Table 2 The Standard Protocol Items-Recommendations for Interventional Trials (SPIRIT)

 Title

1

The effect of a pre- and post-operative exercise programme versus standard care on physical fitness of patients with oesophageal and gastric cancer undergoing neoadjuvant treatment prior to surgery (The PERIOP-OG Trial): Study protocol for a randomised controlled trial.

1

 Trial registration

2a

ClinicalTrials.gov Identifier: NCT03807518

4

2b

N/A

 Protocol version

3

1 November 2019 Version 2

4

 Funding

4

Beaumont Hospital Foundation Trust, Oesophageal Cancer Fund, Royal College of Surgeons in Ireland.

25

 Roles and responsibilities

5a

WR, NMcC, LL conceived the study. WBR, NMcC, PAC, MA, TJM, CGC, OM, LL, RT, JB, PG, CT and JS contributed to the study design. WR, RT, LL and JB drafted the manuscript, which underwent revision by all other authors.

25

5b

Royal College of Surgeons Ireland, 123 St Stephens Green, Dublin, Ireland

Sponsor had no role in study design

1

5c

Mr. William Robb, Principal Investigator

Dr. Noel McCarrfey, Co-investigator

Mr. Thomas Murphy, Co-investigator

Mr. Chris Collins, Co-investigator

Prof. Oliver McAnena, Co-investigator

Mr. Paul A Carroll, Co-investigator

Dr. Lisa Loughney, Coordinator and exercise lead

Dr. Roisin Tully, Coordinator

Mr. Jarlath Bolger, Recruiting and consenting patients

Mr. Mayilone Arumugasamy Co-investigator

Prof. Pamela Gallagher, Psychological lead

Dr. Claire Timon, Nutritional lead

Prof. Niall Moyna, Exercise specialist

Prof. Jan Sorensen, Health Economist Prof. Arnold Hill, Professor of Surgery 

1

5d

Steering committee: William Robb, Lisa Loughney, Roisin Tully

Data management team: Lisa Loughney, Roisin Tully, Jan Sorenson, Jarlath Bolger

 Background and rationale

6a

Oesophagogastric cancers are a considerable health burden. In the past 10 years the 5-year survival for both cancers has doubled. This is due to a number of factors including advances in neoadjuvant and adjuvant chemotherapy and radiotherapy. However, physical fitness significantly declines as a result of neoadjuvant and adjuvant therapy. From studies in other cancers, perioperative training is known to improve physical fitness, yet little research has been performed on its effects in those with upper oesophagogastric cancers. Therefore, the aim of the PERIOP-OG trial is to investigate the effects of a community-based exercise training programme (delivered in a leisure centre or at home, depending on the patient location) pre- and post–operatively compared to usual care on cardiorespiratory fitness and other physical, psychological and clinical health outcomes in people with confirmed oesophagogastric cancer.

5

6b

The usual-care control group (usual care – no formal exercise training) receive routine care throughout their cancer pathway from diagnosis to surgical resection. No specific advice about exercise training is offered.

9

 Objectives

7

The aims of this study were to evaluate the following hypotheses:

Primary hypothesis: A structured community-based exercise programme compared with a usual care control group (usual care – no formal exercise training) will result in a clinically significant increase in cardiorespiratory fitness assessed using a 6-min walk test between the baseline and the pre-surgery time point.

Secondary hypotheses:

A structured community-based exercise programme compared with a usual care control group (usual care – no formal exercise training) will result in improvements in other physical health outcomes assessed using upper and lower body strength test, activity behavior monitoring, body mass index, frailty, and psychological health questionnaires assessed at 5 time points baseline, post NCT, pre-surgery, 4 weeks and 10 weeks after surgery as well as semi-structured interviews assessed pre and post-surgery.

Exploratory Endpoints: Post-operative morbidity, comprehensive complication index, hospital length of stay, nutritional status, immune and inflammatory markers, cancer staging, response to NCT and a medico-economics analysis of cost effectiveness of the exercise intervention on reducing health care costs and burden additionally rates of NCT toxicity, tolerance and complicance will be measured.

7

 Trial design

8

Parallel group randomised 1:1 controlled multi-centre trial.

9

 Study setting

9

Three Irish Health Services Executive (HSE) hospitals are recruiting to this trial: Beaumont Hospital Dublin, Mercy University Hospital Cork (MUHC) and University Hospital Galway (UHG). Assessments and exercise training are being delivered at several sites. For Beaumont hospital Dublin: ExWell Medical; for MUHC, to cater for a large area: Cork Leisure World, Waterford Institute of Technology, Heartwise for Health and the University of Limerick; and for UHG, Cancer Care West gym.

