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. 2023 Oct 26;18(10):e0278252. doi: 10.1371/journal.pone.0278252

Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomised feasibility trial

Kairen McCloy 1,#, Ciara Hughes 1,#, Lynn Dunwoody 2,#, Joanne Marley 1,#, Ian Cleland 3,#, Federico Cruciani 3,#, Catherine Saunders 3,#, Jackie Gracey 1,*,#
Editor: Xian-liang Liu4
PMCID: PMC10602305  PMID: 37883461

Abstract

Background

In 2020 Globocan reported nearly 1.4 million new cases of gynaecology cancer worldwide. Cancer related fatigue has been identified as a symptom that can be present for gynaecology cancer patients many years after treatment. The current evidence around the management of this symptom suggests that exercise has the most positive outcome. However, some ambiguity remains around the evidence and whether it can address all areas of fatigue effectively. More recently, other interventions such as mindfulness have begun to show a favourable response to the management of symptoms for cancer patients. To date there has been little research that explores the feasibility of using both these interventions together in a gynaecology cancer population. This study aims to explore the feasibility of delivering an intervention that involves mindfulness and mindfulness and exercise and will explore the effect of this on fatigue, sleep, mood and quality of life.

Methods/Design

This randomised control trial will assess the interventions outcomes using a pre and post design and will also include a qualitative process evaluation. Participants will be randomised into one of 2 groups. One group will undertake mindfulness only and the other group will complete exercise and mindfulness. Both groups will use a mobile application to complete these interventions over 8 weeks. The mobile app will be tailored to reflect the group the participants have drawn during randomisation. Self-reported questionnaire data will be assessed at baseline prior to commencing intervention and at post intervention. Feasibility will be assessed through recruitment, adherence, retention and attrition. Acceptability and participant perspective of participation (process evaluation), will be explored using focus groups.

Discussion

This trial will hope to evidence and demonstrate that combination of two interventions such as mindfulness and exercise will further improve outcomes of fatigue and wellbeing in gynaecology cancer. The results of this study will be used to assess (i) the feasibility to deliver this type of intervention to this population of cancer patients using a digital platform; (ii) assist this group of women diagnosed with cancer to manage fatigue and other symptoms of sleep, mood and impact their quality of life.

Trial registration

NCT05561413.

Introduction

Gynaecology cancer encompasses 5 main types, ovarian, endometrial, cervical, vaginal, and vulva [1,2]. In the United Kingdom (UK) 21,493 new cases of gynaecological cancer are diagnosed every year [2]. Treatment modalities such as surgery, chemotherapy or radiotherapy can be effective in managing and treating these cancers but may lead to unwanted long term side effects. One side effect is fatigue, the prevalence of which, for all types of cancer, was identified as 52%. For the gynaecology cancer population, this varied between 17–33%, with many women experiencing cancer related fatigue (CRF) years after treatment [3,4]. CRF has been described not only as a physical sensation, but also has emotional and cognitive symptoms suggesting that it is multi-dimensional [5]. To date, few studies have evaluated interventions that target all dimensions of fatigue, suggesting a multi-modal approach that addresses all aspects is required.

Mechanisms

Risk factors for CRF, include depression and insomnia suggesting that the presence of these are not only correlated but may also have an impact on the levels and severity of CRF [6]. Indeed, the term ‘cluster symptom’ has recently been adopted to describe this and the most common symptoms in this cluster have been identified as depression, insomnia, and fatigue [7]. This suggests that managing fatigue may require the incorporation of interventions that deal with the multiple symptoms of depression, insomnia, and fatigue collectively [8,9].

Existing knowledge

Research indicates that exercise can have a positive effects on CRF [10–15]. However, the effect of exercise on CRF and quality of life (QoL) remains unclear [1,16] with some studies having reported positive outcomes and others demonstrating no change [15,17,18]. This ambiguity may suggest that exercise alone may not be enough to ameliorate CRF and improve QoL and a multidimensional approach may be required.

Despite the evidence of the positive effect of exercise on CRF, adherence to exercise remains a problem, with less than 20% of women with ovarian cancer exercising regularly following treatment [19]. Barriers to exercise include time constraints, cost, weather, side effects of treatment or exercise such as fatigue, social aspects, not being aware of physical activity guidelines, fatigue, and psychological barriers, such as motivation [20,21]. In contrast, the facilitators to exercise identified within the literature were improved physical and mental wellbeing, decreased feelings of stress, enjoyment, satisfaction, improved levels of CRF and control over health [22–24].

Research indicates that mindfulness can have a positive effects on both CRF and QoL [25–29]. Mindfulness involves being intentionally aware of the present moment and doing this without judgement. Through practice participants develop an awareness of current emotions and thoughts with compassion and kindness which in turn will lead to better control of cognition, emotion and behaviour [30]. However, some of the effect sizes for mindfulness on psychological and physical outcomes such as depression, anxiety, fatigue were small, and did not reach minimal clinical significance. Despite this, it seems that mindfulness had positive effects on psychological distress, which is defined as an emotion that is not pleasant [31–33]. This is of importance as psychological distress and particularly symptoms of anxiety, depression, sleep, stress and quality of life have been shown to improve following the introduction of mindfulness [34–36]. Some of these symptoms are also present within the ‘cluster symptoms’ previously identified suggesting that there may also be an improvement in CRF alongside these symptoms.

