RECOVARI – E cacy and Safety of Massage on Surgical Stress in Colorectal Cancer Patients: Study Protocol for A Randomized Controlled, Three-Arm Parallel Group, Clinical Trial

Paul Georg Werthmann (  paul.werthmann@ifaemm.de ) Universitätsklinikum Freiburg https://orcid.org/0000-0002-1808-7787 Dirk Cysarz Universitat Witten/Herdecke Johannes Naumann European Insitute for Physical Therapy and Balneology Monique van Dijk Erasmus Medical Centre: Erasmus MC Roman Huber Albert-Ludwigs-Universität Freiburg: Albert-Ludwigs-Universitat Freiburg Ann-Kathrin Lederer University Medical Center Freiburg: Universitatsklinikum Freiburg Gunver Sophia Kienle University Medical Center Freiburg: Universitatsklinikum Freiburg


Introduction Background and rationale {6a}
Stress in humans may lead to insomnia, increased pain perception, loss of concentration and memory, and worsening of immunologic functions [1]. Stress is also associated with increased use of medication such as tranquilizers, sleep medication or pain medication -and consequently a higher risk of medication abuse, dependency and polypharmacy [2]. New and innovative methods to reduce stress and its related conditions are being explored. Stress reduction methods preferably are effective without the risk of complications.
Eligible patients are those diagnosed with colorectal cancer and scheduled for surgery. Inclusion criteria are as follows: patients in an inpatient setting after colorectal cancer surgery; able to ll out questionnaires or answer questions; age from 18 years onwards; legal competence; ability to understand the nature of the trial and the trial-related procedures and to comply with them; ability to understand German language and having provided written informed consent obtained according to international guidelines and local laws. Exclusion criteria are: severe surgical complication; severe cardiac complication; sepsis; cardiac diseases which interfere with the HRV analysis, such as severe arrhythmias or a pacemaker; severe psychiatric disorder; pregnancy or breastfeeding; clinically signi cant comorbidity critically in uencing the patient to adhere to the protocol; hypersensitivity to skincare products; skin conditions in the area of the back or the feet; isolated nursing; participation in a clinical trial within the 3 months before the start of this study or simultaneously -except studies which are not investigating therapeutic or diagnostic procedures and are not interfering with the current study.
Who will take informed consent? {26a} During the pre-surgical visit, eligible patients will be informed about the trial by the surgeons. The patients will be informed that participation is voluntary and that no disadvantages will result from nonparticipation. If patients are interested in participating in the trial, printed patient information will be handed out to them. After having read the patient information, the patients will have the opportunity to ask questions and to decide about their consent. Written informed consent will be obtained by the doctors.
Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable.

Explanation for the choice of comparators {6b}
To differentiate between the pure effect of massage and that of concomitant empathic attention, the control arm involves merely an empathic conversation.

Intervention description {11a}
Patients allocated to two arms will receive RE-therapy -in one arm performed by RE-professionals and in one arm by nursing students. Patients in the third arm will receive empathic conversations with a nursing student. Nursing students (as an alternative: nursing assistants or medical students) will be trained in RE in three teaching units of 3 ½ hours each. The training will be carried out by two professionals certi ed in RE by the International Forum for Anthroposophic Nursing [25] or having trained in a standardized REcurriculum and having working experience with RE-therapy with patients for at least 5 years. RE will be applied as described in the RE-literature and taught in RE-training courses (for a detailed description see table 1) [26].

Intervention
Participants will receive RE of the back and the feet with the application of 2 mL pure almond oil in pharmacopoeial [27] quality for circa 10 minutes between 8 and 10 am and between 6 and 10 pm. The intensity of RE of the back will vary between 1-3, and that of the feet between 1-5 on a scale of 1 = 'softest massage possible' to 10 = 'very intense massage`.
The control intervention will consist of a 10-minute empathic conversation in the same time windows.
The conversation will start with an open question, such as "How are you today?" and then takes a spontaneous course. A list with proposed questions and topics is provided to the students.
All patients will be asked to rest for 20 minutes after the intervention. Staff and patients in the same room will be told about the intervention and resting time and will be asked not to interrupt during these periods. In addition, a sign will be put up on the door signaling 'study intervention, please do not disturb until x:xx'.

Criteria for discontinuing or modifying allocated interventions {11b}
All participants will be informed that participation in the trial is voluntary, and can be stopped at any time.
If a complication associated with the intervention occurs, the principal investigator judges if this necessitates discontinuation of the intervention. After the intervention has been stopped, no other intervention will be given.

Strategies to improve adherence to interventions {11c}
Every intervention is applied and monitored by the study personnel. The intervention is applied and most outcomes are assessed in hospital and supported by the patient's care team. Therefore high adherence is expected and no further speci c strategy implemented.

