EXercise TheRApy in Mesothelioma - A Feasibility Study
Phase: NA
Conditions: Mesothelioma
Sponsor: NHS Greater Glasgow and Clyde

21 
 
     
    
  
 
  
 
 
 
 
 
 
EXTRA-Meso Feasibility Study 
EXercise TheRApy in Mesothelioma – A Feasibility Study 
 
 
 
Protocol Version 1.1 
Version Date 13/09/2023 
IRAS Project ID: 315059 
R&I Reference: GN22ON168 
Chief Investigator: Dr. Selina Tsim 
 
Protocol Authorised by: 
Name: 
Dr. Selina Tsim 
Role: 
Chief Investigator 
Date: 
13/SEP/2023  
Signature: 
 

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RESEARCH CONTACTS 
Chief Investigator 
 
Co Investigators 
Dr. Selina Tsim 
Consultant Respiratory Physician & Honorary Senior Clinical 
Lecturer 
NRS Research Fellow 
Department of Respiratory Medicine 
Queen Elizabeth University Hospital 
1345 Govan Road 
GLASGOW G51 4TF 
 
Tel:        0141 451 6163/07492999818 
E-mail:    Selina.Tsim@ggc.scot.nhs.uk  
 
Dr. Matthew Evison 
Consultant Respiratory Physician 
Department of Respiratory Medicine 
Wythenshawe Hospital 
Manchester University NHS Foundation 
Trust 
Southmoor Road 
MANCHESTER M23 7LP 
 
Tel:    07832238396 
E-mail: Matthew.Evison@mft.nhs.uk  
 
 
 
 
Co-Investigators 
 
 
 
Prof. Kevin Blyth 
Professor of Respiratory Medicine 
School of Cancer Sciences 
University of Glasgow 
Wolfson Wohl Cancer Research Centre 
Bearsden 
GLASGOW G61 1BD 
 
Tel:      0141 451 6163/07540534058 
E-mail:  Kevin.Blyth@glasgow.ac.uk  
 
 
 
Dr Afrodita Marcu 
Research Fellow 
School of Health Sciences 
Faculty of Health & Medical Sciences 
Kate Granger Building 
Prisetly Road 
University of Surrey 
SURREY GU2 7YH 
 
Tel:        01483 682 515 
E-mail:   Afrodita.Marcu@surrey.ac.uk  
 
 
Dr. John Moore 
Consultant in Critical Care & Anaesthesia 
Department of Critical Care 
Manchester Royal Infirmary 
Manchester University NHS Foundation 
Trust 
Oxford Road 
MANCHESTER M13 9WL 
 
Tel:      0161 276 4551 
E-mail:  John.Moore@mft.nhs.uk  
 
 
Ms Zoe Merchant 
Chief AHP Prehab4Cancer 
GM Cancer Alliance 
2nd Floor, PTB Cabin 
Christie NHS Foundation Trust 
Wilmslow Road 
MANCHESTR M20 4BX 
 
Tel:      0161 291 5943/07557169823 
E-mail: Zoe.Merchant@mft.nhs.uk    
 
 
 
Sponsor 
Joanne McGarry 
Sponsor Research Co-ordinator 
NHS Greater Glasgow & Clyde 
Research & Innovation 
Ward 11, Dykebar Hospital 
Grahamston Road 
PAISLEY PA2 7DE 
 
Tel:        0141 314 4001 
E-mail:   Joanne.McGarry@ggc.scot.nhs.uk  

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Contents 
Research Contacts ........................................................................................................................................... 2 
1 
Study Synopsis ......................................................................................................................................... 5 
2 
Abbreviations........................................................................................................................................... 7 
3 
Study Flowchart ....................................................................................................................................... 8 
4 
Summary of study .................................................................................................................................... 9 
4.1 
Plain English Summary...................................................................................................................... 9 
4.2 
Scientific Summary ......................................................................................................................... 10 
5 
Study Objectives .................................................................................................................................... 11 
5.1 
Primary Objective ........................................................................................................................... 11 
5.2 
Secondary Objectives ..................................................................................................................... 11 
6 
Study design .......................................................................................................................................... 11 
6.1 
Study Setting .................................................................................................................................. 11 
6.2 
Study Population ............................................................................................................................ 11 
6.2.1 
Inclusion Criteria ..................................................................................................................... 11 
6.2.2 
Exclusion Criteria .................................................................................................................... 11 
6.2.3 
Identification of participants and consent ............................................................................... 12 
6.3 
Sample size calculation ................................................................................................................... 12 
6.4 
Co-enrolment guidelines ................................................................................................................ 13 
6.5 
Withdrawal of patients from the study ........................................................................................... 13 
7 
Baseline Assessment .............................................................................................................................. 13 
8 
Randomisation ....................................................................................................................................... 14 
9 
Post-randomisation ................................................................................................................................ 14 
9.1 
Standard Care Arm ......................................................................................................................... 14 
9.2 
Exercise Therapy (Intervention) Arm .............................................................................................. 14 
9.3 
Semi-structured Interviews ............................................................................................................ 15 
9.4 
Schedule of Assessments ................................................................................................................ 16 
10 
Statistical Analysis Plan ...................................................................................................................... 17 
11 
End of Trial ......................................................................................................................................... 17 
12 
Safety Reporting ................................................................................................................................ 17 