Digital interventions for health have grown in number with over 50,000 medical or healthcare available on Google Play or the Apple Apps Store [37]. For cancer patients apps can have various aims including to provide education, identify and mange symptoms, lifestyle promotion and functional exercise [38]. A recent review identified how digital and interactive health interventions had a positiveeffect on physical and psychological symptoms on women with breast cancer. This review identified interventions such as music therapy, physical training such as walking, swimming, resistance training, dance, support and education and how they were delivered through a digital platform successfully and showed a favourable response [39]. Mindfulness when delivered digitally has also been shown to be feasible and result in a positive outcome [25,40,41]. Suggesting that the delivery of various interventions for cancer patients can be achieved remotely increasing the scale and inclusivity of a wider population.

Need for a trial

The majority of studies that involve exercise or mindfulness for the management of CRF and psychological distress are in the breast cancer population making it difficult to generalise findings to other cancer populations [42,43]. Both exercise and mindfulness have individually as interventions demonstrated positive effects on CRF, anxiety, depression, and sleep. Whether mindfulness and particularly adding mindfulness to an exercise regime for managing fatigue in women with gynaecology cancer is of benefit, is yet to be explored. Therefore, the aim of this study is to assess how feasible and acceptable the digital delivery of interventions of, mindfulness, and exercise, will be and if there is any effect on CRF for those with gynaecology cancer.

Theoretical model

It has been suggested that for the successful development and implementation of complex interventions a theoretical model should be used [44]. For the interventions within this study the COM-B model [45] was used as to support engagement in exercise and/or mindfulness. This model denotes that for behaviour to occur, three conditions must be met, the individual must have the Capability (both physical and psychological), the Opportunity (social and environmental) and the Motivation (reflective and automatic) to engage in the desired behaviour(s). The COM-B model is a hub that sits within the Behaviour Change Wheel (BCW), which was synthesised from previous frameworks and enhances the development of behavioural interventions [46,47]. The second layer of the BCW includes nine intervention functions (education, persuasion, incentivisation, coercion, training, enablement, modelling, environment restructuring and restrictions), which are linked to the 93 behaviour change techniques (BCTs), as described in the Behaviour Change Techniques version 2 [48]. BCTs are the smallest active ingredients of an intervention, documenting them in a standardised way can aid intervention description and replication [49]. The delivery of intervention functions is supported by the outer layer of the BCW, which includes policy categories of environment/social planning; communication/marketing, fiscal measures, legislation, regulation, service provision and guidelines. The interventions within this study used a range of intervention functions in combination which may then impact the constructs of capability, opportunity and motivation and were linked to appropriate BCTs (Box 1).

Box 1. Description of intervention functions* and behaviour change techniques† used in the interventions

Exercise Intervention

Capability

Physical Capability

    ➢Training: goal setting, reviewing progress and resetting goals, refining goals and (BCT group 1), guidance with the app and through phone calls on increasing difficulty of task and habit forming (BCT Group 8)

    ➢Education: videos and written instructions through app will guide participation to perform the activities (BCT group 6).

Psychological capability

    ➢Training: identifying problems and problem solving, problem solving strategies (BCT group 1), setting regular time for activities, getting environment ready in advance building habits (BCT group 8).

    ➢Education: within the mobile app written and audio information on the health benefits and consequences (BCT group 5).

Opportunity

Physical opportunity

    ➢Enablement: goal setting will be through the mobile app and via weekly phone contact (BCT group 1) and feedback and monitoring will be done via the weekly contact phone call and through the portal where reported data will be viewed by the research team.

Social opportunity

    ➢Environmental restructuring: family support to enable participants to complete activities or buddy up with a family or friend to complete intervention (BCT group3).

Motivation

Automatic

    ➢Incentivisation: given through feedback as praise and encouragement of activities and completion of goals (group 2). Encouraging self-belief through giving feedback at how well participants are progressing (BCT group 15)

Reflective

    ➢Education: through app the information on the health consequences of exercise how may improve symptoms of fatigue, sleep, mood. The pros and cons of the activities (BCT group 5 and 9)

Mindfulness Intervention

Capability

    ➢Education: audio and written instructions through app will guide participation to perform the activities (BCT group 6) and within the mobile app written and audio information on the health benefits and consequences (BCT group 5).

    ➢Training: formal practices within the app along with weekly contact to enable an action plan to perform the practice (BCT group 1), enabling the regular practice which will then lead to habit forming (BCT group 8).

Opportunity

Social opportunity

    ➢Environmental restructuring: family support to enable participants to complete activities along with finding an environment that is quite and suitable for practice (BCT group3).

Motivation

Automatic

    ➢Incentivisation: given through feedback as praise and encouragement of activities and completion of goals (group 2).

