Brief Behavioral Intervention for Insomnia During Chemotherapy
Phase: NA
Conditions: Breast Cancer, Insomnia
Sponsor: Stanford University

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Protocol Version #4.0 
 
 
 
 
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TITLE: Brief Behavioral Intervention For Insomnia During Chemotherapy 
 
NCT02165839 
 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director  
Oxana Palesh, Ph.D., M.P.H. 
401 Quarry Road, Stanford, CA 94305 
 
 
 
Co-Investigators 
Cheryl Koopman, Ph.D. 
401 Quarry Road, Stanford, CA 94305 
 
 
Shelli Kesler, PhD 
401 Quarry Road, Stanford, CA 94305 
 
 
Clete Kushida, M.D. 
450 Broadway Street, Redwood City, CA 94063 
 
 
Ellen Hendriksen, Ph.D. 
648 Beacon Street, Boston, MA 02215 
 
 
Biostatistician 
Booil Jo, Ph.D. 
401 Quarry Road, Stanford, CA 94305 
 
 
Study Coordinator 
Mary Melissa Packer 
401 Quarry Road, Stanford, CA 94305 
 
 
 
 
 
Version # 4.0/ Version Date: (12-14-2015) 
 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (EXAMPLE) ...................... 8 
1. OBJECTIVES ........................................................................................................................ 9 
1.1. PRIMARY OBJECTIVE ......................................................................................................... 9 
1.2. SECONDARY OBJECTIVES ................................................................................................... 9 
2. BACKGROUND .................................................................................................................... 9 
2.1 STUDY DISEASE .................................................................................................................. 9 
2.2 STUDY PROCEDURE ............................................................................................................ 9 
2.3 RATIONALE ......................................................................................................................... 9 
2.4 STUDY DESIGN ................................................................................................................. 13 
2.5 CORRELATIVE STUDIES BACKGROUND ............................................................................. 14 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 16 
3.1 INCLUSION CRITERIA ........................................................................................................ 16 
3.2 EXCLUSION CRITERIA ....................................................................................................... 16 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 17 
3.4     RANDOMIZATION PROCEDURES ........................................................................................ 17 
3.5 STUDY TIMELINE .............................................................................................................. 17 
4. TREATMENT PLAN .......................................................................................................... 17 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................. 18 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 18 
4.3 ALTERNATIVES ................................................................................................................. 18 
5. INVESTIGATIONAL PROCEDURE INFORMATION ................................................ 18 
5.1 
 INVESTIGATIONAL PROCEDURE ........................................................................................ 18 
5.2 AVAILABILITY .................................................................................................................. 20 
5.3 AGENT ORDERING ............................................................................................................ 20 
5.4 AGENT ACCOUNTABILITY ................................................................................................. 20 
6. DOSE MODIFICATIONS .................................................................................................. 20 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 20 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 20 
7.2 ADVERSE EVENT REPORTING............................................................................................ 20 
8. CORRELATIVE/SPECIAL STUDIES ............................................................................. 20 
8.1 LABORATORY CORRELATIVE STUDIES .............................................................................. 20 
9. STUDY CALENDAR .......................................................................................................... 22 
10. MEASUREMENT.............................................................................................................. 23 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 23 
10.2  SECONDARY OUTCOME .................................................................................................. 23 
11. REGULATORY CONSIDERATIONS ........................................................................... 26 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 26 
11.2 DATA AND SAFETY MONITORING PLAN .......................................................................... 26 
11.3 DATA MANAGEMENT PLAN ............................................................................................ 26 

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12. STATISTICAL CONSIDERATIONS ............................................................................. 26 
12.1 STATISTICAL DESIGN ...................................................................................................... 26 
12.2 INTERIM ANALYSES ......................................................................................................... 26 
12.3 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 26 
12.4 PRIMARY ANALYSIS ........................................................................................................ 27 
12.5 SECONDARY ANALYSIS ................................................................................................... 28 
12.6  SAMPLE SIZE .................................................................................................................. 29 
12.7 CRITERIA FOR FUTURE STUDIES ...................................................................................... 30 
13. REFERENCES ................................................................................................................... 31 
APPENDICES ............................................................................................................................. 37 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ............................................................. 37 

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PROTOCOL SYNOPSIS 
 
TITLE 
Brief Behavioral Intervention For Insomnia 
During Chemotherapy 
STUDY PHASE 
Phase III 
INDICATION 
Insomnia 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Brief Behavioral Therapy for Insomnia 
(BBT-I) 
Healthy Eating Education Learning (HEAL) 
PRIMARY OBJECTIVE(S) 
The purpose of this study is to test the 
efficacy of brief behavioral therapy versus 
control condition that accounts for time and 
attention (nutrition education) in the 
treatment of insomnia in humans. 
SECONDARY OBJECTIVE(S) 
To assess the impact of different biomarkers 
on sleep disruption and other patient 
reported outcomes 
TREATMENT SUMMARY 
This research is designed to determine the 
efficacy of the BBT-I in comparison with the 
attention-matched behavioral control in 
reducing insomnia, fatigue, and cognitive 
difficulties in breast cancer patients. In 
addition, this study will examine the 
potential involvement of moderators (age, 
depression, anxiety, and hot flashes), 
specific behavioral mechanisms 
(maladaptive sleep behaviors, dysfunctional 
beliefs and attitudes), and physiological 
mechanisms (dysregulated circadian 
rhythms, disrupted wake-sleep cycles, and 
autonomic tone) as potential mediators of 
intervention-related changes in insomnia and 
the secondary outcomes of fatigue and 
cognitive difficulties. To address these aims, 
180 breast cancer patients with acute 
insomnia during chemotherapy treatment 
will be recruited and randomized to receive 
either BBT-I or a behavioral control focused 
on healthy eating education. Each 
intervention condition will consist of 2 face-
to-face sessions + 4 phone calls, delivered 
over a period of six weeks. Assessments will 
include sleep diary, questionnaires, 
neuropsychological testing, actigraphy, heart 
rate variability measurement, and salivary 
cortisol collection at baseline, post-
intervention, and 6- and 12 months follow 
ups. By offering this intervention during 

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chemotherapy when patients are just 
beginning to develop insomnia, we hope to 
alleviate and avoid the development of 
chronic insomnia in the survivorship phase. 
 
 
SAMPLE SIZE  
180 
STATISTICAL CONSIDERATIONS 
The primary endpoint is insomnia. 
Secondary endpoints include cognitive 
functioning, fatigue, depression, HRV, 
cortisol and biomarkers of sleep and stress. 
The estimated power to detect the group 
difference in change in ISI is 0.88-0.99 
(d=0.4 to 0.6, alpha=.05, two-tailed) with 
N=180 (90 BBT-I, 90 control). 
 
 

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SCHEMA 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (Example) 
 
BBT-I 
Brief Behavioral Intervention for Insomnia 
HEAL 
Healthy Eating Education Learning 
BC 
Breast Cancer Patients 
ISI 
Insomnia Severity Index 
HRV 
Heart Rate Variability 
RCT 
Randomized Clinical Trial 
DSMB 
Data Safety Monitoring Board 
IRB 
Institutional Review Board 
ITA 
Infusion Treatment Area 
RSA 
Respiratory Sinus Arrhythmia 
CBT-I 
Cognitive Behavioral Therapy for Insomnia 
HPA 
Hypothalamic Pituitary Axis 
WRC 
Waking Rise Cortisol 
CTCAE  
Common Terminology Criteria for Adverse Events 
CRF 
Case Report Form 
RA 
Research Assistant 
QOL 
Quality of Life 
PNS 
Parasympathetic Nervous System 
SCN 
Suprachiasmatic Nucleus 
RCT 
Randomized Clinical Trial 
BCC 
Breast Cancer Connections’ Awareness Task Force 
BFI 
Brief Fatigue Inventory 
ISI 
Insomnia Severity Index 
MCAB 
Mobile Cognitive Assessment Battery 
CAD 
Clinical Assessment of Depression 
CTMT 
Comprehensive Trail Making Test 
COWAT 
Controlled Oral Word Association Test 
HVLT-R 
Hopkins Verbal Learning Test-Revised 
GLTEQ 
Godin Leisure Time-Exercise Questionnaire 
SBSRS 
Sleep Behavioral Self Rating Scale 
PSQI 
Pittsburgh Sleep Quality inventory 
DBAS 
Dysfunctional Beliefs about Sleep 
DERS 
Difficulties in Emotion Regulation Scale 
NKQ 
Nutrition Knowledge Questionnaire 
rMEQ 
Reduced Horne Ostberg Morningness Eveningness 
Questionnaire 
EORTC 
European Organization for Research and Treatment 
of Cancer 
WASO 
Wake After Sleep Onset 

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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
 
 To evaluate the efficacy of the BBT-I in treating insomnia among breast cancer patients 
receiving chemotherapy. 
 