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12.1 
Adverse Event (AE) ......................................................................................................................... 17 
12.2 
Serious Adverse Event (SAE) ........................................................................................................... 17 
12.3 
SAEs Related to Study Procedures .................................................................................................. 18 
12.4 
Adverse Event Recording and Reporting ......................................................................................... 18 
12.5 
Expected Adverse Events ................................................................................................................ 19 
12.5.1 
Exercise Therapy ..................................................................................................................... 19 
13 
Feasibility study metrics ..................................................................................................................... 19 
14 
Compliance, Audit and Protocol Deviations ........................................................................................ 19 
14.1 
Good Clinical Practice ..................................................................................................................... 19 
14.2 
Audits ............................................................................................................................................. 19 
14.3 
Protocol Deviation Reporting.......................................................................................................... 20 
15 
Data Handling .................................................................................................................................... 20 
15.1 
Case Report Forms ......................................................................................................................... 20 
16 
References ......................................................................................................................................... 21 
 
 
 

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1 
STUDY SYNOPSIS 
Study Title 
EXercise TheRApy in Mesothelioma – A feasibility study (EXTRA-Meso 
feasibility study) 
Study Sponsor 
NHS Greater Glasgow and Clyde 
Study Design 
Randomised feasibility trial 
Number of Patients 
40 
Patient Population 
Patients with a diagnosis of mesothelioma 
Primary Objective 
To determine the feasibility of recruiting patients with mesothelioma to a 
randomised trial of exercise therapy, in order to inform design of a future 
phase 3 trial 
Secondary 
Objectives 
1. To determine barriers to study recruitment 
2. To determine barriers to study retention 
3. To determine safety and tolerability of the exercise programme 
intervention and study assessments 
Primary Outcome 
Measure 
Number of patients recruited 
Secondary Outcome 
Measures 
1. Proportion of screened patients who are ineligible 
2. Reasons for study ineligibility 
3. Study drop-out rate 
4. Reasons for study drop-out 
5. Intervention adherence rate 
6. Adverse events 
7. Health-related Quality of Life (HRQoL) questionnaire completion rate 
8. Framework analysis from qualitative interviews 
Eligibility Criteria 
Inclusion Criteria: 
1. Diagnosis of mesothelioma, ratified by a mesothelioma MDT 
2. Performance status 0 -2  
3. Clinical frailty score ≤5 
4. Informed written consent 
Exclusion Criteria: 
1. Performance status ≥3 
2. Clinical frailty score ≥6 

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3. Unlikely to be able to participate in an exercise programme 
(clinician/physiotherapist judgement) 
Screening and 
Consent 
Patients with mesothelioma will be identified at mesothelioma MDTs, 
routine respiratory/oncology outpatient appointments, and during inpatient 
reviews. Those meeting all eligibility criteria will be provided with a Patient 
Information Sheet (PIS) and given sufficient time to consider participation. 
Randomisation and 
Allocation 
Following consent and baseline assessments, patients will be randomised 
using an online system (sealedenvelope.com) and allocated 1:1 using random 
permuted blocks to one of two groups: 
A. Exercise Therapy 
B. Standard Care 
End of Study 
Trial participation will end when the last patient has completed their 26 week 
visit 
Study duration 
18 months 
 
 

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2 
ABBREVIATIONS 
 
MPM 
Malignant Pleural Mesothelioma 
WoS 
West of Scotland 
HRQoL 
Health-related Quality of Life 
SD 
Standard deviation 
PS 
Performance Status 
CFS 
Clinical Frailty Score 
PIS 
Patient Information Sheet 
MDT 
Multi-disciplinary team 
FBC 
Full blood count 
CRP 
C-reactive protein 
6MWD 
6 minute walk distance 
STS 
Sit to stand 
BMI 
Body mass index 
MUST 
Malnutrition universal screening tool 
(S)WEMWBS 
Short Warwick Edinburgh Mental Wellbeing 
Scale 
HADS 
Hospital anxiety and depression scale 
SF-36 
36-item short form survey 
EQ-5D-5L 
EuroQol group 5 item survey 
EORTC-QLQ-C30 
European organisation for research and 
treatment of cancer survey 
SACT 
Systemic anti-cancer therapy 
CNS 
Clinical Nurse Specialist 
PROMs 
Patient related outcome measures 
 
 

