GI 1549: PROGRAMS TO SUPPORT YOU DURING CHEMOTHERAPY (PRO-YOU) A Randomized Controlled Pilot Study of Yoga Compared to an Attention Control in Patients Receiving Chemotherapy
Phase: NA
Conditions: Depression, Fatigue, Stage IIA Colorectal Cancer, Stage IIB Colorectal Cancer, Stage IIC Colorectal Cancer, Stage IIIA Colorectal Cancer, Stage IIIB Colorectal Cancer, Stage IIIC Colorectal Cancer, Stage IVA Colorectal Cancer, Stage IVB Colorectal Cancer, Pancreatic Cancer, Esophageal Cancer, Appendix Cancer, Stomach Cancer, Gallbladder Cancer, Liver Cancer, Small Intestine Cancer, Large Intestine Cancer, Anal Cancer, Biliary Tract Cancer, Gastrointestinal Stromal Cancer
Sponsor: Wake Forest University Health Sciences

Protocol Date: July 14, 2019                                             1 of 52 
 
 
Version 6 
 
 
 
CCCWFU 01716: PROGRAMS TO SUPPORT YOU DURING 
CHEMOTHERAPY (PRO-YOU) 
A randomized controlled pilot study of yoga compared to an attention control in patients 
receiving chemotherapy 
 
Study Chairman or Principal Investigator: 
Stephanie Jean Sohl, Ph.D. 
Assistant Professor 
Department of Social Sciences and Health Policy 
Division of Public Health Sciences 
Wake Forest School of Medicine 
 
 
Supported by: 
The National Center for Complementary and Integrative Health 
(NCCIH) 
1 K01 AT008219-01A1 
 
 

Protocol Date: July 14, 2019                                             2 of 52 
 
 
Version 6 
 
 
 
Tool Revision History 
Version Number: 2 
Version Date: June 11, 2015 
Summary of Revisions Made:  
o 
Added the ability to train additional back-up interventionists and have 
phlebotomists conduct blood draws 
o 
Edited the description regarding timing of data abstracted during chart reviews to be 
consistent across sections of the protocol 
o 
Changed wording to clarify that the study staff holding randomization would not be 
the same as those collecting data 
o 
Clarified wording regarding adverse events to state that only AEs related to the 
study intervention or measures will be captured. 
Version Number: 3 
Version Date: December 7, 2015 
Summary of Revisions Made: 
o Modified language for clarification in the description of the active intervention. 
o Modified footer in Schedule of Evaluations to match the data safety and monitoring 
plan regarding identification of adverse events. 
o Modified timeframe from one to two weeks in the plan for handling any 
modifications to the standard schedule.  
o Allows for participant preference in the time daily surveys are sent and the ability for 
a study team member to contact participants to facilitate completion of daily surveys. 
Version Number: 4 
Version Date: March 29, 2016 
Summary of Revisions Made:  
o Adapted wording to be specific to procedures at new recruitment site, the 
Comprehensive Cancer Center of Wake Forest University 
o Changed personnel to be relevant for the new recruitment site 
 
Version Number: 5 
Version Date: December 8, 2016 
Summary of Revisions Made:  
o Changed Co-Investigator Dr. Alistar to Dr. Desnoyers because of her relocation  
 
Version Number:  6 
Version Date: March 1, 2019 
Summary of Revisions Made: 
o Changed Co-Investigator Dr. Desnoyers to Dr. Rocha Lima because of his relocation  
o Changed eligibility criteria and relevant justification  
 
Version Number:  7 
Version Date: July 15, 2019 
Summary of Revisions Made: 
o Updated power analyses to be based upon determining an estimate of the variance. 

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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ............................................................................................................. 3 
STUDY TEAM ROSTER........................................................................................................... 6  
PARTICIPATING STUDY SITES ............................................................................................ 7 
PRÉCIS ....................................................................................................................................... 8 
1. STUDY OBJECTIVES ........................................................................................................... 11 
1.1 
Primary Objective ......................................................................................................... 11 
1.2 
Secondary Objectives ................................................................................................ 11 
2. BACKGROUND AND RATIONALE .................................................................................. 11 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 11 
2.2 
Study Rationale ............................................................................................................. 12 
3. STUDY DESIGN ..................................................................................................................... 15 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 16 
4.1 
Inclusion Criteria .......................................................................................................... 16 
4.2 
Exclusion Criteria ......................................................................................................... 16 
4.3 
Study Enrollment Procedures ....................................................................................... 16 
5. STUDY INTERVENTIONS .................................................................................................. 17 
5.1 
Interventions, Administration, and Duration ................................................................ 17 
5.2 
Handling of Study Interventions ................................................................................... 18 
5.3 
Concomitant Interventions ............................................................................................ 19 
5.3.1 Allowed Interventions ............................................................................................... 19 
5.3.2 Required Interventions .............................................................................................. 19 
5.3.3 Prohibited Interventions ............................................................................................ 19 
5.4 
Adherence Assessment ................................................................................................. 19 
6. STUDY PROCEDURES ........................................................................................................ 19 
6.1 
Schedule of Evaluations ................................................................................................ 20 
6.2 
Description of Evaluations ............................................................................................ 21 
6.2.1 Screening Evaluation ................................................................................................ 24 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 25 
6.2.3 Blinding..................................................................................................................... 26 
6.2.4 Followup Visits ......................................................................................................... 26 
6.2.5 Completion/Final Evaluation .................................................................................... 27 

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7. SAFETY ASSESSMENTS ..................................................................................................... 27 
7.1 
Specification of Safety Parameters ............................................................................... 28 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 28 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 28 
7.4 
Reporting Procedures .................................................................................................... 29 
7.5 
Follow-up for Adverse Events ...................................................................................... 30 
7.6 
Safety Monitoring ......................................................................................................... 30 
8. INTERVENTION DISCONTINUATION ........................................................................... 31 
9. STATISTICAL CONSIDERATIONS .................................................................................. 31 
9.1 
General Design Issues ................................................................................................... 31 
9.2 
Sample Size and Randomization .................................................................................. 32 
Treatment Assignment Procedures ....................................................................................... 33 
9.3  
Definition of Populations .............................................................................................. 33 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 34 
9.5 
Outcomes ...................................................................................................................... 34 
9.5.1 Primary Outcome ...................................................................................................... 34 
9.5.2 Secondary Outcomes ................................................................................................ 34 
9.6 
Data Analyses ............................................................................................................... 36 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 37 
10.1 
Data Collection Forms .................................................................................................. 37 
10.2 
Data Management ......................................................................................................... 38 
10.3 
Quality Assurance ......................................................................................................... 38 
10.3.1 
Training ................................................................................................................. 38 
10.3.2 
Quality Control Committee................................................................................... 39 
10.3.3 
Metrics .................................................................................................................. 39 
10.3.4 
Protocol Deviations ............................................................................................... 40 
10.3.5 
Monitoring ............................................................................................................ 40 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 40 
11.1 
Institutional Review Board (IRB) Review .................................................................... 40 
11.2 
Informed Consent Forms .............................................................................................. 40 
11.3 
Participant Confidentiality ............................................................................................ 41 
11.4 
Study Discontinuation ................................................................................................... 41 
12. COMMITTEES..................................................................................................................... 41 

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13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 41 
14. REFERENCES ...................................................................................................................... 42 
15. SUPPLEMENTS/APPENDICES ........................................................................................ 51 
 
15.2.1  Appendix A: Informed Consent Documents 
15.2.2   Appendix B: Yoga Skills Training Home Practice Guide  
15.2.3  Appendix C: Yoga Skills Training Home Diary  
15.2.4  Appendix D: Attention Control Home Diary 
15.2.5  Appendix E: Treatment Fidelity Forms  
15.2.6  Appendix F: Chart Review Form and Questionnaires 
15.3.7  Appendix G: Semi-Structured Interview Guide 
15.3.8  Appendix H: Daily Survey 
15.2.9  Appendix I: Recruitment Script 
15.2.10 Appendix J: Recruitment Flyer 
15.2.11 Appendix K: Eligibility Checklist 
15.2.12 Appendix L: Protocol Registration Form 
15.2.13 Appendix M: Thank You Letter 
15.2.14 Appendix N: Adverse Events Reporting Form 
 

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STUDY TEAM ROSTER  
 
Stephanie Jean Sohl, PhD, Principal Investigator (PI) 
Department of Social Sciences and Health Policy 
Division of Public Health Sciences 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157-1063 
 
Caio Rocha Lima, MD, Co-Investigator 
Department of Hematology & Oncology 
Wake Forest Baptist Medical Center 
Medical Center Boulevard, Winston-Salem, NC 27157 
 
Janet Tooze, PhD, Co-Investigator 
Department of Biostatistical Sciences 
Division of Public Health Sciences 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157-1063 
 
David Schlundt, PhD, Co-Investigator 
Department of Psychological Sciences 
Vanderbilt University 
323 Wilson Hall 
Nashville, TN, 37203 
 
 
Beth Malow, MD, Co-Investigator 
Department of Neurology 
Vanderbilt University Medical Center 
1211 Medical Center Drive 
Nashville, TN, 37232 
 
Dr. Kumar, MD, Consultant 
Department of Neurology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
Barbara Nicklas, PhD, Consultant 
Department of Gerontology and Geriatric Medicine 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 

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PARTICIPATING STUDY SITES 
 
Sheila H. Ridner, BSN, MSHSA, MSN, PhD, ACNP, FAAN, Site PI 
Vanderbilt University School of Nursing 
461 21st Ave South 
Nashville, TN 37240 
 
 

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PRÉCIS  
Study Title  
 
Programs to Support You During Chemotherapy (Pro-You): A randomized controlled 
pilot study of yoga compared to an attention control in patients receiving 
chemotherapy 
 
Objectives  
 
Aim 1: To conduct a pilot randomized controlled trial of a Yoga Skills Training 
(YST) versus an Attention Control (AC) group among adults with a gastrointestinal 
(GI) cancer receiving chemotherapy to determine preliminary efficacy for the primary 
outcome of fatigue, secondary outcome of depressive symptoms, and possible 
mediators (i.e., psychological stress, circadian disruption, inflammation) as assessed 
by standard measures.  
 
Aim 2: To measure the impact of the YST versus the AC on daily assessments of 
fatigue, depressive symptoms, and proposed mediators in the same trial and explore 
relationships among daily and standard assessments.  
 
Aim 3: To qualitatively assess perceived efficacy of the YST and AC and 
acceptability of new methodology through semi-structured interviews in a subset of 
20-40 participants.  
 
Design and Outcomes  
 
We propose a prospective stratified randomized controlled pilot study of the 
preliminary efficacy of YST as compared to AC on fatigue, depressive symptoms and 
possible mediators in a sample of people with GI cancer receiving first-line 
chemotherapy.  
 
Standard recalled assessments of fatigue, depressive symptoms and possible 
mediators will be collected at four time points (baseline, mid-intervention, post-
intervention, 4-week follow-up). Participants will also be asked to complete daily 
assessments of outcomes, mediators, and adherence to home practice of the 
intervention via an automated daily survey and wear a wrist actigraphy device for two 
weeks before and two weeks following the interventions. Inflammatory cytokines will 
be collected along with patients regularly scheduled blood draws at weeks 2 and 10 
and a semi-structured interview conducted after completion of all assessments. 
 