 
1.2. 
Secondary Objectives 
 
 
 To evaluate the efficacy of the BBT-I in treating cancer-related symptoms such as 
cancer-related fatigue and cognitive difficulties in breast cancer patients receiving 
chemotherapy. 
 
 To examine potential moderators and mediators of BBT-I intervention effects on 
insomnia, cognitive difficulties, and fatigue. In particular, we are interested in age, 
depression and anxiety and side effects (hot flashes) as potential moderators of the 
intervention effects as well as evaluating modifiable behavioral and physiological 
mechanisms as hypothesized mediators  
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
In the United States, breast cancer accounts for nearly 1 in 3 cancers diagnosed among women 
and causes the most cancer related deaths among women after lung cancer. It is estimated that 1 
in 8 women will develop breast cancer during her lifetime in the United States, with over 
230,000 new cases of invasive breast cancer and almost 40,000 breast cancer deaths expected in 
2013 alone.1 One major problem reported by breast cancer patients is sleep disruption, and this 
study looks to understand how receiving BBT-I impacts quality of life in women who have 
breast cancer. 
 
2.2 
Study Procedure 
Cancer-related sleep problems are among the most frequently reported side effects resulting from 
cancer diagnosis and treatment. Nearly 80% of cancer patients report sleep problems during 
chemotherapy or radiation therapy, and 65% of cancer survivors continue to report sleep 
problems six months after the completion of treatments. Although not always specified, “sleep 
problems” or “sleep complaints” generally refer to one or more of the following symptoms of 
insomnia: difficulty falling or staying asleep, poor sleep quality, and short sleep duration. The 
pathophysiology of insomnia in cancer is not understood. However we previously found in breast 
cancer patients that poor sleep is associated with dysregulation of circadian rhythm changes in 
the HPA axis, and attenuation of parasympathetic tone as measured via respiratory sinus 
arrhythmia (RSA). A focus on insomnia is important for a variety of reasons. First, insomnia that 
occurs during acute illness and treatment exacerbates cancer progression and worsens treatment-
related symptoms such as fatigue and cognitive difficulties. Second, insomnia that occurs 
following treatment is linked to reduced quality of life, development of psychiatric illness and 

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poor health status. Finally, our work suggests that objectively measured poor sleep efficiency is a 
significant independent prognostic factor for disease progression in breast cancer (Hazard Ratio 
(HR), 0.96, 95% CI, 0.93 to 0.98, p<0.001) 6 years later. We believe that research focused on the 
etiology and management of insomnia in cancer patients is crucial to help decrease morbidity 
and perhaps mortality associated with poor sleep. 
 
The proposed project extends our previous research (NCI-funded K award) by testing a novel 
Brief Behavioral Therapy for Insomnia (BBT-I) in breast cancer patients receiving 
chemotherapy. Our pilot data suggests that BBT-I is an acceptable and feasible intervention that 
shows promise in reducing insomnia. In addition, we believe that treating insomnia will 
potentially lead to improvement in cancer-related symptoms such as fatigue and cognitive 
complaints, and it may also help produce positive effects on the overall health of cancer patients 
by normalizing circadian rhythms and autonomic tone (RSA). The proposed randomized clinical 
trial has 2 intervention arms (BBT-I vs. Healthy Eating Control). Both interventions consist of 2 
face-to-face sessions + 4 phone calls over a six-week period. The study will recruit 180 female 
breast cancer patients receiving chemotherapy and will test the BBT-I efficacy in reducing 
insomnia and fatigue and alleviating cognitive difficulties. The BBT-I is modeled on standard 
cognitive behavioral therapy for insomnia (CBT-I) and includes both stimulus control and sleep 
scheduling but has been successfully modified to make it more suitable for cancer patients 
undergoing chemotherapy with recently developed insomnia symptoms. In addition, we will 
examine potential moderators of the intervention effects as well as modifiable behavioral and 
physiological mechanisms as mediators of changes in insomnia and other effects of the 
intervention. 
 
For clinicaltrials.gov compliance 
 
2.3 
Rationale 
Background: Sleep disturbance, particularly insomnia, is prevalent in cancer patients 
undergoing chemotherapy. Our preliminary data show that our novel intervention, Brief 
Behavioral Therapy for Insomnia (BBT-I), significantly reduces insomnia in breast cancer 
patients receiving chemotherapy. BBT-I is modeled on standard cognitive behavioral therapy for 
insomnia (CBT-I), including both stimulus control and sleep scheduling, and has been 
successfully modified to make it more suitable for breast cancer patients undergoing adjuvant or 
neoadjuvant chemotherapy with recently developed insomnia symptoms. Our preliminary 
research suggests that BBT-I is an acceptable and feasible intervention for insomnia in breast 
cancer patients that might also lead to improvement in fatigue and cognitive difficulties.  
 
Methods: This research is designed to determine the efficacy of the BBT-I in comparison with 
the attention-matched behavioral control in reducing insomnia, fatigue, and cognitive difficulties 
in breast cancer patients. In addition, this study will examine the potential involvement of 
moderators (age, depression, anxiety, and hot flashes), specific behavioral mechanisms 
(maladaptive sleep behaviors, dysfunctional beliefs and attitudes), and physiological mechanisms 
(dysregulated circadian rhythms, disrupted wake-sleep cycles, and autonomic tone) as potential 
mediators of intervention-related changes in insomnia and the secondary outcomes of fatigue and 
cognitive difficulties. To address these aims, 180 breast cancer patients with acute insomnia 
during chemotherapy treatment will be recruited and randomized to receive either BBT-I or a 
behavioral control focused on Healthy Eating Education Learning. Each intervention condition 
will consist of 2 face-to-face sessions + 4 phone calls, delivered over a period of six weeks. 

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Assessments will include sleep diaries, questionnaires, neuropsychological testing, actigraphy, 
heart rate variability measurement, blood draw, and salivary cortisol collection at baseline, post-
intervention, and 6- and 12 months follow ups. By offering this intervention during 
chemotherapy when patients are just beginning to develop insomnia, we hope to alleviate and 
avoid the development of chronic insomnia in the survivorship phase. 
 
Insomnia in Cancer Patients is Prevalent and Undertreated. Insomnia is defined as difficulty 
falling or staying asleep, poor sleep quality, and/or short sleep duration. It is one of the most 
frequently reported side effects resulting from cancer treatment.2 Our research and that of others 
suggest that insomnia among cancer patients is two to three times higher than in the general 
population.3 Nearly 80% of cancer patients undergoing chemotherapy report insomnia 
symptoms, with 30 to 50% of newly diagnosed cancer patients meeting the criteria for an 
insomnia diagnosis.3-5  Our prospective study showed that low sleep efficiency is a prognostic 
factor for significantly shorter survival in women with advanced breast cancer (BC) independent 
of known other prognostic medical factors.6,7 Despite the high prevalence of insomnia in cancer 
patients, it is commonly undertreated8 and our data shows that it doesn’t respond to traditional 
talk therapy.9 A sizeable number of women with early-stage BC (30%) report having mood 
problems or depression.10 Data from multiple studies indicate that the frequency of depression in 
patients with a variety of diagnoses receiving various treatments can range from 15 to 38% and 
that depression interferes significantly with quality of life (QOL).10,11 Frequently, patients report 
that depression begins with treatment, continues during the course of chemotherapy, and declines 
somewhat but persists at a higher-than-baseline rate after treatment is over. Research supports 
the concept that depression does not occur in isolation but instead occurs in association with 
insomnia. These data are consistent with the concept that depression and insomnia are highly 
correlated and suggest that treatment of insomnia might affect depression and influence 
QOL.9,12,13   
 
Insomnia and Cognitive Decline in Cancer are Understudied and May Share Common 
Causative Factors:  Although insomnia is prevalent in cancer patients, it rarely occurs in 
isolation. Up to 78% of cancer survivors who have received adjuvant chemotherapy demonstrate 
significant difficulties with memory, attention, processing speed, and executive function.14-16 
Cancer is associated with increased risk for cognitive decline, extends disease-related disability, 
and interferes with treatment compliance.17-20 Thus, sleep and cognitive problems may share 
common causative factors that result in an interaction between these two symptoms. 
Additionally, sleep deprivation is associated with cognitive impairment in healthy individuals, 21-
24 and therefore may independently contribute to cognitive difficulties following cancer 
chemotherapy. Thus far, the role of sleep problems in chemotherapy-related cognitive deficits 
has not fully been examined. 
 