Relevant concomitant care permitted or prohibited during the trial {11d}
All study interventions are added to the usual care that participants receive. No care is prohibited.

Provisions for post-trial care {30}
After completion, the study participants will receive standard care during hospitalization and after discharge.

Outcomes {12}
The primary outcome is level of stress as measured with HRV on day 5 overnight from the whole sleeping time as de ned from the HRV and movement data as recorded by the HRV device.
The secondary outcomes are sleep quality, nausea and vomiting, pain intensity, analgesics consumption, sedatives consumption, emetics consumption, mood, grade of mobilization, length of stay in hospital, complications associated with the RE-therapy. Nursing students will be asked regularly about job satisfaction (UWES), empathy and motivation to carry out the RE. Mehrdimensionaler Be ndlichkeitsfragebogen -multidimensional mood questionnaire; RE: rhythmical embrocations. *Inclusion and exclusion criteria will be checked again on day 1.

Sample size {14}
The sample size calculation is based on the data of a previous trial investigating perioperative stress with heart rate variability as outcome measure. In that trial, signi cant changes in the SDNN had been recorded at different perioperative time points [6]. The preoperative SDNN was 116 milliseconds (ms); on day one after surgery it was 65 ms, and on postoperative day seven it was 87 ms (values are approximate values as the concrete values are not given in the article text, but only displayed as a bar chart; because the authors did not answer to our request, we converted the bar chart into numbers using WebPlotDigitizer [28]). Based on these gures, we presume the median SDNN in the conversation group to be 80 ms on postoperative day 5. In the intervention groups, we presume a faster recovery of the SDNN; i.e., 110 ms on day 5 (therefore we set δ=30). In the previous trial, the standard deviation was around 30 (σ=30) for all measurements. Based on a t-distribution, a two-tailed α=0.05 and a power (β) of 0.8, we calculated a sample size of 17 patients per group, and thus 51 in total. To adjust for attrition, we will enroll 60 patients.

Recruitment {15}
In the surgical department 120 patients are operated on each year who match the inclusion criteria of our study. We therefore consider a recruitment rate of 60 in 12 months to be feasible. We expect a small dropout rate because data collection encompasses ve days only and eligible patients are already hospitalized.

Sequence generation {16a}
For allocation to the various trial arms, a computer-generated list of random numbers will be used. The list will be retrieved by an independent researcher only and randomization will be performed from this list for each individual patient after inclusion in the study.

Concealment mechanism {16b}
The allocation sequence is generated by an independent researcher using the website Randomization.com [29]. No strati cation or block randomization is used.

Implementation {16c}
The participants are enrolled by a doctor at the pre-surgical visit. The inclusion and exclusion criteria are checked again after surgery at arrival on the normal ward. After inclusion of a new patient, the investigator and the trial assistant are informed. The investigator or the trial assistant sends the sequential number of the new patient electronically to the independent researcher, upon which the independent researcher sends back the code of intervention from the allocation list.

Assignment of interventions: Blinding
Who will be blinded {17a} All study staff who are directly involved in the intervention (RE experts, nursing students) cannot be blinded. Study stuff providing RE are instructed not to inform the patients if they are treated by experts or students. The patients are informed in the patient information, that they will not be told if they are treated bey experts or students in the intervention arms with RE. Data collection and data analysis will be blinded.

Procedure for unblinding if needed {17b}
Not applicable

Data collection and management
Plans for assessment and collection of outcomes {18a} The primary outcome 'level of stress' will be assessed from the heart rate variability (HRV), which will be recorded on days 1 and 5 overnight using a one-channel electrocardiogram (ECG, Bittium Faros 180 [30]). Data will be processed according to the 1996 guideline of the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology [5].
The secondary outcomes will be assessed as follows: Sleep quality with the Richards-Campbell sleep questionnaire (RCSQ) in its German validated translation [31] on days 2, 3 and 6. The severity of nausea within the last 24 hours will be assessed using a 100 mm visual analogue scale (VAS, from: no nausea to: worst imaginable nausea) [32,33] on days 1, 3 and 6. Number of vomiting episodes within the last 24 hours will be documented [32] on days 1, 3 and 6. Pain within the last 24 hours will be assessed on days 1, 3 and 6 using a 100 mm VAS (from: no pain to: strongest imaginable pain). Consumption of analgesics, sedatives, emetics and other relevant medication will be retrieved from the patient's chart. Mood will be assessed on days 1, 3 and 6 using the Mehrdimensionaler Be ndlichkeitsfragebogen (MDBF, Multidimensional well-being questionnaire, a validated questionnaire measuring well-being in the dimensions of pleasant -unpleasant, awake -sleepy, and calm -restless [34]). For the assessment of activity level, the Evaluationsbogen Mobilität (EBoMo, mobility evaluation sheet, a simple scoring tool for activity level e.g. in nursing homes [35]) will be scored at baseline and on day 6.
Length of stay in the hospital will be recorded as indicated in the patient's chart. Regarding complications associated with the intervention, patients will be asked to report these before the evening treatment.
The RCSQ and MDBF will be mailed to the participants 1 month after discharge. They will be telephoned and asked to ll out the questionnaires and send them back to the study center in the pre-paid envelope. In addition, they will also be asked to indicate current medication consumption, especially sleep medication and tranquilizing drugs. At the start and end of the trial and every 3 months during the trial, the nursing students will be asked to ll out the following validated questionnaires: Utrecht Work Engagement Scale -Short form (UWES-9) [36], Interpersonal Reactivity Index (IRI) [37]. At the end of their work in the trial they will ll out the questionnaire: Inner Correspondence and feelings of Peaceful Relief (ICPH) [38].

Plans to promote participant retention and complete follow-up {18b}
Regarding the short time for each participant in the trial, we expect we do not have to promote participant retention or collect outcome data for participants who discontinue or deviate from intervention protocols.

Data management {19}
HRV data will be extracted and analyzed using Matlab (The Mathworks) [39].
Data of questionnaires and open questions will be collected on paper in prepared questionnaires and data sheets. This data will be collected and managed using REDCap (Research Electronic Data Capture) tools hosted at the University Medical Center Freiburg [40]. REDCap is a secure, web-based application designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. The data will be entered into REDCap 10.0.28 into elds with prespeci ed data ranges and plausibility checks.
The datasets from Matlab and REDCap will then be merged by patient id.

Con dentiality {27}
All patient data is collected and processed pseudonymously. The ID list with the patients' names will only be available to the trial investigator. The trial data is only accessible to the trial investigator and authorized personnel.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable
Statistical methods

Statistical methods for primary and secondary outcomes {20a}
Data analysis will be performed using R 4.0.3 (or higher) [41]. Data-analysis will be performed with an intention-to-treat approach using the full analysis set. A p-value < 0.05 will be regarded as indicating signi cance.
For the primary outcome 'level of stress', the SDNN will be calculated from HRV during sleep from the recording of day 5; the mean and standard deviation of each intervention group will be calculated. The following testing sequence will then be performed: the mean with standard deviation of the control group (empathic conversation) will be compared with mean of the expert RE group using the T-test; if the null hypothesis (no difference between the groups) can be rejected, the control group will be compared to the student RE group; if the null hypotheses can be rejected here as well the expert RE group will be compared with the student RE group.
As secondary analysis, analysis of covariance (ANCOVA) will be performed with SDNN at day 5 and group as variable and SDNN at baseline as a covariable, if preconditions for ANCOVA are ful lled. Cohen's d will be calculated between 2 of the 3 groups and a Cohen's d > 0.5 will be considered a medium effect size. If parametric tests are not possible, non-parametric tests will be performed and the median with the 25th and 75th percentile reported.
For the other secondary outcomes, the same procedures will be performed and for categorical variables the chi-square test will be used. The paired T-test will be performed in continuous variables to compare characteristics of one group between two time points.

Interim analyses {21b}
No interim analyses are planned.
The coordinating investigator is under obligation to monitor the progress of the clinical trial with regard to safety-relevant developments and, if necessary, initiate the premature termination of a treatment arm or the entire clinical trial.
A treatment arm or the entire clinical trial will be terminated prematurely if: the coordinating investigator considers that the termination of the trial is necessary, indications arise that the trial patients' safety is no longer guaranteed, an insu cient recruitment rate makes a successful conclusion of the clinical trial unrealizable/no longer feasible.
If the clinical trial is prematurely terminated, the ethics committee will be informed by the coordinating investigator.
The trial participant can withdraw consent for trial participation at any time, without having to give reasons.
The responsible investigator may only withdraw a patient from participation in the trial for the following reasons: extreme circumstances arise which make any trial-relevant follow-up impossible.
The documentation should be completed as far as possible under these circumstances, e.g. a nal examination and documentation according to the protocol (if possible), a documentation of the premature trial termination on the CRF and in the medical record, giving reasons, should be ensured.

Methods for additional analyses (e.g. subgroup analyses) {20b}
Subgroup analyses will be performed regarding possible confounders such as type of surgery or tumor stage, as these might impact participants' stress levels.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Missing data will be imputed by full-information maximum likelihood method. The per-protocol group will be de ned as having no missing data in the relevant outcome and having participated in more than 5 of 8 treatments.
Plans to give access to the full protocol, participant level-data and statistical code {31c} The full protocol is available as additional content to this article. Because of privacy reasons, the full dataset will not be made publicly available. As the possible harm of the intervention is presumed to be small, no data monitoring committee is planned for this trial.