28 
 
3 
STUDY FLOWCHART 
 

29 
 
4 
SUMMARY OF STUDY 
 
4.1 
Plain English Summary 
Malignant pleural mesothelioma (MPM) is an aggressive, strongly associated with asbestos 
exposure. It most frequently affects the lining of the lung (pleura), but can also affect the other parts 
of the body, including the lining of the heart and abdomen. The incidence of MPM has been 
increasing over the last decade, despite legislative control of industrial asbestos use, due to a long 
latency period between initial exposure and development of the disease, and is predicted to 
continue to increase over the next 5 – 10 years.  
Patients with MPM often experience troublesome symptoms including breathlessness, pain and 
fatigue. They can also experience anxiety and depression and feel like their quality of life is worse 
than before they were diagnosed. Sarcopaenia is a complex condition, where there is an interplay 
between inflammation and cancer, which ultimately results in low skeletal muscle mass. 
Malnutrition and sarcopaenia is common in individuals with MPM, and is associated with worse 
outcomes, including in those who get chemotherapy.  
Unfortunately, the average life expectancy following a diagnosis of mesothelioma is approximately 
12 months. Currently, treatment in patients who are fit enough is aimed at prolonging this life 
expectancy, and involves drug treatment in the form of either chemotherapy or more recently 
immunotherapy. Whether a person with mesothelioma receive this treatment can depend on their 
physical fitness. 
Exercise Therapy 
Improving health-related quality of life (HRQoL) and physical fitness is a key goal for all patients with 
MPM, and maximising treatment opportunity has never been more important, following the recent 
approval of immunotherapy for the treatment of MPM across the UK. Exercise therapy is a rational 
approach to improving HRQoL and could also improve and/or maintain physical fitness to allow more 
patients to ultimately receive treatment. There is a growing body of evidence that exercise therapy 
in other cancers, such as lung cancer, can improve cardio-respiratory fitness, muscle mass, muscle 
strength, anxiety levels and HRQoL. Exercise may also have a role in breaking the vicious cycle of 
cancer, inflammation and sarcopaenia. The Prehab4Cancer programme is a successful initiative 
launched in Greater Manchester for patients with lung cancer. Patients who take part in the 
programme have reported improvement in their functional fitness and quality of life. We also know 
that home-based rehabilitation programmes are safe in patients with MPM. However, there is no 
evidence on the potential benefits of a tailored exercise and nutritional support intervention in 
mesothelioma. This is the focus of the current study and a planned future phase 3 trial. 
EXTRA-Meso Feasibility Study 
An exercise intervention study such as this one has never been done in mesothelioma. Before 
planning a larger phase 3 randomised controlled trial, we are conducting a smaller study to ensure 
that running an exercise trial in patients with mesothelioma is feasible. This study will determine this 
feasibility, the number of centres that will likely be needed to recruit to a larger study and define the 
optimum duration and format of the exercise intervention itself. 

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4.2 
Scientific Summary 
High symptom burden, anxiety and depression are common in Malignant Pleural Mesothelioma 
(MPM), even in those with good performance status (PS). (1,2) Patients with MPM often report poor 
health-related quality of life (HRQOL), which is itself, associated with poorer survival. (3,4) The 
treatment of MPM typically involves systemic anti-cancer therapy (SACT), receipt of which may be 
associated with better maintenance of HRQoL compared with those who decline, as previously 
reported in the SWAMP trial. (5) However, chemotherapy uptake in MPM is low, often due to 
reduced physical fitness in patients who are frequently in their 7th or 8th decade of life.   
Maximising HRQoL is a key goal for all MPM patients and maximising treatment opportunity has 
never been more important, following the recent approval of combination immunotherapy, 
regardless of histology, across the UK. Combination nivolumab and ipilimumab significantly improves 
overall survival in unresectable MPM compared to standard chemotherapy in the first-line setting. 
(6) This survival benefit appears amplified in patients with non-epithelioid histology, with 
maintenance or improvement in HRQOL in responding patients. (7) This is particularly important in 
this sub-group, in whom standard chemotherapy is rarely effective and symptom burden is 
frequently high with poor HRQOL. (5)  
Exercise therapy is a rational approach to improving HRQOL and could also maximise treatment 
opportunities in MPM. This reflects a growing body of evidence for exercise interventions in other 
cancers and particular features of deconditioning associated with MPM recently identified by our 
group. In non-small cell lung cancer (NSCLC), pre-operative exercise therapy in patients undergoing 
resection is associated with improved cardio-respiratory fitness, reduced post-operative 
complications and improved HRQOL. (8) Olivier et al also reported that a home pulmonary 
rehabilitation programme was safe and feasible in patients with lung cancer and a small number of 
patients with MPM (n=17). (9) Our group has recently reported that low skeletal muscle mass 
(sarcopaenia), a feature of the cancer cachexia syndrome is independently associated with adverse 
survival. This effect was more marked on in thoracic musculature ipsilateral to the tumour (10) and 
was observed if sarcopaenia was present prior to starting chemotherapy and if patients lost skeletal 
muscle mass during treatment. (11) These features suggesting a dynamic deconditioning effect, 
driven directly by MPM, which could be predicted and modified to improve outcomes. In these 
studies, the presence of sarcopaenia was also notably associated with systemic inflammation. (11) 
A recent systematic review and meta-analysis has confirmed poorer progression-free survival and 
overall survival in patients with sarcopaenia pre-immunotherapy in solid tumours including lung 
cancer and melanoma. (12) In MPM, malnutrition and ‘pre-sarcopaenia’ has previously been 
reported in 38% and 54% respectively, with lower activity levels in pre-sarcopenic patients. (13) 
Exercise intervention in patients with sarcopaenia may improve muscle mass, muscle strength and 
physical performance. (14) There is also evidence that exercise may have a role in breaking the 
vicious cycle of cancer, inflammation and cachexia (15). Furthermore, there is evidence that exercise 
improves quality of life and reduces anxiety in patients with other cancers. (16,17) The ‘Prehab 4 
Cancer’ programme, which this study will be utilising, reported improvements in functional fitness 
and quality of life in patients with NSCLC. (18) However, there is no evidence regarding the potential 

