A Randomized Clinical Trial Comparing the Effectiveness of Yoga, Survivorship Health Education, and Cognitive Behavioral Therapy for Treating Insomnia in Cancer Survivors
Phase: NA
Conditions: Cancer Survivor, Insomnia, Malignant Neoplasm
Sponsor: University of Rochester NCORP Research Base

 
 
 
 
 
URCC / UNIVERSITY OF ROCHESTER  
NCORP RESEARCH BASE 
 
 
 
A Randomized Clinical Trial Comparing the Effectiveness of Yoga, 
Survivorship Health Education, and Cognitive Behavioral Therapy for 
Treating Insomnia in Cancer Survivors 
 
URCC Protocol:  URCC14040 
NCT number: NCT02613364 
 
 
Study Chair: 
Karen M. Mustian, Ph. D., M.P.H.  
 
URCC NCORP Research Base 
 
University of Rochester School of Medicine 
 
Study Co-Chairs: 
Michelle Janelsins, Ph.D., M.P.H. 
 
Luke J. Peppone, Ph.D., M.P.H. 
 
Supriya G. Mohile, M.D., M.P.H. 
 
Wilfred Pigeon, Ph.D. 
 
Charles Kamen, Ph.D. 
 
Gary R. Morrow, Ph.D., M. S. 
 
 
 
Heather Bowles, Ph.D. 
 
National Cancer Institute 
 
 
Judith O. Hopkins, M.D. 
 
Southeast Clinical Oncology Research Consortium 
 
 
 
Biostatistician: 
Charles E. Heckler, Ph.D., M.S. 
 
 Eva Culakova, Ph.D., M.S. 
 
Victor Kipnis, Ph.D. 
 
 National Cancer Institute 
 
Participating  
NCORP Community Sites Affiliated with the University 
Institutions: 
of Rochester NCORP Research Base 
 
 
 
 
Initial Version: 24-Jun-15 
Amendment 1 Version: 23-Sep-15  
Amendment 2 Version: 05-Feb-16 
 
 
Amendment 3 Version:  17-Mar-17 
Amendment 4 Version:  12-Feb-18 
Amendment 5 Version: 07-Jun-18 
  

 
 
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Protocol Resources 
 
URCC NCORP Research Base: 
Saunders Research Building 
265 Crittenden Blvd 
CU 420658 Rochester, NY  14620 
phone: 585-275-1364 
fax:  585-461-5601 
website: http://www.urcc-ncorp.org/ 
 
Study Chair: 
 
Karen M. Mustian, Ph.D., M.P.H. 
URCC NCORP Research Base 
 
Study Co-Chairs: 
Michelle Janelsins, Ph.D. M.P.H. 
URCC NCORP Research Base 
 
 
Biostatistician: 
Charles Heckler, Ph.D., M.S. 
URCC NCORP Research Base 
 
Regulatory Contact: 
Cathy Lesniewski 
585-275-2282 
cathleen_lesniewski@urmc.rochester.edu 
 
Website/Registration Contact: 
Sebastien Estaque 
585-275-2044 
sebastien_estaque@urmc.rochester.edu 
 
Protocol Contact & 
Data Submission: 
Libby Nagalski 
585-275-1364 
elizabeth_nagalski@urmc.rochester.edu 
 
 

 
 
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TABLE OF CONTENTS 
 
   SECTION 
Page 
 
 
Protocol Resources 
2 
 
 
Study Schema 
4 
 
  1.0 
Introduction 
5 
 
  2.0 
Background 
6 
 
  3.0 
Objectives 
13 
 
  4.0 
Participant Eligibility 
13 
 
  5.0 
Registration, Enrollment & Randomization  
14 
 
  6.0 
Research Protocol 
17 
 
  7.0 
Patient Reported and Functional Measures  
26 
 
  8.0 
Blood Analysis                                                                                                                                30 
 
  9.0  
Design Consideration 
32 
 
  10.0 Data Handling and Statistical Considerations  
32 
 
  11.0 Records to Be Kept  
36 
 
  12.0 Gender and Ethnic/Racial Minorities  
37 
 
  13.0 References  
38 
 
 
 

 
 
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_______________ 
 
Study Schema 
 ________________ 
 
 
 
 
 
 
 
 
 
 
 

 
 
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_______________ 
 
1.0  Introduction 
________________ 
 
Sleep Problems and Cancer: The vast majority of cancer survivors, up to 90%, report some form of sleep quality 
impairment (SQI) post-treatment, such as excessive daytime napping, difficulty falling asleep, difficulty staying asleep, 
and waking up too early.1-10  These SQI are also symptoms of insomnia, which is defined as one or more of these 
symptoms in severe and persistent form.  Insomnia and SQI are among the most prevalent and distressing problems 
reported by cancer survivors and can be severe enough to increase cancer mortality.1-11  Cancer survivors also demonstrate 
dysregulated circadian activity rhythms, impaired physical function (i.e., cardiopulmonary and muscular function) and 
chronically up-regulated inflammatory responses when their sleep is compromised. 4,5,12-48  Despite the ubiquity of 
insomnia and SQI, they are under-diagnosed and under-treated in cancer survivors.1-11,48   
 
Previous research demonstrates that insomnia can begin before cancer 
treatment,4,5 continue during treatment,3,49 and persist for years after 
treatments are completed.6,50  Approximately, two thirds of cancer 
patients who experience insomnia acutely while receiving treatments 
will develop chronic insomnia that persists for years into 
survivorship.3,50  Recent data from a local randomized clinical trial led 
by Dr. Roscoe and investigators in our URCC NCORP Research Base 
shows that 80% of cancer survivors recruited for this study report 
experiencing persistent insomnia during the first 5 years after 
completion of surgery, chemotherapy and/or radiation therapy.51-
53  See Figure 1.  Patients reported that insomnia began during the 
time they were receiving treatments for their cancer and persisted 
up to 30 years into survivorship.51-53  Collectively, prior research3-
6,49,50 and our new data suggest that the insomnia we propose to 
study, during the first 5 years post-treatment, is related to cancer 
and its treatments.   
 
Data from Dr. Roscoe and colleagues also suggests that cognitive 
behavioral therapy for insomnia (CBT-I) is effective for treating persistent insomnia (p < 0.05) among these 
survivors and that the number of years since completing primary treatments for cancer has no impact on the 
efficacy of CBT-I (p> 0.05).51-53  Formally intervening with a behavioral treatment for insomnia was both necessary 
and helpful for cancer survivors regardless of number of years since completion of primary cancer treatments.51-53  
This is supported by other research suggesting that persistent insomnia does not resolve on its own and requires formal 
intervention.3,50,54,55  Finally, we note that the NCCN guidelines for cancer survivors specifically recommend formally 
intervening among cancer survivors to alleviate insomnia with no designated cut-off in terms of years since completion of 
treatment.56   
 
Treatment options for insomnia include: 1) pharmaceuticals, which do not cure insomnia and can lead to toxicities, 
negative interactions with cancer therapeutics, dependency, and rebound impairment after discontinuation, 2) traditional 
exercise, which is recommended in treatment guidelines, but not widely implemented in survivorship care plans beyond 
the use of generalized statements in which survivors are encouraged to be physically active and exercise, and 3) 
psychobehavioral interventions.1-10  Cognitive Behavioral Therapy for Insomnia (CBT-I) is the gold standard 
psychobehavioral treatment for insomnia for the general population, and it is efficacious for treating insomnia among 
cancer survivors.57,58   
 
Yoga is a well-tolerated exercise intervention with promising preliminary evidence for its efficacy in improving insomnia 
and SQI among cancer survivors.  Our research and that of others suggest that yoga may improve insomnia and SQI by 
regulating circadian activity rhythms, improving physical function (i.e., cardiopulmonary and muscular function) and 
decreasing inflammation.14,59-73  We conducted—to our knowledge—the first multicenter, phase III, randomized, 
controlled trial (RCT), in 410 cancer survivors from 12 community oncology practices throughout the U.S., showing that 
Figure 1: Number of Survivors Reporting 
Persistent Insomnia Post‐Treatment
0‐30 years post‐
treatment

 
 
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our standardized yoga intervention (YOCAS©®: 4 wks., 2x/wk., 75 min./session) produced significant moderate to large 
improvements in insomnia and SQI while also improving circadian activity rhythms.  Yoga participants decreased sleep 
medication use, while control participants increased sleep medication use.  Adherence to YOCAS©® was relatively high at 
80%, and there were no study-related adverse events.  All (100%) participants found the YOCAS©® program useful and 
would recommend it to other cancer survivors experiencing sleep problems.   
 
In response to NCI research priorities and PA 11-260, we proposed a follow-on study that aligns with NCI research 
priorities to develop effective supportive care interventions for survivors.  We proposed a multicenter, 3-arm, blinded, 
phase III RCT to fill remaining empirical gaps by comparing the effectiveness of ARM 1) our standard YOCAS©® 
program, ARM 2) standard CBT-I, and ARM 3) a health education intervention controlling for time and attention for 
improving insomnia in 720 cancer survivors 2-60 months following adjuvant treatment. We will also explore three 
possible mechanisms through which YOCAS©® may improve insomnia—circadian activity rhythms, physical function 
(i.e., cardiopulmonary and muscular function) and inflammatory immune responses—based on our biobehavioral model.  
 
Innovation:  This study is innovative because it is the first multi-center, phase III, blinded, RCT to test: 1) the 
effectiveness of YOCAS©® compared to CBT-I and a health education control for improving insomnia and SQI, 2) the 3- 
and 6-month sustainability of insomnia benefits from YOCAS©®, and 3) the role of possible functional and biological 
mediators in the efficacy of YOCAS©®.  CBT-I is an effective gold standard treatment for the general population—this 
trial will provide pivotal scientific data to determine if YOCAS©® should be considered a gold standard treatment option 
for insomnia in cancer survivors.  In addition, this is the first study to examine the associations between both 24- and 12-
hour circadian activity rhythms using a multi-oscillating model, physical function, cytokines, yoga and sleep in cancer 
survivors.  We are not aware of any other group doing this work.   
________________ 
 
2.0  Background 
________________ 
 
If YOCAS©® is shown to be as effective as or more effective than CBT-I and more effective than health education and if 
insomnia improvements are sustained 3 and 6 months later from the yoga intervention, the benefits for cancer survivors 
would include: 1) an additional evidence-based, safe, non-pharmacological, effective, low-cost, enjoyable treatment for 
insomnia—possibly a new gold standard treatment option; 2) a standardized yoga therapy that can be explicitly prescribed 
and reproducibly disseminated in communities as part of survivorship care plans for the treatment of insomnia; and 3) a 
better understanding of the functional and biological pathways through which YOCAS©® works to improve insomnia in 
order to further refine its effective use and applicability in various cancer populations.   
 
Yoga—A Holistic Mind-Body Mode of Exercise:  The many different styles and types of yoga are based on Eastern 
traditions from India (e.g., Classical, Advaita Vedanta, Tantra), Tibet (e.g., Tibetan), and China (e.g., Chi Kung, Tai 
Chi).61,74,75  The word yoga is derived from its Sanskrit root “yuj,” which literally means “to yoke” or join together.  In this 
case, yoga refers to joining the mind and the body.61,74,75  The earliest forms of yoga were firmly rooted in physical and 
mindful (breathing and meditative) practices and led to what is known today as classical yoga which forms the basis for 
most of the yoga currently taught in the U.S.74   
 
Yoga, Sleep Quality Impairment and Insomnia:  The existing evidence suggests that yoga is effective for improving 
SQI, but we were unable to find published studies that specifically addressed the effects of yoga on insomnia in cancer 
survivors.  In addition, no studies in cancer compared the effects of yoga on SQI to a proven effective gold-standard 
treatment for insomnia or SQI, examined the long-term durability of effects, or examined potential mechanisms of action 
through which yoga may improve insomnia or SQI.14,59-61,64,65,71,73,76  
 
Yoga Program Evaluations:  Four evaluations of community yoga programs for cancer patients and survivors 
suggest that yoga may improve SQI.62,63,69,70 These yoga programs were based in cancer centers or community-based 
yoga studios and offered yoga classes specifically for cancer patients receiving treatment and survivors who had 
completed treatments.  The yoga classes included a wide variety of postures and mindfulness exercises from different 
types of yoga, and they were offered 1-2 times a week for 60-90 minutes.  Participants in two of these programs also 
attributed improvements in strength, physical function, and physical fitness to their yoga practice.62,70  However, these 

 
 
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reports utilized convenience samples and did not use research methods designed to answer specific scientific questions 
about the effects of yoga on SQI.  These programs also did not use standardized yoga interventions that can be accurately 
and consistently replicated for dissemination and use in the treatment of insomnia or SQI.  Therefore, this study will be 
a confirmatory phase III RCT and will use our standardized yoga intervention, YOCAS©®.   
 
Phase I and II Pilot Studies:  One phase I and five phase II studies provide preliminary support for the safety, 
feasibility and efficacy of yoga for improving SQI among cancer patients and survivors (See Table 1).59,61,71,73,76  
These studies assessed a range of yoga doses from 1-2 sessions/week with classes lasting 50-120 minutes using a variety 
of different types of yoga over 4-12 weeks.  The interventions included a variety of postures and mindfulness exercises.  
The interventions were deemed safe and feasible for cancer patients receiving treatment and survivors.  Participants 
enjoyed the yoga interventions and in four studies reported improvements in SQI; two studies showed no changes in 
SQI.60,76  Three of the phase II RCTs compared yoga to a waitlist control, one to a support therapy control condition and 
one to a health education control condition.59-61,73,76  The latter two studies suggest that yoga may be more effective for 
improving SQI than counseling, health education, time and attention. Using YOCAS©® we conducted the first—to our 
knowledge--phase III RCT demonstrating the efficacy of yoga for improving insomnia, SQI, and circadian activity 
rhythms among 410 cancer survivors. [See preliminary study 1.]  This follow-on study compares the efficacy of 
YOCAS©® to CBT-I and a health education control, examines the durability of insomnia benefits, and explores 
possible mechanisms (circadian, physical and immune function).  This RCT compares yoga to a health education 
control for time and attention.   
Why We Developed YOCAS©®:  While yoga is increasingly popular in the U.S. and there are many books and DVDs as 
well as cancer center and community programs marketed toward cancer survivors (e.g., “Gentle Yoga for Cancer 
Table 1: Summary of Phase I, II & III Yoga Studies Examining Sleep Among Cancer Patients and Survivors 
Phase I 
Trial Design 
Sample 
Treatment Status 
Type of 
Yoga 
Dose of Yoga 
Outcomes 
 
 
 
 
 
 
 
Ulger et al., 
2010 
1-Arm 
Breast 
Cancer 
(N=20) 
Post-Adjuvant 
Treatment 
Classical 
 
2x’s/week 
60 min/sess 
4 weeks 
 
Sleep     *   
QOL 
CRF   NA 
Phase II 
Trial Design 
Sample 
Treatment Status 
Type of 
Yoga 
Dose of Yoga 
Outcomes 
 
 
 
 
Cohen et al., 
2004 
2-Arm 
RCT w/ 
SC Waitlist 
Lymphoma 
(N=39) 
Mixed receiving active 
treatment and within 
12 months post-
adjuvant treatment 
Tibetan 
 