Adverse event reporting and harms {22}
Complications possibly associated with the intervention will be recorded on a daily basis. Severe complications will be reported immediately to the principal investigator, who then decides about the continuation or discontinuation of the intervention.

Frequency and plans for auditing trial conduct {23}
No auditing is planned Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, The investigator will report every important protocol modi cation to the ethics committee of the University Medical Center Freiburg, to the German trials Registry and the respective study staff.

Dissemination plans {31a}
The investigator will prepare a publication of the results of the study and submit it to a peer-reviewed journal. There are no publication restrictions.

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The effect of human touch is increasingly investigated in psychological and medical research. Especially the bene cial effects of social and therapeutic touch on stress levels have been studied, which has led to the discovery of C-tactile afferents that have special properties to mediate tactile stimuli from another person and calming effects of touch [42][43][44][45]. Massage has shown to be effective in clinical settings of pain and conditions of the musculoskeletal system [46][47][48][49]. In surgical settings, massage before surgical procedures has been associated with anxiety reduction [50,51]. And massage after cardiac surgery reduced pain, anxiety and tension [52]. In further clinical situations it is mostly unknown if massage has a robust clinical bene t for patients. To the best of our knowledge, this is the rst randomized controlled trial on RE and also the rst randomized controlled trial on massage after colorectal surgery investigating the physiologic parameter HRV. With this trial, the impact of massage is investigated in a clinical relevant stress situation. In addition to validated patient questionnaires on clinical signi cant issues, the effects on stress are also evaluated with HRV as a physiologic parameter which is not prone to biases of questionnaires like courtesy responses. Blinding in massage trials is especially di cult, if the control intervention consists of an activity without touch. However, we choose this type of control intervention in concordance with other authors to compare the effectiveness of a speci c massage with empathic attention without touch.
As a limitation it could be discussed, that the primary endpoint HRV is not a clinically relevant outcome parameter and rather endpoints like frequency and severity of complications after surgery or even cancer relapse should be used. However, improvement of HRV through massage has been shown in different clinical settings [53][54][55][56] and is associated with complications after surgery [57] and the course of cancer patients [58]. Therefore, we see HRV as a meaningful parameter to investigate in this setting.
Furthermore, we have added clinically highly signi cant outcomes like pain, nausea and vomiting, mobilization, length of stay in hospital and validated and frequently used questionnaires. Therefore, we regard our outcomes as reliable and clinically meaningful.
With the trial we also realize practical issues of implementing massage therapy into the clinical practice of a university hospital, where the working days of caregivers are stressful and patients are partly overwhelmed by their new diagnosis and the hospital environment. For this setting we also set up the third arm of the study with students carrying out the massage -which might be a future perspective of implementing massage into the clinical setting. Students usually have less stress and more time to empathically carry out such interventions. As massage also might have an effect on the professional providing them [59][60][61], we also investigate the effect of this intervention on the providing students regarding their job satisfaction, empathy and identi cation with the intervention.

Trial status
The trial is currently carried out under the protocol version 1.2. In January 2021 the rst patient was recruited and we have currently 24 patients included in the trial. Recruitment is planned until the end of November 2021. To increase recruiting we are currently planning to change to a multicenter setting and include another trial center. Declarations variability. RH revised the protocol and the article and gave substantial advice on practical and organizational issues. MvD gave advice on the trial design and revised several protocol versions and the article. AKL provided knowledge about the surgical procedures and the procedures of the surgical ward, gave input for the trial protocol and revised the article. GSK gave substantial input for the trial design, revised several protocol versions and the article and is supervisor of the trial. All authors read and approved the nal version of the manuscript.

Funding {4}
The trial is funded by the Dr. Hauschka Stiftung, Bad Boll / Eckwälden, Germany, the Christophorus Stiftung, Stuttgart Germany and the Software AG -Stiftung, Darmstadt, Germany. The funding has no in uence on the design, conduct, analysis interpretation and publication of the study.
The article processing charge was funded by the Baden-Württemberg Ministry of Science, Research and Art and the University of Freiburg in the funding program Open Access Publishing.

Availability of data and materials {29}
The principal investigator has full authority over the nal dataset.

Ethics approval and consent to participate {24}
Ethical Review Board of the University Medical Center Freiburg 356/20, received on 20 th October 2020.
Written, informed consent to participate will be obtained from all participants.

Consent for publication {32}
Not applicable