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

Title

A multi-centre, parallel group randomised controlled trial, in locally advanced rectal cancer patients investigating the effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients (The EMPOWER Trial).

Trial registration

ClinicalTrials.gov: NCT01914068 (received: 7 June 2013)

Protocol version

16/01/2015, version 4

Funding

National Institute for Health Research (NIHR) for Patient Benefit Programme (PB-PG-0711-25093).

Roles and responsibilities

MPWG, SJ, MAW, GJK and HBR conceived the study. LL, MAW, GJK, HBR, SMB, TC, PC, CB, DHP, MGM, MPWG and SJ contributed to the study design. LL drafted the manuscript, which underwent revision by all other authors. All authors read and approved the final manuscript.

Sponsor contact information

Dr Mikayala King, Research & Development Department, University Hospital Southampton NHS Foundation Trust.

Email: Mikayla.King@uhs.nhs.uk

Sponsor and funder

The sponsor and funding course had no role in the design of the study and will not have any role during its execution, analyses, interpretation of the data or decision to submit results.

Committees

The chief investigator (CI: Dr Jack) has overall conduct of the study. The study co-ordinator (SC: Ms Loughney) ensures day-to-day management of the study while working in close contact with the LA Prof. Grocott. The SC is the first point of contact for enquiries from all hospital sites. The SC and CI ensure milestones are achieved in a timely manner.

The study management group (SMG) is constituted by the CI and all co-investigators. This group is responsible for the strategic management of the study. The SMG maintain quarterly teleconferences and meet face-to-face twice per year (minimum of six meetings). The SMG is chaired by the CI. Local study management groups (LSMGs) comprise participating local investigators, data manager, specialist nurses, clinicians and the local patient representative. Each LSMG is chaired by the local study lead. The LSMGs meet monthly, and the CI will call additional ad hoc meetings. Each hospital has its own ICH-GCP standard with random audit of documents.

Background and rationale

The standard treatment pathway for locally advanced rectal cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Neoadjuvant CRT has been shown to decrease physical fitness, and this decrease is associated with increased post-operative morbidity. Exercise training can stimulate skeletal muscle adaptations such as increased mitochondrial content and improved oxygen uptake capacity, both of which contribute to physical fitness. The aims of the EMPOWER trial are to assess the effects of neoadjuvant CRT and an in-hospital exercise training programme on physical fitness, health-related quality of life (HRQoL), and activity levels, as well as post-operative morbidity and cancer staging.

Comparators

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.

Objectives

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

Primary hypothesis: A 9-week in-hospital exercise training programme compared with a usual care control group (usual care - no formal exercise training) will result in a clinically significant difference in oxygen uptake at lactate threshold (\( \overset{\cdotp }{\mathrm{V}}{\mathrm{o}}_2 \) at \( {\widehat{\uptheta}}_{\mathrm{L}} \) ; 2.0 mL.kg^-1.min⁻¹) assessed using CPET, following neoadjuvant CRT prior to elective cancer surgery.

Secondary hypothesis: a) An in-hospital exercise training programme compared with a usual care control group (usual care - no formal exercise training) will result in an improvement in psychological health benefits assessed using semi-structured interviews and questionnaires such as EORTC QLQ-30 and EQ-5D, following neoadjuvant CRT prior to cancer surgery. b) Neoadjuvant cancer treatment will result in a reduction in \( \overset{\cdotp }{\mathrm{V}}{\mathrm{o}}_2 \) at \( {\widehat{\uptheta}}_{\mathrm{L}} \) assessed using CPET.

Exploratory hypotheses: A 9-week in-hospital exercise training programme compared with a usual care control group (usual care - no formal exercise training) will be associated with 1) a change in physical activity, assessed using SenseWear accelerometer, following neoadjuvant CRT prior to cancer surgery; 2) a change in day 5 surgical morbidity (using POMS) and 3) a change in magnetic resonance (MR)-defined local rectal cancer staging assessed using the TNM classification system (tumour, nodes, metastasis) and tumour regression grading (mrTRG).

Trial design

Parallel group randomised controlled multi-centre trial.