Insomnia and Cancer-Related Fatigue (CRF) Frequently Co-Occur: A sizeable minority of 
women with early-stage breast cancer (30%) report having daytime sleepiness or fatigue.25,26 
Data from multiple studies indicate that in patients with a variety of diagnoses receiving various 
chemotherapy treatments the frequency of CRF can range from 70% to 100%. Frequently, 
patients report that fatigue begins with treatment, continues during the course of chemotherapy, 
and declines somewhat but persists at a higher-than-baseline rate after treatment is over, 
sometimes lasting for months or even years after the end of cancer treatment. In addition to the 
limits fatigue imposes on the patient’s ability to engage in desired activities (during or after 
treatment), it also prompts patients to engage in behaviors to cope with their fatigue (i.e., lying 
down, taking naps, spending more time in bed [awake or asleep]). As discussed below, these 

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coping behaviors may set the stage for the development of insomnia. Davidson5 et al. showed 
that patients who reported being overly fatigued were 2.5 times more likely to have insomnia 
than others. A body of literature now supports the concept that CRF does not occur in isolation 
but instead occurs in association with sleep disturbance. While most of these studies are 
correlational in nature, they all suggest that insomnia is: 1) positively correlated with fatigue, 2) 
more severe in fatigued than in non-fatigued patients, and 3) bidirectionally related to fatigue.27-
30 These data are consistent with the concept that fatigue and insomnia are highly correlated and 
suggest that treatment of insomnia might affect fatigue.   
 
The HPA Axis and Circadian Rhythms May Contribute to Insomnia in Cancer Patients. 
The precise physiological pathways involved in the development of insomnia and their 
relationships with cancer and its treatments are unknown. There are many biophysiologic 
processes (e.g., circadian activity rhythms, heart rate variability, inflammation, diurnal cortisol, 
melatonin and other hormonal rhythms) through which behavioral interventions may influence 
sleep. It is not possible (practically or financially) to study all mechanisms in one phase II 
clinical trial. In this phase II trial we will focus on two specific possible biophysiologic 
mechanisms: circadian activity rhythms and heart rate variability.  Circadian rhythms and stress-
related responses—particularly involving the hypothalamic-pituitary-adrenal axis (HPA)—are 
two interrelated regulatory networks that communicate with each other through multiple 
signaling pathways. Research suggests that insomnia is prevalent in cancer patients and 
associated with dysregulated circadian rhythm and HPA axis function.31-35 Studies have indicated 
that circadian disruption is prevalent in cancer patients and survivors, and that circadian 
disruption has been implicated as a risk factor for various cancers.36-39 Flattened diurnal cortisol 
patterns are associated with more awakenings during the night, and are associated with shorter 
survival in metastatic BC.40 
 
In addition to circadian rhythm and 
HPA regulatory systems, emerging 
evidence suggests that the autonomic 
nervous system is implicated in the 
development of insomnia among cancer 
patients.41 Falling asleep involves a 
neurophysiological switch from 
predominantly sympathetic to 
parasympathetic tone.42 Our data 
showed that cancer patients who have 
insomnia also have attenuated 
parasympathetic tone as measured by 
respiratory sinus arrhythmia (RSA).43 
RSA measures the variation of heart 
rate with respiration and changes in 
heart rate and can be used as a proxy measurement of general parasympathetic tone.44 The 
parasympathetic nervous system (PNS) is influenced by the circadian system, while the 
sympathetic nervous system is influenced by the sleep-wake system.45 The suprachiasmatic 
nucleus (SCN) is a master circadian clock, which regulates autonomic and HPA function through 
endocrine modulation.  Emerging evidence in both healthy people and cancer patients suggests 
that circadian rhythms and the autonomic nervous system are dysregulated in those with sleep 
problems via multiple photo (e.g., light exposure) and non-photo sensitizers (e.g., cancer 
treatments, physical activity).  In cancer patients and survivors, circadian rhythm disruption, 
Figure 1. Relationship between sleep disruption, 
circadian rhythms and autonomic nervous system 
SCN 
CIRCADIAN 
RHYTHMS 
Rest/activity rhythm 
Cancer and 
cancer progression 
SNS/PNS 
Vagus nerve/RSA 
BIO-PSYCHOSOCIAL/ENVIROMENTAL  
(e.g., Physical Activity, Light Exposure, 
Depression, Anxiety, Sleep Problems) 

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autonomic dysfunction and sleep problems are prevalent (Figure 1).3,8,9,43,46 However, no studies 
known to the authors have examined all three systems and attempted to intervene. Understanding 
the nature of the relationship between sleep problems, circadian rhythm and autonomic nervous 
system activity is of considerable clinical and research interest in cancer, because it may lead to 
the development of new therapeutic approaches. Treating insomnia in patients may improve 
quality of life and overall health by normalizing circadian rhythms and autonomic tone. 
 
Cognitive Behavioral Therapy for Insomnia (CBT-I). CBT-I is considered the gold standard 
for insomnia management in the general population.47,48 CBT- I is a 7-session therapist-led 
intervention consisting of stimulus control (instructions for behavior modification), sleep 
restriction, and cognitive restructuring to address maladaptive sleep cognitions. Recently, several 
randomized clinical trials have been conducted using CBT-I in cancer survivors.  The largest of 
these studied 150 patients who had completed cancer therapy for various cancers.49 The CBT-I 
group showed significant improvements in insomnia, depression, and QOL symptoms compared 
to no improvements on these parameters in the control group, with effects maintained at 6-
months. Similar results were obtained in earlier RCTs that utilized CBT-I.50,51 However, CBT-I 
is time-consuming (7 sessions), costly (conducted by a clinical psychologist who is certified in 
behavioral sleep medicine), and can make patients feel sleep-deprived.  
 
Behavioral Trials in Cancer Patients Undergoing Chemotherapy are Extremely Limited. 
Although research suggests that patients undergoing chemotherapy have more insomnia and may 
be at risk for developing chronic insomnia compared to patients receiving other treatments or 
survivors, we identified only two RCTs attempts.52-54 The first trial54 utilized a non-specific sleep 
intervention and failed to show efficacy. The second trial 52,53 showed initial improvement, but 
failed to improve sleep at follow-up. The clinical significance of that trial is unclear given that the 
patients did not have clinically significant insomnia at baseline. Currently, there are no treatment 
recommendations specifically developed to treat insomnia in cancer patients undergoing 
chemotherapy. If results of our NCI-funded K award pilot study are confirmed, our intervention 
will impact how we treat symptoms during chemotherapy by showing that behavioral 
interventions can be successfully implemented in a clinic, change the standard of care for 
insomnia (reduce sleep medication use) and improve understanding of the pathophysiology (role 
of circadian and autonomic regulation) of insomnia in cancer patients. 
 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
 Primary purpose for the protocol:  
o Supportive Care: protocol designed to evaluate one or more interventions 
where the primary intent is to maximize comfort, minimize side effects or 
mitigate against a decline in the subject’s health or function.  In general, 
supportive care interventions are not intended to cure a disease.  
 
  Interventional model:  
o Parallel: one of two groups in parallel for duration of study.  
 
 Intervention arms: 
o There are 2 intervention arms:  
Group 1: Brief Behavioral Therapy for Insomnia (BBT-I). 

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Group 2: Healthy Eating Education Learning (HEAL) control group.  
 
 Masked: 
o Open: no masking is used  
 
 Randomization: 
o The study will be randomized. 
 
 Type of Primary Outcome: 
o Efficacy.  
 
2.5 
Correlative Studies Background 
Cortisol: The precise physiological pathways involved in the development of sleep problems 
and their relationships with cancer and its treatments are largely unknown. Circadian rhythms 
and stress-related responses—particularly involving the hypothalamic-pituitary-adrenal axis 
(HPA)—are two interrelated regulatory networks that communicate with each other through 
multiple signaling pathways.  Research suggests that sleep problems are prevalent in cancer 
patients and are associated with dysregulated circadian rhythm.31,33-35,55 In the last two decades, 
studies have indicated that circadian disruption is prevalent in cancer patients and survivors,36 
and that circadian disruption associated with shift work has been implicated as a risk factor for 
various cancers.37-39  Flattened diurnal cortisol patterns are associated with self-reports of more 
awakenings during the night, and are associated with shorter survival time with metastatic breast 
cancer (BC).56 
 
Inflammatory Cytokines and Insomnia:  Data show that sleep disruption and sleep loss are 
associated with dysregulated immune functioning as measured by increased production of 
interleukin-6 (IL-6)19, tumor necrosis factor20, 21 and C-reactive protein.22 Several studies have 
found that insomnia disrupts immune functioning23, 24 to a greater extent than depression, thus 
this increase cannot be explained by the comorbid depression.  To date, the consequences of 
insomnia in cancer patients and survivors have not been fully examined; however, recent 
research suggests that sleep disturbances and/or circadian dysregulation might be adversely 
related to cardiac morbidity25, immune functioning26, cancer-stimulating cytokines, and 
psychiatric morbidity.25,27-29 These preliminary results suggest that examination of pro 
inflammatory cytokines associated with insomnia can shed light on etiology and treatment of 
insomnia.  
 