Reflective

    ➢Education: through app the information on the health consequences of exercise how may improve symptoms of fatigue, sleep, mood. The pros and cons of the activities (BCT group 5 and 9)

*Nine intervention functions identified in the Behaviour Change Wheel framework: education, persuasion, incentivisation, coercion, training, restriction, environmental restructuring, modelling, enablement. [45]

†Behaviour change techniques as grouped in BCT Taxonomy (v1): 93 hierarchically-clustered techniques [50]

Methods and design

Primary aim

To explore the feasibility of conducting an 8-week mindfulness and home-based walking and strength training compared to a mindfulness only programme for the management of CRF in women with gynaecology cancer delivered through an online application. The following objectives will assess feasibility outcomes:

  1. To assess participant intervention adherence, study retention and attrition rate.

  2. Explore the acceptability of using an mobile application for the delivery and data collection of the exercise and mindfulness programme.

  3. Explore the perspectives of participants concerning satisfaction (e.g. intervention and delivery) perceived value, barriers and facilitators of the digital programme.

Hypotheses of efficacy

Compared to active comparator of mindfulness, the combined intervention of mindfulness and exercise will be superior in reducing fatigue and improving mood, sleep and quality of life.

Secondary aim

To evaluate the effect of an 8 week exercise and mindfulness programme on cancer related fatigue as a primary clinical outcome and the effect on anxiety, depression, sleep and QoL as a secondary clinical outcome in an digital setting.

Study design

The Gynaecology Exercise Mindfulness Study (GEMS) will be a randomised controlled open label study. Blinding to this type of study and intervention is not possible, as outcomes are self-reported and in order to complete the programme participants will need to be aware of the arm drawn. Randomisation will be performed as block randomisation using 1:1 ratio. Participants will be randomised into the intervention group, mindfulness and exercise, or the active comparator group mindfulness only. This will allow assessment of effectiveness of the intervention for both groups on the outcome measures.

Following the intervention participants will be invited to join an online focus groups which will form the qualitative evaluation.

Study setting

The GEMS trial will be conducted remotely through a mobile application interface allowing recruitment across the UK and asynchronous delivery of the intervention. This app is a protype that has been developed in collaboration with the School of Computing at Ulster University. Pilot testing of this app has taken place with the 5 user testers and adaptations to the app have been made based on this.

Measurements

Primary measures include the feasibility and acceptability of the study and will be assessed in line with the MRC guidance on developing and evaluating complex interventions [44]. Participant reported outcome measures (PROMs) will be collected for secondary outcomes through a battery of 6 validated questionnaires described below. Estimated completion time of questionnaires is 15 to 20 minutes. See Fig 1 for an overview of schedule of enrolment, interventions and assessments. At baseline participants will also complete demographic information such as age, cancer type, education, income, and education.

Fig 1. Schedule of enrolment, interventions, and assessment.

Fig 1

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Primary outcome measures

Adherence:- -interventions will run over 8 weeks. The completion of 4 weeks for mindfulness and 30 minutes of home-based exercise weekly for two thirds (67%) of the duration of the trial will be regarded as adherence to the program. These levels of adherence are based on previous studies that have used the same levels [30,51]. This will be assessed through the electronic logs that participants will be encouraged to complete along with the app data information- on frequency and duration of participant engagement with each session.

Attrition:- Following a review of web-based mindfulness intervention studies, it is estimated that the attrition rate will be approximately 20% with 10% to 15% of missing data [52,53].

Time to recruit, recruitment and retention rates will be gathered through administrative data during (pre)screening, enrolment, allocation and follow-up. Reasons for non-participation, intervention/study dropouts will be collected when possible. Acceptability of data collection will be retrieved through missing data within questionnaires.

Acceptability of the programme will be assessed using focus groups this will include participants experience on the virtual delivery and data collection along with their experience and reflections on the exercise and mindfulness components of the intervention.

Secondary outcome measures

Fatigue:- The Functional Assessment of Chronic Therapy- Fatigue (FACIT-F) subscale is a 13- item questionnaire that uses a 5 point Likert scale and has been validated for use with various types of cancer and treatments [53,54]. A lower score indicates a greater degree of fatigue, with scores less than 20 representing severe fatigue and scores greater than 45 as normal [14].

Quality of life- The Functional Assessment of Cancer Therapy General (FACT-G) is a 28- item scale. It assesses physical, social, emotional and functional wellbeing. [55]. Higher scores indicate better quality of life [30].

Psychological outcomes will be assessed using the Hospital Anxiety and Depression Scale (HADS) [56]. The HADS consists of 14 questions, 7 each for assessing anxiety and depression [57]. A HADS score of greater than 11 is more defining of anxiety and depression, with a reduction of 3 points indicating a clinical improvement [58].

Sleep- The Pittsburgh Sleep Quality Index (PSQI) is a 19 items questionnaire that measures 7 domains of sleep, scored on a 0–3 scale over 1 month [59]. PSQI scores can range from 0–21, higher scores indicate poorer sleep quality [60].

