Prehabilitation during a pandemic: preoperative exercise to improve fitness in patients undergoing complex surgery for cancer of the lung or oesophagus, the PRE-HIIT trial: an updated study protocol

An Update on the Pre-HIIT Trial

This update relates to the PRE-HIIT study protocol, a randomized clinical trial examining the effect of a pre-operative high intensity interval training (HIIT) programme on cardiorespiratory fitness in patients scheduled for oesophagectomy and major lung resections. This update should be read in conjunction with the original protocol publication¹.

Cancer prehabilitation aims to reduce post-treatment morbidity and improve pre-treatment health status to increase treatment options. There are now multiple opportunities for prehabilitation in oncology care which require further exploration². However, due to the outbreak of the global Coronavirus disease 2019 (COVID-19) virus, there is a need to explore how to deliver safe and effective preparation for surgery during a pandemic. The original PRE-HIIIT study involved the face to face delivery of hospital-based exercise training for patients awaiting major thoracic oncological resections. However, the current delivery of exercise based prehabilitation must balance minimising the risk of nosocomial spread of COVID‐19 against optimising care for acute surgical conditions³.

It continues to be crucial to develop prehabilitation strategies which target modifiable risk factors, such as pre-operative fitness, which may have an impact on postoperative outcomes⁴. For patients in which social distancing recommendations or a COVID-19 infection resulted in them performing less physical activity than their usual baseline, an increase in physiologic operative stress related to cardiopulmonary deconditioning is expected. Decreased physical activity levels may present along with changes in other behaviours that are well documented to be associated with increased surgical risk, such as poor nutrition⁵. Therefore, it is as important as ever to optimise patient’s preparation for surgery through delivering virtual prehabilitation exercise programmes when it is not permissible for participants to attend regular face to face exercise training sessions. The PRE-HIIT protocol has been updated to ensure investigation continues into how strategies, such as HIIT, can be used to optimise patients’ post-operative outcomes during a global pandemic.

Study aims

The overall aim of this work remains unchanged from the original published protocol¹: to examine the impact of a pre-operative HIIT programme on the cardiorespiratory fitness of patients scheduled for major thoracic surgery (transthoracic oesophagectomy or major lung resection).

As per the original protocol, secondary aims will explore the impact of the intervention on physical fitness levels post chemo(radio) therapy, post-operative complications, post-operative physical recovery, and post-operative health care costs. Participants’ experiences of prehabilitation will also be explored. In addition to these existing aims, this revised protocol will also explore participant’s satisfaction with delivery of prehabilitation via telehealth.

Study design

As previously described¹, the PRE-HIIT trial will take the form of a two-armed randomised control trial (RCT); an intervention group who in addition to standard care will undertake a 2-week HIIT exercise programme (PRE-HIIT programme) in advance of their surgery, and a control group who receive standard care only which includes a moderate intensity physiotherapy led exercise programme. The PRE-HIIT programme will now be delivered as a home-based intervention. Both the exercise intervention and standard care will be delivered via telehealth. The study assessments will continue to take place in the Wellcome Trust-Health Research Board (HRB) Clinical Research Facility (CRF) at St James’s Hospital (SJH), Dublin. Approval for this updated protocol has been granted from the Tallaght University Hospital (TUH)/St James’s Hospital (SJH) Ethics Committee. The study will be performed according to the Declaration of Helsinki. The flow of participants through the study is depicted in Figure 1.

Figure 1. The PRE-HIIT trial outline.

Study participants

Inclusion and exclusion criteria are detailed elsewhere¹. In brief, participants must have a confirmed diagnosis of oesophageal or lung cancer, be scheduled for either a transthoracic oesophagectomy or major lung resection, be ≥ 2 weeks from their date of surgery at the baseline assessment, have medical approval to participate, successfully complete a cardiopulmonary exercise test (CPET), and be free from any contraindication for safe exercise prescription. To facilitate remote delivery of prehabilitation participants must also have high speed internet access suitable for video calling.

Recruitment and screening

Participant recruitment and screening procedures will take place in SJH, Dublin, Ireland and will be conducted as per the original protocol¹.

The recruitment target for the study remains 78 participants (39 per study arm). Potentially eligible patients will be informed about the study by a member of the research team (SJH) and will receive a participant information leaflet. Initial eligibility screening will be completed by the research team. In light of the current pandemic participants will give initial consent verbally over the telephone. A participant screening assessment will then be completed over the telephone and, if eligible, participants will be scheduled for an appointment in the Clinical Research Facility in St James’s Hospital. In order to minimise face-to-face contact, where possible, assessment data will be collected via telephone/videocall (e.g. demographic data, dietary interview etc). Questionnaires will be provided to participants to complete before or after their face to face assessment. Written informed consent will then be obtained during the participants first face to face assessment (see extended data⁶).

Randomisation, allocation, concealment and blinding

Randomisation, allocation, concealment and blinding of participants will be conducted as per the original protocol¹. In brief, participants will be randomised in a 1:1 ratio to the intervention or control arm by computer-generated randomisation. Study assessments will be performed by an assessor blinded to treatment allocation.