Telomeres are repeated regions of DNA at the ends of chromosomes that primarily serve to protect 
against loss of integral DNA sequence during DNA replication. However, the length of telomeres 
shorten with time and repeated cell replication, and studies have shown that telomere shortening often 
correlates with early mortality, lifetime depression exposure, psychological stress, oxidative stress, and 
increased risk for certain types of cancer. To date, the link between telomere shortening and sleep 
disruption or maintenance has not been fully explored. Because there is circumstantial evidence linking 
telomere shortening to Obstructive Sleep Apnea Syndrome, exploring the correlation between the length 
of telomere and sleep may uncover a novel way to both diagnose and treat sleep disruption in patients. 
Thus, measurement of telomere length can help explain presence of sleep disturbance. In 
addition, gene expression in relation to insomnia in cancer may be explored if additional funds or 
collaborations develop. 

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Preliminary Data 
 
Pathophysiology of sleep problems in cancer.  In our pathophysiologic study (Palesh et al.)43 in 
women with metastatic BC, sleep was assessed by means of questionnaires and wrist actigraphy.  
Vagal regulation was assessed via respiratory sinus arrhythmia (RSATF). Longer nocturnal wake 
episodes were significantly associated with a flatter diurnal cortisol slope. Sleep problems were 
also associated with diminished RSA. Higher RSA was significantly related to higher sleep 
efficiency and a correspondingly lower number of wake episodes and lower waking after sleep 
onset (WASO), and lower average length of nocturnal wake episodes. While demographics, 
disease severity, and psychological variables all explained some portion of the development of 
sleep problems, 4 of the 6 sleep parameters examined (sleep efficiency, WASO, mean number of 
waking episodes, average length of waking episode) were best explained by RSA. These data 
provide evidence for an association between disrupted nocturnal sleep and reduced RSA the 
following day. They suggest that the stress-buffering effects of sleep may be associated with 
improved parasympathetic tone and normalized circadian rhythmicity as evidenced by cortisol 
patterns during the day and greater RSA. 
 
Impact of BBT-I on Circadian Rhythms. 57,58  Salivary cortisol was measured pre and 1-month 
post BBT-I (5 x/day for 2 days) in 30 women. ANCOVA controlling for baseline waking rise 
cortisol (WRC) entered as a covariate and baseline WRC*Arm (BBT-I vs. education on sleep 
hygiene) yielded a significant interaction. Higher WRC is a sign of a healthy HPA reactivity, as 
having a higher WRC can lead to an increase in homeostatic drive for sleep. For BC patients 
participating in BBT-I, there was a significant difference between those with low and high 
baseline WRC scores at the 1-month follow-up (F (1, 23)=6.46, p=0.018, revised eta 0.47, a 
large effect). However, there were no significant differences for the patients who participated in 
the control group. These findings suggest that BBT-I influences circadian rhythms by improving 
WRC.  
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 Refer to the Participant Eligibility Checklist in Appendix A.  
 
3.1 
Inclusion Criteria 
 
3.1.1 Be female and have a diagnosis of BC (Stage I-III). 
 
3.1.2 Be scheduled for planned cancer treatment (e.g. chemotherapy or biologics such as 
herceptin). 
  
3.1.3 Have at least 6 weeks of cancer treatment (e.g. chemotherapy or biologics such as 
herceptin) remaining. 
 
3.1.4 Be at least 21 years of age. 
  
3.1.5 Be able to understand written and spoken English. 
 

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3.1.6 Report sleep disturbance of 8 or greater on the ISI, and report insomnia that began or got 
worse with diagnosis of cancer or treatment with chemotherapy (to exclude pre-existing, 
chronic insomnia). 
 
3.1.7 Have a Karnofsky score > 70 to ensure that patients are able to participate in intervention 
and assessments. 
 
3.2 
Exclusion Criteria 
 
 MUST NOT have a documented or self-reported, current diagnosis of any of the following 
conditions that would make it unsafe or impossible to adhere to the study protocol &/or 
endorse the last criterion 
 
3.2.1 /Unstable self-reported medical or psychiatric illness (Axis I – current or within the last 5 
years) that would make it unsafe or impossible to adhere to the study protocol 
 
 
 
3.2.3 Substance abuse or dependence or met criteria within past year 
 
Sleep apnea or restless leg syndrome (RLS) 
 
3.2.5 Are unable or unwilling to discontinue anxiolytics within 4 hours of education sessions 
 
 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure. 
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
3.4 
Randomization Procedures 
Participants will be randomized into one of two arms: BBT-I or HEAL. The study data manager 
will use a computerized random number generator to assign participants into arms. In order to 
keep study blinded from assessors, only the interventionist providing the intervention, the data 
manager, and the clinical intervention supervisor will know randomization.  
 
 
3.5 
Study Timeline 
Primary Completion: 
 
The study will reach primary completion 48 months from the time the study opens to accrual. 
 
Study Completion: 
 

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The study will reach study completion 60 months from the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
Breast Cancer Patients: We will recruit our participants from the Stanford Women’s Cancer 
Center utilizing clinician and support group referrals as we have done in our pilot study. The PI 
is the Director of Cancer Survivorship Research Program at Stanford Medical Center, and our 
team has an ongoing relationship with all of the breast medical oncologists at Stanford. Dr. 
Blayney is the Medical Director of Stanford University Cancer Center and Co-Investigator on 
the study. During the breast cancer disease management group meetings and tumor board, new 
cancer patients are discussed and evaluated by Dr. Blayney and the study’s personnel for 
eligibility for the study. The first step, as with all protocols in our lab, is to identify potentially 
eligible patients via our center’s electronic medical records system (EPIC). In the present study, 
at or around the time of the patient's first chemotherapy treatment, approval will be sought from 
the patient’s oncologist to invite patients who meet the preliminary eligibility criteria to 
participate in the study. We also have ongoing support from the Breast Cancer Connections’ 
(BCC) Advocacy Task Force. The BCC sees several hundred breast cancer patients and 
survivors annually and has agreed to continue referring new patients to this study.  
 
Procedures: During the consent process, all study subjects will be screened for eligibility by 
research staff at Stanford University. By signing the consent form, participants will grant 
permission to obtain their cognitive test data from another source (such as another research study 
or clinical testing) for this study if they do not complete the neuropsychological testing portion in 
this study. Participants will undergo four assessments (~one hour each) at baseline, post-
treatment (6 weeks), and 6-month (30 weeks), and 12-month (58 weeks) follow-ups.  During 
each of the assessments, participants will wear a heart rate monitoring device (Bodyguard 
Firstbeat®) that records heart rate variability for 10 minutes at each assessment point. Heart rate 
variability data will not be collected from a participant if she has an implanted device for heart 
failure (e.g., pacemaker, defibrillator, left ventricular assist device,  
etc.).Study participants will be asked to maintain a daily sleep diary for 7 days at baseline, post 
intervention, 6-month follow-up and 12-month follow-up. Patients will also be requested to wear 
an actigraph on their wrist (Actiwatch 64®, MiniMitter) for 7 days at baseline, post intervention, 
and follow-ups, and collect saliva for 2 days at each assessment point. Participants will collect 
saliva starting 2 days prior to their chemotherapy appointments to avoid interaction with 
corticosteroids. The RA responsible for assessment will make follow-up calls at each assessment 
point to each participant to promote compliance, prompt completion, and assess potential side 
effects of the behavioral interventions. In addition, participants will be asked to provide a small 
amount of blood (approximately 1-2 tablespoons) at each assessment. 
 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
The study permits patients to remain on medications prescribed as part of their treatment 
regimen. We are excluding patients on daily sleep medications for our clinical trial.  Our study 
procedures and intervention are supportive care only. They are an add-on to their clinical care for 
breast cancer. 
4.2 
Criteria for Removal from Study 
Patients can be removed from the study if they experience disease progression that requires 
extended hospitalization or experience symptoms that make participation in the study difficult or 
impossible (e g., development of psychosis, extreme pain, nausea). Participants are free to 

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withdraw at any time if the treating oncologist deems withdrawal necessary or if the patient 
decides to withdraw for any reason. All of our participants are receiving the behavioral 
interventions in addition to their usual care. 
4.3 
Alternatives 
The patient may elect not to participate as an alternative to this study. They will continue to 
receive their normal care. During informed consent, we will describe our behavioral 
interventions, study procedures and questionnaires. We will inform our participants about 
potential risks despite their being minimal. We anticipate that a small proportion of our 
participants might potentially experience mild discomfort implementing BBT-I procedures (They 
might experience daytime fatigue and/or sleepiness, and/or memory and concentration 
difficulties).  We will also inform them of the limits in confidentiality, because the intervention 
may take place in an open area in the ITA if absolutely necessary. We do not have an alternative 
treatment. 
 