Mindfulness- The 24 item Five Facet Mindfulness Questionnaire Short Form (FFMQ-SF) is a 5 point Likert Scale which assess mindfulness in daily life. It measures 5 sub-scales: observing, describing, acting with awareness, non-judgement of inner experience and non-reacting to inner experience. Higher scores indicate more mindful in everyday life [61,62]

Participants exercise behaviour will be assessed using the International physical activity questionnaire short form (IPAR-Q -SF). This questionnaire has 7 questions which assess the intensity, frequency and duration of exercise that participants engaged in over the last week.

Data collection and procedure

Data collection and procedure within the study are presented in the flow chart below (Fig 2).

Fig 2. Flow chart of study logistics and data collection.

Fig 2

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Recruitment

Recruitment to the study will be facilitated through cancer charities who will reach out to their service users via social media, forums and groups. The advert will have e-mail contact details for the research team where potential participants can self-refer for further information. When potential participants contact the research team for information the participant information sheet can be e-mailed to them. Those who wish to take part in the study will be screened for eligibility and those who meet the criteria will receive an e-mail link to complete the consent form through Qualtrics© online software. Once consented participants will receive a further Qualtrics© link, containing the online questionnaire (PROMs) that must be filled out (once before randomisation at baseline and then at 8 weeks post intervention).

Allocation

Participants will be randomly allocated to either group through 1:1 allocation. Block randomisation will be used with fixed block sizes of 10 to ensure an even distribution of groups will be achieved. Study randomisation will be done through Study Randomizer (2017) a web based randomisation service. One member of the research team (KMCC) will carry out all randomisation. Once enrolled all baseline questionnaires (PROMs) have been completed Study Randomizer will be used for allocation to groups [63]. Participants will be notified of group via e-mail.

Drop out and data retention. If a participant no longer wishes to take part in the study, they can inform the research team of their decision either through e-mail or phone. The study team will contact the participant who has withdrawn either by e-mail or phone to ask if they are willing to provide a reason for withdrawal. In line with institutional requirements, data will be retained for 10 years.

Inclusion criteria

Participants must fulfil the following criteria to be eligible for inclusion in the study:

  • Women diagnosed with gynaecology cancer

  • Over the age of 18

  • Still be experiencing fatigue at level 4 or above when assessed on a 10 point single-item scale where 0 = ‘no fatigue’ and 10 = ‘greatest possible fatigue’ [64]

Exclusion criteria

  • Currently actively and regularly practising mindfulness

  • Have a confirmed diagnoses of schizophrenia spectrum disorder, bipolar disorder, post-traumatic stress disorder, or risk factors for psychosis (e.g. personality disorder)

  • Have an existing medical condition that may inhibit safe participation in the exercise part of the intervention study.

Interventions

Exercise intervention

The exercise component of the study is based around home-based walking and strength and conditioning exercise which have been shown to not only be effective for cancer-related fatigue but also feasible and acceptable [65,66]. Indeed, the research team have demonstrated the positive effects with women who have gynaecology cancer in a previous study and this work will further progress these findings [15,22]. The overall aim of the programme is to achieve a goal of 30 minutes of walking 3 times per week and 2–3 strength sessions, with major muscle groups per week by the end of the 8-week intervention [15,67]. These goals are suggestions, and this programme will use an inductive approach to goal setting which will be decided through collaboration with participants and individual goal setting. A goal setting diary will be provided to participants to aid them to set and monitor goals throughout the study. Alongside this participants can set goals within the mobile app. This approach has been used in previous research conducted by this team in ‘Back on Track’ and ‘EXACT’ trials [68,69].

All materials including audio, video and written information and demonstrations of individual strength exercises, for the study will be delivered through the mobile app which participants can download following randomisation. This programme is delivered asynchronously so participants can commence the programme as soon as they download the app and choose when they wish to complete the interventions. This also allows for rolling recruitment and no requirement for a set number of participants to be recruited and randomised before any participants can commence the study. Participants will be asked to report their activities daily through the app, a daily reminder will be sent to aid reporting. Participants will be contacted by the researcher every week at a mutually agreed time. Contact will be used to assess if there are any issues, set goals for the following week and capture any missing data a standardised questionnaire will be used to assess this. Engagement and usage of the app will be captured, and this data will be analysed feasibility of delivering this type of intervention through this digital medium.

Mindfulness

The mindfulness component of this study will be based on the mindfulness-based stress reduction developed by Jon Kabat-Zinn [70]. This will involve 8 weeks of homebased formal and informal mindfulness practice which will include body scan, sitting, walking, mountain and loving-kindness practice [27,28,71]. Similar to the exercise interventions all mindfulness practices and materials are within the app allowing participants to access these when it suits them. Each week new materials and mindfulness practices will be added to the app allowing participants to build the practice as the weeks progress. The estimated time to complete each weekly online session will be between 1–2 hours with daily practices varying between 10 minutes in the initial weeks to up to 25 mins for 5–6 days per week by week 8, this can be adapted to suit the individual schedule and goals which will be discussed with participants during the weekly contact call. Logging of mindfulness practice will be encouraged through the daily app reminder. All participants will be screened to ensure there are no contraindications to undertaking mindfulness. Even though it is generally well tolerated, there is a possibility of side effects such as increased anxiety, participants will be made aware of this and encouraged to report any issues to the research team [72].