1x’s/week 
NA min/sess 
7 weeks 
Sleep     * 
Meds      * 
 
Carson et al., 
2009 
2-Arm 
RCT w/ 
SC Waitlist 
Breast 
Cancer 
(N=37) 
Survivors post-
adjuvant treatment 
Yoga of 
Awareness 
 
1x’s/week 
120 min/sess 
8 weeks 
Sleep     *  
  
Vidiraja et al., 
2009 
2-Arm 
RCT w/ SC 
+ Support 
Therapy 
Breast 
Cancer 
(N=88) 
During adjuvant 
radiotherapy 
Integrated 
 
3x”s/week 
50 min/sess 
6 weeks 
Sleep     *  
 
Chandwani et 
al., 2010 
2-Arm 
RCT w/ 
SC Waitlist 
Breast 
Cancer 
(N=61) 
During adjuvant 
radiotherapy 
Patanjali 
from 
VYASA 
2x’s/week 
60 min/sess 
6 weeks 
Sleep  NC   
 
Bower et al., 
2011 
2-Arm 
RCT w/ SC 
+ 
Health 
Education 
Breast 
Cancer 
(N=31) 
Survivors post-
adjuvant treatment 
Iyengar 
 
2x’s/week 
90 min/sess 
12 weeks 
Sleep  NC 
 
Phase III 
Trial Design 
Sample 
Treatment Status 
Type of 
Yoga 
Dose of Yoga 
Outcomes 
 
 
 
 
 
 
 
Mustian et al., 
2013, 2011, 
2010b, 2010a 
2-Arm 
RCT w/  
SC Waitlist 
Mixed 
Cancer 
Survivors 
(N=410) 
Survivors post-
adjuvant treatment 
YOCAS©® 
 
2x’s/week 
75 min/sess 
4-weeks 
Sleep     * 
Insomnia   * 
Meds     * 
Circadian 
Activity    *   
Rhythms  
Notes:  An arrow with an asterisk pointing upward indicates a statistically significant improvement in study 
outcome (i.e., improved sleep quality, less insomnia and reductions in sleep medication use).   
RCT = Randomized, Controlled Trial.  NC = No Change, SC = Standard Care
 

 
 
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Patients,” “Yoga for Breast Cancer Patients and Survivors,” and “Healing Yoga”), there is little, if any, evidence as to the 
efficacy of these programs for improving insomnia or SQI among cancer survivors. These yoga programs are not 
regulated, and there is significant variability in what is offered.  For example, some yoga programs focus on very gentle, 
low-intensity, meditative practices (e.g., Restorative, Integral, Svaroopa), while others focus on vigorous practices (e.g., 
Power, Ashtanga), and yet others focus on both (e.g., Hatha, Iyengar, Kundalini).77  Some programs modify the yoga 
environment by using heaters and humidifiers (e.g., Bikram) or props such as straps, blocks, ropes and chairs (e.g., 
Iyengar).77  Class structure varies considerably; some classes include only physical postures and no mindfulness exercises, 
while others include only mindfulness exercises and no physical postures.  The small number of studies examining the 
safety and effectiveness of only limited types of yoga for improving SQI among survivors coupled with the lack of 
regulation and wide variability of yoga course offerings substantially increases the chance that survivors may spend a 
sizeable amount of time, energy and money participating in yoga programs that may not be safe or effective.  For 
example, yoga in a room heated to over 100 degrees may be contraindicated for some survivors, and vigorous yoga may 
result in excessive muscle soreness and joint pain, increasing insomnia.  
 
We developed Yoga for Cancer Survivors (YOCAS©®) as a standardized program of yoga that can be easily and 
consistently replicated for research, and ultimately, dissemination and used in the treatment of insomnia and SQI.  
YOCAS©® is a standardized yoga program designed by Dr. Mustian and her research team specifically for use by cancer 
patients and survivors.  The YOCAS©® program is a low to moderate intensity mode of exercise that draws from two 
basic types of yoga: gentle Hatha and Restorative yoga.  The program includes 16 specific physical postures (asanas) and 
mindfulness exercises focused on breathing (pranayama) and meditation (dhyana).  The program is designed to be 
delivered by Registered Yoga Alliance instructors in community settings, two times a week for 75 minutes over four 
weeks—an explicit yoga prescription for the treatment of insomnia and SQI.  [See the detailed clinical protocol.]  We also 
developed a training program for yoga instructors, including a written manual and two DVDs.  The training materials 
provide precise instructions for all posture, breathing and meditation exercises with appropriate modifications if 
necessary.  We successfully trained 18 yoga instructors and used the YOCAS©® program in our first multicenter 
study.  We will train additional instructors and use YOCAS©® again in the current study.   
 
Limitations of Previous Phase I-III Studies:  None of the phase I-II studies was a definitive phase III RCT that was 
planned and powered a priori to test the effects of yoga on insomnia or SQI as a primary outcome.  The sample sizes were 
small, ranging from 20-88.  They did not screen for or require a specific level of insomnia or SQI as part of participant 
eligibility.  The studies did not blind participants with the exception of the Bower study.76  Yoga interventions were not 
standardized and were highly variable in content, type, intensity, and duration of yoga, making it impossible to determine 
the actual dose of yoga needed to improve insomnia or SQI.  The yoga interventions were not described in great detail, 
making repeatability and standardized dissemination impossible.  While general comments suggested the interventions 
were safe and that participants enjoyed them, no specific details were provided on the rate of adverse events.  Information 
on participant attendance, compliance and attrition, details of the prescribed yoga dose versus the actual dose achieved 
(e.g., mode, frequency, intensity, duration), and information on sustainability of improvements in SQI stemming from 
yoga were limited.  Furthermore, no studies, including our previous phase III trial, compared yoga to a gold-standard 
treatment for insomnia or SQI such as CBT-I—a required next step in clinical research if yoga is to be determined a gold-
standard treatment option for insomnia.   Moreover, no studies, with the exception of ours, examined possible biological 
mechanisms through which yoga may improve insomnia or SQI.  This phase III RCT capitalizes on the positive 
aspects of our prior phase III RCT and addresses most of the remaining limitations by blinding participants, 
comparing YOCAS©® to CBT-I and a health education time and attention control, examining the durability of 
effects on insomnia and investigating biological mechanisms whereby YOCAS©® may improve insomnia.   
 
Yoga Summary:  Further research is warranted because, despite their limitations, these phase I-III studies collectively 
suggest that: 1) cancer patients can safely participate in yoga during and after cancer treatments, 2) yoga interventions are 
feasible in a variety of cancer centers and community-based yoga studios, 3) cancer survivors participating in these yoga 
programs enjoy them and find them beneficial, and 4) yoga participation ranging from 1-2 sessions/week for 50-120 
minutes per session over a period of 4-12 weeks may lead to improvements in insomnia and SQI.   
 
Pathophysiology of Insomnia and SQI:  The pathophysiology of insomnia and SQI and their relationships with cancer 
and its treatments are largely unexplained.25,48,78  Research suggests that sleep problems may arise through multiple 
pathophysiologic pathways including dysregulated hypothalamic-pituitary-adrenal axis (HPA axis) function stemming 

 
 
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from abnormal sleep/wake homeostasis, hyperarousal, disruptive cognitive and behavioral factors and impaired circadian, 
physical (i.e., cardiopulmonary and muscular) and immune function.  [Note: We acknowledge our model does not include 
ALL potential biopsychosocial mechanisms (e.g., relaxation pathways); it’s not possible to investigate them ALL in a 
single clinical trial.]  Our working model is based on our research and that of others showing that cancer survivors with 
compromised sleep demonstrate dysregulated circadian function (i.e., flattened diurnal rhythms, suppressed morning 
peaks, elevated evening nadirs, and delayed acrophases), impaired physical function (decreased cardiopulmonary and 
muscular function) and dysregulated immune responses (chronically up-regulated pro-inflammatory responses).4,5,12-2425-47  
Based on these data, we theorize that yoga will elicit positive changes in circadian activity rhythms, physical 
function and inflammation that will, in turn, mediate the effect of yoga on insomnia.  We developed a theoretical 
model to serve as a framework to guide our research on these putative mechanisms whereby yoga may improve 
insomnia.  All components of the full biobehavioral model will not be statistically evaluated, as that is beyond the scope 
of any single study, but we will statistically evaluate the direct effects of yoga on circadian activity rhythms, physical 
function (i.e., cardiopulmonary [6-minute walk] and muscular [strength]) and inflammatory responses, as well as, the 
mediating effects of these plausible mechanisms on insomnia.     
 
Integrated Behavioral and Biological Systems Model (See Figure 2):  Our theory is that cancer and its treatments 
directly and negatively influence circadian, physical (i.e., cardiopulmonary and muscular) and immune function; 
in turn, diminished function in these systems leads to insomnia.  Cancer and its treatments also lead to a reduction 
in physical activity/exercise that elicits physical deconditioning responses which, in turn, lead to diminished 
function in these same systems, further impairing sleep.  Yoga, a form of exercise, is capable of positively 
influencing each of these systems and improving circadian, physical and immune function and, consequently, 
improving insomnia as described below.   
 
Yoga and The Circadian Clock System:  Yoga is a form of exercise that may regulate circadian function by acting 
as an exogenous behavioral non-photosensitizer for the circadian system that normalizes dysregulated circadian 
activity rhythms stemming from cancer and its treatments, thereby improving insomnia.  The circadian clock 
system consists of a central component—the suprachiasmatic nucleus (SCN) of the hypothalamus known as the body’s 
“master clock”—and peripheral components involving multiple organ- and tissue-specific “clocks.”  These peripheral 
clocks are synchronized through humoral and neural connections throughout the body that, in turn, affect behavioral and 
physiological output rhythms (i.e., diurnal fluctuations in sleep, physical activity, heart rate, strength, and cytokines).79-81  
Figure 2: Integrated Systems Biological Model 

 
 
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The master clock, however, has its own intrinsic rhythm which is entrained—synchronized to a 24-hour cycle--by 
exogenous photo- and non-photosensitizers. The strongest photosensitizer is light; one of the strongest non-
photosensitizers is exercise (e.g., yoga).81  Our prior study suggests that yoga favorably alters circadian activity rhythms.14  
We will assess circadian activity rhythms using actigraphy as in preliminary study 1 described below.   
 
Yoga and The Immune System—Inflammatory Responses:  Yoga may regulate immune function in the same way 
as other modes of exercise, by dampening the chronically up-regulated pro-inflammatory responses exhibited in 
cancer survivors as a result of their disease and its treatments; this dampening, in turn, may normalize overall 
inflammatory responses and improve insomnia.  Exercise reduces low-grade inflammation by triggering the immediate 
but transient release of IL-6.82  IL-6 is released from skeletal muscle in proportion to exercise intensity and duration; the 
proportion of muscle mass used during an exercise bout, and training status.82  In this environment IL-6 functions as an 
anti-inflammatory molecule by triggering the release of TNFr, IL-10, and IL-1r which, consequently, inhibits the 
production of TNFα, IL-8, IL-1 and IFNg and regulates overall inflammatory responses.82  Research suggests that yoga 
may improve inflammatory immune responses in cancer survivors with SQI.66,67,72  We will assess inflammation with 
appropriate standardized high-sensitivity multiplexed cytokine/chemokine assay kits under GLP compliance as in  
preliminary studies 2 through 5 below.   
 
Yoga and Physical Function in the Cardiopulmonary and Muscular Systems:  Yoga may improve physical function 
(i.e., cardiopulmonary and muscular function) in the same way as other modes of exercise, by eliciting a 
physiological conditioning response.  This physical conditioning response may improve the reduced physical 
function exhibited by cancer survivors as a result of their disease and its treatment, consequently improving 
insomnia.  It is well documented that traditional modes of exercise performed frequently at high enough intensities for a 
sufficient duration improve cardiopulmonary and muscular function as part of a desirable physical conditioning 
response,83,84 and that regular exercise, using traditional modes, which improves physical function (cardiopulmonary and 
muscular), results in medium to large improvements in total sleep time, slow wave or “deep” sleep, nighttime 
wakefulness, sleep onset latency and insufficient sleep.85-88  Research suggests that participation in yoga improves 
cardiopulmonary and muscular function in healthy individuals and those with other diseases,68,77,89-92 but we could find no 
studies showing this in a cancer population.  We will assess physical function with a 6-minute walk test and a 
handgrip dynamometry test as in Dr. Mustian’s preliminary studies 2 through 5.   
 
PRELIMINARY STUDIES BY THE PI AND RESEARCH TEAM 
 
YOCAS©® Multicenter Phase III RCT (URCC04-01/U3905) --Study 1:  Dr. Mustian14,64,65 and her research team 
completed a nationwide, multicenter, phase III RCT examining the effectiveness of a standardized 4-week yoga program 
(YOCAS©®--Yoga for Cancer Survivors) for improving SQI in 410 cancer survivors.  Insomnia, wake after sleep onset, 
sleep efficiency and circadian activity rhythms were also assessed as secondary endpoints.  Study participants were 
recruited through the University of Rochester 
Cancer Center Community Clinical Oncology 
Program (URCC CCOP) Research Base in 
Rochester, NY and 9 affiliated Community Clinical 
Oncology Programs (CCOPs; 12 total community 
oncology practices) across the U.S. —a consortium 
of oncology researchers and practicing community 
oncologists with over 30 years of success 
conducting large, multicenter, phase III RCTs to 
test new treatments for the side effects stemming 
from cancer and its treatments.  The study was 
highly successful and accrued all 410 cancer 
survivors through 12 community oncology practices 
in 12 different cities across the U.S. in 32 months; 
321 participants (79%) provided evaluable data.   
Table 2: Sleep Quality Impairment, Insomnia, and Sleep 
Medication Use in YOCAS Trial 
Outcome 
Mean 
(SEM) 
Yoga 
(N = 168)
Control 
(N= 153)
Between
Group  
P‐value 
Pre 
Post 
Pre 
Post 
Sleep 
Quality 
9.20
(0.25) 
7.23
(0.26) 
8.96
(0.28) 
7.89
(0.26) 
0.009 
Insomnia
22.9
(1.62)
13.4
(1.55)
22.9
(1.76)
20.2
(1.64)
< 0.001
Sleep 
Medication 
Use 
1.01
(0.10) 
0.80
(0.10) 
0.81
(0.10)
0.84
(0.10)
0.018 

 
 
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Results (See 
Table 2 and 
Figure 3):  Our 
standardized yoga 
intervention 
(YOCAS©®; 4 wks., 
2x/wk., 75 min. 
/session; 600 total 
min.) significantly 
improved SQI, 
insomnia, and 
circadian activity 
rhythms among 410 
cancer 
survivors.14,64,65,93  The 
YOCAS©® 
intervention not only significantly improved SQI and secondarily, insomnia, wake after sleep onset, and sleep efficiency, 
but the yoga participants decreased their sleep medication use during the intervention, while the control participants 
increased sleep medication use.    
 
Multi-oscillator modeling revealed a 12-hour, ultradian rhythm model fit the circadian activity rhythms better than a 
single-oscillator, 24-hour model and demonstrated significant rhythm differences between groups post-intervention 
(p<0.05) with a delayed 12-hour acrophase in the yoga group (p<0.05).  The yoga group demonstrated higher physical 
activity during the morning (first 12 hours of the day) and stabilized physical activity throughout the afternoon and 
evening (second 12 hours of the day); whereas, the standard care control group showed a lower physical activity pattern in 
the morning and a higher peak in physical activity in the afternoon and evening.  Blunted morning circadian rhythms (low 
physical activity) and excessive peaks (high physical activity) in circadian rhythms during the afternoon and evening are 
associated with SQI.4,5,12-24   
 
Adherence and Adverse Events:  Survivors assigned to the yoga arm attended an average of 6.5 of the 8 prescribed 
sessions for a total of 480 minutes of the prescribed 600 minutes during the 4-week intervention period.  Survivors in the 
yoga arm also reported extra yoga practice outside of the two required yoga sessions, resulting in a total average of 182 
minutes each week over 3 days with a rating of perceived exertion of 3.4 (moderate intensity).  Contamination in the 
control condition was very low; 7 participants reported an average of 20 minutes of yoga one time each week with a rating 
of perceived exertion of 1.0 (very weak) during the intervention period.  There were no study-related adverse events.  
Survivors liked the yoga intervention; 100% found it useful for improving their sleep and would recommend it to other 
cancer survivors.   
 
Yoga Intervention:  We used the YOCAS©® program previously described in the background section and fully detailed in 
the manual.  To ensure intervention quality, fidelity across study sites and instructors, and to prevent drift over the course 
of the study, Dr. Mustian and her team developed a specialized training program for instructors that included a set of two 
DVDs, a written manual, and a 2-hour web-based teleconference training workshop.  Training updates were provided on a 
regular basis—minimally every six months.  An independent and random observation of class instruction was also made 
during each 4-week YOCAS©® intervention by research staff to assess the quality and fidelity of intervention delivery by 
instructors.   
 
Measures:  Measures included: SQI  and Sleep Medication Use (Pittsburgh Sleep Quality Index; PSQI),94 Insomnia 
(Insomnia Severity Index; ISI).95,96  Wake after sleep onset, sleep efficiency and circadian activity rhythms were assessed 
by actigraphy.20,24,97 
 
Summary:  Results suggest that YOCAS©® can improve insomnia, SQI, and circadian activity rhythms among cancer 
survivors and that survivors like the YOCAS©® intervention, will attend it, will practice yoga on their own, and will 
Figure 3: Circadian Rhythms at Pre- and Post-Intervention 

 
 
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recommend it to others.  These data also suggest that altering circadian activity rhythms is a plausible mechanism 
whereby yoga may lead to improvements in insomnia.   
 
Changes in Physical Function and Inflammation Are Possible Mechanisms Whereby Yoga May Improve 
Insomnia—Studies 2 through 4:   
 
Study 2:  Dr. Mustian and her team conducted a phase II RCT comparing the influence of a Tai Chi Chuan (a Chinese 
form of yoga) intervention (3x/week, 60 minutes/session, 12 weeks) on physical function and inflammation to a 
psychosocial support therapy intervention among breast cancer survivors (N=21) between 2 weeks and 24 months post-
adjuvant therapy.  Results showed better cardiopulmonary function (6-minute walk test) and muscular function 
(handgrip test) as well as more favorable inflammatory responses in the tai chi group compared to the support 
therapy group post intervention.  Participants liked the intervention and attended 72% of the sessions with no 
adverse events.36,38,41-43,45,47 
 
Study 3:  Dr. Mustian and her research team also conducted a phase II RCT examining the influence of a low to moderate 
intensity aerobic and resistance exercise intervention (Exercise for Cancer Patients—EXCAP©®) on SQI, physical 
function (i.e., cardiopulmonary function and muscular function) and inflammatory responses among breast and prostate 
cancer patients (N=38) beginning radiation therapy.  Participants were randomized to 4 weeks of exercise or no exercise.  
Cytokines and receptors were measured using appropriate ELISAs.  Exercise participants exhibited less SQI, better 
physical function (i.e., cardiopulmonary function via 6-minute walk test and muscular function via handgrip 
dynamometer test) and reduced inflammatory responses post intervention compared to participants in the control 
group.  Higher levels of IL-6 and lower levels of TNFR1 were associated with increased SQI.35,46   
 
Study 4:  We also recently completed a phase II RCT examining the influence of the EXCAP©® intervention over 6 
weeks on SQI and physical function (cardiopulmonary and muscular function) in 53 prostate cancer patients.  EXCAP©® 
participants demonstrated improvements in cardiopulmonary function (VO2max) and strength (repetition 
maximal testing), and these improvements were inversely correlated with SQI (all p<0.05).  These changes in 
cardiopulmonary and muscular function significantly predicted changes in SQI (p<0.05, r=0.120) and, collectively, 
accounted for approximately 17% of the variance in SQI.   
 
Successful Experience and Expertise in Collecting Actigraphy, 6-Minute Walk, Handgrip Dynamometry and 
Cytokine Data in a Large Multicenter Research Base Study:   
 
Study 5:  In addition to successfully completing the previously mentioned multicenter RCT examining the influence of 
yoga on insomnia, SQI and circadian activity rhythms (via actigraphy), Dr. Mustian and colleagues are currently 
conducting a nationwide, multicenter, phase III RCT examining the influence of EXCAP©® over 6 weeks on SQI, 
cardiopulmonary (6-minute walk) and muscular (handgrip dynamometry) function, inflammation (cytokines in serum), 
and energy expenditure (actigraphy) among cancer patients receiving chemotherapy.  This study has accrued > 600 
participants in 36 months.  Dr. Mustian and her team have trained 256 CCOP (now NCORP) staff members at 19 
CCOPs affiliated with the Research Base to obtain actigraphy data, administer the 6-minute walk and handgrip 
tests, and acquire and process blood samples for cytokine analyses.  The same methods used to collect data in those 
two RCTs will be used in this multicenter RCT.  We will measure the same cytokines in our follow-on RCT as in 
our previous studies because our preliminary data are positive. 
 
Successful Experience and Expertise in Delivering Group-Based Psychotherapy and CBT-I in a Large Multicenter 
Research Base Study:   
 
Studies 6 and 7:  The URCC Research Base is currently conducting a study testing the efficacy of a modified version of 
standard CBT-I for improving insomnia, sleep quality, circadian activity rhythms and heart rate variability among cancer 
patients receiving chemotherapy (URCC12048).  The URCC Research Base previously successfully conducted a phase III 
RCT testing the effectiveness of group-based psychosocial support therapy for improving quality of life and other 
symptoms among 326 men receiving treatment for prostate cancer through the Research Base (U9994).  The same 
procedures used successfully to implement these group-based psychotherapies will be used in this RCT.   
 

 
 
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Preliminary Studies Summary:  These seven preliminary studies: 1) suggest that YOCAS©® may be effective for 
improving insomnia, SQI and circadian activity rhythms, 2) provide support for testing our theory that YOCAS©® may 
improve insomnia by improving circadian activity rhythms, cardiopulmonary function, muscular function and 
inflammation, 3) demonstrate our expertise and ability to successfully conduct nationwide, multicenter, phase III RCTs, 4) 
demonstrate our abilities to deliver group-based yoga and psychotherapies and to collect objective physical function, sleep 
and circadian activity rhythms data in large multicenter clinical trials, and 5) demonstrate our ability to work with the 
Research Base and NCORP Affiliates.   
 
______________ 
 
3.0  Objectives 
______________ 
 
3.1 
Primary Aim:   
 
1. To determine if YOCAS©® is effective for improving patient-reported insomnia (Insomnia Severity Index) 
compared to CBT-I and a health education control immediately post intervention. 
 
3.2 
Secondary Aims: 
 
 
1.   To examine if YOCAS©® is effective for improving objective symptoms of insomnia (sleep latency, sleep 
efficiency, wake after sleep onset, sleep duration, and daytime napping via actigraphy) and global sleep 
quality impairment (Pittsburg Sleep Quality Index) compared to CBT-I and a health education control. 
 
2.   To examine if YOCAS©®  and CBT-I are effective for maintaining improvements in insomnia (Insomnia 
Severity Index) 3 and 6 months post intervention compared to a health education control. 
 
3.3 
Exploratory Aims: 
 
1. To explore whether YOCAS©® is effective for improving circadian activity rhythms (24 and 12 hour 
amplitudes and acrophases measured via actigraphy), physical function (i.e., cardiopulmonary [6-min. walk] 
and muscular function [dynamometry]), and inflammation (IL-6, IL-8, IL-10, IL-1, IFN-, & TNFR1 via 
standardized ELISAs) compared to CBT-I and a health education control.  
 
2. To explore whether changes in circadian activity rhythms, physical function and inflammation mediate the 
effect of YOCAS©® on insomnia.   
 
3. To explore the time-varying nature of physical activity behavior after cancer treatment and develop a new 
methodological approach to jointly model longitudinally measured exposures and outcomes subject to 
measurement error and modification by personal characteristics in a physical activity intervention study.   
______________________ 
 
4.0  Participant Eligibility 
______________________ 
 
Eligibility criteria for all study participants must be confirmed using the Eligibility Checklist.  The Eligibility 
Checklist must be signed by an NCORP physician or the physician’s designee prior to enrollment on this study. 
 
Inclusion Criteria:  Study participants must:  
 
4.1  
Have a confirmed diagnosis of cancer 
 
4.2  
Have received surgery, chemotherapy, and/or radiation therapy 
 

 
 
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4.3 
Have completed all surgery, chemotherapy and/or radiation therapy within the last 2-60 months  
 
 
4.4  
Meet DSM-V criteria for insomnia and score >10 on the Insomnia Severity Index. (See the screening teleforms 
package for screening criteria forms) 
 
4.5  
Be at least 18 years of age 
 
4.6 
Be able to read and understand English 
 
4.7 
Be able to provide written informed consent 
 
Exclusion Criteria:  Study participants must not:  
 
4.8  
Have contraindications to functional testing or yoga participation according to the physician or the physician’s 
designee.  
 
4.9 
Have practiced yoga ≥ 1 day a week within the 3 months prior to enrolling in the study 
 
4.10  
Be planning to start yoga on their own during the time they are enrolled in the study 
 
4.11  
Have a confirmed diagnosis of sleep apnea or restless leg syndrome    
 
4.12  
Be receiving any form of treatment for cancer with the exception of hormonal or biologic therapy  
 
4.13 
Have distant metastases  
____________________________________________ 
 
5.0  Registration, Enrollment & Randomization 
____________________________________________ 
 
5.1 
CTEP Requirements.  As this study is using the CTSU Regulatory Support System, the CTSU requires the 
following: 
 
5.1.1 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
investigators participating in any NCI-sponsored clinical trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
 
a current Curriculum Vitae (CV) 
 
a completed and signed Supplemental Investigator Data Form (IDF) 
 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For questions, please contact the 
CTEP Investigator Registration Help Desk by email at <pmbregpend@ctep.nci.nih.gov>. 
 
5.1.2 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 

 
 
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The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a web-
based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-
sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-registration) with 
CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator 
Registration Procedures above for information on registering with CTEP as an Investigator, which must be 
completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) 
websites and applications, including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please contact the CTEP 
Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
5.1.3 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit 
IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to 
enroll patients.  Study centers can check the status of their registration packets by querying the Regulatory 
Support System (RSS) site registration status page of the CTSU members’ website by entering credentials at 
https://www.ctsu.org.   
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and tracked in 
the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
      1818 Market Street, Suite 1100 
      Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
 
You can verify your site registration status on the members’ section of the CTSU website.  Go to 
https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
5.2 
To enroll a cohort of participants who meet the inclusion/exclusion criteria and who have signed the informed 
consent document, log on to the URCC NCORP Research Base website at http://urcc-ncorp.org/, enter your 

 
 
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NCORP’s username and password and enter the information outlined in the section below.  If you are unable to 
log on, call 585.275.1364, between 8:30 AM and 4:30 PM (Eastern Time); Monday through Friday.  
 
5.3 
The following information will be requested: 
 
5.3.1 
NCORP site 
 
5.3.2 
Most recent IRB approval date (either initial or annual-not an amendment date) 
 
5.3.3 
Name and telephone number of coordinator following the study participant 
 
5.3.4 
Treating component or subcomponent CTEP institution code 
 
 
5.3.4.1        Enrolling physician CTEP Investigator ID 
 
5.3.5 
Confirmation that participant meets all inclusion/exclusion criteria requirements listed in Section 4.0 
including 
 
5.3.5.1 
Documentation of eligibility screening score of >10 on the Insomnia Severity Index 
Screening Form. 
5.3.5.2 
Documentation of meeting DSM-V Insomnia diagnosis criteria on the DSM-V Screening 
Form. 
5.3.5.3 
Documentation of meeting all eligibility requirements on the Eligibility Checklist.   
 
5.3.6 
Confirmation that the consent form has been signed 
 
5.3.7 
Participant’s identification 
 
 
5.3.7.1    Screening ID# from the Screening Log 
5.3.7.2 
First and last initials 
5.3.7.3 
Birth date (MM/DD/YYYY) 
5.3.7.4 
Gender 
5.3.7.5 
Race and ethnicity 
5.3.7.6 
Five-digit zip code 
5.3.7.7 
Payment code 
5.3.7.8 
Stratification:  ISI severity screening score and current hormone therapy status (yes/no) 
 
5.4 
An email confirmation of registration will be sent from the URCC NCORP Research Base. 
 
5.5 
Registration and randomization of participants will occur when an entire cohort has been consented.  A cohort 
consists of a yoga group, a CBT-I group and a health education group at a single NCORP location.  All 
participants are registered at the same time.  The minimum number of participants to comprise a cohort is 15 and 
the maximum is 30.  The NCORP must notify the URCC when the final participant in a cohort is being consented, 
and provide the total number of participants enrolled to that cohort, the institution’s CTEP ID, and the date of the 
first day of the baseline week.  The Research Base requires a 24-hour turn-around time to open the registration 
site.  The NCORP site must then register the entire cohort of participants within 24 hours and will receive the 
randomization assignment for each participant at that time.  NCORP coordinators will know the randomization 
assignments; however participants are not to be notified of their randomization assignments until they 
have completed all baseline assessments.  The participants randomized to each of the three conditions will all 
participate in the intervention they are assigned together as a group and the sessions will only contain study 
participants.  (Note: The URCC has successfully used this method of randomization in previous studies including 
U3905 (the prior yoga study), U2991 and U9994 where cohorts were randomized to treatments delivered using 
group formats.)  Participant cohorts will be recruited at each NCORP and then randomized; this will allow for 
statistical analyses by site.  

 
 
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5.6 
A total enrollment of 720 participants (accounting for 30% of participants providing non-evaluable data) is 
planned as follows: 
 
Group 
N 
Evaluable 
YOCAS 
240 
168 
CBT-I 
240 
168 
Health Education 
240 
168 
 
5.7 
Randomization will be stratified by ISI severity score obtained during the screening process (ISI score of 10-18 = 
“moderate” and 19-28 = “severe”) and hormone therapy (two levels: yes/no).  In addition, participant cohorts will 
be recruited at each NCORP and then randomized; this will, in turn, allow for statistical analyses by site. 
 
5.8 
The three study arms are as follows:   
 
 
Arm 1 = The standard YOCAS©® intervention 
 
Arm 2 = The standard CBT-I intervention 
Arm 3 = The health education control intervention which is equally matched to YOCAS©® on time and attention.   
 
5.9 
The randomization will assign participants to the three arms in the ratio of 1:1:1 using random block sizes of 3 or 
6 and will be administered at the URCC NCORP Research Base by means of a computer generated random 
numbers table provided by the biostatistician.   
_________________________ 
 
6.0  Research Protocol 
_________________________ 
 
6.1 
Overview and Intervention Groups:  720 cancer survivors 2-60 months post-primary (i.e., surgery, 
chemotherapy, and/or radiation) treatment will be randomized to YOCAS, CBT-I, or the Health Education group.   
 
6.2 
Blinding:  As part of the consenting process, participants will be blinded to study hypotheses and the true nature 
of the health education control condition (which is not expected in any way to improve insomnia; it is there to 
provide a time and attention control condition for the yoga arm).  In the beginning of the study they will be told 
that we are comparing three different interventions for improving sleep, specifically insomnia.  Participants will 
be fully briefed about the nature of the study, the hypotheses we tested, and the true nature of the health education 
control condition upon completing the study during the exit interview. 
 
6.3 
YOCAS©® Group: This is the standardized YOCAS©® yoga intervention which is a low to moderate intensity 
mode of exercise that draws from two basic types of yoga; gentle Hatha and Restorative yoga.  The program 
includes 18 specific physical postures and mindfulness exercises focused on breathing and meditation.  Instructors 
will be allowed to modify the yoga postures to meet the specific needs of participants and participants will be 
allowed to use yoga props.  (See the YOCAS©® manual, “Yoga for Cancer Survivors”.)  The program is delivered 
by Registered Yoga Alliance and/or International Association of Yoga Therapists (IAYT) instructors in 
community settings, 2 times a week for 75-minute sessions over 4 weeks.  Yoga instructor qualifications are 
documented in a resume or CV and submitted to the Research Base along with a copy of their Yoga Alliance 
and/or International Association of Yoga Therapists (IAYT) credentials for approval. 
 
6.4 
CBT-I Group:  This is standard Cognitive Behavioral Therapy for Insomnia (CBT-I).  CBT-I is a standardized 
structured, multi-component cognitive behavioral intervention (sleep education, sleep hygiene, sleep restriction, 
stimulus control, cognitive therapy, and relapse prevention).  (See the CBT-I workbook, “Cognitive Behavioral 
Therapy for Insomnia”.)  CBT-I is delivered by health professionals who are trained (e.g., clinical psychologists, 
licensed clinical social workers, licensed counselors, nurses, etc.) to deliver CBT.  The intervention is delivered 

 
 
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once a week for 90 minutes over an 8 week period.  CBT-I instructor qualifications are documented in a resume 
or CV and submitted to the Research Base for approval. 
 
6.5 
Health Education Control Group:  This group will receive a survivorship health education intervention (equally 
matched to YOCAS©® for time and attention) which is based on the American Society of Clinical Oncology 
cancer survivorship educational recommendations and a booklet entitled “Cancer Survivorship Next Steps for 
Patients and Their Families.”  (See the health education booklet.)  The intervention is delivered by community 
health educators with a minimum of a Bachelor’s degree in a health-related field or Registered Nurse certification, 
and a year of experience working in a clinical oncology setting with patients.  This intervention is delivered 2 
times a week for 75 minutes per session over 4 weeks.  Health professional qualifications are documented in a 
resume or CV and submitted to the Research Base for approval. 
 
6.6 
The participants will all participate in the treatment they are assigned together as a group (1 group for each study 
arm condition) and the treatment sessions will only contain study participants.  Participants will not be charged 
for any of the treatment sessions.   
 
 
6.6.1 
Each participating NCORP will be responsible for finding suitable yoga, CBT-I and health education 
instructors.   
 
 
 
The study PI, Dr. Karen Mustian, along with members of the research team, will be available to assist 
NCORPs in selecting appropriate instructors.  Each instructor will be required to provide the following: 
 
copy of his/her resume or curriculum vitae 
 
documentation of his/her Yoga Alliance or International Association of Yoga Therapists (IAYT) 
instructor training and certification status, CBT instructor training/experience, or health educator 
instructor training/experience in a clinical oncology setting.   
 
personal liability insurance information  
 
in order to be paid as a study consultant, the instructor will complete 
o an IRS W-9 form 
o a University of Rochester Acceptance form to follow the terms and conditions of working 
with the University 
 
Additionally, the instructors will sign an Adherence Statement promising to follow the yoga, CBT-I and 
health education interventions exactly as outlined in the clinical protocols provided.   
 
The NCORP site will submit these materials to the Research Base 
(elizabeth_nagalski@urmc.rochester.edu) for review by Dr. Mustian and members of the research team to 
approve the yoga, CBT-I and health education instructor for consultation and for teaching the 
interventions.   
 
Each instructor will also be required to complete a training session with Research Base staff under the 
direction of Dr. Mustian, prior to final approval as a study instructor.   
 
A decision regarding approval of the instructor will be made within two weeks of providing all the 
necessary materials and fully completing training.  
 
All instructors will be paid directly as consultants by the URCC NCORP Research Base.  Instructors must 
submit an invoice to the Research Base within 7 calendar days of completing the series of 8 intervention 
sessions for processing.  Instructors will be paid a flat fee of $1200.00 per cohort to teach all 8 sessions 
and includes all preparation and travel time.  Instructor invoices should be sent to: Libby Nagalski at 
Elizabeth_nagalski@urmc.rochester.edu. 
 

 
 
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6.6.2 
Details and logistics on where the yoga, CBT-I and health education sessions will be conducted, obtaining 
props, meeting rooms and specifics regarding participant transportation will be individualized by each 
NCORP site.   
 
6.7 
Instructor Training:  Dr. Mustian and her team developed a training program for yoga instructors, including a 
written manual and 2 DVDs, one for instructors and one for participants.  The training materials provide precise 
instructions for all posture, breathing and meditation exercises with appropriate modifications if necessary.  We 
successfully trained 18 yoga instructors and used the YOCAS©® program in our previous yoga study, U3905.  We 
will train additional instructors and use YOCAS©® again in the current study.  Dr. Pigeon and his team have 
developed a CBT-I training program for health professionals that includes a manual and PowerPoint presentation.  
The training materials provide precise instructions for all CBT-I components.  He has successfully trained 
instructors to deliver CBT-I for the University of Rochester Medical Center and the Veteran’s Administration.  
We will use this same training program to train the CBT-I instructors for this study.  Dr. Mustian and her team 
also developed a training program for health educators, including a manual and PowerPoint presentation.  The 
training materials provide precise instructions on the content to be covered in each of the health education 
sessions.  We will use this program to train the health education instructors for this study.  Each study instructor 
must successfully complete all training sessions prior to final approval to serve as an instructor in this study.  
Training sessions take approximately 1 hour.  NCORPs cannot hire and use instructors that are not trained and 
approved by Dr. Mustian and her team.   
 
6.8 
Intervention Quality:  The exact same procedures used to ensure quality and fidelity and to prevent drift that 
were used in the previous yoga study, U3905, will be used in this trial, except we will use videotaping to ensure 
proper class content rather than independent observations.  The interventions will be delivered by professionally 
qualified instructors hired and vetted by Dr. Mustian and members of the research team.  All instructors will 
receive extensive training regarding the information to be taught.  Training updates will be provided minimally 
every year for instructors and NCORP site staff.   Dr. Mustian and her staff will be available to answer questions 
at all times.  Coordinators will be required to videotape the third class in each condition and send the videotape to 
the URCC NCORP Research Base by the end of the next business day.  Tapes will be reviewed within 3 business 
days of receipt by qualified staff under the direction of Dr. Mustian.  Immediate feedback will be provided to the 
instructor and NCORP site staff so that corrections can be made if necessary.  If at any time a coordinator or staff 
member realizes the intervention protocols are not being followed properly, the Research Base and study P.I. (Dr. 
Mustian) must be notified immediately.  Video recordings will be uploaded via the research base’s secure  
encrypted Box data upload system.  Once URCC has reviewed the video recordings and given authorization, the 
sites must destroy them. 
 
6.8.1 
Assessment Data Quality:  The coordinators must submit all baseline data from one individual in each of 
the three arms by the 3rd work day post baseline.  This includes paperwork, fitness assessments, and 
actigraphy.  Data are either uploaded or emailed to URCC.  The Research Base will review and give the 
sites feedback so that corrections can be made if necessary.  Once the site has downloaded the actigraph 
data they must immediately give the actigraphs back to the appropriate participants so they have them 
before the mid-intervention assessment. 
 
6.9 
All instructors will complete an Attendance Log for each session to assist in documenting intervention 
compliance by instructors and participants.  They will return these logs to the study coordinator.  The Coordinator 
will darken the participants names; leaving only the initials visible.  They will in turn submit attendance logs for 
each of the three study arms to the Research Base.  One attendance log is to be submitted at the end of the 
intervention for each intervention session for all 3 study arms.  The names should be darkened to leave just 
participant initials visible. 
 
6.10 
Coordinator Training:  All NCORP coordinators and staff must complete mandatory training conducted by 
Research Base staff and PEAK Lab staff for this study.  The training includes study orientation, actigraphy, 
handgrip testing, 6-minute walk test, and blood drawing, processing, storage and shipping.  The training lasts 
approximately 2 hours.   
 

 
 
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6.11 
Screening:  Cancer survivors 2-60 months post-primary (i.e., surgery, chemotherapy, radiation) treatments, who 
have been treated at NCORP communities affiliated with the URCC NCORP Research Base will be screened.  A 
screening consent form will be used by the coordinators when approaching potential study participants either over 
the phone or face to face.  If the person declines participation in the study, the screening consent form will be 
destroyed.  If the person agrees to discuss the study, a screening consent form will be completed and submitted to 
the Research Base.  At screening, the DSM-V and ISI screening forms will be used to determine eligibility for the 
study.  All persons presented with this study will be entered on a REDCap screening log found on the 
Research Base website. 
6.12 
Consent, Collection and Handling of Sensitive Data: If the person meets all eligibility criteria, the coordinator 
will go over the study in detail using the full study consent form.  Both parties must sign the study consent form if 
the person agrees to be on study.  Participants are asked to provide their medical insurance ID number and their 
social security number in the consent form to follow them as part of future research in the Medicare and Medicaid 
Beneficiary databases and the URCC NCORP Research Base Distributed Research Network (DRN).  Information 
will not be obtained from individuals who do not give us permission to track them for future research in these 
databases.  Permission to follow a participant is voluntary.  They will be able to decline giving this information and 
still participate in the study.   
6.12.1  The URCC NCORP Research Base DRN enables investigators to collaborate with each other in the use of 
electronic health data, while also safeguarding protected health information and proprietary data. It 
supports both single- and multisite research programs. The Network’s querying capabilities reduce the 
need to share confidential or proprietary data by enabling authorized researchers to send queries to 
collaborators holding data (i.e., data partners).  In some cases, queries can take the form of computer 
programs that a data partner can execute on a preexisting dataset.  The data partner can return the query 
result, typically aggregated (count) data, rather than the data itself.  This form of remote querying reduces 
legal, regulatory, privacy, proprietary, and technical barriers associated with data sharing for research.  
This form of querying also provides added protection for research participants.   
The network seeks to build strong and trusted collaborations to support the research that will lead to 
improved health for millions of people around the world.   
6.12.2   The data will be collected in a web-based; encrypted electronic REDCap YOCAS Insurance Information 
form created by URCC NCORP Research Base.  The REDCap system is a secure, web-based application 
that is flexible enough and has an intuitive interface for users to enter data and real time validation rules 
(with automated data type and range checks) at the time of data entry.  NCORP site study staff will meet 
with each participant in a private and secure setting to fill out this form.  The staff member will confirm 
that the subject has consented to giving this information by checking the consent form signed by the 
subject. Only participants that consent to giving this information will fill out a REDCap electronic 
Insurance Information form.  The form must be completely filled out during this session with the subject.  
The study staff will NOT be allowed to save this information in any other form, whether paper or 
electronic, etc. to be uploaded later.  Once the form is complete the sites will no longer have access to it.  
Each REDCap form has a unique ID# for tracking purposes. It will be sent directly to University of 
Rochester’s server in a local data center. The database is secured behind a firewall.  Only the PI, Lead 
coordinator of this study, URCC Research Base IT analyst, and the REDCap Administrator will have 
access to the database. There will also be limited access for two Research Base staff members who will be 
auditing this information.  Once all data for the study have been collected, the file will be transferred to a 
URCC NCORP DRN secured database separate from the study database.  At this point only the data 
custodian (PI of the study), the Lead Coordinator, and Lead URCC IT staff member will have access to it. 
6.12.3   The information collected will allow us to be able to follow the participant’s progress concerning their 
cancer or any new cancers that may arise for up to a 30 year period post their study completion.  In order 
to allow us access to future medical claims it is necessary to collect social security numbers along with 
Insurance ID information.  

 
 
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6.12.4   All study personnel must follow the NCORP Clinical Trial site specific policy on Collection of Social 
Security and Insurance ID numbers.  This Policy should cover privacy regulations regarding the 
collection and transmission of Social security numbers and Insurance ID information.  Each NCI NCORP 
community affiliate site should have a Privacy Policy and an official who will work with the URCC 
NCORP Research Base.  Study sites must document that staff members have read and will follow their 
local policy.  This information must be retained with study regulatory files for URCC NCORP auditing 
purposes.   
6.12.5 Any breach must be reported promptly, within 5 calendar days, to the Research Base (Libby Nagalski and 
Ann_Colasurdo@urmc.rochester.edu) and Study PI (Dr. Mustian).  They in turn will notify the URMC 
Privacy officer and Security official. They may be required to complete follow-up information regarding 
exactly what the breach was and what steps were taken to prevent further breaches.  A breach of privacy 
must be reported to the University of Rochester IRB as well as the NCORP site’s IRB.  
6.12.6    The disclosure of social security numbers, Medicaid and Medicare and Insurance ID numbers by potential 
subjects is optional.  Potential participants can still take part in this study if they decide not to disclose 
this information. 
6.13 
Procedure Overview:  Participants in all three groups will complete a battery of assessments including 
questionnaires, a weekly diary, a 6 minute walk test, a handgrip dynamometer test, actigraphy monitoring, and a 
fasting blood draw.  Within the informed consent process, the coordinator or other study personnel will explain to 
the participants that there will be five assessment periods.  These assessments are completed at: 1) baseline, 2) mid-
intervention, 3) post-intervention, 4) 3 months after post-intervention, and 5) 6 months after post-intervention.  
Reminder phone calls will be made to participants regarding study appointments, wearing the actigraphs, and 
completing questionnaires.  Permission will be obtained to leave messages; however, coordinators must make every 
effort to speak with the study participant for these calls to be considered complete.  Documentation of permission to 
leave a message should be recorded in coordinator notes.  Special arrangements are made to retrieve study materials 
via courier on a case by case basis via each NCORP community if necessary. 
Each assessment will include 1) questionnaires on sleep (ISI, PSQI, MEQ-SA), mood (POMS), anxiety (STAI), 
depression (CES-D), pain (BPI and VAS), fatigue (MFSI, BFI, FACIT-F ), cognitive problems (FACIT-COG), 
exercise (Godin), symptoms (Symptom Inventory), sleep medications and stimulant use (medication and CAM Use 
forms), and quality of life (FACIT), 2) a daily diary for assessing sleep patterns and specific symptoms, 3) one 
week of actigraphy 4) physical function tests (6-minute walk and handgrip tests), 5) and a fasting blood draw.  The 
actigraphs are small, water-resistant devices; one is worn around the wrist for 7 consecutive days to gather data on 
sleep and circadian rhythm. The other is worn on the waist for the same 7 consecutive days to determine physical 
activity.  Participants will complete their questionnaires at the time of their assessments or at home.   
 
6.14 
Requesting Actigraphs, Blood Draw Kits and Other Study Materials:  Study initiation materials will be 
shipped to the NCORP after the entire cohort is registered. These materials are comprised of 1) the coordinator’s kit 
(including equipment for conducting the 6-minute walk test and handgrip test), 2) the video recorder, 3) actigraphs, 
4) yoga kits, and 5) blood supplies.  The study supplies will be shipped from the Research Base via FedEx for 
delivery within 2-3 business days.   
 
6.15  
Baseline Assessments:  Baseline assessments will occur on Study Days -7 to -1, or during study week 1.  The 
coordinator will charge and initialize the actigraphs.  The actigraphs should be initialized no earlier than the 
Wednesday prior to baseline week to ensure adequate data storage.  The coordinator will also instruct all 
participants on how to put each actigraph on and give them written instructions.  An actigraph manual along with 
videos and training sessions are provided for coordinators by the Research Base.  The coordinator will reinforce 
with the participant to wear their actigraphs for 7 consecutive days and to begin filling out their daily diaries on 
day -7.  Only NCORP site staff who have completed the URCC YOCAS©® study actigraphy training can instruct 
participants on how to wear them and give them to participants.     
 
All participants will be asked to complete on study data and clinical information forms as well as a series of 
questionnaires to evaluate insomnia, their emotional state, and their physical health.  The questionnaires will take 

 
 
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approximately 35 minutes to complete and participants are asked to complete them as close to the end of the 
baseline week as possible.  Treatment notes including all cancer-related treatment should be submitted with this 
assessment.  A 6 minute walk and handgrip test will be conducted to measure strength, and a fasting (minimum of 
8 hours) blood draw of approximately 3 tablespoons, will be completed to assess inflammation.  Coordinators will 
call participants to remind them to wear the actigraphs and complete study assessments on the Thursday or Friday 
prior to the start of the baseline assessment.  At the end of the baseline week, a second call is made to remind 
participants to complete study assessments and to inform them of their study randomization assignment.  
Alternatively, these reminders can be made in person at the baseline assessment visit.  Study coordinators are to 
inform participants of their study randomization after fitness testing, fasting blood draw and case report forms 
have been completed.  Only NCORP site staff who have completed the URCC Research Base training on 
functional assessment and blood draw and processing are allowed to perform these assessments and process the 
blood specimens.   
 
6.16  
Intervention:  Participants will begin the intervention immediately after baseline assessments are complete.  
Participant adherence will be monitored by attendance records, daily diaries, and actigraphy.   
 
6.16.1 Participants in the YOCAS©® and health education groups will partake in the intervention twice a week 
for 75 minutes over a 4 week period (study days 0-27 or study weeks 2-5).   
6.16.2 Participants in the CBT-I group will complete one session a week for 90 minutes over an 8 week period 
(study days 0-55 or study weeks 2-9).   
 
6.17 
Mid-Point Assessment: Half-way through the intervention, participants will again complete study questionnaires 
(as detailed in section 6.13 above) as well as the 6 minute walk and handgrip tests, fasting blood draw, 7 more 
consecutive days of wearing the actigraphs, and continue recording in their daily diaries.  The coordinator  will 
call and remind the participants to wear their actigraphs for 7 consecutive days, to continue filling out their daily 
diaries, and to complete all study assessments.   
 
6.17.1 For participants in the YOCAS©® and health education groups, the mid-point assessment will be done 
during study days 7-13 or study week 3.   
6.17.2 For participants in the CBT-I group, the mid-point assessment will be done during study days 21-27 or 
study week 5.   
 
6.18 
Post-Intervention:  At the end of the intervention period, participants will complete all study procedures as 
outlined above and stop entering data in their daily diaries after this assessment.  The coordinator will call 
participants and remind them to wear the actigraphs, complete forms and diaries, and to complete all study 
assessments.   
 
6.18.1 For participants in the YOCAS©® and health education groups, the post assessment will be done during 
study days 21-27 or study week 5. 
6.18.2 For participants in the CBT-I group, the post assessment will be done during study days 49-55 or study 
week 9. 
 
6.19 
3-Month Post Intervention Follow Up:  At this assessment, participants will again be asked to fill out 
questionnaires, complete a 6 minute walk and a handgrip test, a fasting blood draw, 7 consecutive days wearing 
the actigraphs, and filling out daily diaries for that time.  The coordinator will complete a scheduling and 
reminder call during the week prior to the follow-up visit.   
 
6.19.1 For participants in the YOCAS©® and health education groups, the 3-month post assessment will be done 
during study week 17. 
6.19.2 For participants in the CBT-I group, the 3-month post assessment will be done during study week 21. 
 
6.20 
6-Month Post Intervention Follow Up:  At this assessment, participants will again be asked to fill out 
questionnaires, complete a 6 minute walk, and a handgrip test, a fasting blood draw, 7 consecutive days wearing 
the actigraphs, and filling out daily diaries for that time.  Additionally, participants will complete a feedback form 

 
 
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and a 15-minute qualitative exit interview at the end of the 6-month post-intervention assessment period.  All 
participants will be debriefed and the 3 study arms will be explained.  The coordinator completes a scheduling and 
reminder call during the week prior to the follow-up visit.   
 
6.20.1 For participants in the YOCAS©® and health education groups, the 6-month post assessment will be given 
during study week 29. 
6.20.2 For participants in the CBT-I group, the 6-month post assessment will be given during study week 33. 
 
6.21 
Management of actigraphy:  Actigraphy will be handled by the PEAK Laboratory at the Research Base. 
 
6.21.1 Each NCORP site will be responsible for designating someone on the research staff to be responsible for 
receiving the actigraphs and an alternate person to cover in case of vacation or illness. The staff member 
will verify identification numbers on the actigraphs and log all equipment onto the Investigational Device 
Accountability Record.  This form will be used to track actigraphs arriving from the URCC, actigraphs 
given to participants, actigraphs returned from participants, and actigraphs returned to the URCC. 
Recording the identification codes on the devices as assigned to each participant will ensure that the same 
actigraphs are used for each participant.   
   
6.21.2 When the NCORP site notifies the Research Base that the entire cohort has been registered, the actigraphs 
will be shipped from URCC fully charged. The coordinator will recharge them and initialize each 
actigraph.  The actigraphs should be initialized no earlier than the Wednesday prior to baseline week to 
ensure adequate data storage The coordinator will instruct each participant on how to put the actigraphs 
on, care for them and charge them.  The coordinator will also give them written instructions developed by 
URCC, and successfully used in prior studies to aid in proper data acquisition.   
 
6.21.3 The Research Base PEAK Lab staff will ensure that the actigraphs are in good working order before 
shipping the units to the NCORP site.  The NCORP site staff will distribute the actigraphs, actigraph 
chargers and actigraph instructions to each participant at the baseline assessment. The participants must 
have the actigraphs and must be able to start wearing them when they get up on the morning of Study Day 
-7 (Sunday morning).  Participants will wear a wrist actigraph 24 hours a day for 7 consecutive days, and 
a second actigraph will be worn around the participant’s waist 24 hours a day for the same 7 consecutive 
days.  The coordinator will instruct the participant when to remove the actigraphs (the following Sunday). 
Both will be worn during the baseline assessment, the mid-point assessment, the post-intervention 
assessment, the 3-month post intervention follow-up, and the 6-month post intervention follow up.  As the 
actigraphs are water resistant but not waterproof, participants will take the actigraphs off only when they 
shower, bathe, swim or do anything where the actigraphs would be submerged in water. Otherwise, they 
should wear them as described above during each assessment period.   
 
6.21.3.1  NCORP research staff will explain to participants the procedures for wearing the actigraphs and 
reinforce the importance of wearing them through the night.     
 
6.21.3.2  All study participants will keep both actigraphs from baseline throughout study week 5 (this is 
the post-intervention assessment period for yoga and health education groups, and mid-point 
for CBT-I group).   All actigraphs will then need to be retrieved from participants during study 
week 6.  All data needs to be downloaded and sent to URCC.  DO NOT RE-INITIALIZE ANY 
ACTIGRAPHS UNTIL CONFIRMATION IS RECEIVED THAT URCC HAS THE DATA.  
Once it is confirmed the data has been properly downloaded the actigraphs can be reinitialized.   
 
  The coordinator will need to make arrangements within 3 business days following baseline 
assessments to meet one participant in each arm and download their actigraph data to be 
submitted to URCC for the data quality audit at the beginning of the cohort and return the 
actigraphs to the 3 participants prior to the mid-point assessment. 
 

 
 
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The coordinator will need to re-initialize and return the actigraphs to participants in the CBT-I 
group only, during study week 8, so they can wear them for post-intervention assessments 
during study week 9.   
 
The coordinator will need to re-initialize and return the actigraphs to participants in all three 
study groups for both the 3-month and 6-month follow-up assessments.  Actigraphs need to be 
sent to participants during the week prior to the scheduled 3- and 6-month follow-ups.   
 
When not wearing the actigraphs, participants are instructed to plug them into the wall chargers 
and keep them charging.  Every attempt will be made to send the same actigraphs to 
participants for all assessments.   
 
 
 
6.21.3.3  The NCORP research staff will download the data from the actigraphs within 3-4 business days 
of receiving them from the participants and upload them to the URCC NCORP Research Base 
secure website.  DO NOT RE-INITIALIZE ANY ACTIGRAPHS UNTIL CONFIRMATION 
IS RECEIVED THAT URCC HAS THE DATA.  The electronic data file will be saved in a 
privacy-secure electronic file at the Research Base and PEAK Human Performance Laboratory.  
In the event the supply of actigraphs is ample, the Research Base may allow the NCORP to 
keep devices between the post-intervention and the 2 follow-up assessments.  This will be 
determined on a case by case basis.   
 
6.21.4 Assessment Training and Adherence to Assessment Protocols:   The University of Rochester PEAK 
Human Performance Laboratory, a URMC CTSI Clinical Research Core Lab, provides services to aid 
investigators in effectively implementing behavioral interventions and assessing clinical outcomes that 
involve physical activity and function.  The PEAK Lab has been instrumental in standardizing the 
procedures for the collection of actigraphy, handgrip, and 6-minute walk data to ensure adherence to 
protocol.  The staff is also adept at training NCORP site staff to properly collect, process, store and ship 
blood for NCORP studies.  Study Chair, Dr. Karen Mustian, directs the PEAK Lab which has been 
closely involved in URCC Research Base studies since its inception.  PEAK Lab staff have designed 
support materials and trained NCORP site staff to administer the behavioral interventions and outcome 
assessments for the URCC studies involving yoga (U3905), EXCAP intervention (UCCO08106) and 
many other URCC Research Base studies.  The PEAK lab staff are adept at managing and analyzing 
actigraph data and all functional data for NCORP Research Base studies as well as biological samples.   
 
 
The URCC also requires each NCORP staff member to go through training programs which includes, 
overall protocol information, functional and clinical assessments, actigraphy, blood collection and 
processing, videotaping, proper forms completion, and quality control checks.  Refresher training will be 
provided as needed. 
 
 
Adherence will be monitored throughout the study as the information is received at the URCC.  We have 
specifically implemented an extra quality assurance check after baseline, as well as having the NCORPs 
videotape the 3rd intervention class to monitor instructor adherence to the specific program they are to 
teach. 
 
6.22 
Participant Reimbursement:  Participants will receive a $50.00 reimbursement for their time and effort to 
complete each study assessment for a total reimbursement of $250.00.  Participants are only reimbursed for the 
study assessments they actually complete.  Each NCORP will be responsible for dispersing the reimbursements to 
study participants using methods appropriate for their sites.  Each NCORP will invoice the URCC Research Base 
monthly for reimbursement expenses.  URCC will only reimburse for the cash value of $50.00 per assessment; no 
gift card or other fees will be reimbursed if NCORPs choose to use methods of reimbursement that incur extra 
fees in lieu of cash.  Send invoices to:  Christine Bryce, 265 Crittenden Blvd., Box 420658, Rochester, NY 14642 
 
Christine_bryce@urmc.rochester.edu 
 
6.23 
Adverse Events: 

 
 
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6.23.1 Risks from participating in this research:  
 
YOCAS©® may result in muscle soreness, strains, and/or joint pain. 
 
CBT-I may result in temporary increases in daytime fatigue, sleepiness, and memory and 
concentration difficulties.   
 
Participants may feel upset or worried when filling out the questionnaires.     
 
Drawing blood may cause pain and bruising at the site where the blood is taken, and sometimes, may 
cause people to feel light-headed or even to faint.  Rarely, you might get an infection at the site of the 
needle stick. 
 
6.23.2 Adverse events will be reported using the URCC Adverse Event form. This form can be found on the 
URCC NCORP Research Base website. 
 
 
6.23.3 Submit written adverse event reports in one of the following ways: 
 
(1)  PDF by 
email:  
Cathleen_lesniewski@urmc.rochester.edu 
(2)  By mail: 
Cathleen Lesniewski 
URCC NCORP Research Base  
Saunders Research Building 
265 Crittenden Blvd 
CU 420658 
Rochester, NY  14642 
(3)  By fax: 
Cathleen Lesniewski 
585-461-5601 
 
6.23.4 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 until March 31, 
2018 for AE reporting.  CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 
6.23.5 An unexpected adverse event is defined as any adverse experience, the specificity or severity of which is 
not consistent with the risk information described in section 6.23.1.   
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
Unexpected 
and Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
with 
hospital-
ization 
 
without 
hospital-
ization 
 
 
 
with 
hospital- 
ization 
without 
hospital- 
ization 
 
with 
hospital- 
ization 
without 
hospital- 
ization 
 
 
 
 
 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
Not 
Required 
10  
Calendar 
Days 
 
Not 
Required 
10  
Calendar 
Days 
 
10 
Calendar 
Days 
 
Possible 
Probable 
Definite 
 
Not 
Required 
10 
Calendar 
Days 
 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
 
10 
Calendar 
Days 
 
Not 
Required 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
 
 
 
Hospitalization is defined as initial hospitalization or prolongation of hospitalization for ≥ 24 hours, due to adverse event.  
 

 
 
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6.23.6 A serious event refers to any event in which the outcome results in any of the following:  death, a life-
threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability, incapacity, or a congenital anomaly/birth defect.  Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered a 
serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. 
 
6.23.7 Adverse events should be reported to the local IRB as per its requirements. 
 
6.24 
Data Safety and Monitoring: 
 
6.24.1 All adverse events requiring reporting will be submitted to Cathy Lesniewski as described above.  
Adverse events that are serious AND unexpected AND related will be forwarded to the study chair and 
the URCC Data Safety and Monitoring Committee (DSMC) chair immediately upon receipt at URCC.  
Additional information may be requested upon their review. 
 
6.24.2 All adverse events reported to URCC are entered into a protocol-specific spreadsheet. Adverse event rates 
are monitored utilizing the spreadsheet.  If a serious adverse event is being reported frequently, the study 
chair will conduct a detailed review.  The DSMC chair will be notified and will determine if further 
action is required. 
 
6.24.3 The URCC Data Safety Monitoring Committee (DSMC) will review study progress and cumulative 
reports of adverse events at annual meetings.  An overall assessment of accrual and adverse events will 
enable the committee members to assess whether significant benefits or risks are occurring that would 
warrant study closure.   
 
6.24.4 The URCC will notify the NCORPs immediately of any serious safety concerns identified by the DSMC.  
DSMC reports will be available for download on the Research Base website. 
____________________________________________ 
 
7.0  Patient Reported and Functional Measures 
____________________________________________ 
 
7.1 
The On Study Data/Participant Record and Clinical Record Information forms are used to record 
demographic and clinical information.  Diagnostic, treatment and other clinical information will be abstracted 
from the participant’s chart and recorded on these forms.  These data will be used for descriptive purposes, to aid 
in participant monitoring, for moderator analyses and for exploratory analyses. 
 
7.2 
The two Medication and CAM Usage forms will track the participant’s use of prescription and non-prescription 
sleep and stimulant medication, as well as any other sleep and stimulant aids used during each assessment 
conducted during the study.  These forms will also specifically ask participants to report the use of any CAM 
modalities for any reason. 
 
7.3 
Insomnia and Sleep Assessments: 
 
7.3.1 
Insomnia will be measured by the Insomnia Severity Index (ISI), which is a well-validated self-report 
measure of insomnia.98-100 The measure consists of seven questions on a 5-point Likert Scale with a total 
score ranging from 0-28. Reliability and validity of this measure have been established.98-100 Total score 
will be used.  
 
7.3.2 
Sleep quality will be assessed by the Pittsburgh Sleep Quality Inventory (PSQI),101,102 a commonly used, 
24-item psychometrically sound measure scored for both global severity and subscale scores. The PSQI 
will assess sleep initiation and maintenance problems and possible etiologic factors (e.g., pain, 

 
 
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nightmares, and hot flashes). Total score will be used. This measure takes less than 5 minutes to 
complete.  
 
7.3.3 
Number of hours of sleep and intended sleep period will be calculated from the Daily Diary.  For each 
day of the study period when sleep is assessed, participants will indicate time to bed at night and time 
arose in the morning.   
 
7.3.4 
Sleep Chronotype will be measured by the Morningness-Eveningness Questionnaire Self-Assessment 
(MEQ-SA).103  This is a 19-item self-report instrument that characterizes the sleep chronotype of an 
individual.   
 
7.4 
Objective Insomnia Symptoms will be measured via actigraphy.  Participants will have their sleep-wake 
exposure monitored through the use of a wrist-worn actigraphy-based data logger, the Actigraph GT3X 
manufactured by ActiGraph  LLC, Pensacola, FL.  The Actigraph GT3X features a variable epoch length that can 
be set, and has 16MB of non-volatile memory. “Non-volatile” means that even if the battery, which can log 21 
days of runtime before needing to be recharged, becomes exhausted, the data remain intact.  The motion data will 
be analyzed using the ActiLife Analysis Software.  The program uses a validated sleep algorithm to provide an 
assessment of sleep by delineating the “in bed” and “out of bed” portions of the day.  The software and algorithms 
calculate the percent of sleep during these two portions of the day.  The actigraphy, in conjunction with the 
sleep/wake diaries, can be used to approximate the timing of both daytime and nighttime sleep.  While daily sleep 
diaries are a common method used to examine patterns of sleep and wakefulness, we will internally validate the 
at-home monitoring by comparing actigraphy data collected during baseline and follow-up to the daily 
questionnaires.  This measurement strategy allows for an assessment of sleep problems (sleep latency, WASO, 
sleep efficiency, daytime sleep) which is free from either subjective or observer bias and requires minimal subject 
compliance, allows for the detection of periods of wakefulness as brief as 30 seconds in duration.  
 
7.5 
Circadian Activity Rhythm will be assessed using actigraphy.  The exact actigraphs used to objectively assess 
sleep described in section 7.4 will be used.  A two-oscillator cosinor model (12 and 24 hours) will be calculated 
using nonlinear regression methods on the log (activity counts).  This model was found to fit the data for cancer 
survivors (Study 3) better than a single-oscillator model.  Mesor (overall), Amplitude, and Acrophase for the 12- 
and 24-hour cycles will be calculated.   
 
7.6 
Cardiopulmonary Function (aerobic capacity) will be assessed using the 6-Minute Walk Test, which is a sub-
maximal measurement using a 6-minute walk protocol.  A recent systematic review has concluded that this 
method possesses excellent measurement properties, was better tolerated, and was more reflective of activities of 
daily living than any other walk test in use.99  Participants are directed to a specific area designated for walking.  
Participants walk for a total of 6-minutes and cover as much distance as they can during this time.  The walk test 
is optimally performed in a flat, well lit area that allows for a minimum of 100 feet of walking before the 
participant needs to make a turning motion.  For example, the test may be conducted in a hallway (walking back 
and forth) or a larger room that allows for a circular/square walking pattern.  Upon completion of the test, the total 
distance walked (in feet), exercise heart rate (in beats per minute), and exercise rate of perceived exertion (using 
the ACSM revised rating of exertion scale) are recorded.  This test was easy to implement, and well received in a 
busy clinical setting in the pilot study of the proposed exercise intervention.  The total distance walked in six 
minutes can be used to estimate gross VO2 (oxygen consumption).87  Gross VO2 = Resting VO2 + Exercise (or 
net) VO2.  The formula used to estimate gross VO2 is  
 
VO2 (mL *kg-1 * min-1) = [0.1 mL *kg-1 * meter-1 * S (m * min-1)] + [1.8 mL * kg-1 * meter-1 * S (m * min-1) * G] 
+ 3.5 mL *kg-1 * min-1 
 
Where S is speed in meters per minute and G is the percent grade expressed as a fraction. 87  
 
7.7 
Muscular Function (strength) will be assessed using The Handgrip Dynamometer Test, which is a grip strength 
test used to assess the maximal voluntary contraction generated by the arm muscles.  The test is administered with 
the participant standing in anatomical position, the elbow joint angle will be held constant at 180 degrees.  Trials 

 
 
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will be performed in an alternating bilateral sequence for a total of six attempts (three with each arm).  A fourth 
test will be performed if any of the values vary by >3 Kg.  The average score of the three trials will be used for 
right and left limbs to calculate static strength.  The surgically involved arm(s) for breast cancer participants will 
be noted for data analysis.87  This test was also easy to implement and well received in the clinic in the pilot study 
of the proposed intervention.  
  
7.8 
Because many symptoms including cancer-related fatigue (CRF), depression, anxiety, mood disruption, cognitive 
problems and impaired QOL are often present with insomnia, measures of CRF, depression, anxiety, mood, sleep 
and cognitive problems have been carefully selected to minimize potential confounding and enable assessment of 
possible confounds between these concepts.   
 
7.8.1 
General Symptomatology will be measured with the Symptom Inventory (SI), a list of 20 symptoms 
modified from measures created at M.D. Anderson and Memorial Sloan-Kettering Cancer Centers.104  It is 
a series of uniscales where the severity of each symptom is indicated by filling in the appropriate circle on 
an 11-point scale, anchored by 0 = “Not Present” and 10 = “As Bad as You Can Imagine.”  An additional 
eight questions assess the degree that the symptoms interfere with the participant’s quality of life, with     
0 = “Did not interfere” and 10 = “Interfered completely.”  Ten additional questions assess the degree to 
which the participant uses specific mind-body techniques to manage symptoms.  Medical oncologists at 
our Cancer Center use this measure as part of clinical care, and we have used it in numerous studies.  It 
will serve as a concurrent self-report measure of symptoms that will be used in exploratory analyses.   
 
7.8.2 
Cancer-Related Fatigue (CRF) will be assessed subjectively via the revised Brief Fatigue Inventory 
(BFI),105,106 which is a 9-item, patient-report instrument with established reliability and validity that we 
have used in previous studies.92  The BFI allows for the rapid assessment of fatigue level and its 
interference with daily activities in cancer patients, and identifies those patients with severe fatigue.  The 
reliability and validity of the BFI were demonstrated in a study of 305 cancer patients and 290 
community-dwelling adults.  An internal consistency coefficient (Cronbach’s alpha) of 0.96 was 
demonstrated when the BFI was administered to 305 patients with cancer.93  This measure was used in the 
previously mentioned pilot study of the proposed exercise intervention.   
 
7.8.3 
CRF will also be assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale 
(FACIT-F).  The FACIT-F subscale is a 13 item scale that asks questions directly related to the impact of 
CRF on daily activities.90  It was developed by Cella and his group through extensive interviews with 
oncology professionals and patients experiencing symptoms of cancer, and it has been validated in a 
series of studies.  The basic measure has shown very good test/retest reliability as well as validity.94,95  It 
has become one of the most commonly used measures in oncology, and we have used this scale in our 
previous studies including the pilot study designed for this protocol.  
 
7.8.4 
In addition, CRF will be assessed subjectively via the Multidimensional Fatigue Symptom Inventory 
(MFSI).107 The MFSI is a multidimensional 30-item fatigue scale developed specifically for documenting 
CRF.  In addition to a fatigue total score, the instrument includes subscales for assessing general, 
physical, emotional, mental and vigor domains of fatigue.  The self-report instrument was 
psychometrically validated among a sample of 304 cancer patients and has been shown to have good fit 
via confirmatory factor analysis, reliability and validity.96-98  
 
7.8.5 
Depressive Symptoms will be measured with the Center for Epidemiological Studies Depression Scale 
(CES-D).  The CES-D56 is a 20-item depression scale developed and validated for use with a variety of 
populations.  It is in a format similar to that of the Beck Depression Inventory, but with less emphasis on 
physical symptoms of depression that may be confounded with disease symptoms or treatment side 
effects.  It has been shown to reliably and validly measure depression in cancer populations,102 and we 
have successfully used this measure in previous studies.   
 
7.8.6 
Anxiety will be measured using the Spielberger State/Trait Anxiety Inventory (STAI).  In order to reduce 
the overall patient burden, we will use only the state portion of the questionnaire.  This one-page, self-

 
 
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administered questionnaire consists of 20 short statements which people may use to describe their 
feelings.  Participants are asked to indicate the degree to which they generally experience each particular 
feeling, ranging from 1 = “Not at all” to 4 = “Very much so” at that time.  It is one of the most widely-
used assessments of anxiety.  Internal consistency coefficients > 0.90 have been shown, along with 
test/retest reliability coefficients > 0.70.  Concurrent, construct, convergent and divergent validity have 
also been demonstrated.103,104  We have successfully implemented this measure in previous studies.   
 
7.8.7 
General Mood will be assessed using the short form of the Profile of Mood States (POMS).  The POMS 
consists of 30 adjectives in 6 subscales (e.g., anxiety, depression), which subjects rate on a five-point 
scale with “1” = “Not at all” and “5” = “Extremely” to describe their moods over the past week.  The 
POMS has been used extensively in research with cancer patients and has demonstrated reliability and 
validity.105,106 
 
7.8.8 
Cognitive Problems will be assessed using the Functional Assessment of Chronic Illness Therapy-
Cognitive Well-being Subscale (FACIT-Cog).108   The FACIT-Cog subscale is a 50-item scale that asks 
questions directly related to cognition.90  It was developed by Cella and his group through extensive 
interviews with oncology professionals and patients experiencing symptoms of cancer, and it has been 
validated in a series of studies.  The basic measure has shown very good test/retest reliability as well as 
validity.90,94,95  It has become one of the most commonly used measures in oncology, and we have used 
this instrument in our previous studies (e.g., the pilot study designed for this protocol). 
 
7.8.9 
Quality of Life (QOL) will be assessed subjectively via the Functional Assessment of Chronic Illness 
Therapy (FACIT; FACT-F).  The FACIT; FACT-F is a 27-item QOL scale developed specifically for use 
in cancer clinical trials.90  It was developed by Cella and his group through extensive interviews with 
oncology professionals and patients experiencing symptoms of cancer, and it has been validated in a 
series of studies of 542 cancer patients.  The basic measure has shown very good test/retest reliability as 
well as validity.90,94,95  Along with a total score representing QOL, there are psychometrically validated 
subscales of physical, functional, social, and cognitive-emotional status.  It is one of the most commonly 
used measures in oncology, and we have used this instrument in our previous studies, including the pilot 
study designed for this protocol. 
 
7.8.10 Pain will be assessed via the Brief Pain Inventory (BPI) and the Visual Analog Scale (VAS) to evaluate 
the severity and quality of pain experienced.  The Brief Pain Inventory (BPI) has become one of the most 
widely used measurement tools for assessing clinical pain.109 The BPI allows patients to rate the severity 
of their pain and the degree to which their pain interferes with common dimensions of feeling and 
function. Initially developed to assess pain related to cancer, the BPI has been shown to be an appropriate 
measure for pain caused by a wide range of clinical conditions. The BPI has been used in hundreds of 
studies. In some ways, the BPI is a “legacy” instrument—a self-report measure that has, over time, 
become a standard for the assessment of pain and its impact.  The Visual Analog Scale (VAS) is a 
measurement instrument that measures joint pain across a continuum of pictures of faces with values from 
0 (no pain) to 10 (pain as bad as you can imagine).  The question associated with the VAS reads as 
follows:  ‘‘Please score the intensity of the pain you feel in your peripheral joints (knee, wrist, 
fingers/toes, elbow, shoulder, etc.), excluding spine/back pain and pain at the operated area.’’ 
 
7.9 
Physical Exercise/Activity will be assessed subjectively using the Godin Leisure Time Exercise Questionnaire 
and a Daily Diary. 
 
7.9.1 
The amount of leisure time spent in physical activity will be assessed using the Godin Leisure Time 
Exercise Questionnaire (Godin).110 The Godin consists of two questions designed to assess the frequency 
within a typical 7 day week of mild, moderate, and strenuous exercise performed for a duration of at least 
15 minutes during a participant’s free time.  The measure is easily administered and brief, with a retest 
coefficient of .62, a concurrent coefficient of .32 and an objective validity coefficient of .56 compared 
with CALTRAC accelerometry, estimated VO2 max and body composition (via hydrostatic weight).111  
The Godin has also been used successfully in populations of adult cancer patients.112-115    

 
 
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7.9.2 
The Daily Diary is designed to track compliance and participation in the exercise intervention and 
additional daily activities.  The participant will be asked to take 1-2 minutes and complete the journal 
each morning upon wakening and each evening immediately prior to sleeping.  This daily diary was used 
in the piloted version of the proposed study, and participants completed the forms without any problems.   
 
7.9.3 
As an objective measure of physical activity, a GT3X+ actigraph will be worn around the 
waist.  The GT3X+ actigraph provides calculated energy expenditure values for Active Energy 
Expenditure (AEE) in kilocalories and total energy expenditure in Metabolic Equivalents per 
Time (METs) in kilocalories/min/kg.  The GT3X+ actigraph features a variable sample rate 
which can be set between non-volatile memory. “Non-volatile” means that even if the battery, 
which can log 31 days of data, becomes exhausted, the data remain intact. The GT3X+ actigraph 
AEE Algorithm is based on validation studies, copies of which are available upon 
request.  Software supplied by the manufacturer will be used to determine bouts of activity 
during each assessment period. 
 
7.10 
Participant Feedback regarding their views on the experimental treatment they received will be assessed via 
completion of a feedback questionnaire by all participants and open-ended qualitative interviews at the conclusion 
of the study.  The information in the feedback questionnaire and interviews will allow us, for future studies, to 
obtain information needed to alter aspects of the interventions with which participants were displeased and to 
determine participants’ reactions to the intervention.   
 
 
 
 
 
 
8.0  Blood Analysis  
 
 
 
 
 
 
8.1  
Cytokines (IL-6, IL-8, IL-10, IL-1, IFN-, & TNFr1) will be assessed in the blood at all five assessment time 
points.  A fasting blood draw (minimum of 8 hours) will be performed on all participants at all five assessment 
time points.  The standard URCC NCORP Research Base blood collection protocol will be used.  Six tubes of 
blood (approximately 50ml) will be collected including: two red top tubes for serum, two purple top EDTA-
heparin tubes (1 for plasma and 1 for DNA) and 2 Paxgene tubes for RNA.  Cytokines will be analyzed and any 
remaining blood samples including serum, plasma and whole blood for DNA and RNA analyses will be used by 
Dr. Mustian and members of her research team for additional exploratory analyses.  The remaining blood samples 
are not banked or made available for use by investigators outside of Dr. Mustian’s research team.  All NCORPs 
will handle all human biological materials and disposal of biohazard waste in accordance with biosafety level II 
guidelines at their respective institutions for blood collection, handling, disposal, storage and shipping.  All 
NCORP personnel handling human biological materials and laboratories used by NCORPs must have received 
appropriate biosafety certifications and meet routine inspection guidelines according to their facility guidelines.   
 
8.1.1 
All requisitions, blood tubes, microfuge tubes, freezer boxes, pipettes, and labels for blood draws are 
provided by the Research Base in the form of barcoded and pre-labeled patient kits. All patient kits are 
study specific.   
 
DO NOT MIX REQUISITIONS, BLOOD TUBES, MICROFUGE TUBES OR PIPETTES 
ACROSS PATIENT BLOOD DRAW KITS EVEN IN THE SAME STUDY BECAUSE THE 
BARCODES AND LABELS ARE KIT SPECIFIC. 
 
DO NOT MIX THE FREEZER BOXES, LABELS OR EXTRA SUPPLIES PROVIDED ACROSS 
STUDIES EVEN URCC RESEARCH BASE STUDIES, BECAUSE THEY ARE STUDY 
SPECIFIC. 
 
All coordinators will fill in the appropriate patient information on the requisition form in each kit when it 
is assigned to the patient.  Every time a patient blood draw is performed a separate new patient kit is used 

 
 
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and assigned to the study participant.  Each NCORP is responsible for designating an individual that is 
certified and a lab or facility that meets the biosafety level II criteria to perform the blood draws and to 
handle, dispose, store and ship the blood samples appropriately.  The individual designated to perform the 
blood draws, handle, dispose, store and ship the samples must participate in the training provided by the 
URCC NCORP Research Base, previously described in section 6.0, and be approved by the study PI (or 
PI’s designee) prior to any blood collection at each NCORP site.  
 
8.1.2  Serum will be extracted from the two red top tubes for estimation of cytokines (IL-6, IL-8, IL-10, IL-1, 
IFN-, & TNFr1).  Plasma will be extracted from one of the purple top EDTA-heparin tubes for 
estimation of cytokines (IL-6, IL-8, IL-10, IL-1, IFN-, & TNFr1).  To extract the serum and plasma, the 
tubes will first sit upright for 30 minutes at room temperature after blood collection.  Second, the tubes 
will then be put into a centrifuge (note temp) and spun for 15 minutes at 1600 x g.  After 15 minutes, 
there should be a clear separation of the serum or plasma (yellowish liquid on top) from the other cells.  If 
this is not evident, then centrifuge for 15 additional minutes.  The upper layer of serum (red top tubes) 
and plasma (purple top tube) is then gently aliquotted into the 2.0 ml microfuge tubes provided in each 
URCC NCORP patient blood draw kit.  Serum from the red top blood tubes is to be placed into the pre-
labeled pink microfuge tubes.  Plasma from the purple top tube is to be placed in the pre-labeled purple 
microfuge tubes.  All microfuge tubes are then placed in the pre-labeled freezer boxes provided by the 
URCC Research Base and the freezer box is then placed in either a -20 C or a -80 C degree freezer (-80 C 
is preferred if available but not required) for storage until shipped to URCC Research Base.  Cytokines 
(IL-6, IL-8, IL-10, IL-1, IFN-, & TNFr1) will be assessed using Multiplex and ELISA methods as 
appropriate.  The remaining serum and plasma will be stored, as part of study participation, for use in 
future research by Dr. Mustian, the study PI, and her research team at the URCC Research Base.   
 
8.1.3  One purple top EDTA-heparin tube and two Paxgene tubes will be prepared and stored for future DNA 
and RNA extraction.  The EDTA-heparin tube will be rocked 10 times and then placed upright in a -20 C 
freezer for a minimum of 24 hours.  After 24 hours, the EDTA-heparin tube can then be transferred to a -
80 C freezer if available.  The two Paxgene tubes will be rocked 10 times, stored upright for minimum of 
2 hours and a maximum of 24 hours at room temp and then placed upright in a -20 C freezer for a 
minimum of 72 hours.  After 72 hours, the Paxgene tubes can be transferred to a -80 C freezer if 
available.  After the tubes have been frozen upright for their designated time above, they can then be 
placed on their side in the pre-labeled freezer boxes provided by the Research Base.  (Storage in a -80 C 
freezer after 4 days is preferred if available but not required.)  The whole blood in these tubes will be 
stored, as part of study participation, for use in future research by Dr. Mustian, the study PI, and her 
research team at the URCC.  See the Blood Procedures Manual found on the URCC Research Base 
website for complete blood processing instructions. 
 
8.1.4 
Shipping Supplies to NCORPs and Inventory Tracking:  Upon notification of the Research Base that a 
NCORP has registered a cohort for this study, a starter blood drawing package and an initial supply of 
barcoded and pre-labeled blood draw kits will be shipped to the NCORP for distribution and use.  
 
Each NCORP site will be responsible for designating someone on the research staff to be responsible for 
receiving the blood draw supplies and kits.  The staff member will verify that the shipment contains the 
correct number of supplies and kits and that the supplies and kits are in good condition.  The 
identification numbers need to be verified for accuracy and recorded.  The Investigational Device 
Accountability Record (DARF) will be used to track supplies and kits arriving from the Research Base, 
kits given to participants, samples stored, and samples shipped to the URCC NCORP Research Base.  
 
 
 

 
 
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8.1.5 
Shipping Frozen Blood Samples to URCC Research Base:   
 
PRIOR TO SHIPPING SAMPLES, YOU MUST CONTACT THE URCC RESEARCH BASE TO 
MAKEARRANGEMENTS TO RECEIVE YOUR SAMPLES. 
 
Call: 
Libby Nagalski 
585-275-1364 
 
Ship Samples To: 
ATTN: Libby Nagalski 
University of Rochester Medical Center 
Wilmot Cancer Institute, PEAK Laboratory (B-5035) 
601 Elmwood Avenue, Box 704 
Rochester, NY 14642 
 
 
Samples are to be stored in URCC-supplied freezer boxes as outlined in the Blood Procedures Manual 
found on the URCC Research Base website.  Samples must be stored at a minimum of -20C, but 
preferably at -80C.  Samples cannot be stored at -20C for longer than 3 months.  
 
 
The NCORPs are responsible for shipping all samples to the Research Base within 3 months of sample 
collection.  All samples must be shipped priority overnight and frozen on dry ice.  Each NCORP is 
responsible for adhering to Federal Guidelines for shipping biosafety level II biohazards as well as URCC 
NCORP Research Base biosafety level II guidelines (outlined in the blood procedures manual provided), 
their NCORP institutional biosafety level II guidelines and the shipping company guidelines when 
packing and shipping the frozen blood samples to the Research Base.   
 
 
 
 
 
 
9.0  Design Consideration 
 
 
 
 
 
 
9.1 
Decision to conduct a trial comparing YOCAS©® to a gold standard insomnia treatment for the general 
population:  We considered proposing a dismantling trial to determine which component of YOCAS©® is the 
most active.  However, after much deliberation with colleagues, we believe the study comparing YOCAS©® to 
CBT-I has significantly greater potential to impact standard of care for insomnia among cancer survivors and, 
potentially, other populations.   
 
9.2 
Changes From Our Prior Yoga RCT:  In this study, we extend our previous findings by comparing YOCAS©® 
to CBT-I (a gold-standard treatment for insomnia in the general population) and a health education intervention 
controlling for time and attention.  We also blind study participants to control for demand characteristics and bias.  
We provide participants with “Yoga Kits,” including mat, strap, Subject DVD, and manual to facilitate home 
practice during the intervention period and sustained practice during the following 6 months and assess the 
durability of intervention benefits at 3 and 6 months following completion of the interventions.  We add 
assessments of cardiopulmonary function, muscular function and inflammation to test the direct effects of yoga on 
these outcomes and their mediational effects on insomnia through YOCAS©®.   
 
9.3 
Length of Intervention—Why 4 and 8 Weeks:  We used a 4-week intervention period for YOCAS©®in our first 
study for two main reasons: 1) 4 weeks was the minimum length, in the published literature, shown to be 
efficacious for improving sleep problems, and 2) for practical purposes, we felt this length was reasonable for 
implementation in community settings via private oncology practices and would have good adherence.  We have 
chosen to retain the 4-week period for YOCAS©® as it was previously shown to be effective and to compare it to 
CBT-I delivered over the gold-standard 8-week period.  We are aware that new versions of brief and electronic 
CBT-I are currently being evaluated for efficacy among survivors, but we feel it is important to use the form of 
CBT-I shown to be effective among groups of cancer survivors in published literature.   

 
 
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9.4 
Length of Follow-Up—Why 3 and 6 Months:  We chose 3- and 6-month follow-up assessments because they 
will provide good information on the short and longer-term benefits of the yoga intervention, and, while clearly 
reflective of long-term influence, a 12-month follow-up is not practical within the time period of this R01-funded 
project.   
 
9.5 
Decision to Conduct a Multicenter Study:  It is not possible to recruit the necessary 720 cancer survivors at a 
single location within the 5-year time period of an R01.  We have considerable experience successfully 
conducting large, multicenter phase III RCTs through the Research Base with our NCORP affiliates—accrual of 
the required 720 participants in this environment is possible, and our previous studies demonstrate that it is highly 
probable they will be successfully accrued within the timeframe of this R01-funded project.   
__________________________________________ 
 
10.0  Data Handling and Statistical Considerations 
___________________________________________ 
 
10.1 
Sample Size and Statistical Power:  Allowing for 30% of participants who may not provide complete data (as in 
our prior study), we will need to enroll a total of 720 participants to have 504 fully evaluable participants (168 
evaluable in each of the three study arms).  Fully evaluable participants is defined as having completed the On 
Study/ Participant Interview and the Clinical Record Information (baseline), the ISI, PSQI, Daily Diaries, and 
actigraphy (baseline and post-intervention assessments) for primary and secondary endpoints.  With 504 fully 
evaluable participants, will have 80% power at a 0.025 significance level to test our hypotheses.  We will use a 
significance level of 0.025 to control for type I error because two hypotheses (i.e., 1 inferiority [yoga vs. CBT-I] 
and 1 superiority [yoga vs. health education]) will be tested in our primary aim.  [Note:  We will reimburse 
survivors for participating in this study in an effort to decrease attrition and data loss.] 
 
10.2 
Power for Primary Aim 1: The two primary hypotheses to be tested in our primary aim include: (1) YOCAS©® 
will be as effective as CBT-I, and (2) YOCAS©® will be more effective than the health education control.   
 
10.2.1 Power for Hypothesis 1:  Based on baseline data from our previous phase III RCT examining the effects 
of yoga on insomnia and data from Savard58 and Morin,116 we assume an ISI standard deviation of 4.6.  
Since half a standard deviation is commonly accepted as appropriate for estimating a clinically important 
change, we regard a difference of 2.3 (half a standard deviation) between YOCAS©® and CBT-I as 
nontrivial.  Following the same methods as Garland and colleagues,117 we set the non-inferiority margin 
to 1.15 (half of the 2.3 difference).  We will test the null hypothesis that the difference in mean change on 
the ISI between YOCAS©® and CBT-I is greater than 1.15; that is, YOCAS©® is inferior to CBT-I.118,119 
Rejection of the null hypothesis means that YOCAS©® is as effective (non-inferior) as CBT-I.  Using 
ANCOVA to estimate differences in mean change between YOCAS©® and CBT-I, a correlation of 0.576 
(from our prior study), and a sample of 168 subjects per group, we will have sufficient (80%) power to 
detect non-inferiority using a margin of 1.15 at p = 0.025.    
 
10.2.2 Power for Hypothesis 2:  Using ANCOVA to estimate differences in mean change between YOCAS©® 
and health education, a correlation of 0.576 (from our prior study), and a sample size of 168 evaluable 
subjects per group, we will have sufficient power to detect differences on the ISI of at least 1.3, 1.5 and 
1.6 (all larger than our 1.15 non-inferiority margin) at 80%, 90%, and 95% power, respectively.118,119  
(Note: It is already well-established that CBT-I is superior to general health education and equal time and 
attention, as such an overall test of group differences is not necessary or sufficient—the differences in 
question are specifically between yoga and CBT-I and yoga and health education and require two separate 
hypotheses be tested.)  
10.3 
Study Timeline:  Based on our prior experience conducting studies in the URCC Research Base, we anticipate 
that study start-up activities (e.g., obtaining NCI and IRB approvals, presenting the protocol and training NCORP 
site staff, setting up databases, registration and randomization, ordering supplies and making kits and manuals, 
sending kits and other study supplies to NCORPs) will take approximately 6 months. Screening and accruals will 

 
 
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begin during the 7th month and continue through month 54.  The final 6 months will be used to retrieve any 
remaining data, supplies and equipment from NCORPs, to conduct final audits of the data, to conduct analyses, to 
write abstracts and papers, and to present findings at meetings.  We expect it will take between 24 and 47 months 
to accrue the 720 participants needed for this study.   
 
