safety monitoring. At any stage between randomisation and the 48-week 
post-LT visit, a patient may withdraw consent from being a participant in trial, without necessarily 
giving a reason and without any personal disadvantage. The details of withdrawal will be clearly 
documented and communicated to the ExaLT Trial Office. The date and reason the participant 
withdraws consent (state ‘reason unknown’ if no reason provided) will be clearly documented in the 
participant’s medical notes. Should the participant wish to withdraw from the mechanistic ‘muscle’ 
sub-study, they will still, unless otherwise specified remain in the ExaLT trial. 
 
Participants found to be ineligible post randomisation should be followed up according to all trial 
processes and will still have their data analysed unless they explicitly change their level of 
participation. 
 
The changes in levels of participation within the trial are categorised in the following ways: 
 
No trial intervention: The participant would no longer like to receive the trial intervention, but is 
willing to be followed up in accordance with the schedule of assessments (i.e. Participant 
questionnaires completed) and if applicable using any central UK NHS bodies for long-term outcomes 
(i.e. the participant has agreed that data can be collected and used in the trial analysis). To maintain 
trial participation, the participant can also reduce the frequency of their study and follow-up visits, 
especially if they are struggling with the trial commitment (main aim will be to ensure that visit 9 
primary and secondary outcome data points are collected. 
 
No trial related follow-up: The participant does not wish to attend trial visits in accordance with the 
schedule of assessments, but is willing to be followed up at standard clinic visits (i.e. collect frailty 
measures) and if applicable using any central UK NHS bodies for long-term outcomes (i.e., the 
participant has agreed that data can be collected at standard clinic visits and used in the trial analysis, 
including data collected as part of long-term outcomes). 
 
No further data collection: The participant is not willing to be followed up in any way for the purposes 
of the trial AND does not wish for any further data to be collected (i.e., only data collected prior to any 
changes of levels in participation can be used in the trial analysis). 
 
The details of changes of levels in participation within trial (date, reason and category of status 
change) will be clearly documented in the source documents (patient’s medical notes) and the Change 
of status CRF).  
 
The investigators can withdraw a participant from the trial, after consideration of the benefit: risk 
ratio, at any stage of the trial. Justifiable reasons for doing so include: 
 
Removal from the national LT waiting list, due to: 
o poor compliance with clinic/hospital visits and/or medical therapy (i.e. alcohol 
relapse) 
o terminal illness/palliation (i.e. HCC out of LT criteria, irreversible ‘too’ unwell for LT) 

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o ‘too’ well for LT (i.e. liver disease has improved significantly that LT is not indicated) 
o participants request 
 
Technical grounds (e.g. patient moves away from trial area and can no longer meet the 
requirements of the trial protocol) 
 
Pregnancy (very unlikely in this patient population) 
 
Unpredictable events (non-clinical or clinical): any event which at the discretion of the PI 
and/or CI makes further treatment inadvisable (i.e. incarceration) 
All participants will be included in the analysis based on the intention to treat principle, either to the 
point of the end-point of the trial or to the point in which consent was withdrawn from participation 
in the trial. 
 
10. ADVERSE EVENT REPORTING 
10.1. Definitions  
Table 8: Adverse event reporting definitions 
Severity Definitions 
Mild 
Awareness of signs or symptoms that do not interfere 
with the participant’s usual activity or are transient and 
resolved without treatment and with no sequelae. 
Moderate 
A sign or symptom, which interferes with the 
participant’s usual activity. 
Severe 
Incapacity with inability to do work or perform usual 
activities. 
Adverse Event  
AE 
Any untoward medical occurrence in a participant 
participating in the trial which does not necessarily have 
a causal relationship with the intervention received.   
Related Event 
RE 
An event which resulted from the administration of any 
of the research procedures. 
Serious Adverse Event  
SAE 
An untoward occurrence that:  
Results in death  
Is life-threatening*  
Requires hospitalisation or prolongation of existing 
hospitalisation 
Results in persistent or significant disability or incapacity
Consists of a congenital anomaly/ birth defect 
Or is otherwise considered medically significant by the 
Investigator** 

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Unexpected Event 
UE 
The type of event that is not listed in the protocol as an 
expected occurrence. 
Related and Unexpected 
Serious Adverse Event  
N/A 
A SAE that meets both the definition of a Related and 
Unexpected Event. 
* The term life-threatening is defined as diseases or conditions where the likelihood of death is high 
unless the course of the disease is interrupted.  
** Medical events that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardise the participant or may require intervention to prevent one of the other outcomes 
listed in the definitions above. 
 
10.2. Adverse event recording – general  
The recording and reporting of Adverse Events (AEs) will be in accordance with the UK Policy 
Framework for Health and Social Care Research, the Principles of Good Clinical Practice (GCP) as set 
out in the UK statutory instrument (2004/1031; and subsequent amendments) and the requirements 
of the Health Research Authority (HRA). Definitions for AEs reporting are listed in Table 8 in Section 
10.1.  
 
It is routine practice to record AEs in the participant's medical notes and it is also recommended that 
this includes the documentation of the assessment of severity and seriousness and of causality 
(relatedness) in relation to the intervention(s) in accordance with the protocol.  
 
10.3. Adverse event reporting in ExaLT 
The study population have a life-threatening liver disease that requires major curative LT surgery. 
Therefore, due to the nature of the severity of their disease and the symptom burden that 
accompanies the natural history of advanced liver disease, there are expected to be a high number of 
Adverse Events (AEs) in these patients. For this reason, as well as the low-risk nature of the trial 
intervention (HBEP) to study participants, only Serious Adverse Events (SAEs) will be reported. 
 
The reporting period for SAEs in ExaLT will be from the day of randomisation (baseline visit 1) until the 
end of trial follow-up (visit 10). The safety profile for this trial population and interventions are well 
characterised so a strategy of targeted reporting of SAEs will not affect the safety of participants.  
 
10.4. Serious Adverse Advents (SAE) reporting in ExaLT 
For all SAEs, the PI or delegate must do one of the following: 
 
Record safety reporting-exempt SAEs in the medical notes but not report them to the trials office 
on an SAE form as per Section 10.4.1. 
 
 
Report SAEs to the ExaLT Trial Office in a non-expedited manner. This can only be done for the 
pre-defined subset of SAEs as per Section 10.4.2. 
 

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 
Report SAEs to the ExaLT Trial Office in an expedited manner (within 24 hours of the site research 
team becoming aware of the event). All SAEs not covered by the above 2 categories must be 
reported as per Section 10.5 Expedited SAE Reporting process. 
 
Note: when an SAE occurs at the same hospital at which the participant is receiving trial intervention 
or is being followed up for trial purposes, processes must be in place to make the trial team at the 
hospital aware of any SAEs, regardless of which department first becomes aware of the event, in an 
expedited manner. 
 
10.4.1. SAEs not requiring reporting to the ExaLT Trial Office  
At whatever time they occur during an individual’s participation, from the baseline visit to end of 
participant follow-up (visit 10), the following are not considered to be critical to evaluations of the 
safety of the trial:  
 
Hospital admissions that last less than 24 hours (e.g. symptomatic anaemia requiring no 
emergency intervention) 
 
Pre-planned hospitalisation (e.g. elective paracentesis or post-LT elective biliary drain removal) 
 
All events which meet the definition of serious must be recorded in the participant notes, including 
the causality and severity, throughout the participant’s time on trial, including follow-up, but for trial 
purposes these events do not require reporting on the SAE Form. Such events are “safety reporting 
exempt”.  
 
