A Randomised Controlled Trial to Evaluate the Impact of Thoracic PRehabilitation With Inspiratory Muscle tRaining cOmpared to Standard prEhabilitation in People With Lung Cancer for Surgical Treatment . The PRIMROSE Trial
Phase: NA
Conditions: Cancer, Lung Resection, Inspiratory Muscle Training, Prehabilitation, Respiratory Complications, Length of Hospital Stay
Sponsor: Swansea Bay University Health Board

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It is a requirement of Good Clinical Practice (GCP) and the Research Governance 
Framework for Health & Social Care 2017, that all research projects have a 
scientifically sound and ethically valid protocol.  
 
The protocol is the starting point of any high quality research and all research studies 
must be conducted according to the protocol. A protocol provides written evidence 
for the necessity and feasibility of a study, as well as giving a detailed plan of 
investigation.  
 
This document is to be submitted for approval to a Research Ethics Committee (REC). 
This allows the ethical and peer review processes to validate the scientific and ethical 
considerations of the study. The guidance detailed below is for Clinical Trials of Non 
Investigational Medicinal Products (Non CTIMPs). 
 
 

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TITLE OF THE PROTOCOL: A randomised controlled trial to evaluate the impact of 
thoracic PRehabilitation with Inspiratory Muscle tRaining cOmpared to Standard 
prEhabilitation in surgical lung cancer patients. 
 
Short title/Acronym: PRIMROSE Trial 
  
 
 
 
Representative of the Sponsor: 
 
 
 
Lisa Wakeman 
 
Research Governance Manager 
R and D Department 
 
Lisa.wakeman@wales.nhs.uk 
 
 
 
Address:  
 
Swansea Bay University Health Board 
1st floor, Institute of Life Science 2 
Swansea University 
Singleton Park 
SA2 8PP 
 
 
 
IRAS number:  
341315 
REC reference: 
Insert once known 
 
 

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STUDY SUMMARY/SYNOPSIS 
 
TITLE 
A randomised controlled trial to evaluate the impact of 
thoracic PRehabilitation with Inspiratory Muscle tRaining 
cOmpared to Standard prEhabilitation in surgical lung 
cancer patients. 
 
SHORT TITLE 
PRIMROSE Trial 
Protocol Version 
Number and Date 
 
Standard Protocol Version Number 3.5 and date 03/02/25 
 
Methodology 
 
Type of study: randomised control trial 
 
Study Duration 
Two years  
Study Centre 
Cardiothoracic centre, Morriston Hospital 
Objectives 
 
To compare inspiratory muscle training (IMT) with 
standard Prehabilitation (Prehab) to Prehab alone, in lung 
cancer patients for surgery. 
Number of 
Subjects/Patients 
One hundred and thirty-four patients will be recruited for 
the study (67 for each arm) and with an anticipated 
attrition rate of 20-25%, one hundred patients will finally 
be studied. 
Main Inclusion Criteria 
 
All adult lung cancer patients > 18 years diagnosed or 
suspected of non-small cell lung cancer (NSCLC) with 
surgically resectable disease, who are referred for pre-
treatment optimization with Prehab from the lung cancer 
Multi-Disciplinary Teams (MDTs) across South West 
Wales (Swansea lung MDTs, the Hywel Dda lung MDTs 
and Princess of Wales lung MDT).  
Lung cancer patient are referred for pre-treatment 
optimization with Prehab if they meet the following referral 
criteria:  ≥1 Medical Research Council (MRC) dyspnoea 
score; 
or 
≥1 
World 
Health 
Organization 
(WHO) 

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performance status (PS); age ≥ 70 years or frailty index >3; 
borderline or poor pulmonary function (forced expiratory 
volume in one second (FEV1) or diffusion capacity for 
carbon monoxide (DLCO) <50%); sedentary patients 
despite having adequate FEV1 or DLCO. Patients will be 
included in the trial if they are capable of giving consent to 
participation and aged 18 and over. 
Additionally, patients who have no contraindications to IMT 
use. 
Statistical 
Methodology and 
Analysis 
 
Our aim is to evaluate the impact of thoracic Prehab with 
IMT compared to standard Prehab in reducing post 
operative pulmonary complications following surgical 
resection in lung cancer patients in a RCT.  
Descriptive statistics will be used to summarise 
participants’ characteristics and outcome measures.  
Statistical analyses will be performed using SPSS 
statistical software, version 20.0 (IBM Corporation, 
Armonk, NY, USA). Two-sided significance tests will be 
used (a\0.05). Data will be presented as mean and 
standard deviation (SD), or median and interquartile range 
(IQR) for variables with a skewed distribution. Differences 
between groups in categorical variables will be tested with 
Chi square or Fisher’s exact test. For continuous data the 
student’s t test or the Mann–Whitney U test will be used. 
The Wilcoxon signed rank test will be used to compare 
MIP and QoL at T0 and T1 and T2. Relative risk will be 
calculated for post operative pulmonary complications 
(PPCs) graded 1-V using the Clavien Dindo classification 
and impact of IMT on the study group compared to the 
control group. Assuming a 36.7 incidence of PPC after 
surgery in the control arm and using a significance level of 
0.05 and a power of 80%, 50 patients are required in each 
arm. 
 

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Protocol Agreement Page 
 
The clinical study as detailed within this research protocol (Version 3.7, dated 05/06/25), or 
any subsequent amendments will be conducted in accordance with the Research 
Governance Framework for Health & Social Care (2005), the World Medical Association 
Declaration of Helsinki (1996) and the current applicable regulatory requirements and any 
subsequent amendments of the appropriate regulations. 
 
Chief Investigator Name: Professor Ira Goldsmith 
Chief Investigator Site: Swansea Bay University Health Board 
Contact details:  
Tel No: 01792 704084 
 
 
 
Email: Ira.Goldsmith@wales.nhs.uk 
Signature and Date:   Ira Goldsmith   05/06/25 
                        
 
 
Principal Investigator Name: Tracy Jones 
Principal Investigator Site: Swansea Bay University Health Board 
Contact details:  
Tel No: 01792 702222 ext 23670 
 
 
 
Email: tracy.jones6@wales.nhs.uk 
Signature and Date: T.M. Jones 05/06/25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Glossary of Terms and Abbreviations 
 
AE 
 
 
Adverse Event 
 
 
AR 
 
 
Adverse Reaction 
ASR 
 
 
Annual Safety Report 
BACPR 
 
British Association for Cardiovascular Prevention and Rehabilitation 
CA 
 
 
Competent Authority 
CI 
 
 
Chief Investigator 
COPD  
 
Chronic Obstructive Pulmonary Disease 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organisation 
DLCO  
 
Diffusion capacity for carbon monoxide 
DMC  
 
Data Monitoring Committee 
EC 
 
 
European Commission 
EORTC 
 
European Organization for Research and Treatment of Cancer 
FEV1  
 
Forced expiratory volume in one second 
FITT 
 
 
Frequency, Intensity, Type and Time principles of training 
GAfREC 
Governance Arrangements for NHS Research Ethics Committees 
GCP 
Good Clinical Research Practice 
HLOS 
Hospital length of stay 
HRQol 
Health related quality of life  
IASLC  
International Association for the Study of Lung Cancer 
ICF 
 
 
Informed Consent Form 
IQR 
 
 
Interquartile range 
IMT 
 
 
Inspiratory muscle trainer 
IS 
 
 
Incentive spirometry 
IP 
 
 
Intellectual Property 
ISRCTN 
 
International Standard Randomised Controlled Trial Number 
LHC 
 
 
Lung Health Check 
LOA 
 
 
Levels of activity 
LOHS  
 
Length of hospital stay 
MDT 
 
 
Multi-Disciplinary team 
MIP 
 
 
Maximal Inspiratory Pressure 
MRC  
 
Medical Research Council dyspnoea score  
Main REC 
 
Main Research Ethics Committee 

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NHS 
 
 
National Health Service 
NHS R&D 
 
National Health Service Research & Development  
NICE   
 
National Institute for Health and Care Excellence 
NSCLC 
 
Non-small cell lung cancer 
PI 
 
 
Principle Investigator 
PIS 
 
 
Patient Information Sheet 
PPI 
 
 
Patient and public involvement representatives 
PPC 
 
 
Post-operative pulmonary complication 
Prehab 
 
Thoracic Prehab Programme 
PREM  
 
Patient reported experience measure  
PROM  
 
Patient reported outcome measure 
PS 
 
 
World Health Organization Performance Status 
QA 
 
 
Quality Assurance 
QALY  
 
Quality adjusted life years 
QC 
 
 
Quality Control 
QOL 
 
 
Quality of life 
Participant 
 
An individual who takes part in a clinical trial 
RCT 
 
 
Randomised Controlled Trial 
REC 
 
 
Research Ethics Committee 
REDCap 
 
Research Electronic Data Capture 
SAE 
 
 
Serious Adverse Event 
SBUHB 
 
Swansea Bay University Health Board 
SCTC  
 
Society of Cardiothoracic Surgery 
SDV 
 
 
Source Document Verification 
SOP 
 
 
Standard Operating Procedure  
SSA 
 
 
Site Specific Assessment 
TMG  
 
Trial Management Group 
TSC 
 
 
Trial Steering Committee 
UK 
 
 
United Kingdom 
WHO  
 
World Health Organization 
6MWT  
 
6 minute walk test  
 
 
 

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Content 
 
1. 
Introduction .................................................................................................................. 11 
1.1. Background .............................................................................................................. 11 
1.2. Preclinical Data ......................................................................................................... 12 
1.3. Clinical Data ............................................................................................................. 14 
1.4. Rationale and Risks/Benefits .................................................................................... 16 
2. 
Trial Objectives and Design ......................................................................................... 17 
2.1. Trial Objectives ......................................................................................................... 17 
2.2. Trial Design .............................................................................................................. 18 
2.3. Study Scheme Diagram ............................................................................................ 18 
2.4. Statistical Methodology and Analysis ........................................................................ 19 
2.4.1. Sample size, justification and calculations .......................................................... 19 
2.4.2. Analysis Plan ..................................................................................................... 21 
2.4.3. Project statistician / methods expert ................................................................... 21 
3. 
Subject Selection ......................................................................................................... 22 
3.1. Number of subjects and subject Selection ................................................................ 22 
3.2. Inclusion Criteria ....................................................................................................... 22 
3.3. Exclusion Criteria ...................................................................................................... 23 
3.4. Criteria for Premature Withdrawal ............................................................................. 23 
4. 
Study Procedures ........................................................................................................ 24 
4.1. Informed Consent Procedures .................................................................................. 24 
4.2. Screening Procedures .............................................................................................. 25 
4.3. Randomisation Procedures (if applicable) ................................................................. 26 
4.4. Schedule of Treatment for each visit ......................................................................... 26 
4.5. Schedule of Assessment (in Diagrammatic Format) ................................................. 28 
4.6. Follow up Procedures (if applicable) ......................................................................... 28 
4.7. Laboratory Assessments (if applicable) .................................................................... 28 
4.8. Radiology Assessments (if applicable) ..................................................................... 29 
4.9. End of Study Definition ............................................................................................. 29 
4.10. Procedures for unblinding (if applicable) ................................................................. 29 
4.11. Subject Withdrawal ................................................................................................. 29 
4.12. Data Collection and Follow up for Withdrawn Subjects ........................................... 29 
5. 
Safety Reporting .......................................................................................................... 30 
5.1. General Definitions ................................................................................................... 30 
5.1.1. Adverse Event (AE) ............................................................................................ 30 

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5.1.2. Serious Adverse Event (SAE) ............................................................................ 30 
6.1 Investigators Assessment .......................................................................................... 31 
6.1.1. Seriousness ....................................................................................................... 31 
6.1.2. Causality ............................................................................................................ 31 
6.1.3. Expectedness .................................................................................................... 31 
6.1.4. Severity .............................................................................................................. 31 
6.2. Notification and reporting Adverse Events or Reactions ........................................... 31 
6.3. Notification and Reporting of Serious Adverse Events .............................................. 32 
6.3.1. Serious Adverse Event (SAEs) ........................................................................... 32 
6.4. Urgent Safety Measures ........................................................................................... 32 
6.5. Annual Safety Reporting ........................................................................................... 32 
6.6. Procedures for reporting blinded ‘unexpected’ and related’ SAEs ............................. 32 
6.7. Overview of the Safety Reporting Process/Pharmacovigilance responsibilities ......... 32 
7. 
Statistical Considerations ............................................................................................. 32 
7.1. Primary Endpoint Efficacy Analysis ........................................................................... 32 
7.2. Secondary Endpoint Efficacy Analysis ...................................................................... 33 
7.3. Safety Endpoints ...................................................................................................... 33 
7.4. Sample Size ............................................................................................................. 33 
7.5. Statistical Analysis .................................................................................................... 33 
8. 
Data Management ....................................................................................................... 34 
8.1. Data collection .......................................................................................................... 34 
8.2. Data Systems ........................................................................................................... 34 
8.3. Data integrity ............................................................................................................ 34 
8.4. Data monitoring ........................................................................................................ 34 
8.5. Data archiving and destruction ................................................................................. 34 
9. 
Data Handling & Record Keeping ................................................................................ 35 
9.1. Confidentiality ........................................................................................................... 35 
9.2. Study Documents ..................................................................................................... 35 
9.3. Case Report Form .................................................................................................... 36 
9.4. Record Retention and Archiving ............................................................................... 36 
9.5. Compliance .............................................................................................................. 37 
9.6. Clinical Governance Issues ...................................................................................... 37 
9.6.1. Ethical Considerations........................................................................................ 37 
9.7. Quality Control and Quality Assurance ..................................................................... 37 
9.7.1. Summary Monitoring Plan .................................................................................. 37 
9.7.2. Audit and Inspection ........................................................................................... 37 

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9.8. Non-Compliance ....................................................................................................... 38 
10. 
Trial Committees ...................................................................................................... 39 
11. 
Intellectual Property .................................................................................................. 39 
12. 
Publication Policy ..................................................................................................... 40 
13.  
Wellbeing of Future Generations Act………………………………………………….….40 
14. 
References ............................................................................................................... 41 
15. 
Appendices .............................................................................................................. 44 
Appendix 1 – Information with regards to safety reporting in Non-CTIMP research. 
Page 45 to 46 
Appendix 2 – Source Identification List. Page 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Introduction 
 
1.1. Background 
 
Lung cancer is the most common cause of cancer-related deaths in Wales (1). Although 
surgical resection for early-stage lung cancer with curative intent remains the primary 
treatment, patients with significant smoking related underlying cardiopulmonary disease and 
impaired pulmonary function, dyspnoea, frailty and decreased activity levels are unfit for 
surgery and referred for alternative treatment (2,3). Secondly, individuals who proceed to 
lung resection, thoracic surgery and general anaesthesia may have direct effects on their 
respiratory system potentially leading to postoperative pulmonary complications (PPCs), 
which increases hospital morbidity, prolongs hospital length of stay (HLOS) impacts on the 
quality of life (QOL) of patients and adds to health-care costs (4). Our aim is to evaluate 
whether incorporating a breathing training device, POWERBreathe into the existing 
standardised thoracic prehabilitation program (Prehab) will optimise unfit patients physically 
for surgery, and following surgery reduce their risk of developing PPC's, reduce HLOS and 
improve QOL of patients and improve service outcomes (5). 
 
The PRIMROSE study aims to compare two groups of patients referred for Prehab who have 
lung cancer treatable with surgery: (A) standard Prehab and training with the inspiratory 
muscle training (IMT) device; and (B) standard Prehab alone, in non-small cell lung cancer 
patients (NSCLC) undergoing lung resection surgery, with clear primary and secondary 
outcome measures. 
 
One hundred and thirty-four patients will be recruited for the study (67 for each arm) and with 
an anticipated attrition rate of 25%, one hundred  patients will finally be studied (6,7). With 134 
recruited and an attrition rate of 25%, only 100 will remain (50 in each arm). The primary 
outcome measure tested will be the proportion of patients in each group experiencing 
postoperative pulmonary complications (PPC), which will be graded I-V using the Clavien 
Dindo Classification (8). PPCs will be broadly classified as minor (grade 1) and major 
complications (grade 2-5 where 5 is death). What we want to learn from this RCT study is 
whether IMT helps reduce grade ≥2 PPCs to either grade 1 or no complications and thereby 
help shorten the length of stay in hospital for patients undergoing lung resection surgery. 
Secondary outcome measures tested will be Medical Research Council (MRC) dyspnoea 
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thoracoscore, frailty index (FI), six-minute walk distance test distance (6MWD), maximum 
inspiratory pressure (MIP) and quality of life (QoL) data using the EORTC QLQ-30 
questionnaire (9). In addition, researchers will collect safety data on, complication rates, 
mortality and HLOS. The quality of Prehab delivery and outcomes will be closely monitored 
in accordance with good clinical practice in research guidelines.  
Plain English 
1.2. Preclinical Data 
Lung cancer treatment has complex and critical challenges as highlighted by The Welsh NHS 
Confederation (2015), the Welsh Government Parliamentary Review of Health and Social 
Care in Wales (2018) and A Healthier Wales (2018) (10,12). These include shifting 
demographics, an ever-ageing population and increased prevalence of complex and chronic 
conditions alongside fiscal constraints. For example, 63% of patients with lung cancer have 
chronic obstructive pulmonary disease (COPD), resulting in breathlessness and poor exercise 
tolerance and predispose surgical patients to post-operative pulmonary complications (PPC's) 
increased morbidity, longer hospital length of stays (HLOS) and mortality (4,13) 
Smoking accounts for about 90% of all lung cancer cases (13). Patients with resectable 
NSCLC may have smoking related underlying cardiopulmonary disease causing significant 
dyspnoea (due to impaired or poor pulmonary function), impaired performance status (PS) 
and impaired levels of activity (LOA) (14,15). Loss of lung tissue in deconditioned NSCLC 
patients may grossly impair their postoperative ventilatory function, predisposing them to 
significant dyspnoea and cardiopulmonary complications. These patients are considered high-
risk for surgery or inoperable and referred for radiotherapy, systemic anticancer treatment, or 
palliative care instead (2-4, 13-15). In Wales, an average of only 17% of patients undergo lung 
resection annually (16). 
Of those individuals who proceed to lung resection, thoracic surgery and general anaesthesia 
may have direct effects on their respiratory system predisposing patients to PPCs, which 
increases hospital morbidity, prolongs HLOS and adds to health-care costs (4). PPCs in 
patients for thoracotomy and lung resection with chronic lung disease have been reported to 
be as high as 30% (4). Decreased lung expansion due to poor inspiratory muscle strength 
(respiratory muscle weakness) causes atelectasis and PPCs (4)). Reduced respiratory muscle 
function along with reduced mucociliary function and bacterial proliferation promote 
colonisation of the respiratory tract by bacteria leading to pneumonia and acute respiratory 
distress syndrome with patients requiring intensive care treatment and longer HLOS, which 

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increase National Health Service (NHS) costs, places pressures on critical care beds and 
increases mortality (4). 
Annually published lung cancer audit data for Wales consistently demonstrates a wide 
variation in the number of NSCLC patients receiving surgery with curative intent across the 
eight lung cancer Multi-Disciplinary Teams (MDT’s) across South Wales (16).  Fitness for 
surgery and area of deprivation of patients play a major role in this variation. The Equality 
Act (2010) advocates equality of opportunity. The SBUHB Prehab service, ensures that male 
and female patients, elderly patients and patients with diverse backgrounds are given the 
same opportunities to access high quality of surgical care and support. Hence, our proposed 
research project aims to ensure that vulnerable, high-risk, unfit NSCLC patients with 
surgically resectable disease are not denied curative surgery and instead will benefit by 
receiving surgery. Furthermore, to ensure equity in provision of surgical care to patients 
requiring thoracic surgery, the Welsh Government aims to establish a South Wales Adult 
Thoracic Surgical Service based at Morriston Hospital, Swansea by 2027. The aim of our 
SBUHB Prehab service is to ensure that there is equity in the provision of a standardised, 
evidence based Prehab service to all patients across South Wales especially when referrals 
from all South Wales Health Board lung MDTs commence to the thoracic SBUHB Prehab 
service by 2027 (Figure 1). 
 
 

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1.3. Clinical Data 
 
Analysis of our prospective data, which was published in the Lancet journal 
EClinicalMedicine, suggests that patients with dyspnoea, impaired PS, decreased LOA, 
frailty, and borderline or poor lung function can be optimized with a standardized Prehab 
program, allowing them to undergo curative lung surgery safely with acceptable frequency of 
PPC’s, LOHS and mortality (15). Despite optimisation, there remain a section of patients 
who remain unfit for surgery or following surgery develop complications and experience 
longer stays in the high dependency unit and hospital (15).  
There is emerging evidence that adding a hand-held Inspiratory Muscle Training (IMT) 
device (Figure 2) to Prehab further optimises surgical patients and improves post-surgical 
outcomes by reducing PPCs which results in shorter HLOS and reduces mortality (17-20). 
IMT improves the strength and endurance of inspiratory muscles, namely the diaphragm and 
intercostal muscles through a series of breathing exercises and greatly improves the ability 
of individuals to take in deep breaths following surgery and expectorate and clear their 
airway of retained secretions more effectively, which helps reduce PPCs (17-20). IMT is 
analogous to strengthening one’s respiratory muscles with weightlifting and inspiratory 
muscles are able to work for longer duration (17-20). For this study we plan to use the 
POWERbreathe Medic IMT device which does have a CE mark. The device is not being 
used outside of the purposes for which it is CE marked for this research study. The 
POWERbreathe medic IMT device is evidence based for a variety of medical conditions 
such as chronic lung disease and thoracic surgery, and is currently used by multiple patient 
groups, including pre operative cardiac patients as part of routine care in the Health Board. 
The POWERbreathe medic IMT is a single patient use device that is not decontaminated 
and passed onto other patients to use after the study. 
On the contrary, following lung resection, to manage pleural space complications of air leak, 
effusion and empyema, RCT-level evidence suggests that temporarily paralysing the 
diaphragm (an inspiratory muscle responsible for almost 80% of inspiratory effort) with cryo-
neuro-ablation of the phrenic nerve, does not significantly prolong HLOS, PPCs and 
mortality (21). 
 
 

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Figure 2. POWERBreathe Inspiratory Muscle Training Device 
 
In the presence of suggested equipoise, to obtain high level evidence for introducing IMT 
with Prehab into clinical practice for NSCLC surgical patients, we searched the Medline, 
Embase and the Cochrane library databases for English language RCTs, systematic reviews 
and meta-analyses published on “pulmonary rehabilitation” between Jan 1946 to May 2022 
for “inspiratory muscle training”, “POWERbreathe Medic”, “inspiratory spirometry” (IS), 
“surgery”. Our search revealed 181 publications. 4 publications met the search question 
comparing IMT with Prehab and IS. Two RCTs were in cardiac surgery, one ‘pilot’ in upper 
gastro-intestinal surgery and one ‘pilot’ RCT in lung cancer surgery (Figure 3) (22-25). 
 
 
Figure 3. PRISMA flow diagram for a Systematic Review of Inspiratory Muscle 
Training (IMT) vs Standard Prehab 

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The four RCTs, including the pilot RCT in lung cancer surgery, did not describe the impact of 
IMT on the quality of life (QoL) of patients who underwent surgery (22-25). 
 
Whilst the four RCTs suggested that incorporating an IMT device to strengthen the 
diaphragm and muscles of inspiration improved pulmonary function prior to surgery, and 
following surgery reduced PPCs and HLOS, RCT level evidence evaluating the effectiveness 
of IMT in NSCLC surgical patients was graded low as the pilot RCT was underpowered (22) 
(12 patients in IMT group and 9 patients control group). 
 
Lung resection patients commonly have COPD, reduced respiratory function, obesity, are on 
bronchodilators and develop PPCs. The RCT in cardiac surgical patients however, excluded 
these patients who are more likely to develop PPCs. Unlike abdominal and cardiac surgery, 
in lung cancer surgery a large volume of lung tissue is removed, which further compromises 
pulmonary function predisposing patients to increased PPCs, mortality, HLOS and impacts 
QoL. As cardiac and abdominal surgical patients do not reflect the thoracic surgical 
population as lung tissue is not removed at surgery in these patient populations. Hence, it is 
not possible to extrapolate their RCT evidence to lung resection patients (21-25) 
 
Additionally, there is significant research with IMT in the intensive care population (26), 
however these results cannot be generalised to our population of patients for lung resection 
surgery. Whilst there are similarities between the two patient groups, such as chronic 
respiratory conditions and deconditioning, patients can suffer other intensive care related 
conditions such as critical illness polyneuropathy from sepsis. Additionally, outcome 
measures between the two patient populations differ. 
 
1.4. Rationale and Risks/Benefits 
 
We hypothesise that prior to surgery, an IMT device in combination with a standard Prehab 
program compared with Prehab alone, will further improve the strength and endurance of the 
surgical NSCLC patients’ inspiratory muscles used for breathing. By doing so, IMT with 
Prehab will allow patients who have undergone lung resection surgery to clear their airway of 
secretions more effectively in the post-operative period and provide a significant benefit to 
patients by lowering their risk of developing PPCs and shorten their HLOS after surgery, 
improve their overall QoL and additionally reduce NHS costs. 

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There are no expected risks to participants of this trial. Our previous studies, have shown that 
thoracic Prehab safely optimises patients for surgery (14,15). Good tolerance with IMT devices 
have been reported, although can cause feelings of fatigue (27,28). 
 
 
2. Objectives and Design  
2.1. Trial Objectives 
 
Primary Objective: A randomised controlled trial to evaluate the impact of thoracic 
PRehabilitation with Inspiratory Muscle tRaining cOmpared to Standard prEhabilitation in 
surgical lung cancer patients [PRIMROSE Trial]. 
 
Recruitment rate: The study aims to recruit 134 patients for randomisation over twelve 
months, with 67 randomised to the intervention group and 67 to the control group (6).  
 
Retention rate: These are high-risk patients and a high attrition rate in this population is 
considered normal. We anticipate the retention of 50 patients in each arm following 1:1 
randomisation, and is based on our previous study (15), which showed that following 
assessment, 6.8% NSCLC patients fail to attend Prehab and 1.1% died prior to commencing 
Prehab. Likewise, following Prehab, 75.8% patients are ready to proceed with surgery. The 
attrition rate is an estimate and  is anticipated attrition to be 20%-25%.  
 
 
Secondary Objectives: 
 
Adherence to trial procedures: It is anticipated that 80% of participants will adhere to the 
study protocol. 
Collection of participant outcome data and completion rate: It is anticipated that all data 
on each of the individual participants at each time point in each arm of the study will be 
accurately and contemporaneously collected by the research team. The percentage of 
patients in whom all data sets at each time point is accurately and contemporaneously 
obtained will describe the data completion rate, which is an anticipated >95%. 
 

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Follow-up: Following surgery, >80% are expected to successfully complete the post-
discharge assessments. We anticipate a >80% follow-up assessment. 
 
2.2. Trial Design: 
This is a randomised controlled PRIMROSE trial. This trial will be single centred, as there 
are very few centres in the United Kingdom (UK) that deliver this highly specialised service. 
Study population: Lung cancer patients with surgically resectable disease referred for pre-
treatment optimization with Prehab, from the lung cancer Multi-Disciplinary Teams (MDT’s) 
across South West Wales. Eligible patients will be randomised to the trial on a 1:1 ratio to 
either the intervention arm or control arm [figure 4]. 
Participants in group A will receive standard Prehab and training with the IMT device 
(POWERBreathe); participants in group B will receive standard Prehab alone.  
 
2.3. Figure 4. Study Scheme Diagram: 
 
 
To ensure the effectiveness of our study protocol, we have utilised the principles of the UK 
Medical Research Council guidance framework for developing and evaluating complex 
interventions pilot and feasibility studies (6,7). 
 

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2.4. Statistical Methodology and Analysis 
2.4.1. Sample size, justification and calculations 
 
Our literature search did not bring up a suitable RCTs on the use of POWERBreathe 
Inspiratory Muscle Trainer (IMT) in lung resection patients. Hence, we used the outcome data 
from the RCT on cardiac patients on whom POWERBreathe IMT was used and we have 
experience with. We acknowledge that the cardiac surgery patient population are very different 
and do not accurately reflect our study population (as patients undergoing cardiac surgery do 
not undergo lung resection). There is one RCT on the use of inspiratory spirometry used in 
patients undergoing lung resection in order to strengthen their diaphragm function prior to 
surgery (29). Inspiratory muscle training using inspiratory spirometry is different to the 
POWERBreathe IMT. However, the patient population and design of this RCT are more in line 
with our PRIMROSE Trial, making it more pertinent to use the data from this RCT instead of 
the RCT in a cardiac population. Hence, using the data from the lung resection patient trial, 
and assuming a 36.7% incidence of PPC after surgery in the control arm and using a 
significance level of 0.05 and a power of 80%, the online calculator estimates 50 patients are 
required in each arm of the study (Figure 5). 
Figure 5: Online calculator to estimate sample size (29). 
 
This sample size is realistic as Prehab receives on an average of 127 annual patient 
referrals per year.  
 
 
 

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Data collection 
 
QoL data using EORTC QLQ-30 questionnaire will be collected at initial assessment (T0) 
and on completion of Prehab (T1) as final assessment, then post-surgery at discharge (T2) 
and at 1 month following surgery (T3). 
 
 
Subjective outcome measures data include dyspnoea score, PS, thoracoscore, frailty index 
(FI), LOA and objective measures include 6-minute walk distance test (6MWD) at initial 
assessment (T0), after every two weeks in Prehab to assess for improvement, and finally at 
final assessment prior to participants proceeding to surgery (T1) (14,15,30). LOA, measured 
using the Borg scale of perceived exertion, will be recorded as sedentary, moderately active 
or active and supplemented by the 6MWD. The 6MWD will be performed using a 10m 
corridor instead of 30m (31). A 10 metre track along a flat corridor, will be used to measure 
the distance walked in metres within the 6 minutes. A 10m track was used in our previously 
published study and proved very effective. The American Thoracic Society guidelines state a 
distance of 30 metres (100 foot) should be used, however this is difficult practically. It is rare 
to find a 30-metre corridor in a hospital that is quiet and can allow a chair to be positioned for 
seated rests. A 10 metre track will be better from a health and safety point of view, as well as 
giving patient’s privacy to focus on the self-paced walk test. These above outcome 
measures are already standard care for all Prehab patients (14,15). 
 
Calculating the thoracoscore for each individual for lung resection in percentage describes 
the mortality risk of the individual for surgery. This is already standard operating procedure 
(SOP) for obtaining informed consent for lung resection surgery, and will be calculated for 
each participant (T0 and T1) (2,32).  
 
The maximal inspiratory pressure (MIP) for both groups will be measured using a 
POWERbreathe device (Figure 2) at initial assessment (T0), on completion of Prehab (T1) 
and at discharge (T2). Measuring MIP is not standard practice for Prehab and will be an 
additional and essential outcome measure. It is required to assess the progress of each 
individuals improvement with the Prehab. Due consideration regarding IMT contraindications 
in patients to avoid harm or adverse events is included in our inclusion/exclusion criteria. 
 
Following surgery, data on PPC’s and HLOS will be collected by the researcher. This is 
standard practice for the prehab service.  

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Post-discharge assessment: Our primary objective is to determine whether IMT prior to 
surgery with Prehab helps reduce PPC following surgery, which is up to the point of discharge 
from hospital (alive or dead). This is one time point. Hence, it is anticipated that all patients 
will complete the discharge assessment for complications. Thus, the study is not 
underpowered for the primary end point. 
 
Mortality rates will be collected at discharge, 1 month, 3 months, and 365 days post-surgery.  
 
2.4.2 Analysis Plan 
Our aim is to evaluate the impact of thoracic Prehab with IMT compared to standard Prehab 
in reducing post operative pulmonary complications following surgical resection in lung 
cancer patients in a RCT.  
The analysis will include descriptive data (means and standard deviation) on all outcomes 
collected, including levels of missing data, leading to the calculation of clinically important 
differences. Descriptive statistics will be used to summarise participants’ baseline 
characteristics and outcome measures.  
Statistical analyses will be performed using SPSS statistical software, version 20.0 (IBM 
Corporation, Armonk, NY, USA). Two-sided significance tests will be used (a\0.05). Data will 
be presented as mean and standard deviation (SD), or median and interquartile range (IQR) 
for variables with a skewed distribution. Differences between groups in categorical variables 
will be tested with Chi square or Fisher’s exact test. For continuous data the student’s t test 
or the Mann–Whitney U test will be used. The Wilcoxon signed rank test will be used to 
compare MIP and QoL at T0 and T1 and T3. Relative risk will be calculated for post 
operative pulmonary complications (PPCs) graded 1-V using the Clavien Dindo classification 
and impact of IMT on the study group compared to the control group. Assuming a 36.7% 
incidence of PPC after surgery in the control arm and using a significance level of 0.05 and a 
power of 80%, 50 patients are required in each arm of the study for analysis.” 
 
2.4.3. Project statistician / methods expert 
 
Statistical analyses will be performed using SPSS statistical software, version 20.0 (IBM 
Corporation, Armonk, NY, USA) by the chief investigator who is familiar with the use of this 
software and has previously published data in the lancet journals eclinical medicine (15). 

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3. Subject Selection 
3.1. Number of subjects and subject Selection 
 
Daily screening of new prehab referrals by the principal investigator or research team, using 
a consecutive sample approach will be used for participant recruitment. This means 
selecting all patients who meet the eligibility criteria. Patients over a 12-month period (from 
January 2025) will be approached to gain consent. However, if recruitment numbers are an 
issue the study will be extended by six months. 
 
3.2. Inclusion Criteria: 
Lung cancer patients with surgically resectable disease who are referred for pre-treatment 
optimization with Prehab from the lung cancer Multi-Disciplinary Teams (MDTs). The referral 
criteria for Prehab is one or more of the following (15): 
 
≥1 Medical Research Council (MRC) dyspnoea score 
 
≥1 World Health Organization (WHO) performance status (PS) 
 
Age ≥ 70 years 
 
Frailty index >3 
 
Borderline or poor pulmonary function (forced expiratory volume in one second 
(FEV1) < 50% or diffusion capacity for carbon monoxide (DLCO) <50%) 
 
Sedentary patients despite having adequate FEV1 or DLCO 
 
Additionally: 
 
Surgical resection can be performed, including endobronchial excision of tumour, or 
lobectomy, segmental resection, pneumonectomy or wedge resection, either via a 
minimally invasive approach or a standard thoracotomy approach 
 
Patients will be included in the trial if they are capable of providing verbal written 
consent for Prehab, and written consent for undergoing surgical resection for lung 
cancer 
 
Are over 18 years of age 
 
All patients will be considered regardless of their baseline respiratory muscle strength 
 

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3.3. Exclusion Criteria: 
 
 
Inclusion criteria not met 
 
Patients who have undergone recent abdominal surgery and those with an 
abdominal hernia 
 
Patients diagnosed with other cancers namely, patients with metastatic lung cancer, 
mesothelioma, sarcoma, mediastinal tumours, or benign diseases  
 
Patients who decline Prehab 
 
Patients who do not consent to Prehab, do not attend or have died prior to 
commencing Prehab. Patients who do not consent to surgery. 
 
Patients with a high cardiovascular risk for Prehab and awaiting investigations or 
interventions (including unstable angina and syncope)  
 
Patients with a serious concomitant disorder that would compromise patient safety 
during Prehab 
 
Patients with a history of spontaneous pneumothorax and/or evidence of large bullae 
on radiological imaging 
 
Patients who have suffered from or likely to suffer from costochondritis 
 
Patients with marked osteoporosis with history of rib fractures 
 
Patients with pulmonary hypertension 
 
Patient with a perforated ear drum 
 
If a participant is involved in a study similar, with potential to cause bias or conflict of 
interest then they will be excluded 
 
Patients with worsening heart failure signs and symptoms after IMT 
 
To prevent the transmission of respiratory infections, the research team will advise patients 
not to share the device with family members. If patients are suffering from a cold, sinusitis or 
respiratory tract infection they will be advised not to use the device until their symptoms have 
resolved.  
Participants who do not understand written and/or spoken English can access a translator 
through the health board. 
The research team will collect a list of patients that decline to participate in the trial, to 
assess recruitment rates at the end of the study. 

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3.4. Criteria for Premature Withdrawal 
 
Participants will be withdrawn from the study for the following reasons:  
 
Participants are no longer considered suitable for surgical lung resection by the MDT. 
Other treatment options may be considered more prudent such as radiotherapy or 
systematic anticancer treatment or best supportive care. 
 
The participant decides they no longer wish to be part of the study or have decided 
against surgical resection 
 
The research team decide it is unsafe for the participant to continue due to medical, 
safety and regulatory concerns. This includes adverse cardio-respiratory events 
relating to the patients physical conditioning as assessed by the cardiothoracic 
physiotherapists 
 
If the participant becomes lost to follow-up as deemed by the research team 
 
If the participant loses their capacity during the study period (including death) 
 
A significant increase in post-surgical mortality 
Patients have the right to refuse study participation.  
If a participant loses capacity to consent or withdraws consent, they will be withdrawn from 
the study. Identifiable data already collected with consent would be retained and used in the 
study. No further data would be collected or any other research procedures carried out on or 
in relation to the participant.  
4. Study Procedures  
4.1. Informed Consent Procedures 
 
It is the responsibility of the research team, who have been appropriately trained 
cardiothoracic physiotherapists and technicians (as documented in the research delegation 
log) to obtain written informed consent from each subject prior to any study participation. The 
research team will be trained by the PI, on when to approach a potential participant, what 
information they should provide (written and verbally), and how to record details of the 
consent decision.  
 
Informed Consent Forms (ICF) and Patient Information Sheets (PIS) will be available in large 
print, with clear written language and available in English and Welsh.  

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Additionally, the research team will provide adequate explanation of the aims, methods, 
anticipated benefits and potential hazards of the study. 
 
If a participant wishes to speak to a cardiothoracic surgeon, the research team will organize 
a telephone discussion. If necessary, a second consent visit should be arranged and the 
research team will not take consent at this time.  
 
The patient should be given at least 24 hours to consider giving their consent for the study. If 
for any reason, less than 24 hours is given, the reasons should be documented, along with 
justification for this decision. The date that the PIS is given to the patient will be documented 
within the patient’s notes to ensure that a minimum of 24 hours has been provided.  
 
The PI or other member of the research team will explain to the potential participant that they 
are free to refuse any involvement within the study or alternatively withdraw their consent at 
any point during the study and for any reason. 
 
Once  a  patient  has  consented  to  take  part  in the trial  research  study  a  research  label 
should  be  attached  to  their  hospital  case  notes  to  indicate  involvement.   
 
All relevant research related documentation should be filed in the participants physiotherapy 
notes. This will consist of a copy of the ICF and PIS .Written records of each research event 
for example randomization, trial visits or follow up phone calls will be recorded within the 
physiotherapy notes. 
 
If there is any further safety information, which may result in significant changes in the 
risk/benefit analysis, the PIS and ICF will be reviewed and updated accordingly. All subjects 
that are actively enrolled on the study will be informed of the updated information and given 
a revised copy of the PIS/ICF in order to confirm their wish to continue on the study.  
 
The informed consent process will not cease once the ICF has been signed; the practice of 
giving information about the research project to participants will be an ongoing process at 
each contact. Ongoing verbal consent will be confirmed and documented as part of each 
research-contact by the research team. 
 

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4.2. Screening Procedures  
For each patient referred to Prehab, the diagnosis and stage of lung cancer will be validated 
with the data documented on the Welsh Clinical Portal system by the CI and research team. 
This is standard practice in the staging and management of lung cancer. The International 
Association for the Study of Lung Cancer (IASLC) lung cancer staging system, 8th edition, 
will be used for pre-treatment clinical staging of patients with suspected or diagnosed lung 
cancer (33).  
 
4.3. Randomisation Procedures (if applicable)  
Participants will be randomised 1:1 to either the intervention or control group without 
stratification using an online randomisation service, ‘Sealed Envelope’ (www. 
sealedenvelope.com) (34). 
 
4.4. Schedule of Treatment for each visit  
 
On initial face-to-face assessment, conducted within 5 working days of receiving the referral 
for Prehab, the research team will provide participants with participant information sheet and 
informed consent form. Informed consent to participate will be obtained. Patients can bring 
carers to the face-to face assessment if they wish.  
 
Control group: The control group will receive a standard Prehab protocol. 
 
Standard Prehab protocol is described in our previous pragmatic study published in the 
lancet journals eclinical medicine (15). Prehab will be provided to participants over 2–4 
weeks with supervised once weekly sessions with supervised two weekly sessions of 70 
minutes each, along with exercises for patients to carry out at home. Three weeks is an 
anticipated average based on published data and urgency to proceed to surgery as cancer 
can grow and become inoperable by six weeks. This area is much debated in the Prehab 
literature. Our aim is to ensure as many patients benefit with Prehab followed by lung 
resection surgery as possible, with broader health benefits to patients and a positive impact 
on their quality of life. Our previous study showed that patients can be physically optimised 
safely in as little as two weeks (15). However, for patients who may be slower to respond 
there is scope in our program for a more prolonged course of Prehab if required.  
 

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Outcome measures will be collected every two weeks on the Prehab programme by the 
research team, which is standard practice. As patients become eligible, they will withdraw 
from Prehab and proceed to surgery once a surgical date is confirmed. Management of 
individuals deemed unfit for surgery will be discussed at the individuals’ local lung cancer 
MDT for consideration of alternative treatment options namely, radiotherapy, systemic anti-
cancer treatment or palliative care. 
 
Respiratory muscle training and breathing exercises. Both groups will receive incentive 
spirometry devices pre operatively. Participants will be encouraged to practice and train with 
the spirometer device three times daily, so can use the spirometer effectively post 
operatively. This is standard care as spirometers aid lung volumes and removal of secretions 
post operatively. 
 
Cardiovascular exercises: namely, stationary cycle ergometry and upper and lower limb 
resistance exercises will be performed, whilst monitoring the heart rate, blood pressure and 
oxygen saturations (15). The rate of perceived exertion (RPE) will be measured using the 
Borg breathlessness scale and used twice at every session to measure the intensity at which 
each patient is working and guide them to increase or decrease their effort as required. 
 
Home Exercise Program (HEP): individualised home exercise programme includes daily 
walking plan and stair climbing exercise (15). Training enabling them to maintain activities of 
daily living following surgery. The HEP will be continued following discharge after surgery. 
 
Health education and smoking cessation advice will be provided to all current smokers 
prior to surgery and support following surgery (15). Where necessary nicotine replacement 
therapy will be provided. 
 
Intervention group: The intervention group will receive IMT in addition to a standard 
Prehab protocol (as above). An MIP in cmH20, obtained at or greater than 1.5 seconds will 
be recorded, and the highest MIP of 3 valid breaths will be used as baseline. The IMT 
pressure in cmH20 will be set initially at 40% of the patients MIP. Participants will be taught 
to use the device in an upright position and instructed to perform six sets of six breaths with 
the resting times between each set of breaths reducing from 60 seconds, to 45 seconds, to 
30 seconds, to 15 seconds, to 5 seconds. IMT will be used twice-daily preoperatively in the 
intervention group and not post operatively. Training load intensity on the IMT will be 

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increased preoperatively by the patient according to the rate of perceived inspiratory effort, 
on a modified Borg scale.  
 
4.5. Schedule of Assessment (in Diagrammatic Format) 
Figure 6 describes the time points at which assessments and data will be collected. 
4.6. Follow up Procedures (if applicable)  
 
Outcome measures (as highlighted in the above diagram) will be assessed using the 
European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) 
questionnaire, the EORTC QLQ-30 (9). 
 
commencement of Prehab (T0). 
 
every two weeks of Prehab  
 
On Prehab completion (prior to surgery) (T1). 
 
following surgery at the time of discharge from hospital (T2).  
 
one-month post-surgery (T3). 
 
3 months post-surgery (T4). 
 
12-month post-surgery (T5). 
Outcome measures will be assessed via the telephone or face to face in the cardiothoracic 
physiotherapy department at Morriston Hospital, or the satellite center by the CI or research 
team. 

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4.7. Laboratory Assessments (not applicable)  
 
4.8. Radiology Assessments (not applicable)  
 
4.9. End of Study Definition  
 
The parameters that will mark the end of the study will be the recruitment of 100 patients 
with a 12 month follow up period. 
4.10. Procedures for unblinding (if applicable)  
 
Blinding: Research team members independent to the Prehab team will analyse the data 
and outcome measurements of participants and will be blinded to participant group 
assignment. 
 
The cardiothoracic physiotherapists, managing the post-operative care of patients will be 
blinded to which group the participant has been randomised to (the intervention arm or 
control arm). 
If a patient is readmitted to hospital following discharge home, it will not be necessary to 
unblind physiotherapists with the patients new hospital admission. This is because the 
intervention arms will be pre-operative and will not influence the safety of patients post-
operative or influence their medical management. 
 
4.11. Subject Withdrawal  
 
Participants who withdraw/ are withdrawn from the study, will return to standard care without 
negative consequences. This will be made clear in initial conversations with the research 
team and a study withdrawal letter will be attached to the PIS, for participants wishing to 
withdraw at a later stage. 
 
4.12. Data Collection and Follow up for Withdrawn Subjects  
 
All patients will be included in the final data analysis, by using an intention to treat analysis, 
thereby limiting attrition bias if patients withdraw/ are withdrawn.  

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5. Safety Reporting 
 
For non-CTIMP reporting, please refer to the safety (other research) procedural table in 
Appendix 1. For Medical Device reporting, please contact the R&D Office. 
The information in this section applies to HRA’s expectations for safety reporting. 
https://www.hra.nhs.uk/approvals-amendments/managing-your-approval/safety-reporting/ 
 
5.1. General Definitions 
5.1.1. Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a subject which is not necessarily caused by 
or related to the study.  An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporarily associated with 
study activities. There is a possibility of dizziness, coughing, tiredness and a pneumothorax 
with the inspiratory muscle trainer device. 
5.1.2. Serious Adverse Event (SAE) 
 
An SAE fulfils at least one of the following criteria: 
 
Is fatal – results in death (NOTE: death is an outcome, not an event) 
 
Is life-threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is otherwise considered medically significant by the Investigator 
A report of a Serious Adverse Events (SAEs) that are: related to the study (i.e. they 
resulted from administration of any of the research procedures) and 
unexpected (i.e. not listed in the protocol as an expected occurrence) should be 
emailed to the REC using the Non-CTIMP safety report to REC form. These should 

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be sent within 15 days of the chief investigator becoming aware of the event. The 
completed template must also be emailed to the sponsor within 24 hours of 
identifying the SAE: SBU.RandDSafetyReporting@wales.nhs.uk 
6. Investigators Assessment  
6.1.1. Seriousness 
 
The Chief/Principal Investigator responsible for the care of the patient, or in his absence an 
authorised medic within the research team, is responsible for assessing whether the event is 
serious according to the definitions given in section 6.1. 
6.1.2. Causality 
 
The Investigator must assess the causality of all serious adverse events in relation to the 
trial treatment according to the definition given 
6.1.3. Expectedness 
 
The investigator must assess the expectedness of all SAEs according to the definition given.  
If the SAE is unexpected and related, then it needs immediate reporting. 
6.1.4. Severity 
 
The Investigator must assess the severity of the event according to the following terms and 
assessments. The intensity of an event should not be confused with the term “serious” which 
is a regulatory definition based on patient/event outcome criteria. 
Mild: Some discomfort noted but without disruption of daily life 
Moderate: Discomfort enough to affect/reduce normal activity 
Severe: Complete inability to perform daily activities and lead a normal life 
 
6.2. Notification and reporting Adverse Events or Reactions 
 
If the AE is not defined as SERIOUS, the AE is recorded in the study file and the participant 
is followed up by the research team. The AE is documented in the participants’ medical 
notes (where appropriate) and the CRF. 

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6.3. Notification and Reporting of Serious Adverse Events  
Serious Adverse Event (SAEs)  
 
SAEs that are considered to be ‘related’ and ‘unexpected’ are to be reported to the sponsor 
within 24 hours of learning of the event and to the Main REC within 15 days in line with the 
required timeframe. For further guidance on this matter, please refer to Appendix 2 
6.4. Urgent Safety Measures 
 
The CI may take urgent safety measures to ensure the safety and protection of the trial 
subjects from any immediate hazard to their health and safety. The measures should be 
taken immediately. In this instance, the approval of the Licensing Authority Approval prior to 
implementing these safety measures is not required. However, it is the responsibility of the 
CI to inform the sponsor and Main Research Ethics Committee (via telephone) of this event 
immediately once identified on: 
SBU.RandDSafetyReporting@wales.nhs.uk 
 
 
6.5. Annual Safety Reporting – not applicable 
 
6.6. Procedures for reporting blinded ‘unexpected’ and related’ SAEs – not 
applicable 
 
6.7. Overview of the Safety Reporting Process 
  
The information will be displayed within a table in appendix 1.  
 
7. Statistical Considerations 
 
7.1. Primary Endpoint Efficacy Analysis  
 
To test our primary hypothesis the chi-square test will be used to assess whether IMT in 
combination with Prehab is effective in reducing PPCs following lung resection surgery 
compared with its control i.e., standard Prehab using a significance level of 0.05.   4x4 matrix. 

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7.2. Secondary Endpoint Efficacy Analysis  
Secondary end points include improvement in dyspnoea score, PS, LOA, Frailty, 6MWD 
test, MIP and QoL. Differences between groups in categorical variables will be tested with 
Chi square or Fisher’s exact test. For continuous data the student’s t test or the Mann–
Whitney U test will be used. The Wilcoxon signed rank test will be used to compare MIP and 
QoL at T0 and T1 and T3. 
 
7.3. Safety Endpoints  
Safety analysis will include rate of complications and mortality and are categorical data sets. 
The chi-square test or Fisher’s exact test will be used to assess the safety of IMT in 
combination with Prehab compared with its control i.e., standard Prehab using a significance 
level of 0.05. 
The study may be ended prematurely, if there is a significant increase in post-surgical 
mortality or complications in the study group. 
Additionally, if any of the patients in the intervention group experience syncope symptoms 
whilst using the device they will be advised to stop and will be withdrawn from the study. 
 
7.4. Sample Size 
Please see section 2.4.1. Sample size, justification and calculations 
 
7.5. Statistical Analysis  
 
Our aim is to evaluate the impact of thoracic Prehab with IMT compared to standard Prehab 
in reducing post operative pulmonary complications following surgical resection in lung cancer 
patients in a RCT. Statistical analysis will be performed using SPSS statistical software, 
version 20.0 (IBM Corporation, Armonk, NY, USA). Two-sided significance tests will be used 
(a\0.05). Data will be presented as mean and standard deviation (SD), or median and 
interquartile range (IQR) for variables with a skewed distribution. Differences between groups 
in categorical variables will be tested with Chi square or Fisher’s exact test.  
For continuous data the student’s t test or the Mann–Whitney U test will be used. The 
Wilcoxon signed rank test will be used to compare MIP and QoL at T0 and T1 and T2. 

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Relative risk will be calculated for post operative pulmonary complications (PPCs) graded 1-
V using the Clavin Dindo classification and impact of IMT on the study group compared to 
the control group. Assuming a 36.7incidence of PPC after surgery in the control arm and 
using a significance level of 0.05 and a power of 80%, 50 patients are required in each arm.” 
 
8. Data Management 
8.1. Data collection 
 
Outcome measures will be collected by the principal investigator and research team onto 
paper initially, forming part of the physiotherapy notes. These physiotherapy notes will be 
kept in a locked cabinet within a secure room, which only the PI and research team will have 
access to. 
8.2. Data Systems 
 
Outcome measures collected on paper, will be inputted into a password secure excel 
database, on a security- protected computer. 
 
8.3. Data integrity  
 
The Good Clinical Research Practice (GCP) guidelines will be followed with regards to 
maintaining data accuracy and consistency, from data generation, to recording and 
destruction, including any intervening.  
 
8.4. Data monitoring 
 
Data will be monitored electronically by the whole of the research team and escalated to the 
CI accordingly. 
The data will be reviewed by the CI and PI in a monthly meeting. 
 
8.5. Data archiving and destruction 
 

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During the course of research, all records are the responsibility of the CI and will be kept in 
secure conditions. When the research trial is completed all records will be kept for 5 years, 
as per requirement of the Research Governance Framework and Health Board Policy 
that the records are kept for a further 5 years in the Health Board archive facility.  
 
9. Data Handling & Record Keeping 
 
9.1. Confidentiality  
 
The CI has responsibility to ensure that patient anonymity is protected and maintained. 
Information with regards to study patients will be kept confidential and managed in 
accordance with the Data Protection Act, NHS Caldicott Guardian, Research Governance 
Framework for Health & Social Care 2017 and Research Ethics Committee Approval. 
 
All PIS’s will be compliant with the General Data Protection Regulation (2018) (GDPR), 
ensuring, appropriate transparency of data. All of the study essential documents electronic, 
and hard copies, will be archived for 5 years, The R&D department will make provisions for 
archiving and destruction of these documents. 
 
The legal basis for processing and storing/sharing data will be Article 9.2 (j) – pseudo-
anonymised (scientific research).  
 
No patient identifiable information will be collected from subjects. 
 
All study participants will be allocated a unique study code and no identifiable data will be 
captured on the data management system.  
 
As part of the trial, direct, anonymised quotations from participants will be collected. These 
will be disseminated and published as part of the results of the study. For example, how 
subjects managed with the device, patient reported experience measures and outcome 
measures. 
9.2. Study Documents  
 
 
A signed protocol and any subsequent amendments 

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 
Current Summary of Product Characteristics/ Investigator’s Brochure 
 
Sponsor Self-Monitoring template for the trial team to complete on a regular    
basis as detailed by the Monitoring section 
 
Current/Superseded Patient Information Sheets (as applicable) 
 
Current/Superseded Consent Forms (as applicable) 
 
Indemnity documentation from sponsor 
 
Conditions of Sponsorship from sponsor 
 
Conditional/Final R&D Approval  
 
Signed site agreement 
 
Ethics submissions/approvals/correspondence 
 
CVs of CI and site staff 
 
Laboratory accreditation letter, certification and normal ranges for all 
laboratories to be utilised in the study 
 
Delegation log 
 
Staff training log 
 
Site signature log 
 
Patient identification log 
 
Screening log 
 
Enrolment log  
 
Monitoring visit log 
 
Protocol training log 
 
Correspondence relating to the trial 
 
Communication Plan between the CI/PI and members of the study team 
 
SAE reporting plan for the study 
 
9.3. Case Report Form/ Data Collection Tool 
 
The research team will be responsible for completing the data collection tool.  
 
9.4. Record Retention and Archiving 
 
During the course of research, all records are the responsibility of the CI and will be kept in 
secure conditions. When the research trial is completed all records will be kept for 5 years, 

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as per requirement of the Research Governance Framework and Health Board Policy 
that the records are kept for a further 5 years in the Health Board archive facility.  
 
9.5. Compliance 
 
The CI will ensure that the trial is conducted in compliance with the principles of the 
Declaration of Helsinki (1996), and in accordance with all applicable regulatory requirements 
including but not limited to the Research Governance Framework, Trust and Research Office 
policies and procedures and any subsequent amendments. 
 
9.6. Clinical Governance Issues 
9.6.1 Ethical Considerations 
 
To address issues of geographical location, deprivation, poverty, and for people who are 
less likely to have access to Prehab due to for example, transport costs, SBUHB Prehab 
provides satellite clinics closer to patients’ homes, or home visits by physiotherapists for the 
less able. Both male and female patients have equally availed of the service and our Health 
Board has a robust provision of Equality and Diversity training to all staff working in the 
Health Board. 
The study will be registered with the local NHS Research and Development Department of 
the Health Board under the guidance of the NHS Research Ethics Centre and commence on 
receiving ethical approval and conducted to the principles of NIHR Good Clinical Practice in 
research. 
 
9.7. Quality Control and Quality Assurance 
9.7.1. Summary Monitoring Plan 
 
The Sponsor will have the overall responsibility for ensuring the trial is monitored and will 
have oversight of the process.   
The CI will ensure that agreements are in place, the monitoring plan is followed and that the 
PI is compliant with all monitoring requests. 
A completed risk assessment will determine the monitoring required for this study.  

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9.7.2. Audit and Inspection 
 
Auditing: Definition “A systematic and independent examination of trial related activities and 
documents to determine whether the evaluated trial related activities were conducted, and 
the data were recorded, analysed and accurately reported according to the protocol, 
sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the 
applicable regulatory requirement(s).” 
 
This study may be identified for audit by any method listed below:  
1. A project may be identified via the risk assessment process. 
2. An individual investigator or department may request an audit. 
3. A project may be identified via an allegation of research misconduct or fraud or a 
suspected breach of regulations. 
4. Projects may be selected at random. The Department of Health states that Health Boards 
should be auditing a minimum of 10% of all research projects. 
5. Projects may be randomly selected for audit by an external organisation. 
Internal audits will be conducted by the sponsor’s representative 
 
9.8. Non-Compliance    
 
Patients who do not adhere to the proposed intervention will be offered a telephone 
consultation, to consider behaviours and characteristics, preferences, barriers and 
facilitators to enable and explore compliance. This could be done with the carer if the patient 
wishes. If adherence remains an issue patients will be removed from the research and will 
be asked to return their patient diary for analysis. 
     
A noted systematic lack of both the CI and the study staff adhering to SOPs/protocol/ICH-
GCP, which leads to prolonged collection of deviations, breaches or suspected fraud. 
 

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These non-compliances may be captured from a variety of different sources including 
monitoring visits, CRFs, communications and updates. The sponsor will maintain a log of the 
non-compliances to ascertain if there are any trends developing which to be escalated. The 
sponsor will assess the non-compliances and action a timeframe in which they need to be 
dealt with. Each action will be given a different timeframe dependent on the severity. If the 
actions are not dealt with accordingly, the research and development Office will agree an 
appropriate action, including an on-site audit. 
 
10. Trial Committees  
A trial management group (TMG) will provide overall supervision for this study and to take 
steps to reduce deviations from the protocol to a minimum, periodic review of the trials 
progress, to review safety data and to help resolve any differences within the research team 
or between the team and trial sponsor.  The TMG operates on behalf of the Trial Sponsor 
and is to ensure that the trial is conducted according to the UK Research Governance 
Frameworks for Health and Social Care, the principles of Good Clinical Practice (GCP) and 
all relevant regulation and local policies.  The TMG will also ensure the trial runs to time and 
budget as much as feasible. 
 
The TMG will consist of the chief investigator, principle investigator, study staff and 
representatives from the sponsor.  
 
The frequency of the TMG will be meet monthly and then quarterly and can be subject to 
change as the study progresses.  An agenda will be sent before each meeting. Minutes of 
each meeting will be taken, and circulated to the TMG members for accuracy. 
 
11. Intellectual Property 
 
The research question is based upon previous published work and a gap in the literature, 
identifying a new hypothesis. Appropriate credit to previous published work is provided in the 
reference section. 
All manufacturer names and trademark of equipment are listed below to ensure compliance 
with trademark laws: 
POWERbreathe is the inspiratory muscle trainer to be used in this trial 

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The CI has obtained permission to use the European Organization for Research and 
Treatment of Cancer (EORTC) QLQ – C30 QOL questionnaire by completing the online 
Academic User Agreement.  
As this trial is not the development of a device, no intellectual property (IP) will be produced.  
 
12. Publication Policy  
 
The future plans are for amalgamating the two thoracic surgical centres (Cardiff and 
Swansea) and centralising the service to SBUHB. The newly formed South Wales Adult 
Thoracic Surgical Service, based at Morriston Hospital, will provide thoracic surgical service 
to all of South Wales and our Prehab service will be responsible for delivering the Prehab 
program to lung cancer patients across all of South Wales. Hence, the findings will be 
shared with patients, public and clinicians of other Health Boards who will be referring 
patients to our centre. The results will also be shared widely with NHS Trusts outside Wales 
which provide thoracic surgical services to their population.  
The results will be shared widely via the SBUHB web sites with presentations at local and 
national lung cancer meetings and international conferences. Together with dissemination to 
cancer charities such as Cancer Research and Tenovus and the authors plan to publish in 
an appropriate peer review medical journal. The PI will present the findings to her 
physiotherapy peers within the United Kingdom Thoracic Physio Network. Additionally, a 
poster presentation will be submitted for the annual meeting of the Society of Cardiothoracic 
Surgery (SCTC) and the Nursing and Allied Health Professional Sub Committee within this 
society.  
Results will be shared with participants via email or post. Additionally, the research team will 
explore dissemination via ‘public science’ festivals. 
13. Wellbeing of Future Generations Act 
 
This research protocol aligns with the Wellbeing of Future Generations Act, as the 
introduction of an inspiratory muscle training device within the thoracic Prehab programme at 
SBUHB, offers the opportunity to make a positive change to current and future lung cancer 
patients requiring lung resection. 
 

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14. References 
1. Cancer Research. Lung cancer incidence by age. 
https://www.cancerresearchuk.org/healthprofessional/ 
cancerstatistics/statistics-by-cancer-type/lung-cancer/incidence#heading-One. 
2. Lim E, Baldwin D, Beckles M, Duffy J, et al. Guidelines on the radical management of 
patients with lung cancer. Thorax. 2010;Suppl 3:1–27. 
3. Brunelli A, Kim AW, Berger KI, et al. Physiologic evaluation of the patient with lung cancer 
being considered for resectional surgery: diagnosis and management of lung cancer, 3rd ed: 
American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 
2013;143(5 Suppl):e166S–90S. 
4. Miskovic A, Lumb A. Postoperative pulmonary complications. British Journal of 
Anaesthesia. 2017; 118:317-34. 
5. Mainini C, Rebelo P, Bardelli R, et al. Perioperative physical exercise interventions for 
patients undergoing lung cancer surgery: what is the evidence? SAGE Open Medicine. 
2016; 4:1-19. 
6. Skivington K, Matthews L, Simpson SA, et al. A new framework for developing and 
evaluating complex interventions: update of Medical Research Council guidance. BMJ. 
2021:30;374. 
7. Dobkin BH. Progressive Staging of Pilot Studies to Improve Phase III Trials for Motor 
Interventions. Neurorehabil Neural Repair. 2009 Mar-Apr;23(3):197-206. 
8. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 
240(2):205-213. 
9. European Organization for Research and Treatment of Cancer. Available at: 
https://qol.eortc.org/questionnaires/core/eortc-qlq-c30/ 
10. The Welsh NHS Confederation (2015). Available at 
hhtps:www.nhsconfed.org/publications/overview-wellbeing-future-generations-act-2015 
11. The Welsh Government Parliamentary Review of Health and Social Care in Wales 
(2018). Available at hhtps: www.gov.wales/sites/default/files/publications/2018-01/Review-
health-social-care-report-final.pdf 
12. A Healthier Wales (2018). Available at hhtps: www.gov.wales/healthier-wales-long-term-
plan-health-and-social-care 
13. Samet JM. Health benefits of smoking cessation. Clin Chest Med. 1991;12(4):669-679. 
14. Chesterfield-Thomas Gemma, Goldsmith Ira. Impact of preoperative pulmonary 
rehabilitation on the thoracoscore of patients undergoing lung resection. Interact 

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Cardiovasc Thorac Surg 1 November 2016;23(Issue 5):729–32. 
15. Goldsmith I, Chesterfield-Thomas G, Toghill H. Pre-treatment optimization with 
pulmonary rehabilitation in lung cancer: making the inoperable patients operable. E Clinical 
Medicine. 2021; 31:100663. doi.org/10.1016/j.eclinm.2020.100663. 
16. NHS provider results: NLCA State of the Nation Report 2023. Royal college of surgeons 
of England 2022. https://www.lungcanceraudit.org.uk/reports/nhs-provider-results-nlca-state-
of-the-nation-report-2023 
17. Figueiredo R, Azambuja A, Cureau F, et al. ‘Inspiratory Muscle Training in COPD’, 
Respiratory Care. 2022; 65(8):1189-1201. 
18. de Oliveria Vacchi C, Martha B, Macagnan F. Effect of inspiratory muscle training 
associated or not to physical rehabilitation in preoperative anatomic pulmonary resection: a 
systemic review and meta-analysis. Supportive Care in Cancer. 2022;30. 
19. Mans CM, Reeve JC, Elkins MR. Postoperative outcomes following preoperative 
inspiratory muscle training in patients undergoing cardiothoracic or upper abdominal surgery: 
a systematic review and meta-analysis. Clin Rehabil. 2015;29(5):426-38. 
20. Katsura M, Kuriyama A, Takeshima T, et al. Preoperative inspiratory muscle training for 
postoperative pulmonary complications in adults undergoing cardiac and major abdominal 
surgery. Cochrane Database Syst Rev. 2015 Oct 5;2015(10) 
21. Pan XJ, Ou DB, Lin X, Ye MF. Management of Pleural Space After Lung Resection by 
Cryoneuroablation of Phrenic Nerve: A 
Randomized Study. Surg Innov. 2017 Jun;24(3):240-244. 
22. Morano MT, Araújo AS, Nascimento FB, et al. Preoperative pulmonary rehabilitation 
versus chest physical therapy in patients undergoing lung cancer resection: a pilot 
randomized controlled trial. Arch Phys Med Rehabil. 2013 Jan;94(1):53-8. 
23. Matheus GB, Dragosavac D, Trevisan P, et al. Inspiratory muscle training improves tidal 
volume and vital capacity after CABG surgery. Rev Bras Cir Cardiovasc. 2012 Jul-
Sep;27(3):362-9. 
24. Satoto HH, Paramitha A, Barata SH, et al. Effects of Preoperative Inspiratory Muscle 
Training on Right Ventricular Free Wall Longitudinal Strain and ICU Length of Stay in 
Patients Undergoing Heart Valve Replacement Surgery. Indonesian J Cardiol 
2020:41:suppl_A. 
25. van Adrichem EJ, Meulenbroek RL, Plukker JT, et al. Comparison of two preoperative 
inspiratory muscle training programs to prevent pulmonary complications in patients 
undergoing esophagectomy: a randomized controlled pilot study. Ann Surg Oncol. 
2014 Jul;21(7):2353-60. 

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26. Mark Elkins, Ruth Dentice, Inspiratory muscle training facilitates weaning from 
mechanical ventilation among patients in the intensive care unit: a systematic review, 
Journal of Physiotherapy, Volume 61, Issue 3, 2015, Pages 125-134. 
27. Bilyy, A., El-Nakhal, T., Kadlec, J., Bartoski, W., Tornout, F., Kouritas, V. 2020. 
‘Preoperative training education with incentive spirometry may reduce postoperative 
pulmonary complications’, Asian Cardiovascular & Thoracic Annals, 28(9), pp. 592-597. 
28. Sweity, E.M., Alkaissi, A.A., Othman, W. et al. Preoperative incentive spirometry for 
preventing postoperative pulmonary complications in patients undergoing coronary artery 
bypass graft surgery: a prospective, randomized controlled trial. J Cardiothorac Surg. 
2021;16: 241. 
29. Guowei Che, et al. Seven-day intensive preoperative rehabilitation for elderly patients 
with lung cancer: A Randomized controlled trial. Interactive CardioVascular and Thoracic 
Surgery. 2017;25(1). 
30. Komici K, Bencivenga L, Neal N, et al. Frailty in Patients with Lung Cancer a Systematic 
Review and Meta-Analysis. Chest. 2022;2:22. doi.org/10.1016/j 
31. Spruit, M. A. et al. An official American Thoracic Society/European Respiratory Society 
statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care 
Med. 2013;188, e13–e64. 
32. Falcoz P.E., Conti M., Brouchet L., et. al.: The Thoracic Surgery Scoring System 
(Thoracoscore): risk model for in-hospital 
death in 15,183 patients requiring thoracic surgery. J Thorac Cardiovasc Surg 2007; 133: pp. 
325-332. 
33. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage 
classification. Chest 2017;151(1):193–203. doi: 10.1016/j.chest.2016.10.010. 
34. Sealed envelope LTD, 2019. Available: https://www. sealedenvelope. com/ 
simplerandomiser/v1/). 
35. Hulzebos EH, Helders PJ, Favié NJ, de Bie RA, Brutel de la Rivière A, van Meeteren NL. 
Minder longcomplicaties door ademspiertraining bij patiënten die een coronaire 
bypassoperatie moeten ondergaan: een gerandomiseerde trial [Fewer lung complications 
following inspiratory muscle training in patients undergoing coronary bypass surgery: a 
randomized trial]. Ned Tijdschr Geneeskd. 2007 Nov 10;151(45):2505-11. 
 
 
 
 

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15. Appendices 
 
The following is a list of attachments, those with an asterisk* must be submitted to the 
Research Ethics Committee with the protocol: 
Appendix 1 – Information with regards to safety reporting in Non-CTIMP research. Page 45 
to 46 
Appendix 2 – Source Identification List. Page 47 
 
 
 
 

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Appendix 1 – Information with regards to Safety Reporting in Non-CTIMP Research 
 
https://www.hra.nhs.uk/approvals-amendments/managing-your-approval/safety-reporting/safety-
and-progress-reports-other-research-procedural-table/ 
Annual Progress Report link 
https://www.hra.nhs.uk/documents/2996/Annual_Progress_Report_Form_other_research_J
uly_2022_v_4.7_final.odtsm.docx 
End of study report link 
Submit your Final Report - Health Research Authority (hra.nhs.uk) 
 
What and type 
Who 
When 
How 
To Whom 
SAE 
Chief 
Investigator 
 
-Report to 
Sponsor within 
24 hours of 
becoming aware 
of the event 
Report to the 
MREC within 15 
days of 
becoming aware 
of the event 
SAE report form 
for non- CTIMPs, 
available from 
the HRA 
website. 
Sponsor and 
REC which 
issued the 
favourable 
ethical opinion. 
Urgent Safety 
Measures  
Chief 
Investigator or 
Sponsor. Or 
exceptionally by 
the local 
Principal 
Investigator (PI). 
Immediately (by 
telephone) 
Within 3 days (in 
writing) 
By telephone 
Noting in writing 
setting out the 
reasons for the 
urgent safety 
measures and 
the plan for 
further action. 
 
 
 
To Sponsor and 
REC which 
issues the 
favourable 
ethical opinion. 
Approvals 
Officer/REC 
Manager will 
acknowledge 
within 30 days. 
 
 
Declaration of 
the conclusion 
or early 
termination of 
the research 
Chief 
Investigator or 
Sponsor 
Within 90 days 
(conclusion). 
 
Within 15 days 
(early 
termination). 
 
End of study 
declaration 
(EOSD) form, 
available from 
the HRA 
website. 
The REC which 
issued the 
favourable 
ethical opinion. 
 

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The end of the 
trial should be 
defined in the 
protocol. 
Please also 
email the EOSD 
to Sponsor 
Final Report 
 
Note: This is 
only applicable 
for project-
based research 
(i.e., not 
research tissue 
banks or 
research 
databases) that 
have received a 
favourable 
ethical opinion 
from a REC 
Chief 
Investigator 
Within one year 
of conclusion of 
the Research 
 
Final Report, 
submitted via the 
HRA website or 
via IRAS, 
depending on 
the type of study.
Submitted 
centrally to the 
research ethics 
service. 
 
All reports will be acknowledged within 30 days. If any issues are raised, the REC may 
write to the Chief Investigator or sponsor for further information or clarification 
 
 
 
 
 

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Appendix 2 
 
Source Data Identification List 
 
No patient identifiable information will be collected from subjects. 
 
All study participants will be allocated a unique study code and no identifiable data will be 
captured on the data management system.  
 
Communication Plan 
 
The Chief Investigator: will oversee the running of the trial, data management and analysis, 
publishing, presenting and disseminating the results. 
 
The Principal Investigator: will oversee and ensure trial is conducted to agreed protocol, 
legal requirements and participant welfare. In addition, communicating with the research 
team, reporting adverse events, and publishing, presenting and disseminating results.