Intervention

PRE-HIIT intervention. The PRE-HIIT intervention prescription has been previously described¹. In summary the programme is a pre-operative HIIT training programme which is delivered for at least two weeks, five days per week in advance of surgery. Due to the COVID-19 pandemic, public health guidelines in Ireland now advise patients to self-isolate for two weeks in advance of their surgery. Accordingly, it is not appropriate to deliver the intervention as per the original protocol which would involve participants attending the multiple hospital-based exercise sessions within that two-week preoperative period. As a result, participants assigned to the HIIT programme will complete the exercise intervention in their homes. All participants will be provided with a programmable bike on loan for the duration of their intervention. Participants will complete their first home exercise session under in-person supervision from a physiotherapist with experience in exercise prescription and exercise oncology. During the first session, the research team will set up the bike and familiarise the participant with the exercise protocol. All subsequent home exercise sessions will be supervised by a physiotherapist via video call. Exercise intensity will be monitored via Polar heart rate monitors (Polar M200) with information available remotely to the research team.

Maintenance of nutritional adequacy. As described previously, participants randomised to the intervention will receive an additional tailored dietetic assessment with the exercise programme to ensure nutritional adequacy is maintained throughout the duration of the intervention¹. Weight and height will be measured and BMI will be calculated. Dietary intake will be assessed using tailored dietary interview strategies (incorporating 24-hour recalls and qualitative information such as meal pattern and eating strategies). Moreover, gastrointestinal symptoms and dietary complications will be assessed and recorded. The dietetic assessment will now be carried out remotely via video call/telephone by a registered dietitian with experience working with surgical oncology patients.

Standard survivorship care group. The standard care control group will continue to receive standard medical care and nutrition support. This group will not be given specific advice regarding exercise beyond that considered usual medical care. This group will continue to receive standard pre-operative exercise advice and prescription of a moderate intensity exercise programme; now delivered via telehealth.

Outcomes

The updated PRE-HIIT study outcomes are listed in Table 1. The main assessment battery will be performed at: diagnosis (Dx), baseline (T0), and post-intervention (T1). In addition, follow-up data will be collected post-surgery (T2).

In light of the current COVID-19 pandemic, face to face interaction time during assessments will be minimised with trial participants in order to protect participants and research staff whilst the pandemic continues. Where possible data will be collected via telephone/videocall (e.g. demographic data, dietary interview etc.), and questionnaires will be provided to participants to complete before or after their face to face assessment.

Primary outcome – The primary outcome for the trial remains cardiopulmonary fitness, measured by a maximal cardiopulmonary exercise test. Testing will be carried out as previously described¹.

Secondary outcomes

Secondary outcome 1: Postoperative morbidity

No changes have been made to the measurement of postoperative morbidity. A suite of validated instruments will be used to collect data; the Clavien-Dindo Scale, the Postoperative Morbidity index (POMS) and the Comprehensive Complications Index (CCI).

Secondary outcome 2: Pulmonary and physical performance

Measures of pulmonary and physical performance include pulmonary function, ventilatory and peripheral muscle strength, functional capacity and self-reported functional recovery.

Secondary measures of pulmonary function and maximal inspiratory pressure (PImax) will not be completed with participants while the COVID-19 pandemic remains a concern due to the risk associated with aerosol generating procedures.

No changes will be made to measures of peripheral muscle strength (measured by 1 repetition max), self-reported physical activity (measured by the IPAQ), functional performance (measured by the short physical performance battery) or self-reported functional recovery.

Secondary outcome 3: Quality of life (QOL)

As per the original protocol, QOL will be measured using EORTC QLQ-C30 and relevant subsets at Dx, T0, T1 and on POD30. Disease specific modules such as the oesophageal EORTC QLQ-OES18 and QLQ-OES25 and the lung EORTC QLQ-LC 13 will be used in conjunction with the main questionnaire to monitor disease specific symptoms. QOL will be further measured using the EuroQol (EQ) EQ-5D-5L to analyse cost effectiveness of the intervention.

Secondary outcome 4: Programme acceptability

Patients will be asked to complete a self-administered survey to evaluate the acceptability of the PRE-HIIT programme delivered via telehealth⁷.

Qualitative approach

At the pre-surgery assessment (T1) a sub-cohort of the study’s participants will take part in a semi-structured interview⁷. This interview will collect feedback on how the PRE-HIIT study has impacted on their preparation for surgery and participant satisfaction with the delivery of PRE-HIIT via telehealth. Interviews will be held via telephone/videocall with approximately the first 20 participants enrolled on the trial or until data saturation is reached.

Adherence

Adherence to the exercise component of PRE-HIIT will be measured with traditional adherence variables, i.e. completion of supervised home-based sessions, and monitoring of compliance to the prescribed exercise protocol. Compliance to the aerobic component will be documented by the achieved heart rates on the Polar heart rate monitors, and the duration of aerobic exercise. During the supervised home sessions compliance will be monitored by the supervising physiotherapist. During unsupervised homebased sessions participants will record their compliance in a home exercise diary. In addition to these traditional measures of adherence, PRE-HIIT will implement a series of drug trial adapted adherence outcomes as described by Nilsen et al.⁸. These additional adherence variables will include permanent treatment discontinuation, treatment interruption, dose modification, early session termination, and pre-treatment intensity modification. Updated adherence variables are described fully in Table 2.