10.4 
Representation of Women and Minorities:  None of the eligibility criteria for the study involve gender or 
ethnicity.  Past enrollment in our NCORP studies has closely paralleled the gender and ethnic composition of the 
available population.  See section 12.0 on Gender and Minorities.   
 
10.5 
The same protocols and procedures for data quality and control that we have used for our previous URCC 
Research Base protocols will be used for this study.  Data will be entered on scannable forms (Teleform) and 
electronically sent to a Microsoft Access database.  After scanning, data are audited visually for errors, and then 
the entire database is re-audited.  MPLus, R and SAS statistical packages will be used for the analyses.   
 
10.6 
Unless otherwise stated, all statistical tests will be performed at the two-tailed 5% level of significance.  Likewise, 
95% confidence intervals will be constructed for estimation of effects (e.g., difference in mean CRF, aerobic 
capacity, strength and QOL between the active treatment group and the control group).  Data will be analyzed on 
an "intent-to-treat" basis; participant data will be included in the treatment group to which the participant was 
randomized, regardless of any subsequent changes to the treatment (treatment in this study is considered the study 
intervention, i.e., exercise intervention, CBT-I, or Health education standard care).   
 
10.6.1 Assumptions.  The assumptions underlying all statistical analyses will be thoroughly checked using 
appropriate graphical and numerical methods.109,110  For the ANCOVA analyses, the assumptions are 
bivariate normality of the Pre- and Post-treatment responses with common covariance matrices, after 
correction for the model fixed effects.  Bivariate normality will be assessed with Roysten’s procedure, 
and equality of the covariance matrices will be assessed with the Box M test.  The ISI data from our 
previous trial did not show violations of these assumptions.  If distributions are markedly skewed, we will 
apply transformations as appropriate.  The biomarker data will likely require a logarithmic 
transformation, as is common practice.   If heteroscedistic variance is found in the residuals for any of the 
models, a Box-Cox transformation will be applied to the data.  As a last resort, appropriate nonparametric 
methods will be attempted, e.g. Wilcoxon rank sum test on change scores.111,112  If outliers or influential 
data are detected, the accuracy of the data will be investigated.  If no errors are found, analyses may be 
repeated after removing these cases to evaluate their impact on the results.  However, the final analyses 
will include these data points.   
 
10.6.2 Missing Values.  Every effort will be made to facilitate participants' completion of questionnaires and 
provision of actigraphy and physical function data, and blood.120  In the event of missing data, the reasons 
for missing data will be recorded and tabulated according to treatment group.  Some missing data are 
inevitable. Under the missing at random (MAR) assumption, we will use multiple imputation to obtain 
unbiased estimates of key parameters.  If data are suspected to be missing not at random (MNAR), a 
sensitivity analysis using the methods of Liublinska and Rubin (2014)121 will be run to determine the 
impact on results. 112    If the estimates are similar to the ones obtained from the simpler analysis of only 
complete cases, we will report the complete-case analysis results. 112   
 
10.7 
Statistical Analyses:   
 
10.7.1 Primary Aim 1 Analyses:  To determine if YOCAS©® is as effective as CBT-I and more effective than 
health education for improving insomnia (ISI total), two separate analyses will be performed, each 
aimed at estimating the difference between arms in mean change from baseline with associated 
confidence intervals.  The comparison of YOCAS©® to CBT-I is a non-inferiority hypothesis with a one-
sided alpha, and the comparison of YOCAS©® to the health education control is a traditional null 
hypothesis of no difference with a two-sided alpha.118,119 See the Statistical Power section for more 
details.  A linear mixed effects ANCOVA will be used to assess the statistical significance of the 
differences in mean changes from baseline for the two groups (Hypothesis 1 = YOCAS©® vs. CBT-I; 

 
 
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Hypothesis 2 = YOCAS©® vs. health education).  The response will be post-treatment ISI total score.  
The model fixed effects will be Group and Baseline ISI. NCORP Site will be included as a random effect.  
The REML method will be used to estimate the random effect variance components.  If the NCORP Site 
variance component is significant, the fixed effects will be tested using F tests with the Kenward-Roger 
degrees of freedom adjustment.122  If the NCORP Site variance component is not statistically significant, 
we will use ordinary least-squares estimation and F-Tests for testing the fixed effects.  The mean 
difference between groups with associated 95% confidence intervals will be estimated using the 
appropriate contrasts.  An alpha level of 0.025 will be used to adjust for multiple comparisons.  
Additional follow-up analyses will include NCORP site and cohort as covariates and examine possible 
interactions.   
 
10.7.2 Secondary Aim 2 Analyses:  To examine if YOCAS©® is effective for improving objective symptoms 
of insomnia (sleep latency, sleep efficiency, wake after sleep onset, sleep duration, and daytime napping 
via actigraphy) and global sleep quality impairment (PSQI total) compared to CBT-I and a health 
education control, we will use the same methods as for Primary Aim 1 with no multiple comparison 
adjustments.123 
 
10.7.3 Secondary Aim 3 Analyses:  To examine if YOCAS©® and CBT-I are effective for maintaining 
improvements in insomnia at 3 and 6 months post-intervention compared to a health education 
control, we will perform a longitudinal analysis124 using the ISI total score at all five time points as the 
response.  The fixed effects will be Time, Group (all three in this analysis), and Time by Group 
interaction.  Within-subject random effects will initially be modeled assuming an unstructured covariance 
matrix, but will be simplified after inspection of the estimated covariance structure (e.g., compound 
symmetry).  If NCORP Site variance in the primary analysis is statistically significant at the 0.05 level, it 
will be included as an additional random effect, independent of the within-subject random effects.  REML 
estimation will be used.  Fixed effects will be tested using F tests with the Kenward-Roger degrees of 
freedom adjustment.122  The impact of group on the time trajectory of insomnia will be tested via the 
Time*Group interaction.  Least-squares means for each Time and Group combination will be plotted to 
visualize and understand the time trajectories of insomnia.  Differences in time trajectories between the 
three groups will be tested with no adjustments for multiple comparisons.123  
 
10.7.4 Exploratory Mechanistic Aim 4 Analyses:  To explore whether YOCAS©® is effective for improving 
circadian activity rhythms (24 and 12 hour amplitudes and acrophases via actigraphy), physical 
function (i.e., cardiopulmonary [6-min. walk] and muscular function [dynamometry]), and 
inflammation (IL-6, IL-8, IL-10, IL-1β, IFN-γ, & TNFR1 via standardized ELISAs and 
multiplexes) compared to CBT-I and a health education control, we will use the same analytical methods 
as for Primary Aim 1 to assess changes in the estimated parameters of the two-oscillator (12 and 24 
hours) cosinor model97 and the Hill function model.125 These parameters include Mesor (M), Amplitude 
(A1) and Acrophase (Phi1) for the 24-hour oscillator and Amplitude (A2) and Acrophase (Phi2) for 
the 12-hour oscillator.  Estimates will be from the log-transformed activity counts using nonlinear 
regression.  Degree of rhythmicity will be assessed with the Fisher-transformed model multiple 
correlation.  We will also fit single-oscillator models (24-hour Mesor, Amplitude, and Acrophase) for 
comparison with other published studies.20,24 The time participants woke up in the morning and fell asleep 
in the evening will be extracted from weekly diaries.  We will apply the same methods as for physical 
function and inflammation outcomes; inflammatory biomarkers will be log-transformed as needed. 
 
10.7.5 Exploratory Mechanistic Aim 5 Analyses:  To explore whether changes in physical function, 
circadian rhythm and inflammation mediate the effect of YOCAS©® on insomnia, we will use 
separate mediation analyses performed on pre-post ISI change scores (CS) and the above outcomes as 
potential mediators.  Path analysis will be used, where the intervention affects CS, the intervention affects 
the mediator, and the mediator, in turn, affects the CS.  We will also use structural equation modeling.  
Mediation will be assessed via indirect effect estimation using bootstrap-based 95% confidence 
intervals.126,127  Latent variables will be introduced into the model for multiple measures of a common 
entity (e.g., cytokines for inflammation).  If multiple measures are weakly correlated, we will split them 

 
 
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into separate measurement terms (e.g., pro- and anti-inflammatory cytokines).  MPlus software will be 
used, with full-information maximum likelihood (FIML) estimation.  Under MAR, this provides less 
biased estimates due to missing data.   
 
10.7.6 Additional Analyses: The following analyses will be interpreted cautiously for hypothesis generation.  
We will use the same analytical methods described for Aims 2, 3, 4 and 5 to explore the interrelationships 
between insomnia, SQI, sleep chronotype, CRF, depression, anxiety, mood, hormone therapy, pain,  
cognitive problems, symptoms, exercise, cardiopulmonary function, strength, inflammation, stimulant and 
sleep medication use. 
 
10.7.7 
Interim Analyses:  No interim analyses of efficacy data from the trial are planned.  
 
_________________________ 
 
11.0  Records To Be Kept 
_________________________ 
 
 
Measure 
Screening
Baseline 
Mid-Point 
Intervention
Post-
Intervention 
3 Month  
Follow-Up
6 Month  
Follow-Up
Eligibility and Consent 
 
 
 
 
 
 
DSM-V 
 
 
 
 
 
 
Insomnia Severity Index Screening 
 
 
 
 
 
 
On-Study Data/Participant Interview 
 
 
 
 
 
 
Clinical Record Information 
 
 
 
 
 
 
Cancer Treatment Notes 
 
   
 
 
 
 
Sleep Medication and CAM Use 
 
 
 
 
 
 
Stimulant Medication and CAM Use 
 
 
 
 
 
 
Insomnia Severity Index (ISI) 
 
 
 
 
 
 
Sleep Quality (PSQI) 
 
 
 
 
 
 
Sleep Chronotype (MEQ-SA) 
 
 
 
 
 
 
Actigraphy 
 
 
 
 
 
 
6-Minute Walk Test 
 
 
 
 
 
 
Handgrip Dynamometer Test 
 
 
 
 
 
 
Fasting Blood Draw (Blood Requisition 
Form) 
 
 
 
 
 
 
Symptom Inventory (SI) 
 
 
 
 
 
 
Fatigue Interference (BFI) 
 
 
 
 
 
 
Cancer-Related Fatigue (FACIT-F) 
 
 
 
 
 
 
Cancer-Related Fatigue (MFSI) 
 
 
 
 
 
 
Depression Symptoms (CES-D) 
 
 
 
 
 
 
Anxiety (STAI) 
 
 
 
 
 
 
Mood (POMS) 
 
 
 
 
 
 
Cognitive Problems (FACIT-COG) 
 
 
 
 
 
 
Quality of Life (FACIT) 
 
 
 
 
 
 
Pain (BPI)  
 
 
 
 
 
 
Pain (VAS)  
 
 
 
 
 
 
Leisure Time Physical Activity 
(GODIN) 
 
 
 
 
 
 
Daily Diary 
 
 
 
 
 
 
Feedback Questionnaire 
 
 
 
 
 
 
Qualitative Exit Interview 
 
 
 
 
 
 

 
 
14040 Protocol 6-7-18 Amd5 clean 
 
Page 37 of 43 
Call Log 
 
1 
 
 
 
 
Attendance Log 
 
 
 
 
 
 
1A second phone call is made at the end of baseline. 
 
11.1 
All written materials will be kept confidential, locked in the file room at the Research Base that is accessible only 
by Research Base personnel, and identified by study ID numbers.  Electronic databases are password-protected 
with limited access.   
 
11.2 
Any treatment notes related to the study participant’s cancer treatment should be submitted with the baseline 
assessment. 
 
11.3 
The Case Summary should accompany ALL data submissions.  Completed forms must be electronically 
submitted through the URCC Box upload system within 30 days of assessment time point 
 
11.4 
All electronic data collected, i.e., actigraphy files and video recordings must be stored on a HIPAA compliant, 
regularly backed up network storage or computer immediately after collection until notified by URCC to destroy 
it. 
 
______________________________________ 
 
12.0  Gender and Ethnic/Racial Minorities 
______________________________________ 
 
12.1 
Minority Groups or Subgroups:  This clinical trial is open to both women and men who are survivors of cancer.   
 
An estimate of minority participation from our URCC Research Base accruals between 3/1/2011 and 2/29/2012 for 
three large phase III clinical trials in our target population of cancer survivors indicates minority participation will be 
approximately 13%. Our research group found 142 of the 1078 (13.17%) patients accrued to these clinical trials 
categorized themselves as being from an ethnic or racial minority.  One of these studies was Dr. Mustian’s recently 
completed phase III clinical trial testing the effects of an exercise intervention on cancer-related fatigue.   
 
Dr. Mustian has recently had success increasing minority accruals on her local single-site studies in Rochester, NY 
by implementing strategies suggested by the Recruitment and Retention Core of the URMC CTSI.   
 
Male cancer patients have been underrepresented in yoga trials for cancer patients.  In a systematic review and 
meta-analysis conducted in 2012, Buffart et al. found 13 published trials of yoga for cancer patients.118 Twelve of 
these trials focused specifically on breast cancer; 11 recruited only female patients, and one reported that 5% of 
their sample was male.  The thirteenth trial was a small (N=38) pilot trial focused on lymphomas; 39% of this 
sample was male.53  In an analysis of population-based data, similarly, only 3.5% of men in the United States 
reported practicing yoga, compared to 10% of women.119  
 
To ensure sufficient representation of male cancer patients in the current trial, the following steps will be taken.  
Research coordinators at the NCORP sites will be instructed to screen specifically for and oversample male 
cancer patients in their recruitment efforts, to account for the potential reticence of men to engage in a group-
based yoga intervention.  Where possible, coordinators conducting recruitment will be gender matched to the 
patients they are recruiting (i.e., male coordinators recruiting male patients, female coordinators recruiting female 
patients).  Recruitment and study materials, including study manuals include both male and female models. 
 
For this study, our goal is to increase minority recruitment to18% (a 5% increase).  We will work closely with our 
minority-based NCORPs to ensure they have the resources and help they need to open this study and to effectively 
recruit participants and conduct the study.  We will also work closely with our non-minority-based NCORPs to 
support increased minority accruals at all of our affiliated NCORPs.  We will provide each NCORP with culturally 

 
 
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sensitive recruitment materials.  Lastly, our IRB and all of our NCORP IRBs mandate that all study materials and 
measures meet federal guidelines and can be easily understood by individuals without a high school degree.  
 
In addition, we will meet quarterly with Research Base staff and annually with all NCORPs; at face-to-face 
meetings and on audits where we will discuss minority recruitment levels and make adjustments in our 
recruitment strategies as needed in an earnest effort to increase minority recruitment for this trial.   
 
Projected participation is shown below.   
Racial Categories 
Not Hispanic or 
Latino: 
Female 
Not Hispanic or 
Latino: 
Male 
Hispanic or 
Latino: 
 
Female 
Hispanic or 
Latino: 
 
Male 
 
Total 
American Indian/Alaska Native 
11 
2 
0 
0 
13 
Asian 
18 
11
0
0 
29
Native Hawaiian or Other Pacific Islander 
8 
7 
0 
0 
15 
Black or African American 
43 
22 
5 
1 
71 
White  
483 
80 
17 
5 
585 
More Than One Race 
5 
1
1
0 
7
Total 
568 
123 
23 
 
6 
720 
 
________________ 
 
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