Digital procedure

Participants will be sent written detailed information on how to download the mobile app. The first step involves registration via a portal which allows the secure collecting of app data. This will generate an e-mail which gives a link to the downloading of the app dependent on the device the participant uses [73]. Once app is downloaded, logged in and opened participants will view a home page which will give a running total of activity/mindfulness material accessed and walking/exercise goals achieved. The home tab also has a send report feature where participants can upload reports of the activity for the day. The other tabs at the top include activity and mindfulness which once clicked on will display the list of material for these weeks and a visual graph which enables self-monitoring. Within the activity tab participants can set their goals and also send reports via this area. The app is designed to take into account randomisation so that participants will only be able to view the content relevant to the group they drew during randomisation. The data entered by the participants will be able to be viewed by the study team via an administration portal allowing for monitoring and feedback to participants [73]. (Fig 3. screen shots of app).

Fig 3. Mobile app screen shots.

Fig 3

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Process evaluation

Following completion of the 8-week intervention, participants will be invited to take part in focus groups to allow evaluation of acceptability and satisfaction of taking part in the study from the participants perspective. As the whole intervention will be conducted remotely, focus groups will be facilitated online via Microsoft Teams. This format for focus group has certain reported advantages, such as reduced dropouts, more relaxing for participants resulting in better communication, cost effectiveness, time saving in travel and the ability to include participants who live in more remote areas from the study centre [74]. The number and size of groups will be dependent on trial recruitment numbers and continue until data saturation, which will be reached when no new information is generated [75]. Separate groups will take place for each intervention group to ensure that each group can share and reflect on their experience of the intervention they took part in. Probe open-ended questions shaped by relevant literature and study objectives will be used to keep the discussion flowing. All focus group discussion will be audio and video recorded, then transcribed verbatim for analysis [76].

Focus groups data will be subjected to Thematic Analysis. This type of analysis is flexible in that it allows for the in-depth identification and interpretation of themes [77,78]. The phases of the analysis will include: familiarising with data, generating initial codes, searching for themes, reviewing themes, defining and naming themes and integrating these themes into a final report for publication [79].

Sample size

The sample size for this study is based upon feasibility and review of similar studies. The literature indicates that feasibility studies of similar interventions and methodologies within the cancer population recruit on average 40 participants in total [60,80,81]. Therefore, it is anticipated that this study will recruit a total of 40 participants with 20 in each arm of the study.

Statistical analysis

Descriptive statistics will be performed to produce mean values and standard deviations. Groups will be compared at baseline using independent t-test (two independent samples) for continuous data, and the chi-square test for independence for categorical data.

Primary analyses will be performed using the intention to treat on all data and using imputation method where outcomes are missing. Alpha will be set a priori at a level of p = 0.05. Repeated-measures ANOVAs will then be used to determine the effects of exercise and mindfulness and mindfulness intervention on changes in all outcomes of interest.

As this is a feasibility study and preliminary efficacy study, effect sizes (Cohen’s d) will be calculated by taking the mean difference and dividing by the pooled standard deviation to better estimate the meaningfulness of change for each observed outcome following the intervention. The values and meanings for effect size estimates are a small effect size (d = 0.2), a moderate effect size (d = 0.5), and a large effect size (d = 0.8).

Corelation analysis will be performed to determine whether changes in mindfulness/exercise are associated with changes in fatigue, anxiety, depression or sleep.

Adherence will also be assessed via the app through the self-reports of activity that participants complete and usage of the materials. Studies have suggested that dose may have an impact on outcomes with greater adherence showing more favourable outcomes [82]. The relationship between app adherence, dose and outcomes will be explored in this study.

Data management and protection

Participants will be allocated a unique code so that anonymity is protected. All data will be stored on a secure server at Ulster University. Databases will be encrypted, as will any transferred data and held securely on an repository. The key to the participant IDs will be held by the Chief Investigator. Data will be kept on password-protected computers that can only be accessed by the research team. Access to the anonymised data will use authentication and be traceable by login details. Participants will be made aware that confidentiality will be maintained but the research team will be unable to prevent other members that participate in online focus groups to adhere to this confidentiality agreement. Participants will also be informed that if they withdraw from this part of the study that once data has been anonymised it may be difficult to remove it.

Ethics

Ethical approval has been granted from Ulster University Research Ethics Committee (REC.21.0076).

Dissemination policy

The findings of the research will be communicated with those who participated in the study either via email or a local event. The researcher will disseminate the projects findings and outputs via oral and poster presentations at local, national and international conferences and publications in peer reviewed journal papers.