Interventions and Duration  
 
The YST intervention will be administered individually in the clinic during 
chemotherapy infusions and patients will be encouraged practice the YST daily at 
home. Chemotherapy infusions follow a standardized treatment regimen that is given 
during biweekly visits. Dr. Sohl developed the YST for a prior study to teach the key 

Protocol Date 07/15/19 
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elements of yoga in a manner that would accommodate patients’ needs and reduce 
barriers to adherence during chemotherapy. The YST intervention has been modified 
for this study to consist of four 30 minute in-person sessions (weeks 2, 4, 6, 8) that 
instructs skills to enhance mindfulness and promote relaxation. 
 
An empathic attention control group will be employed as the AC to account for the 
added attention and efficacy expectations of the YST as used in previous studies.1–31–
31–3 
In addition, the interventionist will recommend that the patients write brief diary 
entries daily at home. The number of sessions with a professional, recommended 
home practice, and home assessments will also be matched to the YST. 
The total length of time each participant will be on study is approximately 14 weeks 
(see Study Schema).  
 
Sample Size and Population  
The target population is 44 participants, 22 in each group. Randomization will be 
stratified by type of cancer (colon, rectal/other better prognosis GI cancers, poorer 
prognosis cancers) and cancer stage (localized stages II/III or metastatic stage IV) to 
minimize differences between groups (6 strata total). We will add cancers of the small 
intestine, anus and appendix to our existing rectal cancer strata since the survival rates 
are similar. The cancer types with poorer prognoses will be put into the new strata 
(with <50% 5-year survival rate; cancers of the esophagus, stomach, pancreas, 
gallbladder, liver). 
 
 
 

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Study Schema
Patients Referred to Study
Eligible Patients
Blood Draw 1
Yoga Skills Training (YST)
Sessions 1 -3
Patients Enrolled in Study
Questionnaire 1
Randomized
Blood Draw 2
Questionnaire 3
Chemotherapy 8
Week 10
Chemotherapy 2-4 
Weeks 2-6
Blood Draw 1
Attention Control (AC) 
Sessions 1-3
Blood Draw 2
Questionnaire 3
Two weeks of
Actigraphy & 
Daily 
Assessments
Two weeks of
Actigraphy  & 
Daily 
Assessments
Chemotherapy 5
Week 8
Chemotherapy 1 
Week 0
Week 14
Questionnaire 4
Semi-structured Interview
Questionnaire 4
Semi-structured Interview
Questionnaire 2
YST 4
Questionnaire 2
AC 4
*
*
*
*
* Daily home practice 
of the intervention 
encouraged
 

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1. STUDY OBJECTIVES 
1.1 
Primary Objective 
 To conduct a pilot randomized controlled trial of the YST versus an AC group 
among adults with gastrointestinal (GI) cancers receiving chemotherapy to 
determine preliminary efficacy for the primary outcome of fatigue, secondary 
outcome of depressive symptoms, and possible mediators (i.e., psychological 
stress, circadian disruption, inflammation) as assessed by standard measures.  
 
 
Hypothesis: The YST will show trends for reducing fatigue and depressive 
symptoms as assessed with standard recalled measures to a greater degree than 
the AC and these reductions will be associated with decreases in mediators. 
1.2 
Secondary Objectives 
 To measure the impact of the YST versus the AC on daily assessments of fatigue, 
depressive symptoms, and proposed mediators in the same trial and explore 
relationships among daily and standard assessments.  
 
 To qualitatively assess perceived efficacy of the YST and AC and acceptability 
of new methodology through semi-structured interviews in a subset of 20-40 
participants.  
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Burden of fatigue and depressive symptoms in gastrointestinal cancers is high. 
Gastrointestinal (GI) cancers are among the most prevalent cancers for both men and 
women,4 and the number of GI survivors continues to increase.5–7 Fatigue, ‘‘a 
subjective state of overwhelming and sustained exhaustion and decreased capacity for 
physical and mental work that is not relieved by rest,”8  is reported by a majority 
(>50%)9,10 of patients with GI cancers, co-occurs with other common symptoms such 
as depression (>30% in patients receiving chemotherapy),11–13 and is associated with 
a decline in post-treatment quality of life.14,15 There is overlap in some methods for 
assessing fatigue and depressive symptoms; however, these symptoms remain 
moderately correlated even when commonalities are removed.33 There is also 
considerable evidence showing that fatigue and depression are distinctly associated 
with other variables such as quality of life.16–18 Further, although chemotherapy is 
efficacious for increasing survival,19 it leads to increases in fatigue and depressive 
symptoms20,21 such that symptoms peak approximately 3-5 days following treatment 
and then improve;22–24 however fatigue and depressive symptoms do not return to 
pretreatment levels in a substantial subset of patients (20-80%).25–29 Fatigue and 
depressive symptoms experienced during treatment are associated with subsequent 
symptoms.16 Thus, it is important to address elevations of fatigue and commonly co-
occurring depressive symptoms during chemotherapy to improve quality of life in 
patients with GI cancers. 

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Importance of shared biobehavioral mediators of fatigue and depressive 
symptoms. The biobehavioral conceptual framework and data23,30–36 suggest that 
fatigue and depressive symptoms tend to co-occur because they may share underlying 
mechanisms including psychological stress, circadian disruption (i.e., an altered ratio 
of nighttime activity to daytime activity) and inflammation.34,37,38 Figure 1 illustrates 
the potential relationships among these variables using a biobehavioral framework. 
Data support that psychological stress in cancer patients is associated with fatigue, 
depressive symptoms, circadian disruption and inflammation.30,31,33,39 Cancer and its 
treatment can also lead to circadian disruption, which is associated with fatigue in GI 
cancer patients,36 and fatigue and depressive symptoms during chemotherapy.23,34,35 
Further, evidence suggests that circadian disruption precedes fatigue and depressive 
symptoms.23,40 Data also show that increases in inflammation (i.e., sTNF-R1, IL-6) 
specifically 
during 
treatment for 
gastrointestinal 
cancer  is 
related to 
changes in 
fatigue and 
other symptoms 
(e.g., distress).10 
 
2.2 
Study Rationale 
Preliminary efficacy of yoga for fatigue and depressive symptoms. Despite the 
high symptom burden, there are few behavioral interventions designed for GI cancer 
patients that aim to proactively improve fatigue and depressive symptoms during 
treatment.41,42 Guidelines for managing cancer-related fatigue include non-
pharmacologic and pharmacologic interventions that target fatigue itself, comorbid 
medical conditions and coexisting symptoms (e.g., depressive symptoms).43 Both 
psychological and exercise interventions show efficacy for reducing fatigue and 
depressive symptoms and reviews suggest that a combined approach may be 
optimal.29–32 However, most existing interventions for GI cancer patients do not use a 
combined approach.41,42 One intervention designed for a heterogeneous group of 
cancers did apply a combined approach during chemotherapy, yet only found efficacy 
for depressive symptoms and not fatigue.44 Yoga utilizes a combined approach and 
has shown efficacy for reducing fatigue and depressive symptoms when implemented 
as group classes primarily in patients with breast cancer though has not been 
investigated when implemented during chemotherapy except for in my Preliminary 
Research.45,46 The key practices taught by yoga are meditation, body movements, and 
breathing techniques.47 Therapeutic applications of yoga can target the instructed 
practices specifically to a goal, such as fatigue, which may improve upon effects 
found from more general strategies used thus far.44 This notion is supported by a 
systematic review that revealed that behavioral interventions targeted to specifically 
address fatigue have increased efficacy.48 Although the optimal dose of yoga is 

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unknown, the greatest improvements in fatigue were found in cancer survivors who 
practiced yoga an average of three times per week49 and a review of exercise 
interventions (including yoga) during chemotherapy found that 90-120 minutes of 
moderate activity per week was better than higher doses.50 Further, ~20 minutes of 
home yoga practice per day was associated with an improvement in next day 
fatigue.51 Therefore, a reasonable suggested dose for yoga during chemotherapy 
would be 3-6 times per week for about 20 minutes per session. In summary, yoga is a 
promising intervention that incorporates a combined and targeted approach for 
reducing fatigue and depressive symptoms during chemotherapy that has yet to be 
investigated in patients with GI cancers. 
 
Proposed mediators of the effect of yoga on fatigue and depressive symptoms. 
Reviews of yoga research call for the investigation of mediators to explain how yoga 
influences cancer-related outcomes such as fatigue and depressive symptoms.52 The 
Self-regulation Framework can be applied to understand the efficacy of behavioral 
integrative medicine interventions such as yoga.53 This framework posits that people 
are able to consciously alter their cognitive (e.g., mindfulness), emotional (e.g., 
feelings of relaxation) and behavioral (e.g., breathing) responses to various 
experiences (e.g., psychological stress from cancer and its treatment) to obtain desired 
goals (e.g., reduced fatigue).54,55 Conscious attention to and awareness of the present 
moment, or mindfulness, is proposed to be the first step in the self-regulation 
process.56 Yoga aims to increase mindfulness and promote relaxation to strengthen 
patients’ ability to regulate their responses. There is evidence supporting that yoga 
reduces psychological stress,57 and improves subjective and objective sleep quality (a 
component of circadian disruption).58,59 Further, inflammatory cytokines are 
theoretical biomarkers of effective self-regulation60 and there is some evidence that 
yoga reduces inflammation (e.g., IL-6, TNF-α).61–64 Therefore, further study of yoga 
for reducing fatigue is warranted.21  
 
The proposed yoga intervention, Yoga Skills Training (YST), will be 
implemented in the clinical setting to be inclusive of patients most in need of 
intervention. Implementation of the proposed YST individually in the clinical setting 
challenges the current paradigm in the United States that typically implements yoga 
as group classes. A study that recruited cancer patients to group yoga classes found 
that there were some common barriers to participating in yoga classes including, 
transportation, scheduling, being too busy or too sick.58 This was important to 
consider in this study design because such a large portion of cancer patients travel 
long distances for treatment (i.e.,  83% of colorectal cancer patients treated at 
Vanderbilt-Ingram Cancer Center travel more than 10 miles for treatment and 48% 
travel 50 miles or more).65 Patients’ experience of fatigue was also associated with 
attending fewer yoga classes in another study.66 Therefore, patients who are burdened 
by fatigue or depressive symptoms during chemotherapy may be unintentionally 
excluded from yoga interventions due to feasibility issues. The proposed 30-minute 
YST can be taught to 2-3 participants in the time generally allocated to one yoga 
class. Therefore, the number of participants who attend each class is important to 
consider. In summary, the proposed YST is designed to lessen identified barriers to 

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participation by integrating YST into patients’ already scheduled visits for 
chemotherapy. So far, only preliminary research has been conducted to explore if 
yoga can be safe and efficacious when applied in clinical settings related to cancer 
care.62,67 Yet, therapeutic yoga is traditionally implemented individually.68 Data 
supporting the efficacy of the YST would encourage a shift in the practice of 
implementing yoga primarily as a complementary modality to integrating yoga during 
clinical cancer care to broaden the population of patients who may benefit. 
 
Daily measurement of fatigue and depressive symptoms will more accurately 
detect efficacy than more commonly used recalled assessments. Fatigue and 
depressive symptoms are generally assessed in intervention studies through 
retrospective patient-reported outcomes (e.g., “how much fatigue have you 
experienced in the past 7 days”).69,70 However, assessment over a week’s time period 
is likely to miss the acute variation in the experience of symptoms and not capture the 
influence of an intervention on fatigue at its worst 3-5 days after chemotherapy 
infusions.23 That is, daily symptom assessment can improve upon recalled 
assessments by elucidating the immediate effect of an intervention on the trajectory of 
symptoms following chemotherapy. Daily diaries are one method for measuring an 
experience in a participant’s natural setting with low patient burden.71 Fatigue and 
depressive symptoms will be assessed daily to reduce recall bias and enable detailed 
analyses of how experiences interrelate on a daily basis.71 Few studies have utilized 
daily measures of chemotherapy-related symptoms23,24,72 and this study will be the 
first to evaluate the impact of an intervention on daily fatigue and depressive 
symptoms during chemotherapy for GI cancers.  
 
Assessing the impact of yoga on biobehavioral mediators during chemotherapy 
is also novel. The impact of yoga on psychological stress, circadian disruption, and 
inflammation during chemotherapy has not been investigated. Two pilot studies by 
the same research team  have utilized daily assessment to evaluate the impact of yoga 
on “positive” therapeutic processes (i.e., invigoration, acceptance, relaxation), 
however, psychological stress, circadian disruption and inflammation were not 
assessed.51,73 There is some support for the association between yoga and 
psychological stress,57,74objectively measured rest,59 and inflammation,61–64 but these 
relationships have not been explored daily during chemotherapy.  
 
Preliminary Intervention Effects of the YST. Dr. Sohl developed an initial protocol 
for implementing the YST with patients undergoing chemotherapy for ovarian 
cancer.75 Data from seven women who participated in the YST during chemotherapy 
showed an immediate effect. Women completed two Visual Analogue Scale items of 
anxiety and relaxation immediately before and after the YST. Anxiety decreased and 
relaxation increased after the YST. Effect sizes were large (anxiety, d=-0.82; 
relaxation, d=0.83). Hospital staff did not find the YST burdensome and it was 
feasible to conduct the YST in a clinical setting. In addition, this study supported the 
safety of implementing the YST during chemotherapy. Minimal risk including 
potential for muscle soreness from the gentle movements or emotional discomfort 
from breathing and meditation practices is expected from participating in the YST. 

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Preliminary Feasibility of the YST for GI Cancers.  Dr. Sohl also conducted a 
randomized pilot trial of the YST as compared to an attention control group for 
patients receiving chemotherapy for colorectal cancer. Of the 29 patients approached, 
15 (51.7%) agreed to participate with interest from both men (60%) and women 
(40%). Most (80%) of the in-person intervention sessions (YST or active control) 
were completed with missed sessions due to patients not receiving chemotherapy. The 
active control consisted of empathic attention. Thus, these preliminary data support 
feasibility for recruitment and randomization. Based on what the PI learned from this 
initial pilot, and with input from my current mentors and other experts, we plan to 
build upon this previous YST by implementing more robust and innovative 
measurement (i.e., daily assessments of symptoms, objective measure of circadian 
disruption, mixed-methods follow-up assessment) and enhancing the YST 
intervention (i.e., more targeted to fatigue, attention to treatment fidelity, focused on 
adherence to home practice).  
3. STUDY DESIGN 
 We propose a prospective stratified randomized controlled pilot study in a sample of GI 
cancer patients receiving first-line Fluorouracil (5FU)-based chemotherapy (5FU-based 
chemotherapy is the standard treatment for all patients with colorectal cancers and most 
patients with other gastrointestinal cancers). This study will assess preliminary efficacy 
of YST on the primary outcome of fatigue, secondary outcome of depressive 
symptoms, and possible mediators (i.e., psychological stress, circadian disruption, 
inflammation) as assessed by standard measures. Secondary objectives are to measure 
the impact of the YST versus the AC on daily assessments of fatigue, depressive 
symptoms, explore relationships among daily and standard assessments, and explore 
mediators. At study completion, the first 20-40 participants will be selected for semi-
structured interviews to discuss perceived impact of the intervention, and adherence to 
home practice, and acceptability of measures. Overall, the study is designed to help 
inform a larger future study. 
 
Standard recalled assessments of fatigue, depressive symptoms and possible mediators 
will be collected at four time points (baseline, mid-intervention, post-intervention, 4-
week follow-up). Participants will also be asked to complete daily assessments of 
outcomes, mediators, and adherence to home practice of the intervention via an 
automated daily survey and wear a wrist actigraphy device for two weeks before and 
two weeks following the interventions. Inflammatory cytokines will be collected along 
with patients regularly scheduled blood draws at weeks 2 and 10 and a semi-structured 
interview conducted after completion of all assessments. 
 
The YST intervention will be administered individually in the clinic during 
chemotherapy infusions and patients will be encouraged practice the YST daily at 
home. Chemotherapy infusions follow a standardized treatment regimen that is given 
during biweekly visits. Dr. Sohl developed the YST for a prior study to teach the key 
elements of yoga in a manner that would accommodate patients’ needs and reduce 
barriers to adherence during chemotherapy. The YST intervention has been modified 
for this study to consist of four 30 minute in-person sessions (weeks 2, 4, 6, 8) that 

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instructs skills to enhance mindfulness and promote relaxation. 
 
An empathic attention control group will be employed as the AC to account for the 
added attention and efficacy expectations of the YST as used in previous studies.1–3 1–3 
In addition, the interventionist will recommend that the patients write brief diary 
entries daily at home. The number of sessions with a professional, recommended home 
practice, and home assessments will also be matched to the YST. 
 
The total length of time each participant will be on study is approximately 14 weeks. 
The enrollment period for the trial is expected to continue for 30 months.  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Participants must meet all of the inclusion criteria to participate in this study. 
 Adults (≥21 years of age)  
 Scheduled to receive first-line Fluorouracil (5FU)-based intravenous 
chemotherapy treatment for a gastrointestinal cancer (stages II-IV) 
 Has an Eastern Cooperative Oncology Group performance status of ≤1 
 Ability to understand and the willingness to sign an informed consent 
document in English 
4.2 
Exclusion Criteria 
All candidates meeting any of the exclusion criteria at baseline will be excluded from 
study participation. 
 
 Has a self-reported history of diagnosed sleep disorders (e.g., obstructive 
sleep apnea, insomnia), comorbidities associated with poor sleep or fatigue 
(e.g., chronic fatigue syndrome), or a job with night shifts.  
4.3 
Study Enrollment Procedures  
Individuals scheduled to receive first-line 5FU chemotherapy for a gastrointestinal  
cancer will be recruited from the Comprehensive Cancer Center at Wake Forest 
University (CCC-WFU) and the Vanderbilt Ingram Cancer Center (VICC; site-
specific protocol, closed to recruitment). To identify potential patients, a study team 
member (STM) will screen participants using electronic medical records containing 
patients’ schedules and communicate with attending physicians regarding patients’ 
potential eligibility for trial. Subject recruitment will be documented in a Screening 
Log including reasons for ineligibility, eligible patients approached, number who 
declined participation, and number successfully recruited. 
 
If the patient is interested, the STM will approach the patient at a clinic visit or call 
the patient to explain the protocol, answer questions, further determine eligibility, and 
discuss informed consent. After making sure the patient clearly understands the study 

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procedures and agrees to follow them, the patient will be asked to sign the informed 
consent form either in person or remotely (Appendix A: Informed Consent 
Document). If signed remotely, patients will be asked to mail, or fax the form back to 
us, as well as bring the original with them to their next clinic visit. A copy of the 
consent form will be given to the participant in person the next time they are in clinic, 
and the original copy will be kept in the participant’s file.  
 
Eligible participants enrolled in the study will be randomized after baseline 
assessments to YST or AC at week 0.  
 
Randomization. Eligible, consented, and enrolled participants will be randomized to 
YST or AC. To control for type and stage of cancer, randomization will occur within 
both type (colon, rectal/other better prognosis GI cancers, poorer prognosis cancers) 
and stage (localized stages II/III or metastatic stage IV). Randomization (1:1) lists 
within each strata will be generated via a permuted block program developed and 
executed by the study biostatistician with blocks of random sizes between 2 and 6. 
The randomization lists will be held by a STM (not involved with data collection) 
who will allocate each participant to study group. Once assigned, details about that 
arm will be revealed to the PI for study coordination purposes. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Active Intervention. The Yoga Skills Training (YST) intervention will be 
administered individually in the outpatient clinic while patients are in the chair during 
outpatient chemotherapy sessions and patients will be encouraged practice the YST 
daily at home. First-line 5FU-based chemotherapy for gastrointestinal cancers is 
typically given during biweekly visits. Dr. Sohl developed the YST for a prior study 
to teach the key elements of yoga in a manner that would accommodate patients’ 
needs and reduce barriers to adherence during chemotherapy.59  The YST intervention 
consists of four 30 minute in-person sessions (weeks 2, 4, 6, 8) that instructs skills to 
enhance mindfulness and promote relaxation: (a) Awareness – noticing the current 
state and establishing relaxed breathing – 5 minutes; (b) Movement - 7 minutes of 
gentle movements coordinated with the breath (such as raising and lowering the 
arms); (c) Breathing Practice - 3 minutes of inhaling cool air as if through a straw; 
(d) Meditation - 5 minutes of focus on letting go of physical and mental tension. In 
addition, the first five minutes of the YST will address any questions and inquire 
about the participant’s current physical status. The last five minutes will be used to 
review a handout describing the YST (Appendix B: YST Home Practice Guide; 
Appendix C: YST Diary) and to encourage participants to practice daily with 
strategies to increase adherence to home practice described later in this section. 
Participants will also be given an audio recording of the YST and devices to play the 
recording. The content of the YST was informed by the Dr. Sohl’s training from the 
Integral Yoga Academy’s Yoga for People with Cancer Teacher Training taught by 
Jnani Chapman, RN, RYT, the Urban Zen Integrative Therapy training, and was 
modified for this study to further target fatigue and depressive symptoms by 

Protocol Date 07/15/19 
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consulting with expert yoga therapists from the Krishnamacharya tradition (i.e., led 
by Amy Wheeler, Ph.D). Each session will contain the same content, but the 
movement will be individualized based on ability and level of energy that day. Self-
compassion will be highlighted throughout the YST and any medical restriction can 
be accommodated. All yoga instructors (i.e., interventionists) will have completed 
accredited yoga teacher training programs and be experienced teaching patients with 
chronic illness. Minimal risk including potential for muscle soreness from the gentle 
movements or emotional discomfort from breathing and meditation practices is 
expected from participating in the YST.  
 
Attention Control (AC). An empathic attention control group will be employed as 
the AC to account for the added attention and efficacy expectations of the YST as 
used in previous studies.1–3 In addition, the interventionist will recommend that the 
patients write brief diary entries daily at home as used as a control condition in 
another previous study (Appendix D: AC Home Diary).76 The AC will not include 
instruction of movement, meditation or breathing practices, which are the active 
ingredients of the YST. The location, number of sessions with a professional, 
recommended home practice, and home assessments will also be matched to the YST. 
The AC will be implemented by an individual with a background conducting research 
in a medical setting who will be trained to create and maintain a relationship by using 
techniques of active listening, reflection of statements, and avoiding negative 
judgments. This individual will spend approximately 30 minutes with patients for 
four sessions while they are undergoing chemotherapy. S(he) will utilize standardized 
instructions to prompt the patient as adapted from previous studies2,76,77: “What were 
some of the events or circumstances that affected you in the past two weeks?”  
Patients will be encouraged to ‘‘discuss one experience at a time, even if it means 
talking about the same experience each session. However, if you find that you have 
discussed it in adequate detail, please move on to a new topic.’’ The instructions for 
daily diary entries will be, “What were some of the events or circumstances that 
affected you in the past day? Think back over the past day and write down on the 
lines below up to five events that had an impact on you.”76 Minimal risk including 
potential for emotional discomfort from disclosing personal experiences is expected 
from participating in the AC.  
5.2 
Handling of Study Interventions  
Participants will be told that both groups offer programs to support their experiences 
in coping with chemotherapy to match efficacy expectations. Information about both 
arms will be revealed to participants after completion of data collection. 
 
Treatment Fidelity.  A number of steps will be taken to ensure treatment fidelity.78–
80 Dr. Sohl will train interventionists in implementation of the YST and AC during an 
initial four hours of training and monthly meetings. Dr. Sohl will remain an objective 
observer in order to develop a system for establishing treatment fidelity. One primary 
YST and AC interventionist will implement the interventions and at least two 
additional interventionists trained in the intervention protocol will serve as back-ups. 
The interventionists will complete a written test to confirm their understanding, be 

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video recorded during all sessions (using a small device that will not record the 
patient or anyone else present) with 10% of the recordings randomly selected for Dr. 
Sohl’s review, and document each in-person session with a checklist (Appendix E: 
Treatment Fidelity Forms). The checklist will be also used to evaluate consistency of 
implementation. 
 
Adherence Strategies. To optimize adherence to home practice interventionists will 
be trained to adopt brief coaching methods based on motivational interviewing as 
used to encourage yoga practice and walking in other studies of cancer patients.49,81 
Specifically, the interventionists will ask open-ended questions to inquire about goals, 
specific times planned for home practice, and strategies to ensure home practice of 
the interventions. Confidence in the ability to practice will be verbally assessed and 
reports of low confidence discussed.  
5.3 
Concomitant Interventions  
5.3.1 Allowed Interventions 
All participants will continue with routine treatment of medical conditions including 
chemotherapy and medications.  
 
5.3.2 Required Interventions 
 
                  No additional interventions are required except for those propose in the protocol. 
 
5.3.3 Prohibited Interventions 
 
There will be no prohibited medications among patients in this study. Prior approval 
of participation in other behavioral intervention studies is required.  
5.4 
Adherence Assessment  
Adherence will be assessed by: (1) participation in-person sessions (i.e., number of 
sessions completed); (2) number of components completed at each in-person YST 
session; (3) and days of intervention home practice (see Section 6.2 - Description of 
Evaluations). Instructors will directly observe and document adherence to in person 
sessions. We will consider high adherence to protocol if participants complete 75% of 
the planned in-person sessions and 3 or more days of home practice per week in 
between in-person sessions.  
6. STUDY PROCEDURES  
 
 

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6.1 
Schedule of Evaluations 
Assessment 
Screening:  
(Day-14 to 
Day -1) 
Consent 
Enrollment, 
Randomization 
(Day 0) 
Daily 
Survey  
(W0-W2) 
AC or YST 
1 (W2) 
AC or YST 
2 (W4) 
AC or YST 
3 (W6) 
AC or YST 
4  (W8) 
Daily 
Survey 
(W8-W10) 
 (W10) 
Follow-up  
(W14) 
Person(s) Responsible 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
PI, STM 
Permission of Oncologist 
X 
 
 
 
 
 
 
 
 
 
PI, STM 
Informed Consent Form   
 
X 
 
 
 
 
 
 
 
 
PI, STM 
Enrollment/Randomization 
 
X 
 
 
 
 
 
 
 
 
PI, STM 
Demographics 
 
X 
 
 
 
 
 
 
 
 
STM 
Clinical Data  
 
X 
 
 
 
 
 
 
 
X 
STM 
Questionnaire 
 
X 
 
 
 
 
X 
 
X 
X 
STM 
Automated Daily Survey 
 
 
X 
 
 
 
 
X 
 
 
Participant 
Actigraphy 
 
 
X 
 
 
 
 
X 
 
 
Participant 
Treatment Fidelity 
 
 
 
X 
X 
X 
X 
 
 
 
PI, Interventionist 
Intervention Home Practice 
 
 
 
X 
X 
 
 
Participant 
Adherence 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PI 
Blood Draws 
 
 
 
X 
 
 
 
 
X 
 
STM 
Adverse Events  
 
 
 
X 
X 
X 
X 
 
 
 
Interventionists,A PI,B 
STMC 
Interview 
 
 
 
 
 
 
 
 
 
X 
Trained Facilitator 
Note. AC = Attention Control; YST = Yoga Skills Training; PI = Principal Investigator; STM = Study Team Member 
A Interventionists will note any adverse events that occur during the intervention or reported by patients during home practice.  
B The PI will review interventionists’ notes and identify any AE’s that need to be captured. 
C Other Study Team Members (e.g., Research Nurses) will report ratings of 3 or higher on the suicide item from the depression 
assessment (corresponding with Weeks 0, 8, 10 and 14). They will not collect any additional information related to adverse events. 

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6.2 
Description of Evaluations  
Recalled assessments will be collected at four time points (baseline, mid-intervention, 
post-intervention, 4-week follow-up; Appendix F: Chart Review Form and 
Questionnaires) and a semi-structured interview conducted after completion of all 
assessments (either in person or by telephone; Appendix G: Semi-Structured Interview 
Guide). To minimize burden, all assessments via recalled questionnaires and interviews 
will be scheduled to coincide with the patients’ appointment for chemotherapy. 
Therefore, sequencing of each patient’s assessments will be based on the timing of the 
respective patient’s first completed chemotherapy visit. The standard chemotherapy 
timing is every two weeks. The randomized study condition will commence with the 
second chemotherapy visit. Given that there may be slight personal modifications to the 
standard schedule, we have proposed a design that will attempt to control for the possible 
effect of chemotherapy schedule on outcomes. If a chemotherapy visit is rescheduled for 
within two weeks of the standard schedule, the intervention will occur at that next visit 
(and all following assessments will then follow the subsequent standard chemotherapy 
schedule). If the rescheduled chemotherapy visit is more than two weeks later, the in-
person study intervention session for that participant will not occur, the assessments will 
be mailed to the participant for completion, and this will be documented as an aspect of 
treatment fidelity.  
 
Participants will also be asked to complete daily assessments of and adherence to home 
practice of both interventions for two weeks before and after the intervention via an 
automated daily survey and wear a wrist actigraphy device. Participants will also be 
asked to complete daily assessments of outcomes, mediators, adherence to home practice 
of the intervention for two weeks before and after the intervention via an automated daily 
survey (Appendix H: Daily Survey) and wear a wrist actigraphy device. Participants will 
be given the choice to respond to the automated daily diary via an interactive voice 
response system (IVRS) or internet survey hosted through a REDCap platform that will 
verify the date and time of assessments. IVRS and internet surveys have been 
successfully applied in similar research to assess daily symptoms in people with 
cancer73,82,83 and may improve compliance to assessments as compared to more 
commonly used paper daily diaries.84 Participants will be asked to complete surveys in 
the evening. Those who choose to complete the survey via IVRS will be called at 
approximately 6:00pm each evening (unless the participant indicates another strong time 
preference) and have the option to call back before they go to sleep. A paper guide with 
response options for the daily survey will be provided to improve comprehension over 
the telephone. If participants do not complete the first two surveys a STM will call them 
to confirm receipt of calls. If for any reason the automated survey system is not available, 
a STM will call the patient to complete the same survey. Participants will also be given a 
wrist actigraphy device and instructions for its use to measure circadian disruption. 
Instructions for use will be guided by Dr. Malow and Dr. Kumar.  
 
Inflammatory cytokines will be collected via EDTA plasma samples by a Licensed 
Practical Nurse or phlebotomists along with patients regularly scheduled blood draws at 
weeks 2 and 10. Although this method may not account for possible variation in circadian 
patterns release of some cytokines, cytokines were similarly assayed in another study, 

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which associated elevated cytokines to increased fatigue during chemotherapy.10 All 
assays will be conducted by the Cytokine Core Laboratory led by Dr. Nicklas.  
 
Semi-structured interviews will be conducted face-to-face or by telephone and audio 
recorded by a trained facilitator for approximately 45 minutes.85 If the interview is 
implemented by telephone, no personal health information will be revealed unless 
speaking directly to the participant. Additional study process variables will also be 
tracked (e.g., recruitment, adherence to in-person intervention sessions, safety) and 
participants will be asked for feedback regarding reasons for declining participation and 
dropping out of the study.  
 
Measures  
 
Demographics.  Age, race/ethnicity, marital status, education level, ability to pay for the 
basics, alcohol/substance use and malnutrition status will be self-reported at baseline.86  
 
Clinical Data. Cancer type, chemotherapy regimen, stage of disease, recurrence status, 
receipt of other treatments, days since surgery, height, and weight will be abstracted from 
medical charts at baseline. Any chemotherapy dose modifications or symptoms related to 
dehydration (e.g., diarrhea) and medications for fatigue, sleep, anemia, depressive 
symptoms, and pain will be abstracted at follow-up. 
 
Questionnaire 
 
 Fatigue (recalled) “in the past seven days” will be assessed with the 7-item 
measure of Fatigue from the Patient-Reported Outcomes Measurement 
Information System (PROMIS)-Cancer.87,88 Higher scores indicate more fatigue. 
 Depressive Symptoms (recalled) will be assessed with the standadized10-item 
PROMIS-Cancer Depressive symptoms short-form.89  
 Psychological Stress (recalled) will be assessed by the 10-item Perceived Stress 
Scale (PSS).90 The PSS has 2 factors (stress and counter stress).91 
 Regulation of Psychological Stress (recalled) will be determined by ratings on 
four of the seven factors of the Cancer Behavior Inventory92, which assess self-
efficacy for stress management (α = 0.86), coping with treatment-related side-
effects (α = 0.82), accepting cancer/maintaining positive attitude (α = 0.86), and 
affective regulation (α = 0.81). 
 Circadian disruption (recalled) will be assessed with measures of activity and 
rest. Activity will be measured using the 3-item Godin's leisure score index 
(LSI),93 previously used with GI cancer patients during chemotherapy.94 Rest will 
be assessed with the 8-item PROMIS sleep disturbance short-form.87 
 Efficacy Beliefs. Participants will be asked after experiencing their assigned 
intervention how strongly they believe that it will improve their fatigue and 
depressive symptoms as implemented in another randomized controlled trial 
during chemotherapy95 with adapted items.45 
 Outcome Expectancies (specific). Using items adapted from other studies, 
participants will be asked how strongly they believe that various modalities 

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including moderate physical activity, gentle physical activity (e.g., stretching), a 
mind-body practice, writing, counseling or medication would improve their 
fatigue and mood during chemotherapy.95 
 Outcome Expectancies (general). Generalized outcome expectancies will be 
assessed by the Life Orientation Test-Revised.96 
 
Daily Survey 
 
 Fatigue and Depressive Symptoms (daily) “in the last day” will be assessed 
with 3 items selected from the PROMIS measures of fatigue and depression 
validated for use in daily diaries.97 
 Psychological Stress (daily) will be assessed with two items from the 4-item 
PSS90 that would be on the same factor to optimize internal consistency.91 The 
PSS has been successfully applied daily.98  
 Regulation of Psychological Stress (daily) will be assessed with the 3-item 
serenity subscale from the Positive and Negative Affect Schedule-Expanded 
Form.99   
 
Actigraphy (Circadian Disruption - daily) will be assessed with actigraphy, a non-
intrusive alternative to the traditional polysomnogram when monitoring sleep in 
humans.100 The Actiwatch Spectrum model actigraph will be worn for two weeks at a 
time and uses an accelerometer to measure participant movement. This watch-like device 
has the ability to measure rest/activity patterns in a natural setting. Circadian disruption is 
defined as a ratio of nighttime activity to daytime activity with higher scores indicating 
greater circadian disruptions. A similar device and the same ratio has been used in 
patients during chemotherapy.23 Participants will also self-report their bedtimes and 
rising times using the daily automated survey to facilitate interpretation of actigraphy 
data.23  
 
Treatment Fidelity. Each in-person session will be documented with a checklist and 
10% of these sessions will be observed to verify treatment fidelity. 
 
Intervention Home Practice. Throughout the intervention, participants will keep daily 
paper logs of their home practice.101 In addition, one item will ask via the daily 
automated survey how many minutes participants practiced the intervention that day for 
two weeks after completion of the intervention as assessed in another yoga study.51  
 
Adherence. Percent of all assessments completed and the timeliness of completion will 
be tracked.  
 
Blood draws (Inflammation). Inflammatory cytokines (i.e., IL-6, sTNF-R1, TNF-α) that 
have been associated with fatigue during treatment for gastrointestinal cancer 7 and 
influenced by yoga practice61–64 will be measured in plasma extracted from whole blood 
drawn during regularly scheduled clinical blood draws. All assays will be conducted by 
trained technicians in the Cytokine Core laboratory directed by Dr. Nicklas. IL-6 and 
TNF-α will be measured using high-sensitivity Quantikine immunoassay kits (IL-6: 

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sensitivity=0.10 pg/ml, expected detection range=0-10.0 pg/ml; TNF-a : sensitivity=0.12 
pg/mL, expected detection range=0-32.0 pg/ml). In our laboratory, the inter-assay and 
intra-assay CVs for IL-6 are 7.5% and 4.5%, respectively, and for TNF-a are 11.8% and 
6.2%%, respectively. IL-1Ra will be measured using standard Quantikine kits 
(sensitivity=14 pg/ml, expected detection range=0-3000 pg/ml). All samples will be 
assayed in duplicate and the average of the two measures will be used for data analyses. 
To eliminate variability due to reagent conditions, we will pre-order the same lot number 
for all kits needed for a particular assay. In addition, we run all sample time points from 
individual participants on the same assay plate to reduce intra-assay variation. We will 
include an internal laboratory control on each 96-well plate. To date, inter-assay 
variability in this internal control has been low (CV<15%) in this laboratory, indicating 
that cytokine levels can be measured reliably over time. However, if the value for this 
control exceeds this 15% range, we will re-run the samples on that plate.   
 
Interview (Qualitiative Feedback). A semi-structured interview will also implemented 
after all other data collection is complete to solicit feedback on the acceptability of data 
collection methods, the participants’ experience with both the interventions (e.g., 
expected efficacy, what was useful), and barriers and facilitators to home practice.  
 
6.2.1 Screening Evaluation 
Consenting Procedure 
If the patient is interested and referred by the physician, the PI or a STM will approach 
the patient at a clinic visit or call the patient at home to explain the protocol, answer 
questions, determine eligibility, and discuss informed consent (Appendix I: Recruitment 
Script; Appendix J: Recruitment Flyer). After making sure the patient clearly understands 
the study procedures and agrees to follow them, the patient will be asked to sign the 
informed consent form either in person or remotely. If signed remotely, patients will be 
asked to mail or fax the form back to us, as well as bring the original with them to their 
next clinic visit. If consent is obtained via REDCap, an original signature will be obtained 
at their next clinic visit. A copy of the consent form will be given to the participant in 
person the next time they are in clinic, and the original copy will be kept in the 
participant’s file.  
Screening 
Screening evaluations will begin once a patient is scheduled for a consultation related to 
receiving first-line chemotherapy for GI cancers at VICC or CCC-WFU. The allowable 
range of time for screening is up to one year prior to study entry and baseline assessment. 
Electronic medical records of patients planning to receive chemotherapy will be reviewed 
by a STM to identify potential patients that meet enrollment criteria. This screening will 
consist of (Appendix K: Eligibility Checklist): 
 Review of medical history 
 Review of treatment plan 
 

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We will approach patients either in person or remotely (e.g., telephone, myWakeHealth) 
regarding their interest in study participation. For patients interested in the study, research 
staff will verify eligibility through patient interview regarding medical history. 
 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
Enrollment is defined as the randomization date or as the date all of the screening criteria 
are met and the individual agrees to participate. This enrollment date will be recorded 
(Appendix L: Protocol Registration Form). 
Registration Procedures 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer 
control trial, must be registered with the CCCWFU Protocol Registrar or entered into 
Oncology Research Information System (ORIS) Screening Log within 24 hours of 
Informed Consent. Patients must be registered prior to the initiation of treatment.   
 
The following steps must be performed in order to ensure prompt registration: 
 
1. Complete the Eligibility Checklist (Appendix K) 
2. Complete the Protocol Registration Form (Appendix L) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
 
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
 
 
To complete the registration process, the Registrar will:   
 
 assign a patient study number 
 other appropriate actions 
 register the patient on the study 
 
 
Baseline Assessments 
For participants who have successfully been screened for eligibility and are enrolled into 
the study, baseline assessments will be performed.  
 

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Demographics.  Age, race/ethnicity, marital status, education level, ability to pay for the 
basics, alcohol/substance use and malnutrition status will be self-reported at baseline.86  
 
Clinical Data. Cancer type, chemotherapy regimen, stage of disease, recurrence status, 
receipt of other treatments, days since surgery, height, and weight will be abstracted from 
medical charts at baseline.  
 
Questionnaire: Fatigue, Depressive Symptoms, Psychological Stress, Regulation of 
Psychological Stress, Circadian disruption, and Outcome Expectancies  
 
Daily Survey (weeks 0-2) will assess baseline Fatigue and Depressive Symptoms (daily), 
Psychological Stress (daily), Regulation of Psychological Stress (daily), bedtimes and 
rising times 
 
Actigraphy (weeks 0-2) will assess baseline circadian disruption (daily) 
 
Blood draws (Inflammation). Inflammatory cytokines will be assessed at Week 2 prior 
to starting the intervention. 
 
Randomization 
 
Randomization will occur the same day that screening is confirmed and will precede 
intervention initiation by approximately 2 weeks (corresponding with the timing between 
chemotherapy treatments 1 and 2).  
 
6.2.3 Blinding 
 Participants will be told that both groups offer programs to support their experience in 
coping with chemotherapy to match efficacy expectations.  
 All STM will know to what arm participants are assigned. The STM collecting 
outcome assessments will not know which intervention each arm letter represents. 
 A complete description of each study arm will be presented to participants upon their 
completion of all study measures (Appendix M: Thank You Letter). 
6.2.4 Followup Visits 
Adherence to all assessments completed will be tracked throughout the data collection 
period. In addition, the following treatment and followup visit assessments will be 
performed. 
 
 
Weeks 2, 4, 6 
 Treatment fidelity Each in-person session will be documented with a checklist. 
 Intervention home practice. Throughout the intervention, participants will keep 
daily paper logs of their home practice. 
 
 
Week 8 

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 Treatment fidelity the in-person session will be documented with a checklist. 
 Questionnaire: Fatigue, Depressive Symptoms, Psychological Stress, Regulation 
of Psychological Stress, Circadian disruption and Efficacy Beliefs. 
 Daily survey (weeks 8-10) will assess baseline Fatigue and Depressive 
Symptoms (daily), Psychological Stress (daily), Regulation of Psychological 
Stress (daily), bedtimes and rising times, how many minutes practiced the 
intervention that day.  
 Actigraphy (weeks 8-10) will assess baseline circadian disruption (daily). 
 
 
Week 10 
 Questionnaire: Fatigue, Depressive Symptoms, Psychological Stress, Regulation 
of Psychological Stress, Circadian disruption 
 Blood draws (Inflammation). Inflammatory cytokines will be assessed. 
 
6.2.5 Completion/Final Evaluation 
The following assessments will be performed the final visit (Week 14).  
 Clinical data. Any chemotherapy dose modifications, symptoms related to 
dehydration (e.g., diarrhea) and prescription medications for fatigue, sleep, 
anemia, depressive symptoms, and pain will be abstracted at follow-up. 
 Questionnaire: Fatigue, Depressive Symptoms, Psychological Stress, Regulation 
of Psychological Stress, Circadian disruption 
 Interview (Qualitiative Feedback). A semi-structured interview will be 
implemented after all other data collection is complete. 
 
Participants who discontinue study the intervention early (e.g., due to changes in 
chemotherapy treatment location, who choose to withdraw participation) will require no 
specific evaluations. The reason for discontinuation will be documented. We will contact 
participants to obtain follow-up data remotely if they discontinue participation due to 
change in treatment location. Patients terminated from the study will undergo no further 
monitoring once they have stopped the study intervention.  
7. SAFETY ASSESSMENTS  
Expected adverse experiences for each study intervention are as follows: 
            Yoga Skills Training 
 Emotional discomfort  
 Muscle soreness  
Active Control 
 Emotional discomfort  
Expected adverse experiences to the participant related to assessment are as follows: 

Protocol Date 07/15/19 
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 Bruising or minor swelling 
 Emotional discomfort  
Each interventionist will monitor and note any adverse events experienced during the 
interventions (e.g., patients’ experience of disturbed breath, expression of 
physical/emotional discomfort, or request to discontinue the in-person intervention 
sessions). In addition, interventionists will ask participants if they experienced any 
problems when doing the home practices and review notes from the home practice logs. 
These logs will be reviewed by the interventionist at each in-person session.  
 
If a participant reports a 3 (sometimes) or higher on the item, “I thought about suicide” 
from the standardized PROMIS-Cancer Depressive symptoms short-form, we will 
inform the participant’s oncologist regarding concern for depression and need for further 
evaluation from a mental health specialist (psychiatrist and/or clinical psychologist) 
within 24 hours of receiving the questionnaire (all implemented in person with the 
exception of the follow-up, which may be returned by mail). We will also notify 
oncologists if their patient verbally reports severe depressive symptoms or suicidality 
during the course of the study to research staff.  
 
Two or more adverse events attributable to the interventions will prompt modification of 
the protocol.          
7.1 
Specification of Safety Parameters 
See previous section for safety parameters. 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Overall, risks related to the interventions in this study are considered to be minimal and 
are addressed in the protocol and consent form. The study employs gentle seated 
movement, breathing and meditative practices or an empathic attention among people 
diagnosed with cancer4642 who are receiving chemotherapy. Similar yoga interventions 
have been studied in patients with cancer with no published reports of adverse events, 
some of which included participants during the chemotherapy treatment period.46 The PI 
conducted an initial pilot study of 7 participants with the YST during chemotherapy 
infusions at the Mount Sinai School of Medicine from 08/2009 – 01/2010.75 There were 
no adverse events observed related to the yoga practice in this study. From 07/2011-
01/13, the PI conducted a pilot study among 15 participants randomized to YST or AC 
during chemotherapy infusions at the CCC-WFU and observed no adverse events related 
to the interventions. 
7.3 
Adverse Events and Serious Adverse Events  
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 

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from the CTEP web site (http://ctep.cancer.gov). 
 
  
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.   
 
 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study intervention. 
- 
Probable – The AE is likely related to the study intervention. 
- 
Possible – The AE may be related to the study intervention. 
- 
Unlikely – The AE is doubtfully related to the study intervention. 
- 
Unrelated – The AE is clearly NOT related to the study intervention. 
 
SAEs unequivocally due to disease progression are not considered SAEs for the 
purposes of this study and will not be reported as such.  
Only AEs related to the study intervention or measures will be captured with the 
exception of unexpected grade 4 Grade 5 events, which will also be documented and 
reported. 
AEs will be labeled according to severity, which is based on their impact on the 
patient. An AE will be termed “mild” if it does not have a major impact on the 
patient, “moderate” if it causes the patient some minor inconvenience, and “severe” if 
it causes a substantial disruption to the patient’s well-being.  
AEs will be categorized according to the likelihood that they are related to the study 
intervention. Specifically, they will be labeled definitely unrelated, definitely related, 
probably related, or possibly related to the study intervention. 
Interventionists will document and report solicited AEs including physical or 
emotional discomfort. STM will also document self-reported ratings of 3 or higher on 
the suicide item from the PROMIS-Cancer Depressive symptoms measure. No 
additional unsolicited events will be systematically captured. Research staff will 
report AEs according to data safety monitoring plan. Events will be documented in 
the ORIS data entry system including date of event which will avoid double capture. 
7.4 
Reporting Procedures 
The PI will monitor the safety of participants on an ongoing basis by inquiring about 
each participant’s emotional and physical reactions during all regular study meetings 
with the interventionists and offer referrals by consulting with mentors when 
appropriate. The PI will initially assess if the AE is related to the study interventions 
as definitely, probably, possibly or unrelated. AEs reports will be distributed to the 
Independent Monitoring Committee (IMC) electronically via email.  
 

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The IMC will monitor and review adverse events and events that may be related to 
the intervention. This will include verification that, when indicated, these events have 
been reported to the appropriate agencies (e.g. IRB, NCCIH) and that such reports 
have been made in a timely manner. Non-serious adverse events will be reviewed on 
a quarterly basis by the IMC. The IMC will be notified of serious adverse events 
within 24 hours of occurrence and reviewed within 48 hours.  
 
SAEs that are unanticipated, serious, and possibly related to the study intervention 
will be reported to the IMC, IRB, and the National Center for Complementary and 
Integrative Health (NCCIH) by sending the SAE Report Form via email (Appendix 
N: Adverse Event Form). The CCC-WFU Safety and Toxicity Reporting Committee 
(STRC) will also review unexpected grade 4 and all grade 5 events regardless of their 
attribution. 
 
 Unexpected fatal or life-threatening AEs related to the intervention will be 
reported to the NCCIH Program Officer within 7 days. Other serious and 
unexpected AEs related to the intervention will be reported to the NCCIH 
Program Official within 15 days. 
 Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the Independent Monitor(s), IRB, NCCIH, and other oversight 
organizations in accordance with their requirements. In the annual AE summary, 
the Independent Monitor(s) Report will state that they have reviewed all AE 
reports. 
7.5 
Follow-up for Adverse Events 
AEs will be monitored by the IMC and the PI for recurrences, resolution, and ongoing 
toxicities that may be related to the intervention. Documentation and reporting for 
follow-up AEs will occur according to reporting procedures described in Section 7.4. 
The duration for follow-up will be for the length of the study period while 
participants are enrolled in the study. If non-serious adverse events are related to the 
interventions, then the protocol will be modified to avoid adverse events. If the 
frequency of non-serious adverse events is higher than anticipated or alters the benefit 
risk ratio, the study investigators, after conferring with IMC, will also modify the 
protocol.  Two or more specific adverse events among participants will prompt 
modification of the protocol.           
7.6 
Safety Monitoring  
The Independent Monitoring Committee (IMC) for this study is comprised of the 
Wake Forest School of Medicine’s Institutional Data and Safety Monitoring Board 
members who have expertise in clinical trial methodology and conduct, biostatistics, 
ethics, and clinical research. The Institutional Data and Safety Monitoring Board 
members are not part of the key personnel involved in this grant. They are qualified to 
review the patient safety data generated by this study because of their unique 
expertise in the areas of oncology, mental health/ethics and statistics.  

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Study progress and safety will be reviewed quarterly (and more frequently if needed). 
Progress reports, including patient recruitment, retention/attrition, and AEs will be 
provided to the Independent Monitor(s) following each of the quarterly reviews. An 
Annual Report will be compiled and will include a list and summary of AEs. In 
addition, the Annual Report will address (1) whether AE rates are consistent with pre-
study assumptions; (2) reason for dropouts from the study; (3) whether all participants 
met entry criteria; (4) whether continuation of the study is justified on the basis that 
additional data are needed to accomplish the stated aims of the study; and (5) 
conditions whereby the study might be terminated prematurely. The Annual Report 
will be sent to the Independent Monitor(s) and will be forwarded to the IRB and 
NCCIH. The IRB and other applicable recipients will review progress of this study on 
an annual basis. The PI will also send copies of signed recommendations and 
comments from the Independent Monitor(s) or Chair of the IMC to the NCCIH 
Program Officer within 1 month of each monitoring review. 
8. INTERVENTION DISCONTINUATION  
The intervention will be discontinued for a participant if: (1) the intervention is 
associated with an adverse effect for a specific participant (i.e., participant does not 
tolerate the intervention), (2) the participant no longer is interested or willing to 
receive the intervention or participate in the study, or (3) the participant’s healthcare 
provider no longer recommends that the patient receive the intervention for medical 
reasons or (4) the participant no longer receives chemotherapy at designated research 
facility. The IMC and the principal investigator will review cases upon occurrence for 
discontinuation of intervention. 
This study will be stopped prior to its completion if: (1) the intervention is associated 
with adverse effects that call into question the safety of the intervention; (2) difficulty 
in study recruitment or retention will significantly impact the ability to evaluate the 
study endpoints; (3) any new information becomes available during the trial that 
necessitates stopping the trial; or (4) other situations occur that might warrant 
stopping the trial. The PI will include an assessment of futility in the annual progress 
report to NIH and will consult with the study monitors to assess the impact of 
significant data loss due to problems in recruitment, retention, or data collection. 
 
Participants will be followed with their permission if the study is discontinued. The 
duration of follow-up will be length of the proposed study. We will continue to 
document adverse events during the follow-up period. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
 
Inclusion of an active control group was chosen to account for Hawthorne effects, 
attention from a professional, and other non-specific effects. Alternate control groups 
considered include a wait-list control group or stretching. Specifically, the proposed 
empathic attention control was chosen to control for the non-specific effects of the 
intervention without including any of the proposed active intervention components.  

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Stratified randomized control design was selected for this study to enable tighter 
control over known influences on outcome. Statistical control via covariate analysis 
would not suffice. The statistical hypotheses are: 
 
Specific Aim 1 Hypothesis  
 
Primary:  Yoga Skills Training (YST) will demonstrate clinically meaningful 
reduction in fatigue and depressive symptoms compared to an attention control group. 
 
Fatigue and depression will be measured using the Patient-Reported Outcomes 
Measurement Information System (PROMIS)-Cancer specifically designed for use in 
cancer patients (see Section 9.5 Outcomes).  
 
Secondary: Reductions in fatigue and depressive symptoms will be associated with 
decreases in mediators. 
 
Specific Aim 2 Hypothesis: The YST will show trends for reducing levels and 
variability of daily fatigue and depressive symptoms to a greater degree than the AC 
and reductions will be associated with decreases in mediators. 
 
Specific Aim 3: Qualitative data will be used to inform a larger trial. 
9.2 
Sample Size and Randomization 
The primary purpose of this study is to inform the potential efficacy of the YST in 
this population. Thus, it is imperative that in this initial study, effect sizes generated 
from the patients who successfully complete the YST protocol be used for that 
efficacy assessment. Furthermore will be important to understand likely differences 
between the patients who do successful complete the study protocol and those who do 
not. Therefore, patients for whom baseline and post YST/AC completion (Week 10) 
are available will comprise efficacy intention-to-treat (ITT) analysis sample. We used 
the revised CONSORT 2010 guidelines for intention-to-treat (ITT) analysis of 
randomized control trials102  in our sample considerations. Those guidelines dropped 
specific ITT in favor of clear descriptions of exactly who would be (or was) included 
in the analysis per our specification above. We also took into account considerations 
for minimizing missing data within the context of ITT specified by White et al.103 We 
have incorporated flexible windows for the data collection in our protocol and are 
allowing for possible randomly missing interim assessments. Secondary analyses will 
be conducted to evaluate the potential differential effect of the interventions on a one-
month follow-up assessment of outcomes and changes in daily assessments of fatigue, 
depressive symptoms, psychological stress, and circadian disruption. Further 
exploratory (not hypothesis testing) analyses will be conducted with the YST study 
group to examine the association of dose (i.e., days of in-person sessions completed 
plus days of home practice), outcome expectations and efficacy beliefs with changes 
in fatigue, depressive symptoms, psychological stress, circadian disruption, and 
inflammation. 

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Based on prior longitudinal work with patients from similar populations, we are 
anticipating approximately 15% dropout (from N=44).  From previous research in a 
mixed sample of cancer patients,89 the variability in the values of the PROMIS 7-item 
fatigue measure used in this study is a standardized standard deviation of 8 points 
(Mean t-score=53.6).  Effect sizes in preliminary studies of yoga for fatigue as 
compared to an active control in patients with cancer range from 0.33 to 1.50.45,104 
This variability may be explained in part by study quality and patients’ initial levels 
of fatigue.45 We expect that daily assessments of fatigue and depressive symptoms 
will detect these symptoms at their nadir and thus may be more sensitive to such 
phenomena than recalled measures. Therefore, it is important to obtain a good 
estimate of the variance of fatigue in this group to use in future studies. Power 
calculations for a subsequent larger study will be based on clinically meaningful 
differences between the groups on the primary outcome using estimates of SD. 
With a sample size of 44, the probability is 0.80 (80% confidence) that the estimate 
of the standard deviation (SD) will be no more than 10% of the true population SD 
below the true population SD; if the SD varies by group, there is 80% confidence 
that the estimate of the SD is no more than 14% below the true SD.  
Treatment Assignment Procedures 
Eligible, consented, and enrolled participants will be randomized to YST or AC. To 
control for type and stage of cancer, randomization will occur within both type 
(colon, rectal/other better prognosis GI cancers, poorer prognosis cancers) and stage 
(localized stages II/III or metastatic stage IV). There is not a sample size goal within 
strata. Given this relatively small preliminary study, it was deemed more efficient and 
enabled tighter control over known influences on outcome to stratify rather than to 
use statistical control via covariate analysis. The other alternative would have been to 
use only a single type/stage of cancer, which was not feasible due to too few cases at 
VICC and CCC-WFU. The population of the cancer patients with the types/stages 
selected was sufficient at VICC and CCC-WFU to enable randomization within thus 
increasing generalizability potential.  
 
Randomization (1:1) lists within each strata will be generated via a permuted block 
program developed and executed by the study biostatistician with blocks of random 
sizes between 2 and 6. The randomization lists will be held by a staff member (not 
involved with data collection) who will allocate each participant to study group. STM 
who are collecting data will not be informed of group assignment. 
9.3  
Definition of Populations 
Per out description above, we used the revised CONSORT 2010 guidelines for 
intention-to-treat (ITT) analysis of randomized control trials102 in our sample 
considerations. Those guidelines dropped specific ITT in favor of clear descriptions 
of exactly who would be (or was) included in the analysis per our specification above. 
We also took into account considerations for minimizing missing data within the 
context of ITT specified by White et al.103 We have incorporated flexible windows for 
the data collection in our protocol and are allowing for possible randomly missing 
interim assessments. Therefore the population to whom these preliminary efficacy 

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findings will be generalizable to will be that represented by the sample meeting our 
requirements for inclusion in the ITT sample (see above). 
9.4 
Interim Analyses and Stopping Rules 
There are no interim analyses planned for the primary and secondary outcomes in this 
clinical trial. Summaries of process variables (i.e., recruitment, adherence, data 
collection, retention, safety) will be conducted on a rolling basis as the study 
progresses. The PI will present data on subject accrual with research mentors and 
Independent Monitoring Committee (IMC). We anticipate recruitment on average of 
1-2 patients per month or 18 patients in one year completing enrollment over the next 
30 months. Fidelity of implementing the interventions will also evaluated during the 
study period.  If we document fidelity less than 80% during the clinical trial, than 
interventionists will undergo further training with subsequent re-evaluation 
demonstrating sufficient fidelity.  
 
Futility analyses for efficacy or safety will not be conducted in this pilot study. SAE’s 
related to the intervention will suspend enrollment and/or the study intervention until 
a safety review is convened (either routine or ad hoc) by IMC to determine whether 
the study intervention should continue per protocol, proceed with caution, be further 
investigated, discontinued, or be modified and then proceed. If SAEs events are 
related to the interventions, then the relevant intervention protocol will be modified to 
avoid adverse events.  If the frequency of non-serious adverse events is higher than 
anticipated or alters the benefit risk ratio as determined by the IMC and PI, the study 
investigators will also modify the relevant intervention protocol. Two or more 
specific adverse events among participants will prompt modification of the protocol.    
9.5 
Outcomes  
The STM collecting outcome data will be masked to the participant’s intervention 
group assignment.  
9.5.1 Primary Outcome   
Fatigue (recalled) “in the past seven days” will be assessed with the 7-item measure 
of Fatigue from the Patient-Reported Outcomes Measurement Information System 
(PROMIS)-Cancer specifically designed for use in cancer patients (item responses: 1 
= never, 5 = always).87,88 This measure was selected for the primary outcome (at 10 
weeks) because it is standardized, validated in people with cancer, and PROMIS is 
supported by NCCIH and the National Cancer Institute.89,105 
 
9.5.2 Secondary Outcomes   
 
Depressive Symptoms (recalled) will be assessed with the standardized 10-item 
PROMIS-Cancer Depressive symptoms short-form, which was designed to be valid 
for cancer patients.89  
 
Fatigue and Depressive Symptoms (daily) “in the last day” will be assessed with 3 
items selected from the PROMIS measures of fatigue and depression validated for use 

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in daily diaries.97 This subset of items was selected to minimize patient burden and 
because they were the items most sensitive to day-to-day changes. Response options 
are the same as in the recalled measures. 
 
Psychological Stress (recalled) will be assessed by the 10-item Perceived Stress 
Scale (PSS).90 The PSS has 2 factors (stress and counter stress) and is valid for use 
with cancer patients.91  
 
Psychological Stress (daily) will be assessed with two items from the 4-item PSS90 
that would be on the same factor to optimize internal consistency.91 The PSS has been 
successfully applied daily.98  
 
Regulation of Psychological Stress (recalled) will be determined by ratings on four 
of the seven factors of the Cancer Behavior Inventory92, which assess self-efficacy for 
stress management (α = 0.86), coping with treatment-related side-effects (α = 0.82), 
accepting cancer/maintaining positive attitude (α = 0.86), and affective regulation (α 
= 0.81). 
 
Regulation of Psychological Stress (daily) will be assessed with the 3-item serenity 
subscale from the Positive and Negative Affect Schedule-Expanded Form.99   
 
Circadian disruption (recalled) will be assessed with measures of activity and rest. 
Activity will be measured using the 3-item Godin's leisure score index (LSI),93 
previously used with GI cancer patients during chemotherapy.94 Rest will be assessed 
with the 8-item PROMIS sleep disturbance short-form.87 
 
Circadian Disruption (daily) will be assessed with actigraphy.100 Circadian 
disruption is defined as a ratio of nighttime activity to daytime activity with higher 
scores indicating greater circadian disruptions.  
 
Inflammation. Inflammatory cytokines (i.e., IL-6, sTNF-R1, TNF-α) that have been 
associated with fatigue during treatment for gastrointestinal cancer 7 and influenced 
by yoga practice61–64 will be measured in plasma extracted from whole blood drawn 
during regularly scheduled clinical blood draws.  
 
The following table provides a summary of which study week study constructs will 
be assessed. 
 
 
Study Constructs and Times Measured 
  
  
  
Weeks  
0 
0-2 
8 
8-10 
10 
14 
Outcomes 
  
  
  
  
  
  
Fatigue (primary in bold text) 
R Daily R Daily 
R 
R 
Depressive Symptoms 
R Daily R Daily 
R 
R 
Mechanisms 
  
  
  
  
  
  
Psychological Stress 
R Daily R Daily 
R 
R 
Regulation of Psychological Stress 
R Daily R Daily 
R 
R 
Circadian Disruption 
R Daily R Daily 
R 
R 

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Inflammation 
 √ 
  
 √ 
  
Process 
  
  
  
  
  
  
Intervention Home Practice  
  
  
* 
Daily   
  
Outcome Expectancies 
√ 
  
  
  
  
Efficacy Beliefs 
  
  
√ 
  
  
  
Adherence 
All Measures 
Qualitative Feedback 
  
 
 
 
  
S 
Descriptive  
  
  
  
  
  
  
Demographic/Clinical 
√ 
  
  
  
  
 √ 
R  = recalled assessment; S = semi-structured interview; √ = collected 
*Paper diary will be kept throughout the intervention 
  
  
  
9.6 
Data Analyses  
SAS will be used for statistical analysis. Graphical and descriptive statistical methods 
will be applied to examine the shapes of study data distributions and need to 
transform, if necessary, for inferential analyses. Per descriptions above, analyses will 
be conducted using intention-to-treat principles as stated in the CONSORT 2010 
guidelines102 and flexible protocol elements to minimize missing outcome data.103 
Missing data are expected to be of two types: 1) nonrandom (death, deteriorating 
condition, or other lost-to-follow-up) and 2) random (inability to make it into the 
clinic for one of the assessment periods). Because fatigue post-intervention is the 
most critical outcome assessment point, the 1st assessment (study entry) and the post-
intervention assessment point at Week 10 after study entry will be required for 
inclusion in the hypothesis testing analysis. Randomly missing assessments at Week 
10 will be handled within the statistical analysis described. Randomly missing item 
responses within study measures will be handled according to the instructions for 
each instrument when developed and validated. Missing data assessments and drop-
out occurrences will be analyzed to inform future research. We do not expect those 
types of missing data to be random; therefore imputation procedures will not be 
conducted. Maximum Type I error of 0.05 (uncorrected and/or corrected as 
necessary) will be maintained for statistical significance and all analyses will be 
performed in consultation with Dr. Tooze. 
Specific Aim 1. Key statistical tests will involve between group differences in mean 
values and group differences in the patterns (i.e., slopes) of individual changes from 
respective baseline values of the PROMIS fatigue and depressive symptoms scores. 
These tests will be evaluated using mixed-effects (or multilevel) generalized linear 
modeling procedures with robust variance estimation. Of particular relevance to this 
study, the flexibility of generalized linear modeling allows for analysis of not only 
univariate normal error distributions, but also multivariate dependent variable 
distributions and Poisson distributions. Because we expect there to be a correlation 
between fatigue and depressive symptoms, a multivariate approach will provide more 
unified (systemic) statistical tests of the intervention effects. These tests for specific 
effects on single outcome variables tend to be more powerful because standard errors 
are smaller. Our expectation is that there will be group differences in both the post-
baseline means and shape (slope) of the outcome variable trajectories of participants 

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in the YST compared to the participants in the AC. Because of the presence of 
variables known to effect fatigue and depressive symptoms (e.g., use of 
methylphenidate), those variables will be adjusted for in the analysis (i.e., included as 
covariates). Analysis of differences in the intervention effect between gender and 
racial/ethnic subgroups will also be performed. Finally, in addition to statistical 
significance testing of the study and covariate effects in the models, bootstrapping 
methods will be used to generate 95% confidence intervals for all sample descriptive 
statistics and effect estimates. Changes in the proposed mediators will be summarized 
and analyzed using the same approach as described above. If changes in the proposed 
mediators are observed, exploratory longitudinal path analysis will be conducted to 
investigate the actual level of mediation apparent on fatigue and/or depressive 
symptoms. Further exploratory analyses will examine associations of the dose of the 
YST (i.e., days of in-person sessions completed plus days of home practice), outcome 
expectations and efficacy beliefs with fatigue, depressive symptoms, psychological 
stress/regulation of stress, circadian disruption, and inflammation. 
Specific Aim 2. A critical element of this proposal is the inclusion of daily (vs. 
standard recalled) assessments of fatigue, depressive symptoms and proposed 
mediators, during two 2-week periods in the study (initial: 0-2 weeks, later: 8-10 
weeks). Summaries of the proportion and frequency of missing daily assessments will 
inform the feasibility of collecting this type of data. Graphical displays of these daily 
reports will prove invaluable for informing both the patterns of the respective 
symptoms and mechanisms in and of themselves, and also for informing the optimal 
representation of the patterns in analyses with the recalled measures. Depending on 
missing data, study group differences in daily (or mean 2-day) values will be 
evaluated using mixed-effects generalized linear modeling. Findings and effect sizes 
garnered from these analyses will be compared to those resulting from recalled 
measures. Informed by the graphical displays, several summary indices of each of the 
two daily assessment periods (peak value, mean, coefficient of variation) will be 
generated for use in multi-method, multi-trait analyses of similarities and differences 
in the patterns of associations among the daily and recalled measures. This analysis 
will further inform which measures (and/or which summary indices) appear to be the 
best and most sensitive indices to use in future studies. 
Specific Aim 3: Open-ended and interview data will be coded by the Qualitative 
Research Core led by Dr. Schlundt (Collaborator). Dr. Sohl will consult with the Core 
to develop a coding system and also code 10% of the responses to assess reliability. 
Coded responses will be interpreted with a thematic analysis.105 The number of 
participants interviewed (20-40) will be decided by when thematic saturation is 
reached. Qualitative information gained will enrich quantitative results and inform the 
protocol of a larger trial. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Questionnaires and blood draws will be collected by a blinded STM. Data records for 
each participant will be identified by a unique study code number that does not 
contain personal identifying information. Data collection forms which only have ID 

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numbers will be stored in a locking cabinet at CCC-WFU or in the PI’s office 
building while on study at Wake Forest University. Data from these documents, 
clinical data from the medical chart and data collected via daily automated surveys 
will be entered into a REDCap database at Wake Forest University. The actigraphy 
data, audio recorded semi-structured interviews and videos of the intervention 
sessions will also only be coded by study ID number. Data collection forms are 
presented in the appendices as outlined in the Table of Contents. 
 
All participants will be assigned a study ID number; however, it is necessary for the 
study team to know participants names during time on-study. Names will be 
maintained in a participant tracking database accessible only to approved study staff 
through password protected files stored on a secure server, not on laptops or thumb 
drives. To protect confidentiality, all data will be stored in a locked file cabinet 
located in the secured office of a STM or PI. All computers and data files will be 
password protected.  All data processed will be in aggregate form and data collection 
forms will only be labeled with participant’s unique identification number.  
10.2 Data Management  
The clinical site will not be responsible for data collection or management. Some data 
will be extracted from the medical record at the clinical site, though this data is part 
of routine monitoring and care of the patients. 
CCC-WFU will serve as the data coordinating center. Data from Vanderbilt-Ingram 
Cancer center will be transferred securely to CCC-WFU utilizing Accelion. 
Data collection forms are outlined in section 9.5 Outcomes and stored as summarized 
in the following table. 
Summary of Data Storage  
Informed consent document 
Electronic Medical Record 
Protocol registration form 
ORIS 
Study questionnaires (Weeks 0, 10, 14) 
REDCap 
Daily survey data 
REDCap 
Treatment fidelity data 
REDCap 
Clinical data 
REDCap 
Actigraphy data 
Excel Files on Secure Server 
Inflammation data 
Excel Files on Secure Server 
Adherence data 
Excel Files on Secure Server 
Qualitative data 
Box hosted through Vanderbilt 
University and on Secure Server 
Adverse events 
ORIS 
10.3 Quality Assurance  
10.3.1 Training 
All research staff will have completed the online Collaborative Institutional Training 
Initiative Training (CITI) prior to participation in research activities. Dr. Sohl will 

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directly oversee training of research staff in regards to conducting the planned 
research.  
10.3.2 Quality Control Committee  
The study team will generate Study Reports for the IMC and will provide information 
on the following study parameters: recruitment of subjects to the pilot study, 
adherence to the interventions, and adverse events that may be related to the 
interventions. 
The frequency of review for this study differs according to the type of data and can be 
summarized in the following Table. 
Frequency of data review 
Data type 
Frequency 
of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Quarterly 
PI, Independent Monitor(s) 
Status of all enrolled subjects, as of 
date of reporting  
Quarterly 
PI, Independent Monitor(s) 
Adherence data regarding study 
visits and intervention 
Quarterly 
PI, Independent Monitor(s) 
AEs and rates  
Quarterly 
PI, Independent Monitor(s) 
SAEs 
Per 
occurrence 
PI, Independent Monitor(s), 
IRB, NCCIH 
10.3.3 Metrics 
Review of the rate of subject accrual and compliance with inclusion/exclusion criteria 
will occur monthly by the PI during the first three months and then every quarter (4 
months) to ensure that a sufficient number of participants are being enrolled and that 
they meet eligibility criteria and the targeted ethnic diversity goals outlined in the 
grant proposal (Targeted/Planned Enrollment Table). 
 
Adherence of participants will be evaluated by documentation of participation in 
interventions during chemotherapy. We will consider high adherence to the 
intervention if subjects participate in 80% of the in-person interventions. If on review, 
adherence is below this threshold, Dr. Sohl will convene a conference call to discuss 
methods for improving adherence. 
 
Dr. Sohl or study staff will also review all data collection forms on an ongoing basis 
(i.e., quarterly) for data completeness and accuracy as well as protocol compliance. A 

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study member not involved in data collection will enter the data. At least ten percent 
of all data entered from questionnaires will be randomly selected and verified for 
accuracy against original source documents. Any discrepancies will be discussed with 
the Independent Monitors. Data will also be reviewed for outliers and to determine if 
values are missing at random prior to analysis. Dr. Sohl will provide quarterly 
updates to the IMC and research mentors regarding patient accrual. 
 
10.3.4 Protocol Deviations 
Protocol deviations will be captured through direct observation by research staff 
regarding patient recruitment and enrollment, intervention administration, adherence, 
and safety monitoring. Protocol deviations will be reviewed by the principal 
investigator and discussed with research mentors and as needed with the IMC. 
 
10.3.5 Monitoring 
Dr. Sohl will monitor for protocol compliance, data quality, and review of 
documentation to assure protocol compliance. This will include review of informed 
consent process (upon enrollment), adverse event reporting (upon occurrence), and 
data collection (monthly).    
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the IRB or ethics committee responsible for 
oversight of the study.  
11.2 Informed Consent Forms 
Written informed consent will be obtained from each subject at entry into the study. 
Informed consent is obtained by the following process: 
1. The patient will be asked to review the study consent form. 
2. The PI or STM will meet with the patient either in person or by telephone to 
review the form, to confirm the patient understands the study, and to answer any 
questions that the patient might have. 
3. Once the patient demonstrates understanding of the study and agrees to participate 
in the study, the consent will be signed remotely or in person. If signed remotely, 
patients will be asked to send the form back to us by a secure means, as well as 
bring the original with them to their next clinic visit.  
 
A copy of the consent form will be given to the participant the next time they are in 
clinic, and the original copy will be kept in the participant’s file. Patients who cannot 
consent for themselves in English will not be eligible to participate. 

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11.3 Participant Confidentiality  
Any data, specimens, forms, reports, video recordings, and other records that leave 
the site will be identified only by a participant identification number (Participant ID, 
PID) to maintain confidentiality. All records will be kept in a locked file cabinet. All 
computer entry and networking programs will be done using PIDs only. Information 
will not be released without written permission of the participant, except as necessary 
for monitoring by the IRB and the NCCIH. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
12. COMMITTEES 
The Independent Monitoring Committee (IMC) for this study is comprised of 
members of the Wake Forest School of Medicine’s Institutional Data and Safety 
Monitoring Board who are not associated with this research project and thus work 
independently of the PI, Dr. Stephanie Sohl. They are not part of the key personnel 
involved in this grant. They are qualified to review the patient safety data generated 
by this study because of their respective unique expertise in the areas of oncology, 
mental health/ethics and statistics.  
13. PUBLICATION OF RESEARCH FINDINGS  
Any presentation, abstract, or manuscript will be made available for review by the 
sponsor and the NCCIH prior to submission.  
 
 

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14. REFERENCES  
 
1.  
Montgomery GH, Bovbjerg DH, Schnur JB, et al. A randomized clinical trial of a brief 
hypnosis intervention to control side effects in breast surgery patients. J Natl Cancer Inst. 
2007;99(17):1304-1312. doi:djm106;10.1093/jnci/djm106 
2.  
Lang EV, Laser E, Lutgendorf SK, Logan HL, Spiegel D. Empathic attention and self-
hypnotic relaxation for interventional radiological procedures. 1996. 
3.  
Montgomery GH, David D, Kangas M, et al. Randomized controlled trial of a cognitive-
behavioral therapy plus hypnosis intervention to control fatigue in patients undergoing 
radiotherapy for breast cancer. J Clin Oncol. January 2014:JCO.2013.49.3437. 
doi:10.1200/JCO.2013.49.3437 
4.  
Howlader N, Noone AN, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2010. 
Bethesda, MD: National Cancer Institute; 2013. http://seer.cancer.gov/csr/1975_2010/. 
5.  
American Cancer Society. Cancer Treatment and Survivorship Facts and Figures 2012-
2013. Atlanta, GA: American Cancer Society; 2012. 
6.  
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15. SUPPLEMENTS/APPENDICES 
 
15.2.1  Appendix A: Informed Consent Documents and Form for Documentation  
 
01716 Consent 
6-17-16.pdf
01716_Documenting
_the_Consent_Proces 
 
15.2.2   Appendix B: Yoga Skills Training Home Practice Guide  
 
YSTHomePracticeGui
de.docx
 
 
15.2.3  Appendix C: Yoga Skills Training Home Diary 
 
YSTHomeDiary.docx
 
15.2.4  Appendix D: Attention Control Home Diary 
 
HomeDiaryForms.doc
x
 
15.2.5  Appendix E: Treatment Fidelity Forms  
 
FidelityCheckAC.doc
x
FidelityCheckYST.doc
 
15.2.6  Appendix F: Chart Review Form and Questionnaires 
 
Pro-You_ChartRevie
w.docx
Questionnaire 1.pdf Questionnaire 2.pdf Questionnaire 3.pdf Questionnaire 4.pdf
 
 
15.3.7  Appendix G: Semi-Structured Interview Guide 
 
Semi-structuredInter
viewGuide_AC.docx
Semi-structuredInter
viewGuide_YST.docx 
 

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15.3.8  Appendix H: Daily Survey 
 
DailyMeasuresforPar
ticipants.doc
 
 
15.2.9  Appendix I: Recruitment Script 
 
RecruitmentSCRIPT.
docx
 
 
15.2.10 Appendix J: Recruitment Flyer 
 
RecruitmentFlyer.do
cx
 
 
15.2.11 Appendix K: Eligibility Checklist 
 
Appendix_EligibilityC
hecklist.docx
 
 
15.2.12 Appendix L: Enrollment Form 
 
01716 Protocol 
Registration.docx  
 
15.2.13 Appendix M: Thank You Letter 
 
ThankYouLetter.doc
x
 
 
15.2.14 Appendix N: Adverse Events Reporting Form 
 
 
Serious_Adverse_Ev
ents_Form_ver_3.pdf