Safety

As previously described, prior to baseline testing, all participants will require written medical approval confirming their suitability for participation¹. Patients will only be formally enrolled in the study after successfully completing a CPET with electrocardiogram (ECG) monitoring. All CPET will be medically supervised. All incidents will be recorded, and serious incidents will be reported to the research ethics committees. An antibacterial/antiviral filter will be installed in the CPET circuit to minimise infection risk by reducing the amount of droplet aerosol dispersion in the air mitigating the contamination of the environment during testing.

In response to the COVID-19 pandemic, all research staff will wear appropriate levels of PPE and will maintain physical distancing from participants where possible during all assessments and supervised exercise sessions. In line with infection control operating procedures, participants will be screened for symptoms of COVID-19 the day before their assessment/supervised home exercise session via telephone. Participants will be re-screened on arrival at the Clinical Research Facility for their assessment. Participants will be required to sanitise their hands-on arrival and wear a surgical face mask. After each appointment the research team will remove all PPE in assessment area. The research team will wipe down all used surfaces with detergent wipes and perform hand hygiene.

Statistical considerations

Sample size calculation. As outlined previously, the primary response is the change in VO₂peak from baseline (T0) to post-intervention (T1). On the basis of estimates calculated from our pilot study, a sample of size 64 (32 in each arm) is needed in order to detect a mean difference in VO₂peak of 1ml/kg/min between the control and intervention groups.

Statistical analysis, data monitoring, dissemination, public and patient involvement. Information on the study Statistical Analysis, Data Monitoring, Dissemination, Public and patient involvement is described previously¹. A brief overview of each section is provided here:

Statistical analysis

Quantitative data analysis will be performed using R IBM SPSS software. Summary statistics for continuous variables and categorical will be presented. A linear mixed model will be used to model the longitudinal change in the primary response between the groups, allowing for missing data and allowing for within subject correlations in the repeated measures across time. The model will adjust for the baseline response variable and other covariates as necessary.

Qualitative data will be digitally audio-recorded and transcribed verbatim for data analysis. Braun and Clarke’s 6 stage approach to thematic analysis will be used to analyse all data collected. A team of researchers will analyse all transcripts following an agreed process using nVivo 12 (QSR International, Australia).

Data monitoring

Data monitoring will be provided by the trial steering committee, including overall project supervision, progress monitoring, advice on scientific credibility and ensuring the integrity and appropriate running of the project. The research team will make quarterly reports to the trial steering committee.

Data management

The Data Management Plan⁶ will outline how research data will be handled during and after the project. The data management plan is a live document and will be reviewed regularly throughout the study. Source documents for this study will include hospital records, procedure reports and data collection forms. Outcome assessments will be recorded in a paper-based case report form. Data from the case report form will then be entered into a password protected computer data repository. Data validation will be used to avoid erroneous data entry. All participants will be allocated a unique study code. The key to the study code will be stored securely and separately. All paper records will be stored in locked filing cabinets, in a locked office in a restricted access building with swipe access. Electronic records will be stored on password protected encrypted devices. Upon completion of the trial an anonymised data set will be deposited on a secure online repository in line with open access publication requirements.

Public and patient involvement (PPI)

PRE-HIIT will involve a number of PPI initiatives. We will seek feedback on participant documentation, particularly the participant information leaflet and consent form, to ensure readability and clarity. In addition, a patient representative will be invited to speak at the education symposium in the final year of the project.

Dissemination of information

Findings of PRE-HIIT will be disseminated via peer reviewed publications and conference presentations. Aggregate study results will be presented to participants and their families at an education symposium upon study completion. Anonymised data will be made available on an open access repository.

Study status

Recruitment will begin in January 2021.

Ethical statement

Ethical approval has been granted by the Tallaght University Hospital/St James’s Hospital Research Ethics Committee (REC: 2020–02 List 7).

Underlying data

No data are associated with this article.

Extended data

Open Science Framework: Prehabilitation during a pandemic: Preoperative Exercise to Improve Fitness in Patients Undergoing Complex Surgery for Cancer of the Lung or Oesophagus, the PRE-HIIT trial: An Updated Study Protocol. https://doi.org/10.17605/OSF.IO/9SEVW⁶

This project contains the following extended data:

- 190329 APPENDIX I Pre-HIIT_Consent_Form_(PIL A+B) Version 1.0.docx

- 200715 PRE-HIIT Interview Guide Version 2.docx (Focus group/interview guide)

- 201028 PRE-HIIT Data Management Plan (DMP) Version 4.pdf

Reporting guidelines

Open Science Framework: SPIRIT checklist for Prehabilitation during a pandemic: Preoperative Exercise to Improve Fitness in Patients Undergoing Complex Surgery for Cancer of the Lung or Oesophagus, the PRE-HIIT trial: An Updated Study Protocol. https://doi.org/10.17605/OSF.IO/9SEVW⁶

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).