10.4.2. SAEs requiring non-expedited reporting to the ExaLT Trial Office  
Where the safety profile is well established, the causal relationship between the intervention (or the 
participant’s underlying condition), and the SAE, may be known. That is, such events are protocol-
defined as “expected” (see Section 10.5.2 Assessment of expectedness of a related SAE by the CI).  
 
Such events should still be recorded by the trial team in the participant’s notes and reported to the 
ExaLT Trial Office on the follow-up CRF but they do not require expedited reporting (immediately on 
the site becoming aware of the event) since the assessment of expectedness for the specified events 
has been pre-defined. These include: 
 
 
Pre-LT: 
o admission to hospital due to hepatorenal syndrome/AKI, severe hepatic 
encephalopathy, variceal haemorrhage requiring OGD +/- banding, serious 
fall/musculoskeletal 
injury, 
cardiac 
or 
cerebrovascular 
event 
(STEMI/NSTEMI/angina/arrhythmia/CVA/cerebral haemorrhage), sepsis/infection as 
a consequence of SBP and/or pneumonia). 
 
Post-LT: 
o jaundice 
o confusion/delirium 
o fever/night sweats 

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o severe gastrointestinal symptoms (vomiting/diarrhoea/nausea/loss of appetite) 
o significant fall/injury due to physical frailty 
o biliary stricture/anastomosis 
o bile leak 
o wound dehiscence 
o new onset ascites (requiring LVP, admission) 
o abdominal collection (requiring drainage/intravenous antibiotics), 
o haematoma/bleeding (requiring surgical/radiological intervention) 
o anaemia requiring blood transfusion 
o AKI (requiring renal replacement therapy) 
o ileus/bowel obstruction 
o re-laparotomy 
o portal vein thrombosis 
o hepatic artery (or conduit) thrombosis 
o bacteraemia requiring intravenous antibiotics 
o hyperglycaemia requiring insulin infusion 
o infection (pneumonia; cholangitis; urinary tract; wound; peritonitis; CNS; CMV), 
o acute rejection (biopsy proven*) 
 
*mild, moderate or severe 
 
pulsed steroids 
 
T-cell or antibody-mediated rejection 
 
10.4.3. SAEs requiring expedited reporting to the ExaLT Trial Office  
All SAEs not listed in sections 10.4.1 and 10.4.2 must be reported to the ExaLT Trial Office on a trial 
specific SAE form within 24 hours of the site research team becoming aware of the event. Examples 
include: 
 
Death 
 
Re-transplantation 
 
Multi-system organ failure requiring ICU support 
 
10.5. Expedited SAE Reporting process 
On becoming aware that a participant has experienced a SAE which requires expedited reporting the 
PI or delegate should report the SAE to their own Trust in accordance with local practice and to the 
ExaLT Trial Office.   
 
To report an expedited SAE to the ExaLT Trial Office, the PI or delegate must complete, date and sign 
the trial-specific SAE form together with any other relevant, appropriately pseudoanonymised reports. 
Data should be submitted to the ExaLT Trial Office using the information below in accordance with the 
timelines given in Section 10.4.2 and 10.4.3.  
 
 
 

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To report a SAE  
[Within 24 hours of becoming aware of event]  
Complete a SAE form in REDCap online database 
Email the ExaLT Trials Office: ExaLT@trials.bham.ac.uk  
 
Sites should report the expedited SAE within 24 hours of becoming aware of the event. To report a 
SAE, complete a SAE form using the REDCap online database.  In the unlikely event REDCap is not 
available [i.e. due to system failure], a paper SAE Form should be submitted to the ExaLT Trial Office 
via email.  In this case, the site should enter the SAE into the REDCap as soon as it is operational. 
 
Each SAE will be allocated a unique reference number by REDCap [or the ExaLT study Office if online 
system is not available]. The ExaLT study Office will notify the site via email as proof of receipt of SAE.  
The site and the ExaLT Trial Office should ensure that the SAE reference number is quoted on all 
correspondence regarding the SAE and correspondence filed in the ISF.  
 
Where a SAE form has been completed by someone other than the PI initially [or the medically 
qualified delegate], the SAE form must be countersigned by the forenamed PI or the medically 
qualified delegate to confirm agreement with the causality and severity assessments. 
 
If the site has not received confirmation of receipt of the SAE within 1 working day of reporting, the 
site should contact the ExaLT Trial Office.  
10.5.1. Assessment of causality of a related SAE  
When completing the SAE form, the PI (or, throughout this section, a medically qualified delegate) will 
be asked to define the nature of the seriousness and causality (relatedness; see Table 9) of the event.  
 
In defining the causality the PI must consider if any concomitant events or medications may have 
contributed to the event and, where this is so, these events or medications should be reported on the 
SAE form. It is not necessary to report concomitant events or medications which did not contribute to 
the event.  
 
As per Table 9, all events considered to be ‘possibly’, ‘probably’, or ‘definitely’ related to the 
intervention will be reported by the trial office as ‘related’; all events considered at site to be ‘unlikely’ 
or ‘unrelated’ to the intervention will be reported by the trials office as ‘unrelated’. The same 
categorisation should be used when describing AEs and protocol-exempt SAEs in the source data. 
 
On receipt of an SAE form, the ExaLT Trial Office will forward it, with the unique reference number, to 
the CI or delegate who will independently* review the causality of the SAE.  A SAE judged by the PI or 
CI or delegate to have a reasonable causal relationship (“Related” as per Table 9: Categories of 
causality) with the intervention will be regarded as a related SAE. The severity and causality 
assessment given by the PI will not be downgraded by the CI or delegate. If the CI or delegate disagrees 

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with the PI’s causality assessment, the opinion of both parties will be documented, and where the 
event requires further reporting, the opinion will be provided with the report.  
*Where the CI is also the reporting PI an independent clinical causality review will be performed. 
Table 9: Categories of causality 
Category 
Definition 
 
Causality 
Definitely 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
Related 
Probably 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
Possibly 
There is some evidence to suggest a causal relationship. However, the 
influence of other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events or medication) 
Unlikely 
There is little evidence to suggest there is a causal relationship. There is 
another reasonable explanation for the event (e.g., the participant’s clinical 
condition, other concomitant events or medication). 
Unrelated 
Not related 
There is no evidence of any causal relationship. 
 
10.5.2. Assessment of expectedness of a related SAE by the CI 
The CI or delegate(s) will also assess all related SAEs for expectedness with reference to the criteria in 
Table 10. 
 
Table 10: Categories of expectedness 
Category 
Definition 
Expected 
An adverse event that is consistent with known information about the trial 
related procedures or that is clearly defined in the relevant safety information. 
For the purposes of the ExaLT Trial, Section 10 of the approved ExaLT protocol 
will be used as the reference safety information.  
Unexpected 
An adverse event that is not consistent with known information about the trial 
related procedures. 
 