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benefits of a tailored exercise and nutritional support intervention in mesothelioma. This is the focus 
of the current study and the planned future phase 3 trial. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objective 
 To determine the feasibility of recruiting patients with mesothelioma to an exercise therapy 
study 
5.2 
Secondary Objectives 
 To determine barriers to study recruitment 
 To determine barriers to study retention 
 To determine safety and tolerability of the exercise intervention and study assessments 
6 
STUDY DESIGN 
This study is a prospective randomised feasibility study, randomising patients 1:1 to exercise therapy 
intervention versus standard care.  
6.1 
Study Setting 
Patients will be recruited from two mesothelioma centres, the NHS Greater Glasgow and Clyde 
Glasgow Pleural Disease Unit and Wythenshawe Hospital, Manchester NHS Foundation Trust. These 
two centres have high rates of mesothelioma. The West of Scotland (WoS) has had between 65 – 75 
new diagnoses of mesothelioma per year over the last 3 years (data from the Scottish National 
Mesothelioma MDT). Similarly, Greater Manchester have seen approximately 50 cases of 
mesothelioma per year between 2016 – 2018 (data from the National Mesothelioma Audit). The 
Glasgow Pleural Disease Unit hosts the Scottish National Mesothelioma MDT, where cases across 
Scotland are discussed. Wythenshawe Hospital hosts the Greater Manchester regional 
mesothelioma MDT. This set up at both recruiting centres ensures that all patients diagnosed within 
the West of Scotland or Greater Manchester can be considered for this trial. Both centres have 
successfully collaborated on numerous research studies, have a proven track record in recruiting 
patients to mesothelioma trials and have appropriate research infrastructure in place to deliver this 
study. 
6.2 
Study Population 
6.2.1 Inclusion Criteria 
1. Diagnosis of mesothelioma ratified by Mesothelioma MDT 
2. ECOG performance status (PS) 0 – 2  
3. Clinical Frailty Score (CFS) ≤5 
4. Informed consent 
6.2.2 Exclusion Criteria 
1. ECOG Performance Status >2 

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2. Clinical Frailty Score ≥6 
3. Unlikely to be able to participate in an exercise programme (clinician/physiotherapist 
judgement) 
6.2.3 Identification of participants and consent 
Patients will be screened at the respective mesothelioma MDTs and/or identified at respiratory 
and/or oncology outpatient clinics and/or at inpatient review.  Potential participants who meet the 
eligibility criteria will be approached by a member of the study team. If interested, the patient will 
be provided with the study Patient Information Sheet (PIS) and given sufficient time to read it, 
discuss with their family, if they wish, and ask questions before being invited to provide informed 
written consent to enrol in the study. If a patient has a virtual (telephone or video) appointment, 
remote “witnessed verbal consent” can be taken. For witnessed verbal consent to be valid, the 
participant must be witnessed by two members of the research team to agree to each point of the 
consent form. Both research team members must then sign the consent form and indicate on the 
form that the consent was taken remotely. All consent documentation will be scanned into the 
patient’s clinical notes. Detailed screening logs will be kept to record reasons for non-enrolment. 
Should the patient read the patient information sheet but decline to take part, they may be asked to 
consent to a semi-structured interview with a member of the study team, to explore their reasons 
for declining to participate, in order to inform future study design. Potential participants who decline 
to participate will be signposted to locally available community activities and services that are 
available to promote long-term health improvement if they wish. There is no time limit on time of 
diagnosis to study enrolment.  
 
6.3 
Sample size calculation  
The current feasibility study will aim to recruit 40 patients. No formal sample size is feasible or 
appropriate, but this number is sufficient to allow identification of barriers to recruitment and 
retention (the latter informing the likely drop-out rate for the future phase 3 trial) and the duration 
and design of the exercise therapy intervention.  
The primary objective of the future phase 3 trial will be to determine whether exercise therapy 
results in a clinically meaningful improvement in HRQOL at 16 weeks post-randomisation. Assuming 
a mean population score of 60 (SD 20) based on QoL scores previously reported in other 
mesothelioma studies, we currently estimate that a sample size of 84 patients in each arm is 
required to detect a 10-point improvement in EORTC QLQ C30 quality of life scores, with 90% power 
at 5% two-sided significance level. With a currently assumed 25% drop-out rate, based on the 
‘Prehab4Cancer’ dropout rate in patients with NSCLC, we estimate that we would require a total 
sample size of 224 patients.  Data from the current feasibility study will (a) provide a more robust 
estimate of baseline mean HRQOL score (based on the population score recorded from all patients at 
baseline assessment), (b) allow a more precise estimate of drop-out rate based on an optimised 
exercise intervention and (c) allow us to calculate the number of centres needed based on the 
recruitment rate achieved. 
 

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6.4 
Co-enrolment guidelines 
Patients may not be entered into any other clinical trial that aims to deploy an exercise programme 
for the duration of their participation within the study. Access to trials of systemic anti-cancer 
therapies, radiotherapy or surgery is permitted.  
 
6.5 
Withdrawal of patients from the study 
Patients will be withdrawn from the study if any of the following occur: 
 Patient withdrawal of consent 
 Clinical opinion of the doctor that the patient should withdraw 
If a patient moves to another area during the trial follow-up period, efforts will be made to complete 
follow-up in conjunction with the new primary physician / team or general practitioner. 
7 
BASELINE ASSESSMENT 
Having provided written or witnessed verbal informed consent to participate in the study, 
participants will all undergo the same baseline assessment. This will include recording of: 
 Patient demographics, disease characteristics, including subtype and stage, co-morbidities 
and medication history (including current or prior systemic anti-cancer therapy). 
 Routine blood results, including full blood count (FBC), C-reactive protein (CRP) and albumin 
  Body Mass Index (BMI) and malnutrition universal screening tool (MUST) score 
 Functional fitness measurements in the form of: 
o Hand grip strength 
o 6 minute walk distance (6MWD) 
o 30 second sit-to-stand (STS) test 
 Patient related outcome measures (PROMs) via completion of the following questionnaires 
related to HRQoL, wellbeing and symptoms: 
o Euroquol quality of life survey (EQ-5D-5L) 
o 36-item short form survey (SF-36) 
o European organisation for research and treatment of cancer (EORTC) QLQ-C30 
o Hospital Anxiety and Depression Scale (HADS) 
o Short Warwick Edinburgh Mental Wellbeing Scale ((S)WEMWBS) 
 Presence/absence of features of sarcopaenia utilising: 
o Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-
F) screening questionnaire 

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o Skeletal muscle area and visceral fat index measurements on routinely-acquired 
clinical CT scan within the preceding 3 months  
8 
RANDOMISATION 
Randomisation should occur immediately after baseline assessment has been completed. Eligible 
participants will be randomly allocated using an online system (sealed envelope) to either ‘Standard 
Care’ or ‘Exercise Therapy’ in a 1:1 ratio using random permuted blocks. Randomisation will be 
performed using an online system (sealedenvelope.com).  
9 
POST-RANDOMISATION 
9.1 
Standard Care Arm 
Participants randomised to Standard Care will undergo routine clinical follow-up. Refer to schedule 
of assessments. Relevant clinical updates, including hospital admissions and any treatment updates 
(e.g. commencement or discontinuation of SACT) will be recorded at 8, 16 and 26 weeks post-
randomisation. Participants will complete the questionnaires as per the above PROMs performed at 
their baseline assessment visit at 8, 16 and 26 weeks post-randomisation. If required, questionnaires 
can be posted out to patients and returned to the study team using a pre-paid addressed envelope. 
Study members can assist participants with completion of these questionnaires remotely if required. 
A study visit will be arranged at week 16 post randomisation to repeat functional fitness 
measurements as detailed above. Wherever possible, this study visit will be co-ordinated with the 
patient’s routine clinic appointment. If the patient has had any follow-up CT scans performed as part 
of their routine clinical care during their study follow-up period, this will be reviewed to measure 
total skeletal muscle area and visceral fat index.  If their MUST score indicates malnourishment at 
baseline assessment, a referral to NHS dietetic services will be made.  During the follow-up period, 
patients will be sign-posted to local community activities and services that are available to promote 
long-term health improvement. It will be made clear to participants within the standard care arm 
that they are free to undertake exercise or increased physical activity if they wish. Any increase in 
exercise activity or participation in local generic community exercise programmes will be recorded at 
follow-up visits.   
9.2 
Exercise Therapy (Intervention) Arm  
Participants randomised to the Exercise Therapy arm will undergo an individualised assessment by 
either a physiotherapist or a qualified exercise professional with specialist cancer training, either in 
hospital or in the community. Refer to schedule of assessments. Following this initial assessment, 
patients will receive a personalised exercise, wellbeing and nutritional support package. The exercise 
programme will incorporate 3 sessions per week. One session per week will be supported by the 
physiotherapist or qualified exercise professional and the other 2 sessions will be independent 
sessions done in the participant’s own home or local health club/gym if available. The total duration 
of the programme is 12 weeks. The exercise programme will incorporate both cardiovascular and 
resistance training, and will be progressive throughout the duration of the programme. The exercise 
programme will be tailored to take into account the participant’s current level of fitness and 
familiarity/confidence with exercise, available equipment and injuries. Participants will be given a 
diary to record completion of each exercise session. If their MUST score indicates malnourishment at 
baseline assessment, a referral to NHS dietetic services will be made. 

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Relevant clinical updates, including hospital admissions and any treatment updates (e.g. 
commencement or discontinuation of SACT) will be recorded at 8, 16 and 26 weeks post-
randomisation. Participants will complete the questionnaires as per the above PROMs performed at 
their baseline assessment visit at 8, 16 and 26 weeks post-randomisation. If required, questionnaires 
can be posted out to patients and returned to the study team using a pre-paid addressed envelope. 
Study members can assist participants with completion of these questionnaires remotely if required. 
A study visit will be arranged at week 16 post randomisation to repeat functional fitness 
measurements as detailed above. Wherever possible, this study visit will be co-ordinated with the 
patient’s routine clinic appointment. If the patient has had any follow-up CT scans performed as part 
of their routine clinical care during their study follow-up period, this will be reviewed to measure 
total skeletal muscle area and visceral fat index.  During the follow-up period, patients will be sign-
posted to local community activities and services that are available to promote long-term health 
improvement. 
Any clinical concerns arising during the exercise programme will be highlighted to the patient’s 
clinical team via the mesothelioma CNS.  
9.3 Semi-structured Interviews 
Up to five patients who were deemed as potentially eligible at screening, read the patient 
information sheet but decline to participate will be invited to participate in a semi-structured 
interview to explore their reasons for declining to participate, in order to determine barriers to 
recruitment.  
A further 10 – 20 study participants, including participants who drop-out of the study before 
completion and those who complete the study, will be invited to a semi-structured interview to 
examine their views on the randomisation process, the exercise therapy intervention, study outcome 
measures (including the functional fitness assessments and questionnaires) and follow-up, in order 
to determine barriers to study retention and inform design of the phase 3 study.  
Interviews can be conducted in person, ideally co-ordinated with a routine clinic appointment, or 
remotely. Audio recordings will be transcribed and anonymised audio transcriptions will be reviewed 
for qualitative analysis at the University of Surrey. 

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9.4 Schedule of Assessments 
Visit 
Pre-
screening Baseline 
Week 1 
(+/- 7 
days) 
Week 8 
(+/- 2 
wks) 
Week 
16 (+/- 
3 wks) 
Week 26 
(+/- 4 
wks) 
Routine Clinical Activity 
Mesothelioma MDT review 
X 
  
  
  
  
  
Outpatient clinic review 
  
X 
  
  
  
  
Contrast CT thorax 
X 
  
  
  
  
X 
Routine clinical follow-up 
  
  
  
X 
X 
X 
Study Activity 
Review eligibility criteria 
  
X 
  
  
  
  
If eligible, introduce study and provide PIS 
  
X 
  
  
  
  
Informed written consent 
  
X 
  
  
  
  
Study registration 
  
X 
  
  
  
  
Record baseline data 
  
X 
  
  
  
  
Complete HRQoL questionnaires1 
  
X 
  
  
  
  
Functional fitness assessment2 
  
X 
  
  
  
  
SARC-F screening questionnaire 
  
X 
  
  
  
  
Review recent# CT for total skeletal muscle 
area and visceral fat index 
  
X 
  
  
  
  
Record BMI + MUST score 
  
X 
  
  
  
  
Randomisation 
  
X 
  
  
  
  
Remote qualitative Interview (optional) 
  
  
  
  
X 
X* 
   Post-randomisation standard of care arm 
Record relevant clinical and/or physical 
activity updates 
  
  
  
X 
X 
X 
Complete HRQoL/wellbeing questionnaires1 
  
  
  
X 
X 
X 
Functional fitness assessment2 
  
  
  
  
X 
  
Review follow-up CT for total skeletal 
muscle area and visceral fat index 
  
  
  
  
  
X 
   Post-randomisation intervention arm 
Record relevant clinical updates 
  
  
  