Discussion

Fatigue continues to be a distressing symptom for many cancer patients either pre diagnosis, diagnosis, during and post treatment. For some it continues to be a long term symptom that effects all aspects of life including social, biological, financial and emotionally leading to reduced quality of life. The current evidenced based advice and interventions offered for managing this symptom include exercise, nutrition advice, sleep hygiene, or prioritising, pacing and planning activities [83]. In recent years other interventions such as mindfulness, have been shown to have a favourable responses for CRF, which in turn also demonstrated a positive effect on stress and sleep all of which are identified as part of the cluster symptom for fatigue [84]. However, there appears to be little research that examine the use of more than one intervention simultaneously. This study will not only explore whether this is feasible but also if the simultaneous delivery of interventions results in any additionally effect. Furthermore, the use of an active comparator will be of value, as it has been suggested previously that a usual care or wait list control can result in a greater result in the experimental arm [35]. Additionally, it has been indicated that assessing the levels of fatigue prior to entering a study can have an impact on the effectiveness of the intervention. This was demonstrated in a meta-analysis that examined the effectiveness of physical activity on fatigue for colorectal cancer patients. It found that levels of fatigue in some of the included studies within this review were equivalent to the normal population which resulted in participant outcome measures showing little improvement therefore described as a ceiling effect for the interventions [42]. Therefore, this study has been designed around these concepts and will be both assessing levels of fatigue as part of the screening process and incorporating mindfulness as the active comparator arm.

This study will also use a digital platform for delivering this intervention. By exploring the feasibility of delivering the intervention through this platform it may also make it feasible in the future to diversify this app and its delivery for other types of cancer populations and possibly management of other symptoms.

Supporting information

S1 Checklist. SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents*.

(DOC)

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S1 File. UREC application.

(DOCX)

Click here for additional data file. (2.6MB, docx)
S2 File

(DOCX)

Click here for additional data file. (13.9KB, docx)

Data Availability

No datasets were generated or analyses during the current study. All relevant data from this study will be made available upon study completion.

Funding Statement

This study is being undertaken as part of a PhD studentship (KMCC) at Ulster Univeristy and funded by the Department for the Economy (DfE) studentship. The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PONE-D-22-31105Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomised feasibility trialPLOS ONE

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6. All Clinical Trials, Registered Reports, Registered Report Protocols, and Study Protocols carrying the CT flag must provide their original protocol as a Supporting Information file. Please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed. PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: No

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: No

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a study protocol of a randomized clinical trial to explore the feasibility of delivering an intervention that involves mindfulness and mindfulness and exercise and will explore the effect of this on fatigue, sleep, mood and quality of life. Participants will be randomized into one of 2 groups. One group will undertake mindfulness only and the other group will complete exercise and mindfulness. Both groups will use a mobile application to complete these interventions over 8 weeks. This trial will hope to evidence and demonstrate that combination of two interventions such as mindfulness and exercise will further improve outcomes of fatigue and wellbeing in gynecology cancer. I have some concerns on the study design and statistical analysis plan.

1. This is a protocol of an ongoing randomized trial. I do not see the innovative contribution to the health research society before the researchers conduct comprehensive quantitative analysis and make some conclusion.

2. The authors need to provide the sample size calculation and power analysis to justify the design of the study.

3. For the quantitative analysis section, there is no detailed statistical analysis description on how to deal with the collected data, such as data quality control, statistical summary, statistical modeling and analysis pipeline.

Reviewer #2: Review

Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomized feasibility trial

Previously, some literature has shown that exercise alone is an effective way of addressing CRF however there is some ambiguity in its effectiveness across all areas of fatigue. The authors discuss the relevance of mindfulness and a combination of exercise plus mindfulness on CRF, sleep and overall, the quality of life.

Some questions that need to be addressed before manuscript should be considered for publication are as follows

1. The authors should discuss some known activities that involves both mindfulness as well as exercise e.g., Yoga or other practices.

2. How will the protocol take into account the state of mind, physical and mental support of the patient before the interventions?

3. Does the protocol take into account the physical activity level of individuals before the interventions?

Reviewer #3: The investigative team seek to use a RCT design to explore the feasibility of delivering interventions of mindfulness alone compared to in combinations with physical exercise in gynaecology cancer patients to help alleviate fatigue and improve sleep and quality of life. Outcomes for the two treatment arms will be measured pre-, and post- intervention. Data collection will be augmented using a mobile app over 8 weeks. Recruitment, adherence, and retention will be used to assess feasibility, while acceptability will be assessed will be assessed via focus group interviews.

Comments:

1. What incentives will the participants be provided to encourage them to complete the study?

2. Since the study will enrol very sick patients, how will general safety and adverse events be monitored? What if the intervention triggers a participant to become distressed? Is there a Safety Committee which has similar functions of a Data Safety and Monitoring Board (DSMB).

Strengths

1. Participants will be block-randomized to open label treatment groups.

2. The study is based on the COM-B conceptual model for behaviour change techniques, a construct within the Behaviour Change Wheel

3. The outcomes for each of the three objectives are clearly described.

4. Questionnaire to be used are validated.

5. Participant burden of 15-20minutes is light.

6. Adherence data will be objectively collected via electronic logs via the app.

7. The proposed recruitment pan appears adequate

8. Inclusion and exclusion criteria will help other researchers replicate study findings.

9. Randomization will, in theory, even out known and unknown confounding factors.

Weaknesses,

1. Given that there are five main types of gynaecology cancers it might strengthen the study if these types of cancers are balanced between the study arms. A balance might be achieved via stratified sampling.