Study setting

In-hospital. Hospitals include: the University Hospital Southampton NHS Foundation Trust; Aintree University Hospitals NHS Foundation Trust; Royal Hampshire County Hospital, South Tees Hospitals NHS Foundation Trust; and Royal Bournemouth Christchurch Hospitals.

Eligibility criteria

Eligibility criteria for inclusion at cancer diagnosis include the following: age ≥18 years, with MR-defined locally advanced (circumferential resection margin threatened) resectable rectal cancer (≥T2N + M0), undergoing standardised neoadjuvant CRT, and with no distant radiological defined metastasis. Exclusion criteria include the following: inability to give informed consent, non-resectable disease, distant metastasis, inability to perform CPET or bicycle exercise, and patients who declined surgery or neoadjuvant CRT, or who received non-standard neoadjuvant CRT.

Interventions

Patients are randomised (1:1) to either an in-hospital exercise training programme or usual care control group following neoadjuvant CRT (week 0).

Exercise intervention group

The exercise training programme was designed to improve physical fitness in the time interval between the end of neoadjuvant CRT and surgery. Exercise training begins on the first week following completion of the neoadjuvant CRT with patients exercising in pairs for camaraderie. The exercise training programme is described below.

Outcomes

Following completion of neoadjuvant CRT (week 0) prior to surgery, patients are randomised to an in-hospital exercise-training programme (aerobic interval training for 6 to 9 weeks) or a usual care control group (usual care -no formal exercise training). The primary endpoint is oxygen uptake at lactate threshold (\( \overset{\cdotp }{\mathrm{V}}{\mathrm{o}}_2 \) at \( {\widehat{\uptheta}}_{\mathrm{L}} \)) measured using cardiopulmonary exercise testing assessed over several time points throughout the study. Secondary endpoints include HRQoL, assessed using semi structured interviews and questionnaires, and physical activity levels assessed using activity monitors. Exploratory endpoints include post-operative morbidity, assessed using the Post-Operative Morbidity Survey (POMS), and cancer staging, assessed by using magnetic resonance tumour regression grading.

Participant timeline

CPET is used to assess physical fitness over a series of time points (which vary in each hospital dependent on cancer treatment and time interval between CRT – surgery): baseline (pre-neoadjuvant CRT), mid-chemotherapy-CRT, post-neoadjuvant CRT (week 0), week 3, week 6 and week 9. HRQoL is assessed in two ways: 1) Semi-structured interviews are conducted at week 0 (following neoadjuvant CRT) and at week 6 to 9 (prior to surgery) to explore patients’ perceptions of quality of life, which allows the patients to focus on personal accounts of their HRQoL within a specific context (for example, exercise participation and active cancer treatment); 2) HRQoL questionnaires are administered over several time points during the study: baseline (pre-neoadjuvant CRT), mid-chemotherapy CRT (in UHS only), mid neoadjuvant CRT, post neoadjuvant CRT (week 0), week 3, week 6, week 9 and 30 days post-surgery. Daily physical activity is measured over three consecutive days and nights at a series of time points; baseline (pre neoadjuvant CRT), mid-chemotherapy-CRT (in UHS only), post-neoadjuvant CRT (week 0), week 3, week 6 and week 9. Physical activity is measured using a multi-sensory accelerometer ((SenseWear Pro® armband (Model MF-SW, display model DD100); BodyMedia, Inc., Pittsburgh, PA, USA)) (see Table 1).

Sample size

A sample of 46 patients is required to detect a difference between groups of 2.0 mL.kg^-1.min⁻¹\( \overset{\cdotp }{\mathrm{V}}{\mathrm{o}}_2 \) at \( {\widehat{\uptheta}}_{\mathrm{L}} \) using a two-sample t-test at the 5 % significance level with 90 % power. This is based on a standard deviation of the change in \( \overset{\cdotp }{\mathrm{V}}{\mathrm{o}}_2 \) at \( {\widehat{\uptheta}}_{\mathrm{L}} \) values of 1.8 ml.kg⁻¹.min⁻¹ and is inflated to allow for 20 % patient drop-out. This estimate was calculated using the sampsi function in Stata/IC 12.0.

Recruitment

If recruitment is not achieving the target sample size, additional hospitals will be opened to recruit participants.

Allocation:

Sequence generation

Patients are randomised (1:1) to either an in-hospital exercise training programme or usual care control group using the Trans European Network for patient randomisation in clinical trials system (TENAELA System).