If the event is unexpected (i.e. it is not defined in the protocol as an expected event) it will be classified 
as a related and unexpected SAE.  
The CI will undertake review of all related SAEs and may request further information from the clinical 
team at site for any given event(s) to assist in this.  
 
 
 

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10.5.3. Provision of SAE follow-up information 
Following reporting of an SAE for a participant, the participant should be followed up until resolution 
or stabilisation of the event. Follow-up information should be provided using the SAE reference 
number provided by the ExaLT Trial Office. Once the SAE has been resolved, all critical follow-up 
information has been received and the paperwork is complete, a copy of the final version of the 
completed SAE form must be submitted to the Trial Office and the original kept in the ISF. 
 
10.6. Reporting SAEs to third parties 
The independent Data Monitoring Committee (DMC) may review any SAEs at their meetings. 
The ExaLT Trial Office will submit a progress report to the Research Ethics Committee (REC), UoB 
Research Governance Team (RGT) annually starting 12 months after the date of the favourable opinion 
was given. An electronic copy should be emailed to the REC within 30 days of the end of the reporting 
period. The Trial Office will report all events categorised as Unexpected and Related SAEs to the REC 
and RGT within 15 days of being notified. 
Details of all Unexpected and Related SAEs, and any other safety issue which arises during the course 
of the trial will be reported to the PIs. A copy of any such correspondence should be filed in the ISF 
and Trial Master File (TMF).  
 
10.7. Urgent Safety Measures 
If any urgent safety measures are taken, the Trial Office shall immediately, and in any event no later 
than 3 days from the date the measures are taken, give written notice to the REC of the measures 
taken and the reason why they have been taken. 
 
10.8. Follow-up of pregnancy outcomes for potential SAEs 
In the highly unlikely event that a participant was to become pregnant from date of consent until the 
end of the intervention period, the participant would be withdrawn from the intervention. We would 
however ask the participant if they were willing to continue being followed-up (data collection only).  
The low risk (and general) nature of the intervention means that we would not follow-up the 
pregnancy or resulting offspring for SAEs.  
 
 
 

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11. DATA HANDLING AND RECORD KEEPING 
11.1. Source data 
Source data is defined as all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. To allow for the accurate reconstruction of the trial and clinical management 
of participants, source data will be accessible and maintained.   
Some data variables may be entered directly onto the CRF; these are clearly identified and detailed in  
Table 11. 
Table 11: Source data in ExaLT 
Data 
Source 
Participant Reported 
Outcomes (i.e. trial  
questionnaires) 
The original participant-completed paper CRF is the source and will be 
kept with the participant’s trial record at site. Sites will enter data into 
the REDCap online database.  
Lab results 
The original lab report (which may be electronic) is the source and will 
be kept and maintained, in line with normal local practice. Information 
will be entered by Sites onto the relevant CRFs in the REDCap online 
database. 
Imaging (i.e. muscle 
USS) 
The source is the original imaging usually as an electronic file. Data may 
be supplied to the ExaLT Trial Office as a password-protected, 
pseudoanonymised, copy of the electronic file, or as an interpretation 
of the imaging provided on a CRF. Where data is interpreted, the CRF 
onto which it is first entered becomes the source.   
Physical 
function/physical 
activity data (i.e. CPET, 
accelerometer) 
The source is the original test out-puts which will usually be provided 
as an electronic file. Data may be supplied to the ExaLT Trial Office as a 
password-protected, pseudoanonymised copy of the electronic file, or 
as an interpretation of the test provided on a CRF. Where data is 
interpreted, the CRF onto which it is first entered becomes the source.
Clinical event data 
The original clinical annotation is the source document. This may be 
found on clinical correspondence, or electronic or paper participant 
records. Clinical events reported by the participant, either in or out of 
clinic (e.g. telephone calls), must be documented in the source 
documents. 
Recruitment 
The original record of the randomisation is the source. It is held on 
BCTU servers as part of the randomisation and data entry system. 
Withdrawal 
Where a participant expresses a wish to withdraw, the conversation 
must be recorded in the medical notes. 
 

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11.2. Case Report Form (CRF) completion 
ExaLT will use an online REDCap database.   Sites will enter data directly onto the relevant form in 
REDCap.  Paper CRFs completed prior to the REDCap database release will be stored in the investigator 
Site File [ISF]. The REDCap online database will include (but will NOT be limited to) the following Forms 
(see Table 12). 
Table 12: Case report forms in ExaLT trial. 
Form Name 
Schedule for submission using online system 
Randomisation form 
At the point of randomisation 
Baseline and follow-up CRFs including participant 
reported outcome measures (i.e. DASI; SF-36v2; 3 x 
behavioural questionnaires) and non-expedited 
SAEs. These include visits 1-10, in addition to Day of 
LT CRF and inpatient admission post-LT CRF. 
As soon as possible after each follow-up assessment 
time point 
Mechanistic ‘muscle’ sub-study CRF 
As soon as possible after each sub-study assessment 
time point (visit 1, 2 and 9) 
SAE form 
If expedited: within 24 hours of site research team 
becoming aware of event. 
Pregnancy notification form 
As soon as possible after becoming aware of 
participant’s pregnancy 
Change of status form 
As soon as possible after the point of reduced 
participation or death 
A CRF should be completed for each individual participant. 
It remains the responsibility of the PI to ensure that the CRF has been completed correctly and that 
the data are accurate. The Site Signature & Delegation Log will identify all personnel with 
responsibilities for data collection.  Site staff will be given individual unique usernames and will create 
their own private password to use the online REDCap database.  
 
The delegated staff completing the CRF should ensure the accuracy, completeness and timeliness of 
data reported. This will be evidenced within the REDCap online database.  
Data reported on each CRF will be consistent with the source data and any discrepancies will be 
explained. Missing and ambiguous data will be queried. Staff delegated to complete CRFs will be 
trained to adhere to the ExaLT Trial Protocol.  
 
The following guidance applies to data and partial data: 
 
Only CRFs provided by the Trial Office should be used.  
 
Time format – all times should be in accordance with the 24 hour clock. 
 
Rounding conventions – rounding should be to the nearest whole number: If the number you 
are rounding is followed by 5, 6, 7, 8, or 9, round the number up. E.g. 3.8 rounded to the 
nearest whole number is 4. If the number you are rounding is followed by 1, 2, 3 or 4, round 
the number down. E.g. 3.4 rounded to the nearest whole number is 3. 

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 
Trial-specific interpretation of data fields – where guidance is needed additional information 
will be supplied. 
 
Entry requirements for concomitant medications (generic or brand names) – generic names 
should be used where possible. 
 
Missing/incomplete data – should be clearly indicated/verified – all blank fields will be queried 
by the ExaLT Trial Office. 
 
Repeat laboratory tests – the data used to inform clinical decisions should always be supplied. 
If a test is repeated it is either to confirm or clarify a previous reading. Confirmatory tests 
should use the original test values. 
 
Protocol and GCP non-compliances should be reported to the ExaLT Trial Office upon 
discovery. 
 
