The study will take place in the premises of the University Hospital Wuerzburg Radiotherapy/Palliative Care Unit. Written informed consent will be obtained from all participants. To answer the research questions, a combination of two RCTs will be implemented (see Fig. 1). In the first part, eligible patients will be randomized to the IG (8-week yoga intervention) or CG. The CG will also receive the yoga intervention, but nine weeks later than the IG. At the end of the yoga intervention, the second RCT will be implemented: all patients will be again randomized to get reminder-emails (email group) or no reminder emails after the yoga-interventions. The email group will receive a weekly email over 24 weeks a week, in which one asana out of the yoga intervention is repeated and described in detail. In addition, through the reminder-email participants will be encouraged to practice by themselves regularly. The first RCT is described in 2.1 and will be used to answer research questions 1 and 2, the second RCT is described in 2.2 and will be used to answer research questions 3 and 4.
First RCT (yoga intervention)
Study-setting and eligibility criteria
The participants will be at least 18 years old, will have a previous oncological disease and will undergo treatment at the radiotherapy outpatient clinic or the interdisciplinary oncological therapy outpatient clinic (IOT) at the time of screening and they report fatigue in Fischer screening (intensity ≥4, impairment ≥5). Exclusion criteria will be insufficient knowledge of German and severe emotional or physical impairment as well as more than 50 km distance to the university hospital which would require travelling.
Study design and measurement occasions
Eligible patients will receive the first set of questionnaires as a baseline assessment (T0). All participants will receive psychoeducation intervention (coping with fatigue). Subsequently, they will be randomized to IG or CG. The IG starts with the yoga intervention 1 week after T0, the CG starts 10 weeks after T0. The yoga intervention will be conducted for 8 weeks plus an additional lesson in the ninth week to give the participants the opportunity to catch up on a missed session. Primary and secondary outcomes will be assessed 10 weeks after the start of yoga intervention (T1) via questionnaires. Participants of the CG will also answer a questionnaire at the begin of the yoga intervention (T1) and at the end of the yoga intervention (T2, this will be used in the second RCT).
Yoga-intervention
Certified yoga teachers will carry out yoga intervention. The sequence of exercises will remain constant from beginning to end. The asanas (physical exercises from Yoga) were inspired by John-Kabat Zinn and adopted for cancer patients by Dr. Jentschke (psychooncologist, physiotherapist and yoga teacher). One yoga session will last 1 hour. It consists of physical exercises (asanas), conscious breathing (Pranayama) and deep relaxation (Savasana). Nonviolence (ahimsa) as an important basic principle of yoga is to be repeated every hour and helps to encourage the participants to deal gently with their bodies. Participants should not perform any physical exercises that cause pain. The subsequent body exercises are structured from lying to sitting to standing. The following sequence of exercises will be repeated in each yoga unit: 1) Relaxation: conscious breathing, body scan, mindfulness 2) Vein pump 3) Pelvis and back rotation (adapted variation of the “nakrasana”) 4) Pelvis opening (adapted variation of the “supta baddha konasana”) 5) Shoulder bridge (“setu bandha sarvangasana”) 6) Forward folds (Paschimottanasana and variations with Pranayama) 7) Backbend: intense east stretch (Purvottasana) 8) Diagonal static yoga cat (Majariasana 1 and resting pose) 9) Standing exercise 10) Upward Salute(Urdhva Hastasana) 11) Warrior 1 (Virabhadrasana 1) 12) Warrior 3 (Virabhadrasana 3) 13) Tree (Vrkasana variation) 14) Relaxation (Savasana). In all exercises, participants are reminded to breathe slowly, deeply and consciously. Adverse events and complications during yoga therapry are recorded by yoga teachers on a standardized basis.
Sample size calculation
Two randomized intervention studies investigating yoga therapies in cancer patients of comparable type and duration using an intervention condition and a waiting-list control group condition produced intergroup effect size in fatigue self-assessment scales of d = 0.66 [29] and d = 0.51 [18]. Based on the lower effect size of d = 0.50 alpha = 0.05 and Power = 0.80 result in a case number of n = 64 per group, i.e. 128 patients in total, for a t-test for independent samples with two-sided testing.
Recruitment
Oncological patients from the radiotherapy outpatient clinic and the interdisciplinary oncological therapy outpatient clinic who score high in fatigue screening will be invited to a non-binding event via mail where they will receive further information on the study. If no response is received within a week of the invitations being sent, patients will be contacted again by telephone to clarify any ambiguities. Through this recruitment, we hope to maximize participation rate in the first information event. At the first event, the patients will be explained the purpose and procedure of the study and asked to participate in the study.
Randomization
The information events will take place every 4 weeks. The participants of the study will be recruited on each information event. All patients who met inclusion criteria will be asked to participate. Participants who will have signed the consent form and completed the first questionnaire set will be randomly assigned to the IG or CG. To ensure that enough patients will be randomized to the intervention group to perform the intervention, a block randomization procedure will be used. Patients meeting the same information event will form a block. The randomization list with computer-generated numbers will be created by the Institute of Clinical Epidemiology and Biometry of the university of Wuerzburg.
Second RCT (reminder e-mails)
Study design and measurement occasions
After the yoga intervention, all participants are randomly assigned to group “Email” who will get weekly reminder e-mail or to group “NoEmail” who will receive no reminder e-mails. Participants of both groups will receive a practice book and a practice CD. Outcomes will be assessed 6 months after the end of the yoga therapy (T3).
Reminder e-mail
Reminder e-mails are used for the second question. The e-mails in the first 12 weeks contain descriptions of the twelve asanas - one asana each week - and an encouragement to practice yoga during this week. The asanas are described analogously to the order of the yoga classes. In the following 12 weeks, the 12 reminder e-mails will be repeated in the same order.
Randomization
All participants of the Yoga study will be randomly assigned to the group “Email” or “NoEmail”. A block randomization procedure will be used. Patients assigned to a group (IG or CG) after the information event form a block. The randomization list with computer-generated numbers is compiled by staff members of the interdisciplinary Palliative Medicine Centre.
Outcomes, ethics, data management and statistics
Outcomes and other measures
Outcomes will be assessed using patient questionnaires or will be extracted from the patient-documentation system. Unless otherwise specified, all outcomes are recorded at all measurement times (T0, T1, T2, T3).
Primary outcome: self-reported fatigue
Self-reported fatigue will be assessed using the German version of EORTC QLQ-FA13 13 Items (European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire – Fatigue) [30]. This questionnaire can be used in all tumor diseases in all stages and phases of the disease and in all areas of treatment (chemotherapy, radiation, surgery) or care (acute care, rehabilitation, aftercare or palliative care) [31]. Fatigue is measured using 13 items. Response categories of all items are ‘not at all’, ‘a little’, ‘quite a bit’, and ‘very much’, coded with scores from 1 to 4. All Items are summed up to one fatigue score. The scores range from 0 to 100. Higher values indicate a higher level of fatigue symptoms. The internal consistency for the German version was good with Cronbach’s alpha values ranging from .79–.90 [30, 32].
Secondary outcomes
Depression
The Patient Health Questionnaire (PHQ-9) will be used to assess depression. The 9 items assess depression symptoms according to DSM-IV/DSM-V and are scored on a 4-point Likert scale (0 = not at all, 1 = several days; 2 = more than half of the days; 3 = nearly all days). All items are summed up to one sum score, ranging from (0–27). Higher values indicate higher depression. The internal consistency for the PHQ-9 proved to be good with Cronbach’s α = 0.79 for cancer patients [33].
Quality of life
The EORTC QLQ-C15-PAL is a short form [34] of the QLQ-C30 for palliative care settings. The 15 items of the questionnaire assess nine categories: physical function, emotional function, global QoL, pain, fatigue, appetite, dyspnea, constipation, and sleep. The four response categories are coded with scores from 1 to 4 (1: not at all; 2: a little; 3: quite a bit; 4: very much) and are transformed to a 0–100 scale range.As an exception, global QoL is scored from 1 (very poor) to 7 (excellent). A higher score represents better function and QOL, while for symptom scale, it indicates greater symptom burden.
Symptom assessment
The German version of the Edmonton Symptom Assessment Scale (ESAS) [35] will be used to assess symptom severity. The nine symptoms pain, fatigue, nausea, sadness, anxiety, drowsiness, appetite, general condition and shortness of breath are assessed on a numerical rating scale from 0 = none to 10 = worst possible. Higher values in the summed scale score indicate high symptom burden. The internal consistency according to Cronbach’s alpha range between 0.67–0.73 [35].
Distress thermometer
The distress thermometer is used to measure psychosocial stress. It uses a numeric rating scale ranging from 0 (no distress) to 10 (extreme distress) and is widely used in clinical practice [36]. A cut-off value of ≥5 is referred to as high distress. Both the dichotomous classification and the sum score of the district thermometer are to be recorded in the study. As a short screening instrument, the Distress Thermometer is well suitable for identifying high loads recorded by Hospital Anxiety and Depression Scale > 11 (AUC values 0.71–0.76) [36].
Sense of coherence
The German version of the short form of Sense of Coherence Scale (SOC L9) [37] will be used to record the sense of coherence. This is a reliable, valid and economic alternative short form of the SOC developed by Antonovsky (1983). The 9 items are scored on an 8-point Likert scale. Response formats vary between items. Higher values indicate a high degree of coherence, whereby age- and gender-dependent norms must be applied. The internal consistency of the SOC L9 can be rated as good (Cronbach’s alpha = .87) [37].
Sociodemographic and health data
The following socio-demographic data will be assessed at T0: age, gender, marital status, number of children, level of education, professional status. Individual coping with the tumor disease, treatment status and use of analgesics and psychopharmaceuticals will be assessed at each measurement occasion. In addition, previous experience with yoga and expectations of the participants on yoga will be asked at T0.
Program evaluation and training time
At the end of the intervention (IG: T1; CG: T2), participants comprehensibility and applicability of the yoga theory and psychoeducation as well as subjective benefit will be assessed on a scale from 0 (not at all) to 3 (very). Furthermore, the current scope of the exercise duration (yoga) and the application frequency of the recommendations for handling fatigue will be measured at T1(IG)/T2(CG) and T3(IG and CG). Reasons for continuing or ending yoga practice are documented.
Data management and confidentiality
In order to guarantee the confidentiality of data, the data will be pseudonymized using an allocation list. A research code will be assigned to each study participant so that only the code and no personal data will be used on all questionnaires. All questionnaires will be kept in locked cabinets and/or password protected computers. The allocation list will be only accessible to the data manager of the University Hospital Wuerzburg responsible for allocating medical data. The allocation list is deleted after the end of the study. It will contain the name, address, date of birth, SAP research number and contact data of the patients. During the period of this assignment, the research data will be considered “personal data” and the data protection laws are to be complied. The questionnaires will be scanned by the software EvaSys. The data will be exported to statistical programs for further statistical analysis. The data manager will compare the transferred data of the questionnaires item by item with the original questionnaires. Additional data, such as treatment duration and intensity, will be taken from the electronic patient file. The data manager will also advise on storage, back up and archiving of data to ensure databases are regularly backed up to ensure data is safeguarded from accidental loss. The study master file and all study documentation will be archived for at least 10 years.
Statistical analysis
To answer the first research question, analyses of covariance (ANCOVA) will be performed, using fatigue score T1 (primary outcome) as dependent variable, type of treatment (IG vs. CG) as independent variable and fatigue at baseline as covariate. The second research question will be analyzed by including the moderator (e.g. gender, age) and the interaction terms (for example group X gender) in the model.
The third research question will be tested again by using ANCOVA, with fatigue T3 as dependent variable, fatigue after the intervention (IG: T1, CG: T2) as covariate and type of reminder (e-mail vs. no email) as independent variable. The fourth research question will be tested by computing a mediation model using structural equation modeling framework [38, 39].
Ethics, consent and permission
The investigation will conform to the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the University Wuerzburg on 15/05/2018 (Nr. 59/18 sc). If interested, all potential participants will receive detailed written information on all relevant aspects of the study. Participants will be informed that they could withdraw from the study at any given time and without reason and that participation in the study is voluntary. Participants will be assured that any future treatment will not be affected in any way should they choose to withdraw. The patients will consent to the study after detailed information. The study is registered on German Clincial Trials Register (DRKS00016034, 12/2018). This paper contains the original study protocol. Material changes to the study protocol will be submitted to the Ethics Committee of the University of Wuerzburg for approval. These changes are documented in detail in the German Register of Clinical Trials and described transparently in study reports.