X 
X 
X 
Physiotherapist/exercise professional 
assessment 
  
  
X 
  
  
  
Commence 12 week exercise programme 
  
  
X 
  
  
  
Complete HRQoL/wellbeing questionnaires1 
  
  
  
X 
X 
X 
Review exercise session attendance and 
exercise compliance 
  
  
  
X 
X 
X 
Functional fitness assessment2 
  
  
  
  
X 
  
Review follow-up CT for total skeletal 
muscle area and visceral fat index 
  
  
  
  
  
X 
Record adverse events 
  
  
  
X 
X 
  
1EQ-5D, SF-36, HADS, (S)WEBWMS and EORTC QLQ-C30 questionnaires, can be returned by post if no F2F routine clinical visit scheduled 
230 seconds sit-to-stand test, 6 minute walk test and hand grip strength 
#Within preceding 3 months 
*If not previously done 

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10 STATISTICAL ANALYSIS PLAN 
We will use descriptive statistics to describe the demographics and clinical characteristics of the study 
population. Means (with standard deviations) or medians (with inter-quartile ranges) will be used to 
summarise continuous variables, depending on their distribution and proportions to summarise 
categorical variables.  
Total recruitment, recruitment rate, study drop-out rate and intervention adherence rate will be 
reported by simple descriptive statistics, or proportions where appropriate.  
Semi-structured interviews will be analysed using Framework Analysis19, which will involve a five-step 
process: 
1. Familiarisation with the data 
2. Identifying a thematic framework 
3. Indexing 
4. Charting 
5. Mapping and interpretation 
The analysis will be predominantly deductive, as it will specifically focus on facilitators and barriers to 
study retention, and to the uptake and experience of the exercise intervention.  
11 END OF TRIAL 
Trial recruitment will terminate either 12 months after opening or after 40 patients have been 
recruited, whichever is soonest. Trial participation will cease once the final patient has completed their 
26-week follow-up. 
12 SAFETY REPORTING 
All Adverse Events will be reported directly to the sponsor. 
12.1 Adverse Event (AE) 
An adverse event is any untoward medical occurrence that the patient experiences whilst participating 
in the clinical trial. This includes occurrences that are not necessarily caused by or related to the trial 
intervention. 
12.2 Serious Adverse Event (SAE)  
A serious adverse event (SAE) is defined as any of the following, whether or not considered related to 
the trial intervention. 
 Results in Death 
 Life-threatening (i.e. at the time of the event)* 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation** 
 Results in persistent or significant disability or incapacity 

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 Is a congenital anomaly/birth defect 
 Is considered medically significant by the Investigator*** 
*Life threatening means that the patient was at immediate risk of death from the event as it occurred. 
It does not include an event that, had it occurred in a more serious form, might have caused death. 
**Requires in-patient hospitalisation should be defined as a hospital admission required for treatment 
of an adverse event. 
***Considered medically significant by the Investigator are events that may not result in death, are 
not life threatening, or do not require hospitalisation, but may be considered a serious adverse 
experience when, based upon appropriate medical judgement, the event may jeopardise the patient 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
12.3 SAEs Related to Study Procedures 
Related SAEs will be any SAE that is reported as possibly, probably or definitely related to the 
prescribed exercise programme. See below for all definitions for the relationship to the protocol 
intervention. 
Relationship 
 
Description 
Unrelated 
There is no evidence of any causal relationship 
 
Possible 
There is some evidence to suggest a causal relationship (e.g. the 
event occurs within a reasonable time after administration of the 
trial intervention) However the influence of other factors may 
have been contributed to the event (e.g. the patient’s clinical 
condition, other concomitant treatments) 
Probable 
There is evidence to suggest a causal relationship and the 
influence of other factors in unlikely 
Definitely 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out 
 
12.4 Adverse Event Recording and Reporting  
All AEs must be recorded on the patient’s medical records. AEs must be recorded as they are reported 
during the visit. Full details of AEs including the nature of the event, start and stop dates, severity, 
relationship to study intervention and outcome must be recorded. AEs must be followed until 
resolution, or for at least 30 days after the trial intervention, whichever comes first or until toxicity 
has resolved to baseline or ≤ Grade 1, or until the toxicity is considered to be irreversible. Perceived 

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lack of efficacy is not an AE. An exacerbation of a pre-existing condition is an AE. 
12.5 Expected Adverse Events 
12.5.1 Exercise Therapy 
Common (1 in 10 to 1/100) 
 Fatigue 
 Musculoskeletal injury 
 Joint pain 
 Muscle soreness 
Rare (<1/100,000) 
 Cardiac event such as heart attack or heart rhythm disorder 
 
13 FEASIBILITY STUDY METRICS 
Feasibility success metrics collected during this study  on recruitment and adherence to study intervention, 
defined as completion of ≥18 exercise sessions across the 12 week programme) will determine if it is feasible to 
proceed to a phase 3 randomised trial and defined as: 
- Green (proceed with no/minor changes to study design) 
- Amber (significant changes to study design before proceeding) 
- Red (do not proceed) 
Status 
Total Study Recruitment 
Adherence to study intervention 
Green 
≥ 20 patients 
≥ 50% patients 
Amber 
5 – 19 patients 
10 – 49% patients 
Red 
< 5 patients 
< 10% patients 
 
14 COMPLIANCE, AUDIT AND PROTOCOL DEVIATIONS 
14.1 Good Clinical Practice 
This study will be conducted in accordance with the protocol, the Sponsor’s standard operating 
procedures, national regulatory requirements, provisions of the relevant ethics committees and 
Good Clinical Practice (GCP) principles. 
14.2 Audits 
The study may be subject to audit by NHS Greater Glasgow and Clyde under their remit as Sponsor. 

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14.3 Protocol Deviation Reporting 
A protocol deviation is any departure from the approved protocol. All deviations will be recorded 
and reported to the sponsor. The sponsor will not authorize prospective protocol 
deviations/waivers, unless the deviation is necessary to eliminate and immediate hazard.  
 
15 PATIENT AND PUBLIC INVOLVEMENT 
 
A group of patients with mesothelioma and relatives of patients who have previously been diagnosed with 
mesothelioma were consulted for their views on the overall study premise and study design. Patient facing 
documentation was also reviewed by these two groups.  
 
16 DATA HANDLING 
Data generated by the study will be stored in a linked anonymised fashion in a password-protected 
computer. Subject paper notes will be stored in a locked filing cabinet in a locked office of a secure 
building.  
16.1 Case Report Forms 
Entries to the CRFs will be made in black ballpoint pen and must be legible. Any errors must be 
crossed out with a single stroke, the correction inserted and the change initialled and dated by the 
Investigator. Correction fluid must not be used. All data submitted on CRFs are verifiable in the 
source documentation or that any discrepancies are recorded and explained. 
Trial sites should keep a copy of all completed CRFs. The original CRFs should be returned to the 
Pleural Disease Unit, Queen Elizabeth University Hospital for data entry and computation of relevant 
end-points and ultimately, statistical analysis. CRFs from the trial will be stored in line with current 
regulatory requirements. Other essential documents, including source data, consent forms, and 
regulatory documentation, will be archived by the Investigator, in an appropriate archive facility in 
line with current regulatory requirements and made available for monitoring, audit and regulatory 
inspection as required.16. Study Closure / Definition of End of Trial 
The end of the trial should be outlined clearly, below is sample text. 
The study will end when the steering committee agrees that one or more of the following situations applies: 
 
Last patient last study visit; 
OR 
i. 
The planned sample size has been achieved; 
ii. 
The Independent Data Monitoring Committee has advised discontinuation, e.g. because of safety 
concerns about the trial, or a statistically significant difference in clinical outcomes is evident between 
the two treatment arms; 
iii. 
There is insufficient funding to support further recruitment, and no reasonable prospect of additional 
support being obtained; 

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iv. 
New information makes it inappropriate to continue to randomise patients to one or other arm of the 
trial; 
Recruitment is so poor that completion of the trial cannot reasonably be anticipated 
 
17. Protocol Amendments 
Any change in the study protocol will require an amendment.  Any proposed protocol amendments 
will be initiated by the CI following discussion with the Sponsor and any required amendment forms 
will be submitted to the, ethics committee and sponsor.  The CI will liaise with study sponsor to 
determine whether an amendment is non-substantial or substantial.  All amended versions of the 
protocol will be signed by the CI and Sponsor representative.  Before the amended protocol can be 
implemented favourable opinion/approval must be sought from the original reviewing REC and 
Research and Development (R&D) office(s). 
17. Ethical Consideration 
The study will be carried out in accordance with the World Medical Association Declaration of Helsinki 
(1964) and its revisions. 
Favourable ethical opinion will be sought from an appropriate REC before patients are entered into 
this clinical trial.  Patients will only be allowed to enter the study once either they have provided 
written informed consent. The CI will be responsible for updating the Ethics committee of any new 
information related to the study. 
17. Finance and Indemnity 
 
Brief details on how the study is funded should be included here. 
 
NHS employed researchers will be covered for negligent harm through the NHS CNORIS indemnity 
scheme. If you are a University employee you may need extra cover for non-negligent harm through 
your University. Please check this with your Research and Enterprise department. 
 
Example text: The XXX study is sponsored by NHS Greater Glasgow & Clyde.  The sponsor will be 
liable for negligent harm caused by the design of the trial.  NHS indemnity is provided under the 
Clinical Negligence and Other Risks Indemnity Scheme (CNORIS). 
17. Publications 

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Study results whether, negative or positive, should be disseminated.  Details of your plan for 
dissemination should be included here. 
 
 

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18 . REFERENCES 
 
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