11.3. Participant completed questionnaires  
Participant completed questionnaires will be administered by a member of the research team at site 
and will be completed by the participant, during their visit. A member of the research team will check 
the questionnaires for missing data, whilst the participant is still in attendance. If missing data is 
identified, the participant will be asked if they intentionally didn’t complete the data and if that is the 
case their wish will be respected.  
 
11.4. Data management 
Processes will be employed to facilitate the accuracy and completeness of the data included in the 
final report. These processes will be detailed in the trial specific data management plan and include 
the processes of data entry, data queries.  
Missing and ambiguous data will be queried using a data clarification system in line with the ExaLT 
data management plan and will focus on data required for trial outcome analysis and safety reporting. 
Single data entry by Site, with central monitoring by BCTU will be employed.  
Site staff will enter data into the REDCap online database. The system will include in built data 
validation to improve data quality (e.g. to prevent nonsensical dates or numerical values).  
Changes to the data, on the system will only be made by Site. BCTU staff will not have access to alter 
data on the online database but will be given a ‘read-only view’ of the trial data on the database.   
Site staff will be given unique log-in usernames and will create their own private password to use the 
online system. These unique log-in details must not be shared with other staff. In no circumstances 
should staff at sites access the trial database using another person’s login details. The ExaLT Trial Office 
will be unable to edit data in the online system.  
 
11.5. Data security  
UoB has policies in place, which are designed to protect the security, accuracy, integrity and 
confidentiality of Personal Data. The trial will be registered with the Data Protection Officer at UoB 
and will hold data in accordance with the Data Protection Act (2018 and subsequent amendments). 

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The Trial Office has arrangements in place for the secure storage and processing of the trial data which 
comply with UoB policies.  
 
The Trial Database System incorporates the following security countermeasures: 
Physical security measures: restricted access to the building, supervised onsite repairs and storages 
of back-up tapes/disks are stored in a fire-proof safe. 
Logical measures for access control and privilege management: including restricted accessibility, 
access-controlled servers, and separate controls of non-identifiable data. 
Network security measures: including site firewalls, antivirus software and separate secure network 
protected hosting. 
System management: the system will be developed by the Programming Team at the Trial Office and 
will be implemented and maintained by the Programming Team. 
System design: the system will comprise of a database and a data entry application with firewalls, 
restricted access, encryption and role based security controls.   
Operational processes: the data will be processed and stored within BCTU. 
System audit: The system will benefit from the following internal/external audit arrangements: 
 
Internal audit of the system  
 
Periodic IT risk assessment  
Data Protection Registration: UoB’s Data Protection Registration number is Z6195856. 
 
11.6. Archiving 
It is the responsibility of the PI to ensure all essential trial documentation and source documents (e.g., 
signed ICFs, Investigator Site Files, participants’ hospital notes, and paper CRFs (if used)) at their site 
are securely retained for the contractual period. Archiving will be authorised by BCTU on behalf of 
UoB following submission of the end of trial report. No documents should be destroyed without prior 
approval from the BCTU Director or their delegate. 
 
The TMF will be stored at BCTU for at least 3 years after the end of the trial. Long-term offsite data 
archiving facilities will be considered for storage after this time; data will be stored securely and 
confidentially for at least 10 years in accordance with the Sponsor’s policies and procedures.  
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Site set-up and initiation  
All PIs will be asked to sign the necessary agreements including a site signature and delegation log 
between the PI and the ExaLT Trial Office and supply a current CV and GCP certificate. All members of 
the site research team are required to sign the site signature and delegation log, which details which 
tasks have been delegated to them by the PI. The site signature and delegation log should be kept up 
to date by the PI. It is the PI’s responsibility to inform the ExaLT Trial Office of any changes in the site 
research team. 

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Prior to commencing recruitment, each recruiting site will undergo a process of site initiation, either 
a meeting or a tele/videoconference, at which key members of the site research team are required to 
attend, covering aspects of the trial design, protocol procedures, adverse event reporting, collection 
and reporting of data and record keeping. Sites will be provided with an ISF containing essential 
documentation, instructions, and other documentation required for the conduct of the trial.  
 
12.2. Monitoring 
The central and on-site monitoring requirements for this trial have been developed in conjunction 
with the trial specific risk assessment and are documented in the trial specific monitoring plan. 
 
12.2.1. On-site monitoring 
For this trial, all sites will be monitored in accordance with the trial risk assessment and monitoring 
plan. Any monitoring activities will be reported to the ExaLT Trial Office and any issues noted will be 
followed up to resolution. Additional on-site monitoring visits may be triggered. PIs and site research 
teams will allow the ExaLT Trial Office staff access to source documents as requested. The monitoring 
will be conducted by BCTU/UoB staff. 
 
12.2.2. Central monitoring 
The ExaLT Trial Office will check received ICFs and CRFs for compliance with the protocol, data 
consistency, missing data and timing at a frequency and intensity determined by the data 
management plan. Sites will be sent Data Clarification Forms (DCFs) requesting missing data or 
clarification of inconsistencies or discrepancies.   
 
12.3. Audit and inspection 
The PI (or delegate) will permit trial-related monitoring, audits, ethical review, and regulatory 
inspection(s) at their site and provide direct access to source data/documents. The PI (or delegate) 
will comply with these visits and any required follow-up. Sites are also requested to notify the ExaLT 
Trial Office of any relevant inspections or local audits. 
 
12.4. Notification of Serious Breaches 
The sponsor is responsible for notifying the REC of any serious breach of the conditions and principles 
of GCP in connection with that trial or of the protocol relating to that trial. Sites are therefore 
requested to notify the ExaLT Trial Office of any suspected trial-related serious breach of GCP and/or 
the trial protocol as soon as they become aware of them. Where the ExaLT Trial Office is investigating 
whether or not a serious breach has occurred, sites are also requested to co-operate with the Trial 
Office in providing sufficient information to report the breach to the REC where required and in 
undertaking any corrective and/or preventive action.   
Sites may be suspended from further recruitment in the event of serious and persistent non-
compliance with the protocol and/or GCP, and/or poor recruitment. 

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13. END OF TRIAL DEFINITION  
The end of trial will be the date of the last data capture (i.e. Final Patients Final Visit [FPFV]) including 
resolution of DCFs. This will allow sufficient time for the completion of protocol procedures, data 
collection and input and data cleaning. The ExaLT Trial Office will notify the REC and the Sponsor within 
90 days of the end of trial. Where the trial has terminated early, the Trial Office will notify the REC 
within 15 days of the end of trial. The Trial Office will provide the REC and the Sponsor with a summary 
of the clinical trial report within 12 months of the end of trial. 
Ethical approval for the mechanistic ‘muscle’ sub-study will be granted as part of the main ExaLT 
protocol. Therefore, the date of last data capture (i.e. FPFV) will include the final processing of all 
samples (including the sub-study specialist biomarkers), as specified in the protocol. 
  
14. STATISTICAL CONSIDERATIONS 
14.1. Sample size 
The mean PCS of the SF-36v2 QoL survey for patients with advanced liver disease or on the LT waiting 
list is approximately 39-42, with a standard deviation [SD] ranging from 8 to 24.(21, 36, 44, 63) 
Previous studies have indicated that LT alone improves PCS by +4 points (≈10%) compared to pre-LT. 
In contrast, small studies post-LT have highlighted that basic, supervised exercise interventions 
improve the PCS by +8-9 points (≈20%). However, no studies to date have incorporated a pre- and 
post-LT exercise programme, with the addition of theory-based motivational support.  
 