7

 Eligibility criteria

10

Eligibility criteria for inclusion at cancer diagnosis include the following: age ≥ 18 years, with multidisciplinary team (MDT) referral for neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NCT) prior to planned oesophagectomy or gastrectomy; with confirmed MDT evidence of adenocarcinoma or squamous cell cancer of the oesophagus, oesophago-gastric junction or stomach requiring planned surgical resection; with recorded measurement (endoscopic or otherwise) that the tumour starts more than 5 cm below crico-pharyngeus. Exclusion criteria include the following: inability to give informed consent; inability to participate in exercise training (unable to perform 6MWT); patients with high-grade dysplasia (squamous cell or adenocarcinoma), distant metastatic disease at time of enrolment or during their NCT therapy, or showing evidence of previous/concomitant malignancy that would interfere with this treatment protocol; or pregnancy.

8

 Interventions

11a

Participants are randomised (1:1) to either a structured exercise training programme or usual care control group at baseline

9

11b

The intervention will be discontinued for a given participant should they no longer wish to participate.

10

11c

Strategies to improve adherence to intervention protocols include the following: the participants will meet the instructors face to face at the structured exercise sessions, and in addition, they will receive phone calls from the team to monitor their progress and answer any questions they may have on a regular basis.

10

11d

All routine cancer care is permitted for both groups

9

 Outcomes

12

The primary endpoint is cardiorespiratory fitness measured by the 6-min walk test between the baseline assessment and the pre-surgery time point. Secondary endpoints include the measurement of cardiorespiratory fitness, physical health assessed using upper and lower body strength tests, activity behaviours, body mass index, and frailty; and psychological health assessed using health-related quality of life questionnaires and semi structured interviews. Exploratory endpoints include post-operative morbidity, comprenhensive complication index, hospital length of stay, nutritional status, immune and inflammatory markers, cancer staging, response to NCT, medico-economics analysis of cost effectiveness of the exercise intervention on reducing health care costs and burden additionally rates of NCT toxicity, tolerance and compliance.

13

 Participant timeline

13

Outcome measurements are taken for all participants at baseline, post-NCT, pre-surgery, 3 days post-surgery, 5 days post-surgery, 4 weeks post-surgery and 10 weeks post-surgery.

7

 Sample size

14

The sample size calculation was based on results from the Minnella et al. study, which identified a pre-operative score gain in 6 MWT of 60 m from a baseline score of 450 m (standard deviation 85 m), which is an approximate 13% improvement. Assuming a similar baseline score, a 15% score gain can be detected with p value of 0.05 and power 80% with a sample of 26 participants with full data in two groups. With an anticipated 20% drop-out, recruitment of 62 participants is anticipated.

18

 Recruitment

15

Inclusion of three clinical sites and seven exercise sites with the additional option of a home programme.

7

  sequence generation

16a

Randomisation is performed using a central data management to generate a random allocation sequence (1:1).

9

  Allocation concealment mechanism

16b

Randomization allocation is stored in opaque envelops at the lead exercise site (ExWell Medical, Dublin).

9

  Implementation

16c

Randomisation is generated by the lead coordinator and exercise lead (LL).

9

Blinding (masking)

17a

Due to the nature of the intervention, blinding of patients or psysiological assessors is not possible. Treating surgeons and their teams are blinded to randomisation as is the primary analyst.

9

17b

Unblinding will not be permissible

9

 Data collection methods

18a

The outcomes are listed in Table 1: Outcomes and assessment measures.

13

18b

The participants are contacted by telephone during the intervention to promote participant retention and complete follow-up. Baseline data to be collected for participants who discontinue or deviate from intervention protocols, unless they withdraw consent.

13

 Data management

19

Data will be double data entered, and data validation will take place according to the procedures set out in the data management plan and data validation plan. Prior to any statistical analysis, all variables will be checked for the number of missing values, impossible values and improbable values. Impossible and improbable values will be defined by clinical opinion. Improbable values will also include values that are outside three standard deviations of the mean value. Any questions regarding the data will go back to the data manager. Descriptive statistics will be calculated for all variables, and distributional assumptions will be checked.

20

 Statistical methods

20a

The analysis will be performed as an intention-to-treat analysis. No interim analysis will be conducted. Data validity will be conducted prior to analysis and corrected as appropriate. This includes tabulation of discrete score values and graphical representation of continuous variables (e.g., histograms and box plots).

The study population will be described separately for two randomised groups using variables obtained at baseline. The variables will be described as mean (SD) and numbers (%) as appropriate.

The primary analysis of the primary outcome will be conducted as t-tests of independent group mean differences in 6MWT at each time point. The mean difference and 95% confidence interval will be reported and illustrated graphically. Individual change in 6MWT will be calculated from baseline and compared at different time points using t-tests. In addition, binary outcome variables indicating ability to walk more than the combined median distance at baseline will be constructed, and the group distribution will be tested at different time points using chi-squared tests.

18

20b

The secondary analysis of the primary outcome will use mixed-level analysis with intervention group, time point and interaction of intervention and time points. This analysis will include baseline score for the outcome measure as covariate. The estimated parameter for the interaction variables will be interpreted as the difference-in-difference between the two groups over time. A separate analysis will explore potential differences in the intervention group between participants who received the intervention at a training centre and those who trained at home. This analysis will be expanded to include descriptive baseline variables such as sex and age. The secondary analysis will use mixed-level analysis and include baseline score and baseline characteristics as covariates.

The cost-effectiveness analysis will be conducted from a societal perspective over the duration of the trial period. No extrapolation of long-term economic outcomes is planned. The EQ-5D-5 L data reported at each time point will be used to estimate quality-adjusted life years using time-weighted utility scores. The utility scores will be calculated for each individual at each data point using the Irish scoring algorithm for EQ-5D-5. The area under the curve denotes the QALY, and incremental QALY is determined as the mean group difference.

Cost of the intervention and subsequent resource use will be calculated for each individual using average cost per participant for the intervention programme and self-reported data on healthcare utilisation. Unit costs will be obtained from national sources and assigned to the resource utilisation and aggregated over the whole trial period for each individual. Net monetary benefit (NMB) will be estimated as the cost minus the QALY gain multiplied by an assumed threshold value per QALY. The NMB estimates will also be analysed using regression methods to account for variation in group characteristics and to identify sub-populations where the intervention might have an incremental cost-effectiveness ratio.

20c

Participants with missing data, because of early drop-out, loss to follow-up or missed participation in the data collection, can bias the results. By design, no data will be missing at baseline because only participants with complete baseline data will be randomised.

Missing variables in outcome measures will be handled according to instrument developers’ guidelines. As a general rule, if more than 20% of the items of an instrument are missing, the summary score will be assigned as missing.

Missing data will be reported as part of the summary presentation of the raw data.

Logistic regression will be used to explore whether participants with missing data have different characteristics than the completers or whether missing data can be assumed missing by random. If a pattern in missing data can be observed, missing data will be handled using “multiple imputation” techniques where missing variables are predicted in multiple dataset using descriptive variables identified as important covariates for missing data (sex, age, intervention group and baseline score).

19

 Data monitoring

21a

Data are monitored after the first complete patient at each site to ensure high-quality data. Data will be double data entered, and data validation will take place according to the procedures set out in the data management plan and data validation plan. Prior to any statistical analysis, all variables will be checked for the number of missing values, impossible values and improbable values. Impossible and improbable values will be defined by clinical opinion. Improbable values will also include values that are outside three standard deviations of the mean value. Any questions regarding the data will go back to the data manager. Descriptive statistics will be calculated for all variables, and distributional assumptions will be checked.

20

21b

No interim analysis will be conducted.

18

 Harms

22

Adverse events will be recorded in the relevant case report form by the researcher. Fatal or life-threatening serious adverse events are reported within 24 h of the research team becoming aware of the event. The serious adverse events form documents the nature of the event, date of onset, severity, corrective therapies given, outcome and causality (i.e., unrelated, unlikely, possibly, probably, or definitely). Queries relating to adverse event reporting will be directed to the chief investigator in the first instance.

17

 Auditing

23

Complete compliance will occur with any auditing processes required by sponsor.

17

 Research ethics approval

24

Beaumont Hospital Ethics (Medical Research) Committee REC Ref: 18/58

Dublin City University Research Ethics Committee Ref: DCUREC/2018/255

University Hospital Galway Clinical Research Ethics Committee Ref: C. A 2160

Mercy Hospital Cork CREC Review Reference Number: ECM 4 (mm) 19/04/19

Waterford Institute of Technology REF:WIT2019REC0011

24

 Protocol amendments

25

All site leads will be contacted by telephone if a significant amendment is made to the protocol. The amended protocol will then be emailed to all site leads.

 Consent or assent

26a

The study will be discussed with patients after their initial diagnosis is known but before neo-adjuvant treatment has started. No patient will have the study discussed with them on the day that they find out their diagnosis. Potentially eligible patients will have the study discussed with them by the principal investigator, or a nominated senior non-consultant hospital doctor at their next OPD appointment. Interested patients will receive an information leaflet and consent form for the study. After a period of 72h, patients will be contacted by telephone to confirm their interest in the study. Consent forms will be signed at their patient visit.

25

26b

Additional explicit consent will be sought for collection and use of participant data and biological specimens in ancillary studies.

25

 Confidentiality

27

Data will be entered with all direct patient identifiers removed; patients will be identified by study codes. All physiological data are held in an encrypted format. All data will be stored on a secure password protected desktop in a secured locked room.

20

 Declaration of interests

28

The authors declare that they have no competing interests

25

 Access to data

29

The data will only be accessed by the designated members of the research team.

 Ancillary and post-trial care

30

After the trial, the structured exercise classes will continue, and participants may continue to use the facilities.

 Dissemination policy

31a

The results will be published in peer-reviewed journals and disseminated at conferences and scientific meeting internationally. The findings of the trial will also be published in patient information magazines and booklets as informed with the help of the patient public involvement group.

31b

Authorship eligibility guidelines will be discussed and agreed with all contributors prior to publication, and the use of professional writers is not intended.

31c

No plans exist to grant public access to the full protocol, participant-level dataset, and statistical code.

 Informed consent materials

32

Model consent form and other related documentation are given to the participants and authorised surrogates.

 Biological specimens

33

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable. (Not applicable)