5. 
INVESTIGATIONAL PROCEDURE INFORMATION 
5.1 
 Investigational Procedure   
BBT-I  Intervention Group: 90 BC patients will be randomized to receive the BBT-I. BBT-I 
includes both stimulus control and sleep scheduling, however it has been modified from CBT-I 
to make it more suitable for cancer patients undergoing chemotherapy with recently developed 
sleep problems. The main intervention component is one face-to-face 60-minute session with a 
trained staff member during which time an individually tailored “sleep prescription” is 
developed. There will also be four 15-minute phone calls and a second 60-minute face-to-face 
“booster” session. The second face-to-face session will ideally occur during the third or fourth 
week depending on the patient’s chemotherapy regimen.  
 
BBT-I is a novel intervention that applies innovative cancer-specific chronorehabilitation 
techniques to effectively treat acute insomnia among patients receiving chemotherapy in the 
infusion clinic.  It is comprised of the following four components:  1) chronorehabilitation 
education (e.g., information on the contribution of circadian disruption to insomnia in the 
context of cancer and cancer treatment, a review of the cancer-specific behavioral model of 
insomnia, and discussion regarding how insomnia and fatigue may co-occur and interact.); 2) 
light and stimulus control (e.g., decrease light exposure at night and increase light exposure 
during the day, do not go to bed until sleepy, and get out of bed if not sleeping); 3) 
encouragement of physical activity and discouragement of napping (e.g., increase exercise 
and limit naps to 2 per day and no longer than 45 minutes); and 4) sleep compression (e.g. 
increasing motivation to regulate sleep and wake cycles, and go to bed later by at least 15 
minutes if sleep efficiency is less than 85%). Patients are told that on their sick days (e.g., days 
post chemotherapy) they can nap and sleep as much as they need to. In our pilot, we found that 
patients successfully moderated their sleep prescription on the days when they were not feeling 
well.  
Healthy Eating Education Learning (HEAL) control group: 90 BC patients will be randomized to 
receive HEAL. HEAL will control for attention and provide a behavioral “placebo.” This control 
condition will consist of 2 face-to-face sessions and 4 phone calls. The content of the 
intervention is provided by the NCI: PDQ® Nutrition in Cancer Care. The topics will include 
nutritional implications of chemotherapy, nutrition screening and assessment, and nutritional 
suggestions for symptom management (e.g., nausea). To improve the credibility of HEAL 

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intervention for sleep; the therapists will discuss the connection between healthy eating and good 
sleep. We expect this to be an aspect of intervention that should bolster the credibility of the 
control condition as there are sound reasons to think that nutrition could have some effect on 
insomnia.  Nevertheless, we anticipate the effects of HEAL on insomnia would be weak given 
the evidence behind behaviors that influence sleep which are not targeted by HEAL. In addition, 
the healthy eating education control has successfully been used as an attention control group for 
sleep intervention during chemotherapy.52,59  
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
Intervention Description  
Women diagnosed with breast cancer receiving chemotherapy will be randomized to either Brief 
Behavioral Therapy for Insomnia (BBT-I) or Healthy Eating Education Learning (HEAL) 
control group. BBT-I is a novel intervention that combines chronorehabilitation and cognitive 
behavioral therapy for insomnia (CBT-I) techniques that are specifically adapted for women 
diagnosed with breast cancer who are undergoing treatment.  Patients randomized to BBT-I will 
receive 2 face-to-face sessions and 4 phone calls. The control group is patterned after the control 
group used in a large RCT 52,53. HEAL will control for the non-specific components of time, 
attention, and health education that are not specifically related to sleep management. The control 
treatment will involve 2 face-to-face sessions and 4 phone calls exactly like BBT-I. 
5.2 
Availability 
Personnel who are trained in the BBT-I and HEAL interventions and are supervised by a clinical 
psychologist will conduct the sessions with each participant. 
5.3 
Agent Ordering 
N/A; There is no drug utilized in this study. 
 
5.4 
Agent Accountability 
N/A; There is no drug utilized in this study. 
 
6. 
DOSE MODIFICATIONS 
Half of the participants will be randomized to BBT-I and the other half will be randomized to 
HEAL.  Both groups will receive 6 sessions.  There will be no modification in the number of 
sessions received. 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
BBT-I may result in temporary increases in daytime fatigue and/or sleepiness, and/or memory 
and concentration difficulties.  Blood drawing may cause pain and bruising at the site where the 
blood is taken, and sometimes, it causes people to feel light-headed or even to faint.  Rarely 
people might get an infection at the site of the needle stick. Heart rate monitor electrodes and the 
gel used to attach them may cause a skin reaction. 
 

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7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event 
(AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochure, and related to the investigation. All Serious Adverse 
Events (SAEs) will be tracked until resolution, or until 30 after the last dose of the study 
treatment.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 
Laboratory Correlative Studies 
8.1.1 
(Inflammation, Telomeres and Circadian Disruption and Sleep – Laboratory 
Correlative Study #1) 
 
8.1.1.1 
Blood collection will be done to estimate hematocrit, hemoglobin, and cytokines (and 
telomere length. Patients will collect saliva 5 times a day over a course of two days (when they 
first wake up, 30 minutes after waking, 12PM, 5PM and before bedtime).  Saliva will be stored 
in the patients’ refrigerator over the course of two days and then returned at assessment to be 
stored at the Department of Psychiatry. 
 
8.1.1.2 
Blood draws will be conducted at either Stanford Hospital Drop-In or CTRU labs. 
Ideally, the blood samples will be drawn first thing in the morning after patients have fasted 
since midnight. A minimum of 4 hours is required if the patient is unable to come for a blood 
draw the first thing in the morning. A one- hour resting period is required. However, if an 
afternoon fasting sample is the only time that a patient is available, then we will collect at that 
time point. Whether the collection time is in the morning or afternoon, the collection time will 
remain consistent within each subject once the baseline is collected. We will keep records of the 
patient’s last meal, length of resting period and time of blood draw. 
 
8.1.1.3 
Samples will be processed at Stanford Labs where they will be spun and aliquoted, if 
shipment to another site is warranted, the samples will be shipped de-identified via FedEx and 
following bloodbourne pathogen protocol for shipping.  All of the study staff arranging shipment 
will be certified and trained in handling of bloodbourne pathogens for shipment.  
 
8.1.1.4  
Blood analyses will be conducted at HIMC and saliva analyses will be conducted at 
Stanford Labs.  
 
8.1.1.5 Blood collection tubes and saliva salivettes will be bar coded with study number rather 
than PHI. Each Tube will be labeled with the following information: MOSAIC, Subject#, 

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Date&Time Collected.

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9. 
STUDY CALENDAR 
   
Baseline 
Post Intervention  
6 Month Follow-up 
12 Month Follow-up 
 
On Study Data (Demographic 
and clinical data) 
 
X 
 
 
 
 
 
 
 
Clinical Record Information 
(Clinical data) 
 
X 
 
 
 
 
 
 
Demographic 
Questionnaire/Medication 
 
X 
 
 
 
 
 
 
 
Insomnia Severity Index (ISI)  
 
X 
 
X 
 
X 
 
X 
 
Brief Fatigue Inventory (BFI)   
 
X 
 
X 
 
X 
 
X 
Hopkins Verbal Learning Test 
(HVLT) 
X 
X 
X 
X 
Clinical Assessment of 
Depression (CAD) 
X 
X 
X 
X 
Mobile Cognitive Assessment 
Battery (MCAB) 
X 
X 
X 
X 
 
Comprehensive Trail Making 
Test (CTMT) 
 
X 
 
X 
 
X 
 
X 
 
Controlled Oral Word 
Association Test (COWAT)  
 
X 
 
X 
 
X 
 
X 
 
Heart Rate Variability 
 
X 
 
X 
 
X 
 
X 
 
Blood Draw 
 
X 
 
X 
 
X 
 
X 
Actigraphy 
 
1 week  
 
1 week 
 
1 week 
 
1 week 
Saliva Collection 
 
X 
 
X 
 
X 
 
X 
 
Sleep Behavioral Self Rating 
Scale (SBSRS)  
 
X 
 
X 
 
X 
 
X 
 
Pittsburgh Sleep Quality 
inventory (PSQI) 
 
X 
 
X 
 
X 
 
X 
 
Dysfunctional Beliefs about 
Sleep (DBAS) 
 