Hence for the sample size calculation we are proposing a +4 point (10%) improvement in the control 
arm and +12 point (30%) improvement in the experimental arm. Therefore, a meaningful clinically 
important difference [MCID] of 8 points with a SD of 16 will be used. The MCID is the smallest change 
in an outcome sufficiently important to influence management and is crucial for designing and 
interpreting comparative effectiveness trials. A MCID of +8 in QoL (using SF-36v2 questionnaires) has 
been previously reported in patients who rated their health as "excellent" or "very good" after 
abdominal surgery.(67) Members of the LT PPI group stated that improvement differences in PCS (SF-
36v2) of up to 20% between the control and experimental treatment arms, would imply that the 
treatment has had a significant impact on the patients’ QoL.  
 
To detect an MCID of 8 points with SD of 16, 90% power and a type I error rate of 5%, using the 
standard method of difference in means (2-sided), a total of 172 participants will be required. NHS 
data reports that approximately 30-35% of patients on the waiting list for LT will not have their 
transplant within 1-year of randomisation (NHSBT database 2015 to 2020). Hence the sample size 
needs to be inflated to account for this and other possible dropouts. Adjusting for a 35% 
attrition/drop-out rate, a total of 266 participants (133 per group) will need to be recruited. 
 
This sample size is predicted to be large enough to measure the impact of the intervention on surgical 
complications post LT using the CCI (i.e. key secondary outcome measure). The mean CCI post LT in 

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European centres is approximately 40 (range 0-100). A 25% reduction in CCI with intervention versus 
the control (10-points i.e. 40 vs. 30 by 6 months post transplantation) is considered a clinically 
meaningful improvement. With a total of 172 participants (before inflating for any attrition/drop-
outs), we estimate that there will be approximately 74-87% power (alpha 5%, 2-sided test, SD 25) to 
detect a mean CCI difference of 10-12 points between the intervention versus control. We feel these 
are realistic, yet conservative estimates of power, as simulation methods (Stata 16) revealed higher 
power for non-parametric data – which is very possible with CCI post-LT. 
 
14.2. Analysis of outcomes 
A separate Statistical Analysis Plan will be produced and will provide a more comprehensive 
description of the planned statistical analyses. A brief outline of the planned analyses is given below.  
 
The primary comparison groups will be composed of those randomised to the intervention group 
(group 1) versus those randomised to the control group (group 2). Analyses will be based on the 
intention to treat (ITT) principle, i.e., participants will be analysed in the intervention group to which 
they were randomised irrespective of adherence to randomised intervention or protocol deviations. 
In the first instance, for the primary outcome and any relevant secondary outcomes, analysis will be 
based on the modified ITT set, with the modified ITT set being those patients that have had a LT within 
52 weeks (+ 2 weeks) from randomisation.  
 
For all major outcomes, appropriate summary statistics and differences between groups (e.g. mean 
differences, relative risks, hazard ratios, etc.) will be presented with 95% confidence interval from two-
sided tests.  Analyses will be adjusted for the minimisation variables and baseline scores (where 
appropriate). There will be no adjustment for multiple testing.  
 
14.2.1. Primary outcome(s) 
The primary outcome is the PCS from the SF-36v2 QoL at 24-weeks post-LT. The SF36v2 QoL 
questionnaire will be administered at baseline for all randomised patients, during the pre-LT period 
(which will be variable between patients depending on how early they have their LT) and then at set 
intervals following their LT (i.e. at 6, 12, 24 and 48 weeks post LT). The data for this outcome is 
continuous and therefore will be summarised at each time-point (pre and post-LT) using the mean and 
standard deviation along with minimum and maximum values with respect to the two intervention 
arms and overall. 
 
Modified ITT set analysis (Post-LT) 
For the analysis of the primary outcome, initially the data collected at baseline and after LT will be 
considered in the first instance. The difference between group means and associated 95% confidence 
interval (CI) at the primary time point (i.e. 24 weeks post-LT) will be estimated through the use of a 
repeated measures, mixed-effects linear regression model. Data collected at assessment times for 
baseline and the post-LT time points up to 24 weeks will be included. Data collected at 48-weeks post 
LT will not be included. Parameters allowing for participant, intervention arm, baseline score, time 
and the randomisation minimisation variables will be included (all as fixed effects). Time will be 

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assumed to be a categorical (fixed) variable. To allow for a varying treatment effect over time, a time 
by treatment interaction parameter will be included in the model. Estimates of the least-squares mean 
differences between groups at the relevant time-points will be estimated from the model including 
this interaction parameter.  
 
ITT set analysis (Pre-LT) 
Given there is a possibility that some patients that are randomised may not end up having a LT within 
52 weeks (+ 2 weeks) of being randomised, they are initially excluded from the primary outcome 
analysis. However, to ensure we account for all randomised patients, we will undertake a secondary 
analysis which will include all randomised patients regardless of having had a LT.  
 
This analysis will only include data for the PCS of SF36v2 collected at baseline and for the pre-LT time-
points only (excluding any data collected post-LT). Given patients will have a LT at different time-points 
(with some possibly never having a LT within 52 weeks of being randomised), we will analyse the time 
to LT between the groups. Patients that do not have a LT within 52 weeks (+ 2 weeks) post 
randomisation will be censored at 52 weeks (+ 2 weeks). A Cox proportional hazard model will be 
fitted on the time to LT data, and results will be expressed as the hazard ratio with 95% confidence 
intervals. Kaplan-Meier curves will be constructed for visual presentation of time-to-event 
comparisons. As a further analysis, we will explore the time to LT and pre-LT SF36v2 data using a joint 
model approach. This method of analysis will jointly fit the time to event (i.e. LT) data with the 
longitudinal PCS data collected at pre-LT time-points for all randomised patients. The results from 
these analyses will be interpreted alongside the findings from main primary outcome results, i.e. 
modified ITT set analysis.  
 
14.2.2. Secondary outcomes 
The secondary outcomes are a combination of continuous, time-to-event and categorical data.  
Continuous outcomes: 
The secondary outcomes that are continuous data (e.g. CCI, MCS, DASI, LFI, length of ICU and hospital 
stay) will be analysed using the same analysis methods as described for the primary outcome modified 
ITT set.    
Time-to-event outcomes:  
The secondary outcomes that are time-to-event data (e.g. mortality) will be analysed using survival 
analysis methods.  Kaplan-Meier survival curves will be constructed for visual presentation of time-to- 
event comparisons.  A Cox proportional hazard model will be fitted, and results will be expressed as 
the hazard ratio with 95% confidence intervals. 
Categorical outcomes: 
The secondary outcome, LFI, can be summarised as continuous data (as above) or categorised into 
robust, pre-frail, or frail. The data for this outcome is summarised in 3 orderly categories; 1 = “≤3.2 
(robust)”, 2 = “3.2-4.5 (pre-frail)”, 3 = “>4.5 (frail)”. The analysis for this outcome will be conducted 
using a multilevel mixed-effects ordered logistic regression model and results will be expressed as 
odds ratio with 95% confidence intervals.   
 