Implementation

Randomisation will be generated by the research nurse/Physiologist at each hospital site.

Blinding

Two independent physiological data assessors are blind to group allocation and are independent to the intervention.

Data collection methods

For the primary and secondary outcomes, CPET measures changes in physical fitness. Questionnaires and semi-structured interviews will assess changes in HRQoL and physical activity monitoring measures changes in activity levels. Other outcomes are listed in Table 1: Outcomes and assessment measures used in the EMPOWER trial.

Data management

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 number of missing values, impossible 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 checked.

Statistical methods

The effect of neoadjuvant CRT and the exercise intervention on physical fitness will be assessed using a two-sample t-test, and a 95 % confidence interval on the mean difference between the two groups will be presented. In order to assess the sensitivity of results to covariates, a further ‘adjusted’ effect will be calculated using linear regression where up to three candidate covariates will be identified. Basic exploratory analysis of physical fitness at each time-point will be undertaken to investigate the longitudinal response of fitness. Linear mixed modelling will then be employed to compare more formally the fitness at each time-point. Confirmatory analysis using ordinal regression will be used to assess the suitability of the t-test for comparing HRQoL between groups. The effect of an in-hospital exercise training programme on physical activity will be analysed in the same way as physical fitness. The presence/absence of post-operative morbidity as defined by a POMS score > 0 will be compared between groups by calculating the relative risk with a 95 % confidence interval. Cancer staging will be reported as tumour, node metastasis version 5 (TNM) staging, Response Evaluation Criteria in Solid Tumours (RECIST) and MR tumour regression grading (mrTRG) criteria. Pathological outcomes will be graded according to the pathological tumour regression grading (TRG) and TNM). Univariate logistic regression analysis will be used to analyse the association between demographic variables (patient age and sex), MRI parameters and pathologic tumour response This enabled calculation of odds ratios (OR) for the probability of an unfavourable pathological outcome. Analyses of sensitivity, specificity, positive and negative likelihood ratios will be performed.

Data monitoring

Data is monitored after the first complete patient at each site to ensure high quality data. Additionally, quality checks are carried out on all CPET’s. An interim analysis will be conducted at the half-way point of the trial.

Harms

All adverse events are recorded in the relevant case report form; adverse events during CPET are reported to the chief investigator and adverse effects during exercise training (pain and muscle soreness) are recorded in the relevant case report form by the research physiologist/nurse. Fatal or life-threatening serious adverse events (SAEs) are reported within 24 hours of the local site becoming aware of the event. The SAE form documents the nature of the event, date of onset, severity, corrective therapies given, outcome and causality (that is, unrelated, unlikely, possibly, probably, definitely). Any questions concerning adverse event reporting are directed to the chief investigator in the first instance.

Research ethics approval

Ethical approval: North West Centre for Research Ethics Committees (13/NW/0259, Date: May 2013)

Protocol amendments

Protocol amendments will be agreed and approved by the North West Centre for Research Ethics Committees.

Consent or assent

All potentially eligible patients are identified at multi-disciplinary meetings and approached with written information about the trial at the oncology/surgical outpatient appointment. Patients are contacted by telephone to provide additional information about the trial and to confirm their eligibility. If the patient chooses to participate in this trial, the first research visit is organised where written informed consent is obtained and all baseline measurements are undertaken.

Confidentiality

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 in a secured locked room.

Declaration of interests

The authors declare that they have no competing interests.

Access to data

Only members of the clinical and research team will have access to patient records.

Dissemination policy

Dissemination of findings to the academic community will be led by the lead applicant guided by the SMG. Dissemination of research findings to patients and the general public will be led by the patient representatives guided by the SMG. The SMG will give public engagement interviews/talks in support of the patient representatives. Active patient involvement will be sought for radio and television interviews, together with issuing of patient statements that can be used at local hospital level to raise awareness regarding prehabilitation and an active life-style in general. The SMG have extensive experience of disseminating medical information to the public and the media, due to the involvement of Professor Grocott as founder member of the Improving Surgical Outcomes Group. He is also involved in the Caudwell Xtreme Everest project, which was widely publicised. The group delivered more than 100 lectures to schools, colleges and in other public forums.