X 
 
X 
 
X 
 
X 
 
Difficulties in Emotion 
Regulation Symptoms (DERS) 
 
X 
 
X 
 
X 
 
X 
 
European Organisation for 
Research and Treatment of 
Cancer (EORTC) Quality-of-
Life-Questionnaire-C30 
 
X 
 
X 
 
X 
 
X 
Godin Leisure Time  Exercise 
Questionnaire (GLTEQ) 
 
X 
 
X 
 
X 
 
X 
Reduced Horne Ostberg 
Morningness Eveningness 
Questionnaire (rMEQ) 
 
X 
 
X 
 
X 
 
X 
Nutrition Knowledge 
Questionnaire (NKQ) 
 
X 
 
X 
 
 
 
 
Sleep Diaries 
 
1 week 
 
1 week 
 
1 week 
 
1 week 
Daily Diaries 
 
1 week 
 
1 week 
 
1 week 
 
1 week 
BBT-I/HEAL Checklists 
 
6 times during intervention 
 
 
Feedback 
 
X 
 
X 
 
 
 
 

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10. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Primary Outcome Measure Insomnia. 
 Title: Insomnia Severity Index 
  Time Frame: Pre, post intervention and at 6 and 12 months follow-ups. 
 Safety Issue: No 
 
Note: Each outcome measure listed within the protocol will necessitate legally required 
results reporting to clinicaltrials.gov within one year after the completion of the primary 
outcome measure.   
 
10.1  Primary and Secondary Outcome measures 
Primary Outcome Measure of Insomnia. The effects of the BBT-I intervention on insomnia 
will be measured by the Insomnia Severity Index (ISI), which is a well-validated self-report 
measure of sleep.60-62 The primary outcome will be the change from baseline to 6-month follow-
up.  A change score of -6 is considered a minimally clinically significant difference for the ISI.60-
62 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.60-62 The ISI is the 
primary outcome measure for the study.   
 
Secondary Outcome: Fatigue will be assessed with the revised Brief Fatigue Inventory (BFI), a 
9-item, patient-report instrument that we have used in previous studies with established 
reliability and validity.63 The BFI allows for rapid assessment of fatigue level in BC patients and 
identifies those with severe fatigue.  
 
Secondary Outcome: Cognitive Difficulties will be assessed using a cognitive battery of self-
rating questionnaires including the Clinical Assessment of Depression (CAD), as well as the 
Self-Rating subtest of the Mobile Cognitive Assessment Battery (MCAB). CAD has been shown 
to discriminate between chemotherapy-treated BC patients and controls and also correlate 
significantly with neurobiologic and immunologic deficits in BC. 64-66 We will additionally 
administer a battery of neuropsychological assessments, including the Comprehensive Trail 
Making Test (CTMT), Hopkins Verbal Learning Test Revised (HVLT-R), Controlled Oral Word 
Association Test (COWAT), and the Mobile Cognitive Assessment Battery. The CTMT is an 
objective, standardized neuropsychological measure of executive function (switching/inhibition), 
attention, sequencing and processing speed.67 The International Cognition and Cancer Task 
Force recommends the CTMT for harmonizing studies of cognitive function in cancer 
populations.68 The CTMT requires 5 to 12 minutes to administer and is normed for individuals 
aged 8 to 74 years. It has a reliability coefficient of 0.90 or higher for all ages. 69-71 The COWAT 
is a verbal fluency task that assesses complex cognition. This test has been used in previous 
studies with breast cancer patients and has shown strong differences between cancer patients and 
controls.72 The COWAT takes 4-5 minutes to administer. The HVLT-R is a list memory exercise 
that measures verbal learning and memory, as well as delayed recall. The test requires a total 
time of ten minutes with a 20-25 minute period between delayed recall and recognition. HVLT-R 
has been used in many clinical populations, including breast cancer.73,74 The MCAB was 
specifically designed to be more sensitive at capturing cognitive impairments in the clinical 

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setting. The MCAB is comprised of three neuropsychological tests (in addition to a self-report 
measure) measuring cognitive flexibility, accuracy, processing speed, working memory and 
multitasking.  The battery has been shown to be clinically significant in breast cancer 
populations and shows increased sensitivity compared to traditional tests.75 This battery is 
delivered through the MCAB iPad application and takes approximately 15 minutes to complete. 
 
Physiological Mediators Heart Rate Variability (HRV) will be calculated with the ambulatory 
monitoring heart-rate device Firstbeat® that measures RR intervals with a rating sample of 1ms.  
The device utilizes a valid and reliable method for sampling RR intervals and provides software 
to analyze the raw data.76-78 We will calculate time and frequency domain measures of HRV: 
SDNN, (the standard deviation of all normal RR intervals measured between consecutive sinus 
beats) and RMSSD (the root mean square of successive differences between adjacent normal R-
R intervals).76,79 In addition, we will measure frequency domain measures, natural log of high 
frequency (HF, total spectrum power of all NN intervals between 0.15 to 0.4Hz) for vagal 
tone/RSA and natural log of low frequency (LF, total spectrum power of all NN intervals 
between 0.04 to 0.15Hz) and LF/HF ratio. Given our preliminary data in BC patients, we will use 
RSA as a primary HRV outcome. Heart rate variability data will not be collected from a 
participant if she has an implanted device for heart failure (e.g., pacemaker, defibrillator, left 
ventricular assist device, etc.).  
 
Circadian Rhythm will be assessed using actigraphy and salivary cortisol at each of the 4 
assessment points (sleep diaries are used for cross-checking the going to sleep and waking up 
times). 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 
survivors80 better than a single-oscillator model. Mesor (overall), Amplitude, and Acrophase for 
the 12- and 24-hour cycles will be calculated. In addition, we will collect salivary cortisol per 
modified McArthur protocol81 for 2 days at wake, wake +30, 12PM, 5PM and before bedtime 
(baseline, 6-, 30-, and 58-weeks). Saliva samples will be refrigerated after collection and stored 
at -70 °C within a couple of days of collection. Samples will be assayed using a luminescence 
immunoassay (Immuno-Biological Laboratories Inc, Germany) at Stanford Labs.  
 
Reduced Horne Ostberg Morning Evening Questionnaire (rMEQ) will determine the chronotype 
of the participant to help assess activity of various physical functions. This questionnaire is a 
shortened version of the Horne-Ostberg Morning Eveningness Questionnaire.82 It is a seven-item 
questionnaire that asks various questions of daily choices regarding sleep and other activities.   
 
Behavioral Mediators and Moderators  Maladaptive sleep behaviors will be assessed with the 
Sleep Behavioral Self- Rating Scale (SBSRS),83 the Pittsburgh Sleep Quality Inventory (PSQI)84 
sleep diaries and actigraphy. The SBSRS is a validated measure that helps understand patient’s 
adherence to stimulus control. Sleep continuity will be assessed subjectively using Daily 
Sleep/Wake Diaries and via PSQI. These sleep continuity measures will be used in the 
meditational analyses and will provide important supplemental data on frequency, severity, and 
type of sleep problems encountered by patients, as well as contributing factors. 
 
Participants will also have their sleep-wake exposure monitored through the use of a wrist-worn 
actigraphy-based data logger (Actiwatch-64, MiniMitter, Bend OR). We will set the Actiwatch 
to record activity counts every 1 minute; at this setting it can record up to 45 days worth of data 
before the internal memory is full. Actigraphy data will be analyzed using Actiware® software 
(v.5.04.003, MiniMitter, Bend OR). The program uses a validated sleep algorithm to provide an 

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assessment of sleep by delineating the “in bed” and “out of bed” 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 and provide information on maladaptive sleep behaviors (i.e., 
increased time in bed, bedtime and rise time variability).85 While daily sleep diaries are a method 
commonly 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-ups to the 
daily diaries. This measurement strategy allows for an assessment of sleep problems (WASO), 
that 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, and allows 
for the continuous assessment of sleep and wakefulness for periods of up to 30 days. 
 
The dysfunctional beliefs about sleep will be measured utilizing the Dysfunctional Beliefs and 
Attitudes about Sleep Scale,86 a self-report measure that was designed to examine changes in 
erroneous sleep beliefs and attitudes. Potential moderators will be assessed using age, baseline 
anxiety and depression (Clinical Assessment of Depression), hot flashes (daily diary), caregiver 
status (questionnaire), as well as emotional regulation (Difficulties in Emotion Regulation 
Symptoms). The Nutrition Knowledge Questionnaire (NKQ) will also be used to control for 
attention.  
 