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14.2.3. Planned subgroup analyses 
Subgroup analyses will be limited to the same variables used in the minimisation algorithm (see 
Section 6 – ENROLMENT, RANDOMISATION and BLINDING) and performed on the primary outcome 
only. The effects of these subgroups will be examined by including an intervention group by subgroup 
interaction parameter in the regression model, which will be presented alongside the effect estimate 
and 95% confidence interval within subgroups. The results of subgroup analyses will be treated with 
caution and will be used for the purposes of hypothesis generation only. 
 
14.2.4. Missing data and sensitivity analyses 
Every attempt will be made to collect full follow-up data on all study participants; it is thus anticipated 
that missing data will be minimal. Participants with missing primary outcome data will not be included 
in the primary analysis in the first instance. This however presents a risk of bias, and so sensitivity 
analyses will be undertaken to assess the possible impact of the risk. In brief, this will include using 
multiple imputation with chained equations to impute any missing data.  
Further sensitivity analysis will include a Complier Average Causal Effects (CACE) analysis for the 
primary outcome. 
 
Full details will be included in the Statistical Analysis Plan. 
 
14.2.5. Planned final analyses 
The primary analysis for the trial will occur once:  
 
The last randomised patient has had their LT and their 24-weeks follow-up assessment post 
LT completed, OR  
 
When the last randomised patient has not had their LT within 1 year (52 weeks) of being 
randomised and once all corresponding outcome data has been entered onto the trial 
database and validated as being ready for analysis. 
 
15. SUB-STUDY: Mechanistic ‘Muscle’ sub-study (n=100) 
The main aim of the ‘muscle’ sub-study is to undertake a detailed evaluation of the biological and 
physiological mechanisms that may underlie any exercised-induced improvements in clinical 
outcomes, including QoL and physical function/frailty. A better understanding of how exercise works 
(i.e. on the muscular and cardiopulmonary systems) will guide future studies in terms of exercise dose-
responses (‘frequency’, ‘intensity’, ‘duration’) that are required in patients with end-stage liver disease 
to maximise the efficiency and longevity of LT.  
 
The objectives of the ‘muscle’ sub-study are: 
1. To calculate the ‘dose’ of exercise (frequency, intensity, duration) completed before (after 6-
weeks intervention) and after LT (after 25-72 weeks intervention, depending on the timing of 
LT). 
2. To determine if ‘dose’ of exercise achieved before and after LT is associated with changes in: 

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a. QoL (PCS, MCS) 
b. physical frailty (LFI and its 3 components) 
c. cardiopulmonary fitness (DASI, CPET, 6MWT) 
d. muscle mass/thickness (quadricep ultrasound)  
3. To investigate if the HBEP improves the following before and after LT: 
a. muscle mass/thickness (quadricep ultrasound) 
b. cardiopulmonary fitness (CPET, 6MWT) 
c. serological markers of oxidative stress/muscle inflammation (specialist biomarkers) 
and whether these improvements are associated with clinical measures of physical frailty (LFI) 
and QoL (PCS, MCS). 
 
A sub-group of 100 participants (from a total of 266 patients enrolled in the ExaLT trial) will be 
recruited to the mechanistic ‘muscle’ sub-study. Participants will be recruited continuously on a 
voluntary basis at both trial sites, until the target of 100 participants is achieved. Participants will have 
to provide written consent for the sub-study at the same time as providing consent for the main ExaLT 
study. The ‘muscle’ sub-study will contain the same proportion of participants in group 1 (n=50, 
exercise/motivation programme) and group 2 (n=50, control arm) as randomisation for the ExaLT trial 
will be minimised for participation in the ‘muscle’ sub-study (in addition to age, UKELD, gender and 
trial site). In addition, the DMC will be able to review (based on annual reports) that the baseline 
characteristics of the muscle sub-study population are representative of the main ExaLT trial. 
 
At any stage between randomisation and 24 weeks post-LT (end-of-treatment [EOT]), a patient may 
withdraw consent from being a participant in the ‘muscle’ sub-group study, without necessarily giving 
a reason and without any personal disadvantage. The details of withdrawal will be clearly documented 
and communicated to the Trials Office. The date and reason the patient withdraws consent (state 
‘reason unknown’ if no reason provided) will be clearly documented in the patient’s medical notes. By 
withdrawing from the ‘muscle’ sub-study, unless specified, the patient will continue to be a participant 
for the remainder of the ExaLT trial, as this will not impact on the primary outcome measure (QoL). 
 
On patient withdrawal from sub-study, blood samples already collected may have had extensive 
analysis performed on them, therefore we request that “withdrawal of approval for use of previously 
donated samples” is not permitted in the sub-study. Participants will be made aware of this in the 
patient information sheet prior consenting to the sub-study.  
 
After randomisation, participants who have consented for the ‘muscle’ sub-study will undergo sub-
study investigations at the following time points:- 
 
Baseline visit (visit 1), within 3 days of randomisation, prior to starting the study intervention 
(or control): 
 
6 weeks of study intervention (pre-LT visit 2)  
 
24 weeks after LT (post-LT visit 9; end of intervention) or sub-study visit 6 (48 weeks + 28 days) 
if received no LT. 
 

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The following investigation will be performed at each time point:- 
 
CPET to determine standard measures such as anaerobic threshold and peak oxygen 
consumption (i.e. integrated response to the physiological stress of maximal exercise) 
 
Quadricep muscle ultrasound to assess skeletal muscle thickness.  
 
Venous blood sampling to assess the following specialist biomarkers: 
 
Common measures of oxidative stress: Total redox status, malonyldialdehyde, 
Myeloperoxidase, 4-Hydroxynonenal.  
 
Serum antioxidant capacity: catalase, glutathione peroxidase and superoxide dismutase.  
 
A profile of key myokines, including: interleukin(IL)-6, IL-10, IL-15, Irisin, leukaemia 
inhibitory factor, and secreted protein acidic and rich in cysteine (SPARC)  
 
Tumour necrosis factor alpha (TNF-) (not a myokine, but an inflammatory marker).  
 
The baseline (visit 1) to 6 week (visit 2) pre-LT datasets will determine the short-term effect of the 
study intervention whilst on the LT waiting list. In the event that the participant undergoes LT prior to 
visit 2 (i.e. between weeks 0 to 6; unpredictable timing), the investigations will not be repeated until 
post-LT visit 9 (end of intervention). The post-LT dataset (visit 9) will determine the longer-term effect 
(i.e. prehabilitation and 24-weeks rehabilitation post-LT) of the study intervention on muscle, 
inflammation and cardiopulmonary fitness, alongside the main ExaLT trial primary and secondary 
outcome measures. Throughout the ‘muscle’ sub-study the control arm will provide the benchmark 
for the investigations performed on the pre-LT waiting list and 24-weeks after the LT.  
 
In the event that a patient has not undergone a LT in the pre-LT timeframe (1 year), they will be given 
the option if they would like to consent to a muscle sub-study (CPET etc) at visit 6. As they will not be 
undergoing a LT within the study timeframe, the Visit 6 (+ 28 days’ time window) optional sub-study 
visit will enable us to understand if the changes identified between weeks 0 (visit 1) and weeks 6 (visit 
2) have been sustained. 
 
A full standard operating procedure (SOP) will be produced for this sub-study.   
 
15.3. Blood and Urine Samples for Future Research  
Participants enrolled into the mechanistic sub-study will be given the option for remaining blood 
samples (i.e. post analysis) to be safely stored and used in future ethically approved research.  At the 
QEUHB site only, urine samples will also be collected for future research. Urine is considered 'relevant 
material' under the Human Tissue Act 2004.  The tracking, storage and consent for future research 
within the ExaLT study is in accordance with this current legislation. Participants taking part in the 
mechanistic sub-study will be given the option for a maximum of three 20-30ml urine samples taken 
as part of their routine care, to be collected and safely stored for future ethically approved research. 
Urine samples will be collected at similar time points as the research blood samples for the 
mechanistic study (i.e. visit 1, visit 2 pre LT and visit 9 (post LT) or visit 6 (+ 28 day- time window) if no 

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LT at 52 week. Participants will be informed that general health information accompanies these 
samples and that the samples may be shared with a wide range of researchers and institutions and 
there is a possibility of commercial or therapeutic applications.  
 
15.4. Sample tracking  
All human tissue samples should be traceable from the point of collection to the point of disposal. An 
individual or individuals at each site will be delegated the role of sample collection and tracking. 
Tracking will occur wherever samples are transported or transferred between separate physical 
locations.   
 
When samples are transported for storage or for analysis, documentation detailing the date of 
shipment, the number of samples being shipped and the nature of the samples will be maintained and 
filed within the ISF or TMF as appropriate.  The laboratory receiving the samples will provide a signed 
receipt confirming that the correct number of samples have been received in an appropriate 
condition. Details of all shipments and receipts will be filed in the TMF/ISF.  The sponsor and the CI 
will be notified of any issues identified during sample shipment. 
 
A contractual agreement must be in place between the sponsor and external body prior moving 
material (i.e. samples and associated general medical data) to an external body for analysis or future 
research.  The model Non-Commercial Agreement (mNCA) agreement between sponsor and each NHS 
trust will cover the movement of samples from trust sites to the Institute of Biomedical research (IBR) 
at the University of Birmingham for storage prior analysis. 
 
15.5. Sample storage  
The analysis of the bloods samples will be undertaken as part of the data collection before the end of 
study declaration.  If consent for future research has not been given, samples will be destroyed prior 
the end of study declaration. Where consent for future research has been given, samples must be 
transferred to a HTA licensed storage facility or ethically approved research study prior the end of 
study declaration.  Consent forms must be retained for the duration of sample storage. Sample 
disposal must be documented and retained by the laboratory. All documents pertaining to sample 
management must be retained by the laboratory. 
 
16. TRIAL ORGANISATIONAL STRUCTURE 
16.1. Sponsor 
The Sponsor for this trial is University of Birmingham (UoB).  
 
16.2. Coordinating centre 
The trial-coordinating centre (ExaLT Trial Office) is Birmingham Clinical Trials Unit (BCTU), based at 
UoB. 

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16.3. Trial Management Group (TMG) 
The Trial Management Group (TMG) comprises of individuals responsible for the day-to-day 
management of the trial: the CI, Co-CIs, PIs, Co-applicants, Trial Statisticians, Trial Manager and Data 
Manager. The role of the group is to monitor all aspects of the conduct and progress of the trial, ensure 
that the protocol is adhered to and take appropriate action to safeguard participants and the quality 
of the trial itself. The TMG will meet sufficiently frequently to fulfil its function. 
 
16.4. Trial Steering Committee (TSC) 
A Trial Steering Committee (TSC), comprising independent and non-independent members, will be 
established for the ExaLT Trial and will meet as required depending on the needs of the trial. 
Membership and duties/responsibilities are outlined in the TSC Charter. In summary, the role of the 
TSC is to provide oversight of the trial. The TSC will monitor trial progress and conduct, and provide 
advice on scientific credibility. The TSC will consider and act, as appropriate, upon the 
recommendations of the Data Monitoring Committee (DMC). The TSC will operate in accordance with 
a trial specific TSC Charter. 
 
16.5. Data Monitoring Committee (DMC) 
The role of the independent DMC is to monitor the trial data, and make recommendations to the TSC 
on whether there are any ethical or safety reasons as to why the trial should not continue or whether 
it needs to be modified. To this end, data on safety outcomes and (where appropriate) primary and 
major secondary outcomes will be supplied to the DMC during the trial. Reports will be supplied in 
confidence. The DMC will operate in accordance with a trial specific DMC Charter which will define 
the membership, roles and responsibilities of the DMC.  The DMC will meet at least annually as a 
minimum.  Additional meetings may be called if needed e.g., recruitment is faster than anticipated or 
a safety issue is identified. 
 
16.6. Finance 
The research costs of the ExaLT trial are funded by the National Institute of Health Research (NIHR) 
Efficacy and Mechanism Evaluation Programme (Ref: NIHR129318) awarded to Dr Matthew 
Armstrong, University of Birmingham. The trial has been designed to minimise extra ‘service support’ 
costs for participating hospitals as far as possible. Additional costs, service support costs and excess 
treatment costs associated with the trial, e.g., gaining consent, are estimated in the Statement of 
Activities. These costs should be met by accessing the Trust’s Support for Science budget via the Local 
Comprehensive Research Network. 
 
17. ETHICAL CONSIDERATIONS 
The ExaLT trial will be conducted in accordance with the UK Policy Framework for Health and Social 
Care Research and applicable UK Acts of Parliament and Statutory Instruments (and relevant 

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subsequent amendments), which include Data Protection Act 2018; Human Tissue Act 2004; Mental 
Capacity Act 2005; and the Principles of GCP as set out in the UK Statutory Instrument (2004/1031; 
and subsequent amendments). The protocol will be submitted to and approved by the REC prior to 
the start of the trial. Before any participants are randomised into the trial, the PI at each site is required 
to obtain the necessary local approval.  
 
It is the responsibility of the PI to ensure that all subsequent amendments gain the necessary local 
approval. This does not affect the individual clinicians’ responsibility to take immediate action if 
thought necessary to protect the health and interest of individual participants. 
 
18. DATA PROTECTION AND CONFIDENTIALITY  
Personal data and sensitive personal data recorded on all documents will be regarded as strictly 
confidential and will be handled and stored in accordance with the Data Protection Act 2018 (and 
subsequent amendments). Personal data categories that will be collected and analysed include name, 
date of birth, NHS number and primary/secondary NHS healthcare records (including past medical 
history, GP practice, drug history).  
 
Participants will only be identified by their 3 digit unique trial identification number and initials on 
routine correspondence with the ExaLT BCTU Trial Office. The following personal identifiable data 
(PID) will be collected on the CRFs: 
 
Table 13: PID captured in the ExaLT trial. 
Form name 
PID 
Randomisation form 
Trial number, participant’s full name, date of 
birth, gender and NHS number   
Baseline 
and 
follow-up 
CRFs 
including 
participant reported outcome measures (i.e. 
DASI; SF-36v2; 3 x behavioural questionnaires). 
These include visits 1-10, in addition to day of LT 
CRF and inpatient admission post-LT CRF 
Mechanistic ‘muscle’ sub-study CRF 
Change of status form 
Trial number and initials  
SAE form 
Pregnancy notification form 
Trial number and partial date of birth 
 
At site data will be securely handled and maintained in controlled access locations and follow local 
NHS policies and procedures for information security. The sponsor (UoB) will ensure Patient consent 
forms and randomisation forms are kept separately to the rest of the CRFs, in a locked filing cabinet, 

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in an office with controlled swipe access. Data will be entered onto a Redcap database held on secured 
University of Birmingham servers with restricted access and permissions. 
Participants will acknowledge the transfer and storage of their informed consent form to the ExaLT 
Trial Office. This will be used to perform central monitoring of the consent process. Participants will 
acknowledge the transfer of their personal data for the purpose of medical research to BCTU at UoB. 
Participants will acknowledge the transfer of their personal data to BCTU at UoB, who will be 
processing data on behalf of the trial.   
In the case of specific issues and/or queries from the regulatory authorities, it will be necessary to 
have access to the complete trial records. Representatives of the ExaLT Trial Office and sponsor (UoB) 
may be required to have access to participants’ notes for quality assurance purposes, but participants 
should be reassured that their confidentiality will be respected at all times. The ExaLT Trial Office will 
maintain the confidentiality of all participant data and will not disclose information by which 
participants may be identified to any third party.  
 
19. FINANCIAL AND OTHER COMPETING INTERESTS 
There are no financial or other competing interests related to the results of this trial. Members of the 
TSC and DMC are required to provide declarations on potential competing interests as part of their 
membership of the committees. Authors are similarly required to provide declarations at the time of 
submission to publishers.  
 
20. INSURANCE AND INDEMNITY 
UoB has in place clinical trials indemnity coverage for this trial which provides cover to UoB for harm 
which comes about through the University’s, or its staff’s, negligence in relation to the design or 
management of the trial and may alternatively, and at UoB’s discretion provide cover for non-
negligent harm to participants. 
 
With respect to the conduct of the trial at site and other clinical care of the patient, responsibility for 
the care of the patients remains with the NHS organisation (QEUHB or RFH) responsible for the clinical 
site and is therefore indemnified through the NHS Litigation Authority.  
 
21. POST-TRIAL CARE 
In keeping with the Declaration of Helsinki 2013, all trial participants will be followed up in their 
routine NHS post-LT clinics and will receive the standard of healthcare in place at the time. If the 
participant has any ongoing additional healthcare needs at the end of the trial (i.e. disability, mental 
health illness) they will be referred onto the relevant specialist (i.e. physiotherapist, social care worker, 
psychiatrist) by the clinical/research team (i.e. PI or local clinician). There will be NHS trust funding 
(QEUHB, RFH) to prescribe the physiotherapist delivered ‘home-based exercise and theory-based 
motivation support programme’ in the future if the trial proves that the intervention is safe and 
efficacious (i.e. meets the primary end-point).  

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22. ACCESS TO FINAL DATASET 
The final dataset will be available to members of the Trial Management group (TMG) and co-applicant 
group who need access to the data to undertake the final analyses. 
 
Requests for data generated during this study will be considered by BCTU. Data will typically be 
available 6 months after the primary publication unless it is not possible to share the data (for 
example: the trial results are to be used as part of a regulatory submission, the release of the data is 
subject to the approval of a third party who withholds their consent, or BCTU is not the controller of 
the data).  
 
Only scientifically sound proposals from appropriately qualified Research Groups will be considered 
for data sharing. The request will be reviewed by the BCTU Data Sharing Committee in discussion with 
the CI and, where appropriate (or in absence of the CI) any of the following: the Trial Sponsor, the 
relevant TMG, and independent TSC.  
 
A formal Data Sharing Agreement (DSA) may be required between respective organisations once 
release of the data is approved and before data can be released. Data will be fully de-identified 
(anonymised) unless the DSA covers transfer of participant identifiable information. Any data transfer 
will use a secure and encrypted method. 
 
23.  PUBLICATION PLAN 
Outputs from the ExaLT trial will be submitted for publication in peer reviewed journals and the 
findings of the trial will be made public. Manuscripts will be prepared by the writing group as defined 
in the trial publication plan. Manuscripts should be submitted to the TMG in a timely fashion and in 
advance of being submitted for publication to allow time for review. The participants will be provided 
with a lay written summary of the outcome of the trial, alongside provision of the publication.  
 
In all publications, authors should acknowledge that the trial was performed with the support of the 
NIHR, University of Birmingham and BCTU. Intellectual property rights will be addressed in the site 
agreement between Sponsor and site. 
 
24. ADDITIONAL PLANNING 
24.1 Virtual study visits - Protocol planning during significant UK events and/or consistent inability to 
visit the trial site.  
 
A significant UK event would include: 

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 
Viral pandemic (Local, regional, or national lockdowns) restricting hospital visits/travel and 
the re-introduction of social distancing. 
 
Industrial strike action (i.e. transport, education/university, NHS healthcare) limiting access to 
hospital care or trial visits. 
 
Terrorist or war threat to the UK. 
 
In the event of one of the above or severe mitigating circumstances (i.e. prolonged hospital admission 
meaning unable to attend a series of trial visits or the ‘key’ primary end-point visit 9) there will be the 
option (approved by the local PI or CI/Co-CI) of minimal trial data capture via: 
 
Face-to-face trial visit on the inpatient ward (if patient hospitalised at QEUHB or RF): 
o As judged appropriate by the local PI/CI the patient will undergo trial visit 
investigations as per a pre-LT or post-LT visit, as described previously and with 
particular emphasis on: 
 
SF-36v2 (primary end-point) 
 
Record ‘new’ clinical events since last visit: Current/recent illnesses (<6 
weeks) 
 
Record Serious Adverse Events (SAEs) 
 
Nutritional/physical/functional indices (including HGS, MAMC, LFI, DASI) 
 
Study Questionnaires (HCCQ, Basic PNSE, BREQ-2) 
 
Blood tests – as per visit 1 or visit 9 
 
 
Telecall and/or video call trial visit: 
o As judged appropriate by the local PI/CI the patient will undergo trial visit 
investigations over the phone as per a pre-LT or post-LT, as described previously and 
with particular emphasis on: 
 
SF-36v2 (primary end-point) 
 
Record ‘new’ clinical events since last visit: Current/recent illnesses (<6 
weeks) 
 
Record Serious Adverse Events (SAEs) 
 
Study Questionnaires (DASI, HCCQ, Basic PNSE, BREQ-2) 
 
5 Sit-to-stand (STS) chair stands – if video call 
 
3 Balance tests (as part of LFI) – if video call 
 
Wet weight (kg) – if video call 
 
Blood tests – if local clinician (GP/hospital) are able to undertake and email 
using secure NHS approved email addresses. 
 
In the event of a ‘Virtual’ trial visit the rationale will be clearly documented. A ‘Virtual’ trial visit will 
be under exceptional circumstances and will not reverted to as an easier/more convenient default 
trial visit. 
 
 

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