2. Inclusion criteria should include women who have been diagnosed for a minimum period such as for 6 months or longer. That way there is not mixing of effects (or confounding) that comes with patients with newly diagnosed cancer.

3. For statistical analysis, multiple imputation is appropriate for missing covariate not for outcomes.

4. It is not stated how composite scores for various Likert-based instruments will be calculated. The specific study continuous variables or outcomes for which t-test and repeated measures ANOVA will be used were not explicitly stated.

5. It us stated that Recruitment, adherence, and retention will be used to assess feasibility. By this definition of feasibility, the outcome measure is not q quantitative/continuous variable, yet statistical analysis in line 394 states that "effect sizes ... will be calculated by taking the mean and dividing by pooled standard deviation "this proposed analysis is not consistent with the variable being analyzed.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Phil Gona

**********

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Attachment

Submitted filename: PONE-D-22-31105_review.docx

Click here for additional data file. (14.5KB, docx)
PLoS One. 2023 Oct 26;18(10):e0278252. doi: 10.1371/journal.pone.0278252.r002

Author response to Decision Letter 0

22 Apr 2023

Reviewer 1:

1.This is a protocol of an ongoing randomized trial. I do not see the innovative contribution to the health research society before the researchers conduct comprehensive quantitative analysis and make some conclusion.

2. The authors need to provide the sample size calculation and power analysis to justify the design of the study.

3. For the quantitative analysis section, there is no detailed statistical analysis description on how to deal with the collected data, such as data quality control, statistical summary, statistical modeling and analysis pipeline.

Response:

Thank you for your comments they are very welcome.

1. 1. The need for this trial is highlighted in the need for the trial section which will contribute to health society whether it is feasible to combine two interventions and if either is superior to the other (lines 138-142). Also, the further contribution will include the use of digital platforms to deliver this intervention as highlighted in the aims section (lines 183-185).

2. 2. As this is a feasibility study sample size justification is more in keeping with this type of study rather than power calculation. Justification of sample size is described in lines 398-403. For further information on sample size for feasibility and pilot study please see Billingham SA, Whitehead AL, Julious SA. An audit of sample sizes for pilot and feasibility trials being undertaken in the United Kingdom registered in the United Kingdom Clinical Research Network database. BMC Med Res Methodol. 2013 Aug 20;13:104. doi: 10.1186/1471-2288-13-104.

3. 3. Additional description of statistical analysis on how the collected data will be handled for feasibility (adherence, retention and attrition). Alongside this, a detailed description of the data will be scored, summarised, missing data and the outcome measures used (lines 404-442). This replaces the original statistical analysis description which has been removed (lines 443-458).

Reviewer 2:

1.The authors should discuss some known activities that involves both mindfulness as well as exercise e.g., Yoga or other practices.

2. How will the protocol take into account the state of mind, physical and mental support of the patient before the interventions?

Response:

Thank you for your comments they are very welcome.

1.A further section has been added with other interventions including the pros and cons of using interventions such as yoga or Tai Chi (lines 108-118).

2. Eligibility screening will take place to assess physical and mental issues and support before the consent and randomisation process. Further description of is this included in lines 275 and 276. Ethical approval has been confirmed excluding those participants that have a confirmed diagnosis of schizophrenia spectrum disorder, bipolar disorder, post-traumatic stress disorder, or risk factors for psychosis (e.g. personality disorder) or an existing medical condition that may inhibit safe participation in the exercise part of the intervention study and will therefore not meet the criteria to take part as stated in the exclusion criteria (lines 307-310).

3. The protocol takes into account individual levels of activity prior to entering the study through screening (lines 275 and 276). The inclusion criteria currently approved by ethical committee will assess the levels of activity before intervention (lines 300 to 303).

Reviewer 3:

1. What incentives will the participants be provided to encourage them to complete the study?

2. Since the study will enrol very sick patients, how will general safety and adverse events be monitored? What if the intervention triggers a participant to become distressed? Is there a Safety Committee which has similar functions of a Data Safety and Monitoring Board (DSMB).

Strengths

1. Participants will be block-randomized to open label treatment groups.

2. The study is based on the COM-B conceptual model for behaviour change techniques, a construct within the Behaviour Change Wheel

3. The outcomes for each of the three objectives are clearly described.

4. Questionnaire to be used are validated.

5. Participant burden of 15-20minutes is light.

6. Adherence data will be objectively collected via electronic logs via the app.

7. The proposed recruitment pan appears adequate

8. Inclusion and exclusion criteria will help other researchers replicate study findings.

9. Randomization will, in theory, even out known and unknown confounding factors.

Weaknesses,

1. Given that there are five main types of gynaecology cancers it might strengthen the study if these types of cancers are balanced between the study arms. A balance might be achieved via stratified sampling.

2. Inclusion criteria should include women who have been diagnosed for a minimum period such as for 6 months or longer. That way there is not mixing of effects (or confounding) that comes with patients with newly diagnosed cancer.

3. For statistical analysis, multiple imputation is appropriate for missing covariate not for outcomes.

4. It is not stated how composite scores for various Likert-based instruments will be calculated. The specific study continuous variables or outcomes for which t-test and repeated measures ANOVA will be used were not explicitly stated.

5. It us stated that Recruitment, adherence, and retention will be used to assess feasibility. By this definition of feasibility, the outcome measure is not q quantitative/continuous variable, yet statistical analysis in line 394 states that "effect sizes ... will be calculated by taking the mean and dividing by pooled standard deviation "this proposed analysis is not consistent with the variable being analyzed.

Response:

Thank you for your comments they are very welcome.

1.Due to limit funds were not able to provide financial incentives for participants to complete the study. The download, use and longer term use of the app is all included within the study and potential for improvement in participant symptom management is the currently the only incentive for participants.

2.Participants will be screened to ensure safety is maintained. Participants will be post treatment therefore not deemed very sick. However, the research team are qualified professionals and have many years’ experience working with and conducting research with oncology participants will be used to review progress, establish collaborative goals and check for any adverse events. Weekly telephone contact with all participants. Alongside this, research member (KMCC) undertook further training for professionals in mindfulness, which include contraindications to therapy. A distress protocol is in place for both interventions which has been approved by the ethical Committee (please see lines 336-341 and 358-359).

Thank you for your comments they are very welcome.

1.Feasibility study with 20 participants in each arm does not lend it self to stratified sampling and therefore not appropriate. However, stratified sampling will be considered for the fully powered randomised control trial.

2. The inclusion criteria currently approved by ethical committees includes women who are 3 months post-treatment and up to 5 years (see line 303), hence negating the potential impact of a new diagnosis.

3.On reflection imputation may not be appropriate as this is a feasibility study but an assessment of app data including usage, patterns of navigation of the app as well as retention, attrition and recruitment. This has been removed (lines 446-447).

4.The Likert-based instruments are standardised scales, as such will be scored using the exact methods outlined by authors’ of the outcome measures. Below are links to the various patient reported outcomes used and the instructions on how to calculate scores.

FACT-G: https://www.facit.org/measures/FACT-G

FACIT-F: https://www.facit.org/measures/FACIT-F

HADS: https://www.svri.org/sites/default/files/attachments/2016-01-13/HADS.pdf

PSQI: FFMQ: https://www.goodmedicine.org.uk/files/assessment,%20pittsburgh%20psqi.pdf

https://ogg.osu.edu/media/documents/MB%20Stream/FFMQ.pdf

A detailed description of the above questionnaires and scoring and handling of missing data is given in lines 418-442.

5.The primary aim (lines 178-182) is feasibility so recruitment, retention, adherence and attrition will be reported using descriptive statistics. As part of the secondary aim (lines 192-195) outcome data will be collected to determine whether the intervention resulted in any change (lines 418-421).

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Response:

1.Have ensured that the style requirements and file names are in keeping with the PLOS ONE guidelines.

2.The delay in registering the trail was related to Covid-19 and ongoing iterations of the app. Recruitment and randomisation took time by which point the process of registration to Clinical Trials had commenced.

1)Please see above for reasons for delay this has been included in methods section (lines 198-200.

2)This statement has been added to the methods section (line 200).

3.The ethics statement is within the methods section of the manuscript (lines 470-472).

4.Permission for use of figure 3 has been sought. Permission form has been filled and signed giving permission from the original copyright holder to publish the content under the CC BY 4.0 license.

a.Permission from the original copyright holder of figure 3 to publish the content under the CC BY 4.0 license sought and forms completed and uploaded.

In the figure caption of the copyright figure 3 the following phase has been added ‘Reprinted from [76] under a CC BY licence, with permission from Cold Spring Harbour Laboratory Press, original copyright 2022’ (lines 376-377).

5. There is no supporting information all the figures and tables are within the manuscript.

6. A clean copy of the protocol has been uploaded to PLOS ONE online system.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (36.8KB, docx)

Decision Letter 1

Xian-liang Liu

14 Jun 2023

Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomised feasibility trial

PONE-D-22-31105R1

Dear Dr. Mccloy,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Xian-liang Liu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all my comments in the revised manuscript. I have no other comments on it.

Reviewer #2: The authors have address all of my queries to satisfaction therefore the manuscript should accepted without any further changes.

Reviewer #3: The research team has satisfactorily addressed all my comments. I do not have additional comments. This is a well written manuscript.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Philimon N. Gona

**********

Acceptance letter

Xian-liang Liu

26 Jun 2023

PONE-D-22-31105R1

Evaluating the effectiveness of mindfulness alone compared to exercise and mindfulness on fatigue in women with gynaecology cancer (GEMS): Protocol for a randomised feasibility trial

Dear Dr. Mccloy:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

Dr. Xian-liang Liu

Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

    S1 Checklist. SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents*.

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    Data Availability Statement

    No datasets were generated or analyses during the current study. All relevant data from this study will be made available upon study completion.

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