The Difficulties in Emotion Regulation Scale (DERS) 87will be used to determine emotion 
regulation. The DERS is a brief, 36-item, self-report questionnaire devised to assess several 
aspects of emotion dysregulation. The measure yields a total score as well as scores on six scales 
produced through factor analysis: Nonacceptance of emotional responses 
(NONACCEPTANCE), difficulties engaging in goal directed behavior (GOALS), impulse 
control difficulties (IMPULSE), lack of emotional awareness (AWARENESS), limited access to 
emotion regulation strategies (STRATEGIES), and lack of emotional clarity (CLARITY).  This 
measure has been found to have high internal consistency, good test–retest reliability, and 
adequate construct and predictive validity. 
 
Other variables. We will extract the following medical variables from the patients’ medical 
records: disease stage, chemotherapy type (e.g., doxorubicin), prior treatment (e.g., surgery), and 
receptor status. We will record the treatment that the patient is on during each assessment point 
to account for differences that might be associated with their particular treatment regimen. We 
will also determine exercise and physical activity through the Godin Leisure Time Exercise 
Questionnaire (GLTEQ). The GLTEQ is a 4-item test that asks the frequency of strenuous, 
moderate and mild exercise. It has been validated to examine changes of behavior in activity. 88 
The NKQ will be given to enhance the validity of the control intervention. It is a 15-item 
questionnaire that measures competency of nutrition. 
 
Expectancy/Feedback will be obtained by 2 checklists assessing the usefulness and acceptability 
of the experimental interventions and intervention outcome expectancy. Participants will 
complete the expectancy checklist at the end of their first face-to face session and feedback 
questionnaire at post-intervention to assess whether they found our interventions helpful for their 
symptoms. For these baseline variables that are not considered as potential moderators, given our 
strong design based on random assignment to treatment and control groups, it is reasonable to 
assume that they will be balanced between the intervention and control groups (i.e., no need to 
worry about controlling for them). Nonetheless, we will test sensitivity of our results to 
presence/absence of these potential baseline covariates, especially those that differ between 
groups due to natural experimental error. 

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10.1.1 Relevant Subset 
 
N/A 
  
10.1.2 Measurement Definition 
 
The measurement is self-report of changes in symptomatology. 
 
10.1.3 Measurement Methods 
 
The measures are self-report (questionnaires), objective (actigraphy, saliva, heart rate monitor, 
blood sample).  
 
10.1.4 Measurement Time Points 
Baseline, 6 weeks, 6 months and 12 months.  
 
10.1.5 Response Review 
N/A 
10.2  Secondary Outcome 
Described in section 10.1. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
11.3 
Data Management Plan 
The Protocol Director, or her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 

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Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms 
will be developed using the Qualtrics and SPSS database system and will be maintained by the 
data manager. CRFs will be kept in a locked office, only accessible to the research team. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Statistical Design 
This is a 2 arm randomized control clinical trial phase III. 
 
12.1.1 Randomization 
After consent has been obtained, patients will be randomized 1:1 by a computerized random 
number generator to one of two arms: BBT-I or HEAL. In order to ensure blinding of assessors, 
only the data manager, intervener delivering intervention and clinical intervention supervisor will 
know the randomization assignment. All other study staff will be blinded.  
 
 12.2 Interim analyses 
There are no interim analyses planned. 
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
As hypothesized mediators, we will carefully examine behavioral (measured by DBAS, SBSRS 
and sleep diaries) and physiological mechanisms (measured by HRV, salivary cortisol and 
actigraphy). Examination of moderators will be exploratory. As potential moderators, we will 
examine age, baseline anxiety and depression, baseline hot flashes and baseline emotion 
regulation. Among these potential moderators, some will not be qualified as moderators but 
predict outcome regardless of the intervention assignment status (we will classify these as non-
specific predictors of the outcome). For the moderator/mediator investigation, we will apply the 
McArthur framework. Our analysis strategy in detecting moderators and mediators is mixed 
effects modeling, where the McArthur approach will be embedded. We will also look at 
cognitive data to analyze whether interventions change cognitive domain. 
 
12.4 
Primary Analysis  
Aim 1 (Primary): To evaluate the efficacy of the BBT-I in treating insomnia among breast cancer patients 
receiving chemotherapy. 
 
Hypothesis 1 (Primary): BBT-I compared to an attention control group, will be associated with greater 
reduction of insomnia symptoms (as measured by the Insomnia Severity Inventory) from baseline to the 
12 month follow up.  
 
12.4.1 Analysis Population 
Include treatment of missing data and handling of non-adherence to protocol described in 12.4.2 
and 12.5.1. 
 
12.4.2. Analysis Plan 
For our primary Hypothesis 1, we will examine whether the BBT-I group will show more 
improvement, compared to the attention control group for insomnia symptoms measured by ISI 
from baseline to the 12-month follow-up. The group comparison will be made in line with the 

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intention to treat principle. We will analyze the data using mixed effects (growth curve) 
modeling89,90 fully utilizing outcome data repeatedly measured four times for most participants 
(baseline, 6, 30, and 58 week). For estimation of mixed effect models, maximum likelihood 
(ML) estimation will be used. For ML estimation of these models, the Mplus program version 
7.11 or above will be used.91 Data points that are missing due to subject attrition will be handled 
assuming that data are missing at random92 conditional on observed information, which is less 
restrictive than missing completely at random92 assumed in fixed effects analyses such as 
ANCOVA and regression analysis. In this procedure, all available cases including the ones with 
missing information will be included in the analyses. By including every subject who completed 
at least one assessment, we are not only more likely to conserve power, but also less likely to 
produce biased effect estimates. Given the sample and baseline covariates we will be collecting, 
we believe mixed effects modeling using ML is a reasonable approach. Nonetheless, we will 
conduct additional analyses at least for key hypotheses as a form of sensitivity analysis. For this 
purpose, we will apply the multiple imputation approach93 utilizing various auxiliary variables in 
the data. We will conduct additional analyses allowing for some deviation from MAR, for 
example assuming MAR conditional on intervention adherence status.94-97 
 
In our mixed effects analyses, the change in the outcome will be modeled as the key dependent 
variable predicted by the treatment status. The results of these longitudinal analyses can be easily 
converted to treatment effect at each assessment point to directly respond to our specific 
hypotheses. In particular, we are interested in the main effect of treatment (BBT-I vs. Control) at 
12-month follow-up (58 week) assessment. The same analysis strategy will be employed for 
Hypothesis 2, where we will examine the treatment effects on secondary outcomes such as 
fatigue (measured by BFI) and cognitive difficulties (measured by Cognitive Battery). In 
Hypothesis 3, we will examine the mediators of treatment effects on insomnia, fatigue, and 
cognitive difficulties.  
12.5 
Secondary Analysis 
Aim 2 (Secondary): To evaluate efficacy of the BBT-I in treating cancer-related symptoms such 
as cancer-related fatigue and cognitive difficulties in breast cancer patients receiving 
chemotherapy. 
 
Hypothesis 2 (Secondary): BBT-I compared to an attention control group will be associated with 
greater improvements in fatigue and cognitive difficulties (as measured by the Brief Fatigue 
Inventory, and our Cognitive Battery that includes neuropsychological testing) from baseline 
through the 12 month follow up.  
 
Aim 3 (Secondary): To examine potential moderators and mediators of BBT-I intervention effects 
on insomnia, cognitive difficulties, and fatigue. In particular, we are interested in age, depression 
and anxiety, emotion regulation and side effects (hot flashes) as potential moderators of the 
intervention effects as well as evaluating modifiable behavioral and physiological mechanisms as 
hypothesized mediators. 
 
Hypothesis 3 (Secondary): In women with breast cancer receiving chemotherapy, intervention 
effects on insomnia, fatigue, and cognitive difficulties will be mediated by select behavioral 
mechanisms [i.e., maladaptive sleep behaviors (The Sleep Behavior Self-Rating Scale, sleep 
diaries, actigraphy), dysfunctional beliefs and attitudes (Dysfunctional Beliefs and Attitudes 
about Sleep) and physiological mechanisms [i.e., dysregulated circadian rhythms (measured by 
salivary cortisol), disrupted sleep wake cycles (actigraphy), and autonomic tone (RSA)]. 

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As hypothesized mediators, we will carefully examine behavioral (measured by DBAS, SBSRS 
and sleep diaries) and physiological mechanisms (measured by HRV, salivary cortisol and 
actigraphy). Examination of moderators will be exploratory. As potential moderators, we will 
examine age, baseline anxiety and depression, baseline emotion regulation and baseline hot 
flashes. Among these potential moderators, some will not be qualified as moderators but predict 
outcome regardless of the intervention assignment status (we will classify these as non-specific 
predictors of the outcome). For the moderator/mediator investigation, we will apply the 
McArthur framework.98,99 Our analysis strategy in detecting moderators and mediators is mixed 
effects modeling, where the McArthur approach will be embedded. 
 
12.5.1 Analysis Population 
All patients contributing both baseline measurement and 12-month follow up will define the 
efficacy population. 
 
Missing data 
In our primary analytical strategy, we proposed to employ the statistical analysis method widely 
known as the mixed effects modeling approach using the maximum likelihood (ML) estimation. 
The use of mixed effects modeling is critical in implementing the intention-to-treat principle and 
therefore maintaining the validity of our inferences in the presence of missing data. Data points 
that are missing due to attrition and nonresponse will be handled assuming that data are missing 
at random (MAR100), conditional on observed information. We would like to emphasize that our 
method is less restrictive and therefore less likely to result in bias and misleading conclusions 
than alternative procedures utilizing missing completely at random (MCAR100), assumed in fixed 
effects analyses such as ANOVA and regression analysis. In analyses utilizing MCAR, cases 
with missing information are simply excluded from the computations. By including every 
participant who completes at least one assessment in the analysis utilizing MAR, we are not only 
more likely to conserve power, but also less likely to produce biased effect estimates. Given the 
sizable sample and baseline covariates assessed, we believe mixed effects modeling using ML is 
a reasonable approach. Nonetheless, we are aware that the assumption of missing at random 
conditional on observed information can be somewhat violated in practice (because we cannot 
possibly collect every variable related to the missing data). To address this concern, we will 
conduct additional analyses at least for the key hypotheses (1 & 2) as a form of sensitivity 
analysis. For this purpose, we will apply the multiple imputation approach101 utilizing various 
auxiliary variables in the data. Additionally, we will conduct sensitivity analysis allowing for 
some deviation from MAR, for example assuming MAR conditional on intervention adherence 
status.97,102-104 
 
We recognize that the best way to handle missing data is to minimize the missing data during the 
study. To minimize missing data, our questionnaires will be collected electronically utilizing 
Qualtrics and having participants complete these assessments on either iPads or study computers, 
a strategy that we have now successfully piloted in our randomized clinical trial of bone marrow 
recipients, resulting in minimal missing data. If warranted, we will add another site to recruit 
additional patients. However, in our pilot study, attrition was about 8%, and missing data in the 
completers were very low (0 to 7%) for the key variables.  
12.5.2 Analysis Plan 
The group comparison will be made in line with the intention to treat principle. We will analyze 
the data using mixed effects (growth curve) modeling89,90 fully utilizing outcome data repeatedly 

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measured four times for most participants (baseline, 6, 30, and 58 week). For estimation of 
mixed effect models, maximum likelihood (ML) estimation will be used. For ML estimation of 
these models, the Mplus program version 7.11 or above will be used.91 
 
12.6  Sample Size 
12.6.1 Accrual estimates 
Stanford Cancer Center sees approximately 500 new breast cancer patients per year and about 
341 patients (Range 318-376) are currently undergoing chemotherapy per STRIDE database. In 
our pilot, we were able to recruit a new participant every week.  Thus, we anticipate that we 
would be able to meet our recruitment goal within 4 years even after accounting for attrition. 
 
To minimize attrition, we will schedule participants for assessments during their clinic days. We 
budgeted funds for participants’ travel, parking, and refreshments to improve retention. We will 
maintain close contact with participants with letters and projects updates, call or email (based on 
their preference) to remind participants to follow the study procedures. We also will send 
birthday cards and provide recruitment updates on our website to keep participants interested 
throughout the duration of the study. The proposed study involves a lower participant burden 
than our pilot that required more follow-ups, longer actigraphy and saliva collection and more 
measures. We found that we were able to minimize attrition in our current pilot with the above 
mentioned strategies. We will work closely with the Breast Cancer Connections advocacy group 
as we have done in the past, to provide training to our staff to ensure supportive and rewarding 
experiences for our participants. We will monitor our accrual closely and based on our current 
experience, we anticipate being able to recruit our participant sample. However, if we are unable 
to meet our recruitment target during the first year, we will expand our recruitment area to other 
local oncology clinics. 
 
12.6.2 Sample size justification 
For the primary Hypothesis 1 (BBT-I will show greater reduction of insomnia symptoms 
measured by ISI from baseline to the 12-month follow-up compared to the control), we estimated 
power in the proposed mixed effects modeling framework fully accounting for the longitudinal 
study design and projected attrition rate. The primary outcomes, ISI, will be measured at 
baseline, 6 weeks (end of treatment), 30 weeks, and 58 weeks (primary end point).  For our 
power estimation, we used ML based mixed effects modeling assuming a linear trend. We 
assumed that at least 60% of variance is explained by the growth model for the primary outcome 
(i.e., reliability of 0.6), given that previous studies reported reliability ranging from 0.65-
0.83.105,106 For attrition, we assumed gradually increasing attrition over time, resulting in 25% 
attrition by the 6-month follow-up assessment. We assumed a medium effect size, Cohen’s d of 
0.4 to 0.6, based on a previous study.107 We also consider this range of effect size as the lower 
bound of a clinically meaningful treatment effect. Under this scenario, the estimated power to 
detect the group difference in change in ISI is 0.88-0.99 (d=0.4 to 0.6, alpha=.05, two-tailed) 
with N=180 (90 BBT-I, 90 control). We estimated power for the secondary Hypothesis 2 (BBT-I 
compared to the control will show greater improvements in fatigue and cognitive difficulties) 
using the same mixed effects modeling strategy. We assumed a moderate effect size of d = 0.35 
to 0.4, based on a previous study. 108,109 We do not adjust for testing of multiple outcomes given 
that fatigue and cognitive difficulties are secondary outcomes. Under this scenario with reported 
reliability of 0.67 and higher, 108,109 the estimated power to detect the group difference in change 
in BFI is 0.84-0.91 (d=0.35 to 0.4, alpha=.05, 2-tailed). For the mediator Hypothesis 3, we 
estimated power focusing on the main effect of the mediator on the outcome.98,99 We assumed a 

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moderate correlation between the hypothesized mediators and the outcome (r=0.2 to 0.3). We do 
not adjust for testing of multiple mediators given our concerns in failing to detect possible 
mediators due to insufficient power (note that our trial is powered based on our primary 
hypothesis). Under this scenario, the estimated power to detect the mediation effect is 0.76-0.99 
(r=0.2 to 0.3, alpha=.05, two-tailed). For all hypotheses, we will carefully monitor both statistical 
(i.e., p-value) and clinical (i.e., effect size) significance, with more emphasis on clinical 
significance in the secondary hypotheses. 
 
12.6.3 Effect size justification 
See above. 
 
12.7 
Criteria for future studies 
This study is fully powered to determine efficacy of BBT-I versus attention and time-controlled 
group.  Changes on the ISI measure of 6 points constitute clinically meaningful results. If this 
trial replicates our pilot findings, future studies will focus on dissemination of this intervention 
via multicenter clinical trials. 

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13. 
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37 
Behavioral Intervention for Insomnia in Cancer 
Protocol Version #4.0 
 
 
 
 
December 14, 2015 
 
APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
 
Protocol Title: 
Brief Behavioral Intervention For Insomnia During 
Chemotherapy 
Protocol Number: 
 
Principal Investigator: 
Palesh, Oxana 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Be female and have a diagnosis of breast 
cancer (Stage I-III) 
 
 
      
2. Be scheduled for planned cancer treatment 
(e.g. chemotherapy or biologics such as 
herceptin) 
 
 
      
3. Have at least 6 weeks of cancer treatment 
(e.g. chemotherapy or biologics such as 
herceptin) remaining 
 
 
      
4. Be at least 21 years of age 
 
 
      
5. Be able to understand written and spoken 
English 
 
 
      
6. Report sleep disturbance of 8 or greater on 
the ISI, and report insomnia that began or 
got worse with diagnosis of cancer or 
treatment with chemotherapy (to exclude 
pre-existing, chronic insomnia) 
 
 
      
7. Have a Karnofsky score ≥ 70 to ensure that 
patients are able to participate in 
intervention and assessments 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Have an unstable self-reported medical or 
psychiatric illness (Axis I – current or 
within the last 5 years) that would make it 
unsafe or impossible to adhere to the study 
protocol 
 
 
      
2. Be currently pregnant or nursing 
 
 
      
3. Meet current or within 1 year criteria for 
current alcohol abuse or dependence 
 
 
      

38 
Behavioral Intervention for Insomnia in Cancer 
Protocol Version #4.0 
 
 
 
 
December 14, 2015 
4. Have a self-reported history of sleep apnea 
or restless leg syndrome (RLS) 
 
 
      
5. Are unable or unwilling to discontinue 
anxiolytics within 4 hours of education 
sessions 
 
 
      
6. Have irregular heartbeats or arrhythmia 
(self-reported or in the medical record) 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
Study Coordinator Signature: 
Date: 
Printed Name: