Testing mHealth Delivery of Cognitive Behavioral Therapy for Insomnia to Breast Cancer Survivors
Phase: NA
Conditions: Breast Cancer Survivor, Insomnia
Sponsor: Medstar Health Research Institute

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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INSTRUCTIONS: 
 
PROTOCOL TITLE: 
Testing mHealth Delivery of Cognitive Behavioral Therapy for Insomnia to Breast 
Cancer Survivors 
PRINCIPAL INVESTIGATOR: 
Hannah Arem 
Healthcare Delivery Research 
202-893-2430 
Hannah.Arem@medstar.net 
 
VERSION NUMBER/DATE: 
Version 3.0 February 2, 2022 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent 
Change? 
 
10/7/2022 
CBOs will receive a $50 incentive for each 
individual who enrolls and cites the CBO as 
the referral source   
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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Table of Contents 
1.0 
Study Summary ...................................................................................................... 3 
2.0 
Objectives* ............................................................................................................. 5 
3.0 
Background* ........................................................................................................... 5 
4.0 
Study Endpoints* .................................................................................................... 8 
5.0 
Study Intervention/Investigational Agent ................................................................ 9 
6.0 
Procedures Involved* ........................................................................................... 10 
7.0 
Data and Specimen Banking* .............................................................................. 11 
8.0 
Sharing of Results with Subjects* ........................................................................ 12 
9.0 
Study Timelines* .................................................................................................. 13 
10.0 Inclusion and Exclusion Criteria* .......................................................................... 13 
11.0 Vulnerable Populations* ....................................................................................... 14 
12.0 Local Number of Subjects .................................................................................... 14 
13.0 Recruitment Methods ........................................................................................... 14 
14.0 Withdrawal of Subjects* ....................................................................................... 15 
15.0 Risks to Subjects* ................................................................................................ 17 
16.0 Potential Benefits to Subjects* ............................................................................. 18 
17.0 Data Management* and Confidentiality ................................................................ 18 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* ....................... 21 
19.0 Provisions to Protect the Privacy Interests of Subjects ........................................ 24 
20.0 Compensation for Research-Related Injury ......................................................... 25 
21.0 Economic Burden to Subjects .............................................................................. 25 
22.0 Consent Process .................................................................................................. 25 
23.0 Process to Document Consent in Writing ............................................................. 27 
24.0 Setting .................................................................................................................. 28 
25.0 Resources Available ............................................................................................. 28 
26.0 Multi-Site Research* ............................................................................................. 29 
 
 
 
GHUCCTS Questions  
 
GHUCCTS is the Georgetown-Howard Universities Center for Clinical and Translational 
Science. 
 
Is this study a GHUCCTS Study?   ____Yes 
__X__No 
 
Is the project being sponsored or funded by GHUCCTS?  ____Yes 
__X__No 
 
Does the project utilize GHUCCTS services or facilities?  ____Yes 
_X___No 
(e.g., is the study conducted on the Clinical Research Unit (CRU), is the study supported 
by a GHUCCTS biostatistician, etc.) 
 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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1.0 STUDY SUMMARY 
 
Study Title 
Testing mHealth Delivery of Cognitive Behavioral Therapy 
for Insomnia to Breast Cancer Survivors 
Study Design 
Randomized controlled trial 
Primary Objective 
To determine whether the smart speaker group will have 
significantly greater reductions in insomnia severity compared 
to the website-based group as recorded by the Insomnia 
Severity Index (ISI). 
Secondary 
Objective(s) 
Secondary Objective: To measure differences between 
intervention and control arms for and CSD metrics 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
In the intervention arm participants will receive an Amazon Dot 
device with a pre-loaded Sleep Helper program, using an 
account created by Media Rez (study prime) so Amazon does 
not have access to participant names (for patient privacy 
purposes). Participants will be asked to engage with the 
program daily, either using the voice-activated speakers or an 
accompanying smart-phone app. The study duration is six-
weeks and is completed individually using fully automated 
interaction to deliver components of cognitive behavioral 
therapy for insomnia.  
IND/IDE #  
N/A 
Study Population 
We will recruit female breast cancer survivors over age 18. 
Women must have been diagnosed with stage I-III breast 
cancer or stage IV with high functioning (Eastern Cooperative 
Oncology Group status 0-1). Curative treatment (not adjuvant) 
must have been completed >3 months prior to enrollment.  
Sample Size 
n=76 breast cancer survivors 
Study Duration for 
individual 
participants 
Individuals will fill out sleep and medical history forms at 
baseline and will be randomized to a six-week protocol. 
Study Specific 
Abbreviations/ 
Definitions  
ACP 
American College of Physicians 
AE 
Adverse Event 
AI 
Artificial Intelligence 
ANCOVA 
Analysis of Covariance 
AWS 
Amazon Web Services  
BCS 
Breast Cancer Survivors 
CBT-I 
Cognitive Behavioral Therapy for 
Insomnia 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting 
Trials 
CRF 
Case Report Form 
CSD 
Consensus Sleep Diary 
DCC 
Data Coordinating Center 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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DHHS 
Department of Health and Human 
Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and 
Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Council on 
Harmonisation  
ICMJE 
International Committee of Medical 
Journal Editors 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
MOP 
Manual of Procedures 
NCCN 
National Comprehensive Cancer 
Network 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research 
Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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2.0 
Objectives* 
 
 
Specific Aim 
To determine the impact of the voice-activated smart speaker Cognitive 
Behavioral Therapy for Insomnia (CBT-I) components on insomnia symptoms among 
breast cancer survivors. We will conduct a randomized controlled trial of n=76 breast 
cancer survivors to test the impact of a six-week in-home utilization of the CBT-I smart 
speaker program compared to static internet-based educational content on insomnia.  
 
Objectives 
 
2.2  
We hypothesize that our program will reduce insomnia measured by the 
insomnia severity index (ISI) to sub-clinical threshold levels overall (intent to treat 
analysis). We also will test whether those with higher adherence report greater 
improvement in insomnia symptoms. 
 
3.0 
Background* 
Breast cancer survivors (BCS) numbered 3.6 million in the United States as of 
2016; a number that is growing thanks to advances in early detection and treatment. 
However, long-term side effects such as persistent insomnia are experienced by ~30-
50% of BCS and can have detrimental impacts on cardiometabolic and immune system 
health, neurobehavioral function, depression, fatigue, and quality of life, each of which in 
turn affect mortality. The National Comprehensive Cancer Network and the American 
College of Physicians recommend cognitive behavioral therapy for insomnia (CBT-I) as 
the first-line therapy for cancer survivors experiencing persistent sleep disruption. CBT-I 
targets physiologic, cognitive, behavioral, environmental, and social factors to improve 
sleep. CBT-I is a structured, systematic program which delivers better and safer 
outcomes than prescription sleep medications. However, identifying trained providers for 
CBT-I is challenging. Web-based therapy has shown efficacy, but published studies 
report dropout rates of up to 40%, which may be even higher in the real world. We 
propose developing and testing delivery of CBT-I treatment components using an in-
home, voice activated smart speaker device. Our Phase I “Sleep Helper” prototype 
delivers important components of CBT-I interactively using a smartphone app and two 
paired smart speakers. As the system learns each user’s sources of insomnia, daily 
habits, and sleep schedule. it offers recommendations for changing sleep patterns based 
on CBT-I principles (going to bed an hour earlier, drinking less caffeine, leaving the 
OBJECTIVES 
Primary 
To determine the impact of the voice-activated smart speaker CBT-I components on insomnia 
symptoms among breast cancer survivors using a randomized clinical trial. 
Secondary 
To determine differences in specific CSD metrics by intervention arm. 
Tertiary/Exploratory  
To determine whether there are differences in ISI change by frequency of engagement or 
satisfaction with the intervention. 

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Insomnia to Breast Cancer Survivors 
 
 
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bedroom when you can’t sleep, using a nighttime relaxation script, etc.). The system 
then monitors user progress for signs of improvement, building on what works and 
changing recommendations that are not working according to both subjective participant 
feedback and collected sleep data. Sleep Helper uses the core principles of CBTI to 
dynamically adapt each individual’s treatment regimen, much like a sleep therapist 
would, and records it in a backend database for participant monitoring. The goal of this 
study is to develop a scalable, voice-activated smart speaker program to treat insomnia 
symptoms among BCS. Our long term-goal is to address insomnia among BCS and then 
adapt it for other high-risk populations. 
 
Cognitive behavioral therapy was developed by Aaron Beck, MD in the 1970s with the 
goal of modifying depressed and anxious patient’s negative thoughts and behavior 
patterns with sustainable improvements in mood, social and workplace functioning 
{Beck, 1970 #44}. Based on CBT principles, CBT-I was developed to address a complex 
set of symptoms, cognitions and behaviors that are specific to insomnia (Figure 1) 
{Yang, 2006 #52}. Therapists used validated tools to assess the contribution of 
psychophysiological and environmental factors that predispose a patient to insomnia, 
and used these to address specific symptoms including events that precipitate sleep 
disruption and negative attitudes about sleep that perpetuate insomnia, referred to as 
the “3 Ps” {Glovinsky, 2008 #47}. While CBT-I shares cognitive and stimulus control 
intervention strategies with CBT, the additional specialized components of CBT-I 
intervention include, sleep restriction, sleep education, hygiene training, and relaxation 
therapies.  
 
Overview of CBT-I content, participant-directed enhancements, and Sleep Helper 
integration: In Phase I we built prototypes for core CBT-I techniques, tailored to BCS 
preferences as expressed during the focus groups. These techniques have been shown 
to be efficacious in improving sleep outcomes in a meta-analysis of internet delivered 
CBT-I {Zachariae, 2016 #135}, and will be developed to as closely as possible mimic 
therapist-delivered CBT-I.  
 
1) Psychoeducation and cognitive restructuring.  Cognitive behavioral therapy helps to 
shift common insomnia misconceptions and perceived poor sleep quality. For instance, 
participants learn that nighttime wakening is normal, and are coached to notice negative 
thoughts and replace them with positively framed messages. Phase I focus groups 
suggested that BCS appreciated educational content (e.g. circadian contribution and to 
sleep regulation and timing) and that they want short, targeted information as generally 
delivered during in-person CBT-I, with a “tell me more” prompt available if more 
information is desired. Phase I participants also expressed an interest in short quizzes 
after each section in order to enhance engagement. However, we will include options to 
turn off quizzes to meet individual preferences.  
 
2) Sleep hygiene. Practical and general information about optimal sleep health, sleep 
hygiene and sleep/wake regulation are key CBT-I techniques to facilitate behavior 
change and set sleep health priorities. Phase I focus groups suggested that users were 
willing to receive sleep hygiene prompts from the Alexa program. Types of sleep hygiene 
recommendations that participants found acceptable and helpful included sleep 
schedule modifications, eliminating daytime napping, modified use of caffeine, nicotine, 
and alcohol, optimizing exercise and the bedroom environment, and curtailment of 
screen time use at night. Sleep Helper will use daily feedback on these behaviors to 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
Insomnia to Breast Cancer Survivors 
 
 
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make personalized change recommendations. Learning the importance of these 
behaviors has been found to significantly impact insomnia among cancer survivors 
{Recklitis, 2018 #63}. In addition to traditional CBT-I content, we will include information 
about breast cancer diagnosis, treatment and sequelae (e.g. hot flashes and frequent 
awakenings to use the bathroom) as it relates to insomnia, guided by input from Dr. 
Kaltman (co-I). 
 
3) Relaxation exercises. Progressive muscle relaxation is a technique commonly used in 
CBT-I. Phase I participants expressed an interest in relaxation therapies with varying 
lengths and scripts to listen to in preparing for sleep. Participants will be able to sample 
a wide variety and keep the ones that work best for them by accepting or rejecting them 
through the program. We will include a smart speaker or pillow speaker/Bluetooth mask 
so as not to disturb a bed partner. The volume will slowly lower throughout playback until 
it is nearly silent by the end, to minimize the risk of re-awakening (participants can turn 
this feature off).  
 
4) Stimulus control.  Dissociating wakefulness and frustration lying in bed awake is a key 
component of CBT-I. The Echo is programmed so that the light ring maintains a faint 
glow that ends after 20 minutes. Thus, if the participant is awake when the light goes 
out, she knows to leave the bedroom without an audio prompt that could disturb a bed 
partner. A device in an alternate room will suggest that she read or listen to non-
stimulating material, or will provide ideas for other calming activities initiated by voice 
commands (i.e., no use of screens). There will then be occasional prompts to query the 
degree of sleepiness. Users will only be prompted to return to the bedroom when sleepy. 
 
5) Sleep restriction. Sleep restriction is a challenging aspect of CBT-I that directs 
individuals to use utmost discipline to reduce their sleep duration as a means of 
increasing their homeostatic sleep drive to ultimately consolidate and improve sleep 
continuity and quality. The amount of time spent in bed will be restricted to the user’s 
average total sleep time based on data from their automated sleep diary as determined 
by algorithms prescribed by CBT-I therapists Drs. Lewin and Zhou (Co-Investigators).  
 
3.2 Describe any relevant preliminary data. 
In Phase I of this project (R43CA232905) we assessed the feasibility and acceptability of 
the prototype for delivering CBT-I components using a smart speaker. After prototype 
demonstration, nearly 79% (11/14) of participants reported an interest in and perceived 
feasibility of using the virtual assistant to record sleep patterns. Approximately two-thirds 
of the participants thought lifestyle modification (9/14, 64%) and sleep restriction (9/14, 
64%) would be feasible and were interested in this feature of the program (10/14, 71% 
and 9/14, 64%, respectively). Relaxation exercises were rated as interesting and 
feasible using the virtual assistant by 71% (10/14) of the participants. Usability was rated 
as better than average, and all women reported that they would recommend the program 
to friends and family. 
 
We are currently conducting additional formative work with the prototype, and 
preliminary results from Aims 1 and 2 suggest participants found the delivery of CBT-I 
components using a smart speaker acceptable (Mean = 3.6/5 and 3.94/5 for Aim 1 and 2 
respectively) and appropriate (Mean = 3.4/5 and 4.0/5 for Aim 1 and 2 respectively). 
System usability was rated above average (76% and 78% for Aims 1 and 2 respectively) 

PROTOCOL TITLE: Testing mHealth Delivery of Cognitive Behavioral Therapy for 
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3.3  
Insomnia is common in breast cancer survivors (BCS), affecting an estimated 30-
50% of the 3.6 million breast cancer survivors in the US; insomnia has myriad 
psychological and medical sequelae that compound late and long-term effects of cancer 
diagnosis and treatment. Insomnia has detrimental health consequences for 
cardiometabolic and immune system health, neurobehavioral function, depression, 
fatigue, and quality of life. Compared with normal sleepers, those with insomnia had 
more physician-office visits, were hospitalized twice as often, and used more medication. 
Causes of insomnia may be multi-faceted, including cancer related physiological 
processes, iatrogenic effects of oncotherapies, menopause, and co-morbid mood 
disorders associated with cancer diagnosis and psychosocial and economic stressors. 
While pharmacotherapy for insomnia may rapidly address symptoms in the short-term, 
most have negative side effects, including decreasing efficacy over time, tolerance and 
dependence. Cognitive Behavioral Therapy for Insomnia (CBT-I) is considered to be the 
gold standard insomnia treatment and is recommended as first line treatment by the 
American College of Physicians (ACP) and the National Comprehensive Cancer 
Network (NCCN). Previous studies have shown efficacy of CBT-I in the BCS population. 
However, CBT-I trained practitioners are scarce (even in accredited sleep centers) and a 
standard regimen of multiple follow-up visits can inhibit completion, particularly among 
cancer survivors who are likely to have myriad health concerns as well as financial 
toxicity from disruptive cancer treatments. To address this, automated therapies 
delivered via the internet have been developed and shown to be effective. However, 
most of these programs are more didactic than interactive and require concerted effort 
on the part of the patient to adhere to the treatment protocol, resulting in declining 
participation over time. Where it is accessible, CBT-I is traditionally delivered in-person 
in 5-8 sessions, although recent studies have shown efficacy with a three session, brief 
treatment among cancer survivors. Still, these trials have shown dropout rates of 20-
30% despite considerable effort from research staff to engage patients; it is likely that in 
real world settings non-adherence would be even higher.   
 
Smart speaker devices may improve adherence as they embed a voice-activated 
program in the home and can provide real-time CBT-I patient-tailored strategies This 
study aims to further develop and test our voice-activated technology to deliver 
components of cognitive behavioral therapy for insomnia (CBT-I) to breast cancer 
survivors (BCS). CBT-I is a structured, systematic program which delivers better and 
safer outcomes than prescription sleep medications. Non-pharmacologic approaches 
target physiologic, cognitive, behavioral, environmental, and social factors to improve 
sleep. Insomnia has numerous health consequences, particularly for this high-risk 
population, and too few trained CBT-I therapists are available to offer treatment. Online 
programs suffer from high dropout rates and are not appropriate to use “just-in-time” 
before sleep (i.e. in the bedroom) due to stimulating screen exposures. Participants will 
interact with an internet-connected speaker to report sleep patterns and receive 
feedback, more closely mimicking the experience of an in-person provider than web-
based programs. 
 
4.0 
Study Endpoints* 
 

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Insomnia to Breast Cancer Survivors 
 
 
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Completion of the six-week study, and relevant assessments- primarily the insomnia 
severity index. See below for the endpoints corresponding to the described objectives. 
 
4.1 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To determine the impact 
of the voice-activated 
smart speaker CBT-I 
components on 
insomnia symptoms 
among breast cancer 
survivors using a 
randomized clinical trial. 
 
We will collect data on the Insomnia Severity Index (ISI) total 
score pre- and post-intervention as our primary outcome. The ISI 
is a seven-item questionnaire with response categories from 0-4 
(total score 0-28) asking about sleep patterns and specifically 
characterizing insomnia over the two weeks prior. The ISI 
defines ‘no clinically significant’ insomnia as a score of 0-7, ‘sub-
threshold’ insomnia as a score of 8-14, ‘moderate severity 
clinical’ insomnia’ a scores of 15-21, and ‘severe clinical’ 
insomnia as a score of 22-28. Our clinically relevant target for 
success is to achieve sub-threshold or better scores (≤14) 
among >80% of the intervention participants. 
Secondary 
 
To determine differences 
in specific CSD metrics by 
intervention arm. 
 
CSD Metrics: sleep efficiency, wake after sleep onset, sleep onset 
latency, total sleep time and sleep quality. 
 
Tertiary/Exploratory  
 
To determine whether 
there are differences in ISI 
change by frequency of 
engagement or satisfaction 
with the intervention. 
Among the intervention group we will also examine frequency of 
participant engagement and the system usability scale (SUS), 
including participant satisfaction with the program, and whether 
these factors affect ISI change. 
 
 
5.0 
Study Intervention/Investigational Agent 
 
 
Intervention Condition.  
 
After randomization to the intervention arm participants will receive an Amazon Echo Dot 
with the Sleep Helper skill and will be asked to enroll either by giving responses to voice 
prompts for setup or entering baseline information via an accompanying smart phone 
application. Participants will receive written instructions for how to enroll. The MHRI 
research team will reach out to participants by email and/or phone after delivery 
confirmation to ensure that participants have enrolled and initiated the program. 
Participants will receive written instructions to complete morning, night, relaxation and 
educational modules daily. Participants will also be instructed on security settings that 
will be pre-set for maximal security.  
 
Intake. At the start of the intervention participants will be provided with written 
instructions on setting the program up and asked to complete an intake form on 
background information, which can be completed via the smart phone app. Participants 
will be able to use a smart phone app to enter standard insomnia intake assessment 
information that includes sleeping patterns, sleep hygiene practices (e.g. timing and 

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Insomnia to Breast Cancer Survivors 
 
 
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frequency of caffeine use of screens, primary meals and exercise, etc.), whether they 
have a bed partner, and general background information for the study. The smart phone 
app will be linked with the smart speaker device so that information added in any format 
enters the same user backend database. 
 
Participants will be encouraged to complete the morning and night modules daily, and to 
listen to relaxation and educational content or review written educational content on the 
accompanying smart phone app. Media Rez will maintain a technical support system 
through the app for user difficulties and will track all inquiries using de-identified 
participant ID numbers. App support rather than phone support will be utilized to 
maintain participant privacy so that phone numbers will not be revealed. The morning 
module collects sleep diary data from the preceding night and provides participant 
specific reminders based on participant data on naps, exercise and other daily activities. 
The morning module also walks the user through the sleep schedule (e.g., 
recommended sleep bedtime schedule based on sleep restriction algorithm and 
participant specific bedtime routine guidance), questions about intake of caffeine and 
nicotine, napping, and exercise (data collection), and automated control of lighting to 
facilitate preparation for sleep. Educational programming includes short sleep education 
content and cognitive restructuring. The evening module gathers data regarding 
productivity, tiredness, and mood from that current day. The relaxation modules are 
prompted upon completion of the night module, although users are able to request a 
relaxation exercise at any point in time. 
 
Control Condition. Controls will have access to a website with information about CBT-I 
and breast cancer survivorship and will be told to engage with the website as desired. 
The content will be drawn from the same education script that is programmed into the 
Alexa device. 
 
6.0 
Procedures Involved* 
 
Type of study design. We will conduct a six-week, individual randomized controlled trial 
with two arms. While recruitment is being conducted at various locations, the 
intervention is delivered remotely and all data collection and analyses will be conducted 
through Medstar Health Research Institute.  
 
Individuals who express an interest in the study will be screened for eligibility by phone. 
Questionnaires will be completed in REDCap. Study staff will download screening 
results and calculate ISI scores. Participants will be notified of eligibility by phone or 
email within 3 business days of completing the eligibility screening. 
 
If the participant is eligible and wishes to proceed with study enrollment, she will receive 
a personalized REDCap link by email with baseline forms. Study staff will be available to 
administer the forms by phone or to send hard copies by mail if the individual prefers. Prior 
to randomization we will collect information on basic demographics (e.g. age, body mass 
index, education, income, marital status), medical history (e.g. comorbidities, time since 
treatment, concurrent medication), and lifestyle habits (e.g. physical activity, smoking, 
alcohol consumption, diet) as well as our primary outcome of the Insomnia Severity Index 
(ISI). The ISI defines ‘no clinically significant’ insomnia as a score of 0-7, ‘sub-threshold’ 
insomnia as a score of 8-14, ‘moderate severity clinical’ insomnia’ a scores of 15-21, and 
‘severe clinical’ insomnia as a score of 22-28. 

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Randomization. After screening for eligibility, participants will complete informed 
consent. Our biostatistics consultant will provide randomization assignments in a 1:1 
allocation ratio using a block randomized design with random block sizes between 4-6. 
 
During the study the Sleep Helper program will collect sleep diary data via voice in an 
ongoing manner. At the completion of the six-week intervention individuals will complete 
forms via a personalized REDCap link. If individuals complete >50% of the items on a 
scale mean substitution of missing values with respondent’s average response on 
remaining scale items will be used. 
 
This study will use Amazon Alexa Echo Dots. Participants will also receive a hotspot and a 
smartphone, so that they do not have to rely on personal wifi (thus further protecting their 
identity). These devices will be supplied to participants at no cost. We do not foresee any 
significant risk in using this device. This device is exempt from IDE regulation as it is in 
commercial distribution and is used in accordance with the indications in labeling.  
 
 
Data collection. Baseline data before randomization will be collected from all participants 
using REDCap. We will have a separate link to a password protected recruitment 
document (with name and contact information) where unique study IDs will be assigned, 
thus further protecting the identity of participants. In the de-identified REDCap forms we 
will collect information on basic demographics (e.g. age, race/ethnicity, body mass index, 
education, marital status), medical history (e.g. comorbidities, time since treatment), and 
lifestyle habits (e.g. physical activity, alcohol consumption) as well as our primary outcome 
of the Insomnia Severity Index (ISI). Before randomization and upon completion of the 
intervention and control, participants will be administered surveys of relevant questions 
from the CSD through REDCap. We will collect basic sleep information including time 
getting into bed, time attempting to go sleep, time awake during the night, time awake in 
the morning, time getting out of bed, number of awakenings, and quality of sleep. We will 
also collect information on the PROMIS 29-item scale to see how co-occurring symptoms 
such as fatigue and anxiety are distributed by group. Additional information to be collected 
includes a morning/eveningness questionnaire to assess chronotype and participant 
expectations and motivations. All data will be self-reported.  
 
Ongoing data collected through the Alexa app includes basic sleep information including 
time getting into bed, time attempting to go sleep, time awake during the night, time awake 
in the morning, time getting out of bed, number of awakenings, and quality of sleep. The 
ongoing data collected is used to inform treatment recommendations, but is not 
considered in the primary or secondary outcome analyses, which are based on the ISI 
and CSD. 
 
Upon completion of the program, participants in the intervention arm will complete a 
system usability scale as well as a set of open-ended feedback questions after completion 
of the other REDCap forms.  
 
7.0 
Data and Specimen Banking* 
 

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No specimens are being collected for the purposes of this study. 
 
MHRI will maintain appropriate medical and research records for this trial, in compliance 
with ICH GCP and regulatory and institutional requirements for the protection of 
confidentiality of participants. As part of participating in a NIH-sponsored or NIH-affiliated 
study, each site will permit authorized representatives of the NIH, sponsor, and regulatory 
agencies to examine (and when permitted by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits, and evaluation of the study safety, 
progress, and data validity. Only trained study staff who need access to data for research 
purposes related to this project will have access to the data. Any data shared with Media 
Rez (software developer) will be deidentified. 
 
Data Collection and Management Responsibilities  
 
Data collection will be the responsibility of the MHRI trial staff at the site under Dr. Arem’s 
supervision. Dr. Arem will be responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported, as well as for storing all informed consent 
documents and for managing any other identifiable information, including any audio 
recordings or transcripts.  
 
Data will be entered into REDCap, a 21 CFR Part 11-compliant data capture system 
provided by MHRI. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  
 
While participants will be recruited from multiple sites, all records will be collected and 
stored by MHRI and only MHRI research staff who have a need will be able to see 
identifiable information. 
 
Study Records Retention  
 
Study documents will be retained for a minimum of 3 years after the last annual Federal 
Financial Report (FFR) is submitted.  
 
8.0 
Sharing of Results with Subjects* 
Individuals can view their own ongoing data in the app at any point in time. Data 
collected through REDCap will not be shared with those outside the research team 
and will only be reported in the aggregate. 
Publication and Data Sharing Policy  
 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 

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National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination 
of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study 
may be requested from other researchers 1 year after the publication of the primary 
endpoint by contacting Dr. Hannah Arem at Medstar Health Research Institute. 
 
All ongoing monitoring or self-reported data will be available to participants at any 
time during the study via the app. To maintain patient engagement, we will send 
electronic study updates twice a year on study progress (enrollment, process 
data, etc). At the study conclusion, we will send an electronic newsletter to all 
involved patients who do not opt out with summary findings from the study.  
 
9.0 
Study Timelines* 
9.1  
• 
Individuals will participate in the study for six weeks. 
• 
We anticipate beginning recruitment for the study in late 2021, 
and enrolling the last participant by early 2023 (14 months 
total) 
• 
We hope to complete the last data collection by Feb 2023, with 
analysis conducted by March 2023. 
 
10.0 Inclusion and Exclusion Criteria* 
The research coordinator will contact potentially eligible participants by phone to 
discuss the study and conduct screening informed consent. Those who agree to 
be screened for eligibility will complete the screening questionnaire with the 
research coordinator by phone.  
Inclusion and Exclusion criteria 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
1. Willingness to maintain a consistent dosing pattern if currently taking sleep 
medications or using cannabis for sleep 
2. Females; Age 18+ 
3. Self-reported or documented diagnosis of breast cancer stage I-III or stage IV 
ECOG 0-1 
4. Completed curative treatment (surgery, radiation, chemotherapy) > 3 months 
prior to enrollment [ongoing adjuvant therapy permitted] 
5. Has not undergone other behavioral sleep treatment within the prior 12 months 

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6. Score greater than or equal to 8 on the Insomnia Severity Index 
7. Able to understand and speak English 
 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
 
1. Diagnosed, untreated obstructive sleep apnea syndrome, narcolepsy, restless leg 
syndrome, periodic limb movement disorder, delayed sleep phase syndrome, 
central apnea  
2. Bi-polar disorder, schizophrenia, initiation of psychological treatment within three 
months, alcohol or drug abuse in the prior year (Alcohol >2 drinks/day or 
consuming 5+ drinks in a single day in the prior month). (Moderate ADHD, 
depression and anxiety will not be exclusion criteria.) 
3. Shift-work in the prior three months or anticipated during the study time 
4. Planned regular travel out of time zone (>1 hour) during the study period. 
5. Currently or planning to become pregnant during the study period 
Indicate specifically whether you will include or exclude each of the following 
special populations:  
• 
Adults unable to consent- NO 
• 
Individuals who are not yet adults (infants, children, 
teenagers)- NO 
• 
Pregnant women- NO 
• 
Prisoners- NO 
 
 
 
11.0 Vulnerable Populations* 
N/A-  
We will not include adults who are unable to consent. 
 
We will not include individuals who are not yet adults. 
 
We will not include pregnant women. 
 
We will not include prisoners. 
 
12.0 Local Number of Subjects 
12.1 We plan to enroll up to 76 patients in the study total, with about one 
third accrued locally.  
We anticipate screening approximately 150 women in order to identify n=76 for the RCT.  
 
13.0 Recruitment Methods 
 
We will only screen women over age 18 who have been identified as breast cancer 
survivors who completed treatment and self-report disrupted sleep. Thus, we anticipate 
that main reasons for ineligibility will be due to other criteria such as planned travel out of 

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the time zone, ineligible ISI score (7 or less), or other diagnosed untreated sleep disorder 
such as sleep apnea.  
 
We are using multiple recruitment sources as detailed below to facilitate rapid enrollment. 
 
a) Participants will be recruited from the Medstar Washington Hospital Center Cancer 
Institute, and Georgetown University’s Lombardi Comprehensive Cancer Center. 
The research coordinator will screen daily patient appointment schedules coming 
in for routine medical oncology visits after treatment completion to determine which 
patients might be eligible for the study. With consent from the treating physician, 
the research coordinator will call potentially eligible participants by phone or 
arrange to meet them in person if preferred to discuss the study, conduct 
screening, and informed consent. We will also distribute study brochures to 
MedStar Health breast cancer clinics to reach out to survivors who report insomnia. 
If recruitment is slow, we will reach out to the other MedStar cancer clinics to 
determine if clinic-based recruitment is feasible. 
b) We will also reach out to local survivorship groups to distribute brochures, as was 
done in our previous studies of insomnia among BCS.  
c) We will recruit from the Georgetown Lombardi Comprehensive Cancer Center’s 
Survey, Recruitment, and Biospecimen Collection Share Resource (SRBSR), 
which includes nearly 2,300 cancer survivors who have consented to be contacted 
for future research.  
d) We will recruit from the Susan Love Research Foundation Army of Women, a 
resource of 383,000 men and women interested in cancer research will also recruit 
participants. The recruitment flyer approved by Army of Women is attached to this 
application. 
e) Additional participants will be recruited from the Dana-Farber Cancer Institute 
(DFCI)/Harvard Cancer Center using procedures proven successful in previous 
studies. The DFCI team will use medical records to identify potentially eligible 
patients from the breast oncology clinics, and recruit them at the time of a 
scheduled outpatient visit. This clinic-based recruiting strategy previously accrued 
56 adult survivors in a 12-month period. The DFCI team will use medical records 
to determine clinical eligibility (cancer diagnosis, age, and time since treatment) 
and will approach women at their regular clinic visit whether they have trouble 
sleeping that began or got worse after their breast cancer diagnosis. The screening 
checklist is included in this submission. Those who answer affirmatively to the 
basic screening questions will be referred to the MHRI team (via a private Box 
folder using a password protected spreadsheet) and submitting the completed 
screening form to administer the sleep screening questionnaire. The DFCI team 
will not collect data for this study after enrollment, and will not share medical 
records with the MHRI team. 
 
 
All participants will receive a $75 incentive through electronic gift card at the completion 
of the 6-week post-intervention forms. At study completion (once all participants have 
completed the study), those who completed the post-intervention forms will also receive 
an Amazon Dot device (no account linked) that they can keep for personal use. 
 

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Incentives will be delivered through an E-Gift card reward system, Tango. Tango 
provides instant delivery of their reward in which participants can redeem reward by 
visiting the website provided in their reward email to select the gift card of choice. 
Participants will have the option to either receive their gift card through email or can opt 
to receive their incentive in the form of a check delivered by mail to their home address. 
If participants opt to receive an e-gift card, they will receive an email to an address 
(supplied by the participant) with the subject line “Thank you for supporting research at 
MedStar Health Research Institute.” The email contains the following language: “Your 
contributions to science are invaluable. MedStar Health Research Institute appreciates 
you taking the time to participate in one of our projects. Instructions to redeem will then 
be provided.” A member of our research team will generate the incentives according to 
participant preferences. 
 
To incentivize referrals for recruitment, incentives will be delivered through Tango to CBOs 
who refer individuals to the study. CBOs will receive $50 for every individual who 
completes enrollment into the study and cites them as a referral source.  
 
 
14.0 Withdrawal of Subjects* 
DISCONTINUATION 
OF 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
 
When a subject discontinues using the Sleep Helper skill but does not withdraw from the 
study, remaining study procedures will be completed as indicated by the study protocol. 
The investigator or qualified designee will determine if any change in participant 
management is needed.  
 
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods 
for determining the need to discontinue 
• 
The participant will be asked to complete the post-interventions assessments, 
even though not participating in the intervention 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Lost-to-follow up; unable to contact subject  
• 
Any event or medical condition or situation occurs such that continued collection 
of follow-up study data would not be in the best interest of the participant or might 
require an additional treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
 

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The reason for participant discontinuation or withdrawal from the study will be recorded 
on the Case Report Form (CRF). The CRF will include the subject ID, the date the subject 
left the study, who initiated withdrawal (subject vs PI), and reason for withdrawal. Subjects 
who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are 
discontinued from the study, will not be replaced. 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to complete the post 
intervention forms and study staff are unable to contact the participant after 5 attempts.  
 
The following actions must be taken if a participant fails to return post-intervention forms 
or equipment: 
 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, up to 5 
telephone calls and/or emails, and if necessary, a mailed letter to the participant’s 
last known mailing address or local equivalent methods. These contact attempts 
will be documented in the participant’s study file.  
• 
Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
15.0 Risks to Subjects* 
We anticipate minimal risk to participants for participating in the study. 
Known Potential Risks  
Primary risks of the study include: a) embarrassment or discomfort with study questions; 
b) emotional, social, or physical harms resulting from the suggested behavioral 
modifications; c) inadvertent disclosure of data; d) Inadequacy of informed consent; or e) 
other risks that are unlikely to occur, but could. We discuss below methods to protect 
against these risks: 
 
Embarrassment or discomfort with detailed behavioral questions or institutional structure 
can occur. This risk is minimized by ensuring that participants know they do not have to 
participate or may only answer the questions that they feel comfortable answering. We 
will refer patients to seek care from their regular medical doctor in the event the 
participant experiences any emotional or physical discomfort or will remind them that 
they can stop participation in the study at any point in time.  
 
 
Data security: 
• 
Data will be encrypted at all times, from the point of entry into RedCAP to the point of 
backup and to analysis. Data will be encrypted using standardized software (e.g., 
128-bit, PGP).  

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• 
Data entered into RedCAP will be de-identified at all times. RedCAP results will be 
linked to a Survey ID number rather than names to minimize risk of inadvertent 
disclosure.  
• 
Transfer of data will be overseen by Dr. Arem and conducted using password 
protected and encrypted files. 
• 
Data will not be released to non-study staff at any time.  
• 
Any audio-recorded data will be transcribed without identifiers and audio recordings 
will be destroyed after quality control or within five years. 
 
16.0 Potential Benefits to Subjects* 
Known Potential Benefits  
 
The potential benefits from participation in this study include improvement in insomnia 
symptoms among randomized controlled trial intervention participants and in the longer 
term, dissemination of cognitive behavioral therapy for insomnia for breast cancer 
survivors. Knowledge gained from this project will be used to inform design of a 
commercial product to treat insomnia among cancer survivors. In view of the potential 
information to be gained, and how it will ultimately be able to contribute to new approaches 
to providing care to this survivor population, the minimal risks do not outweigh the potential 
for benefit. 
 
17.0 Data Management* and Confidentiality 
O STATISTICAL HYPOTHESES 
• 
Primary Endpoint(s):  Insomnia Severity Index 
We hypothesize that, compared to participants who receive a control intervention, 
participants who receive Cognitive Behavioral Therapy for Insomnia via the Sleep 
Helper skill will have lower ISI scores at the end of the six-week intervention. 
Alternatively, our null hypothesis is that there will be no difference in the ISI score 
between groups at the end of the six-week intervention. Thus our primary efficacy 
outcome is based on the continuous ISI scale. We plan to also conduct a categorical 
analysis: we further hypothesize that a greater percentage of those in the intervention 
arm will have a clinically significant reduction in ISI score to <14, or sub-threshold 
insomnia, than in the control arm. 
 
• 
Secondary Endpoint(s): CSD Metrics  
Our statistical objective is exploratory in that we are interested in whether we are 
seeing changes in metrics of the CSD. We will evaluate the following CSD metrics: 
sleep efficiency, wake after sleep onset, sleep onset latency, total sleep time and sleep 
quality. 
 
• 
Exploratory Endpoint(s): We will analyze whether we see differences in ISI change 
by level of engagement and satisfaction with the intervention. 
 
O SAMPLE SIZE DETERMINATION 

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We based our power calculations on the null hypothesis of no significant mean adjusted 
difference between groups post-intervention on a continuous total ISI score, after 
controlling for baseline score using Analysis of Covariance (ANCOVA). A systematic 
review and meta-analysis published in 2016 showed a large effect size of d=0.77 (95% CI 
0.60-0.93) at post-treatment across seven randomized controlled trials {Johnson, 2016 
#740}. A recent study of internet-based CBT-I among breast cancer survivors found an 
effect size of 1.17 where the outcome was the ISI {Zachariae, 2018 #69}.  
We used Proc GLMPOWER in SAS Version 9.4 to calculate a series of required sample 
sizes with covariate-outcome correlations (0.5-0.8) with a desired power of 80% to detect 
effect sizes between .50 and .80 (medium to large). N values included in the table are for 
total sample size.  Alpha was set at .05 (2-sided test). 
Effect size 
Correlation 0.5 
Correlation 0.6 
Correlation 0.7 
0.5 
N=98 
N=84 
N=68 
0.65 
N=58 
N=50 
N=40 
0.8 
N=40 
N=34 
N=28 
 
Estimating a conservative effect size (based on prior literature) of 0.65 and a pre-post 
correlation of 0.5, we would need N=58 participants, or n=29 per arm. We will aim to recruit 
N=76 total (n=38 per arm) to allow for drop out of up to 30%. 
O POPULATIONS FOR ANALYSES 
 
For our primary and secondary analyses we will be using intent to treat. In tertiary analyses 
we will conduct analyses by adherence (median frequency of engagement). 
 
O STATISTICAL ANALYSES 
General Approach 
Aim 3. In the clinical trial analysis we will follow CONSORT guidelines to descriptively 
present means and frequencies of baseline characteristics in Table 1, and will follow 
guidelines in all analyses and reporting. We will consider p<0.05 as the level of 
significance and will use 2-tailed tests. 
 
Analysis of the Primary Endpoint(s) 
The ISI is a seven-item questionnaire with response categories from 0-4 (total score 0-28) 
asking about sleep patterns and specifically characterizing insomnia over the two weeks 
prior. Our primary analysis endpoint will use this continuous ISI score.  
 
We will test for assumptions of linearity of regression, homogeneity of error variances, 
independence of error terms, normality of error terms, and homogeneity of regression 
slopes. We will use analyses of covariance (ANCOVA) to compare the two groups, 
which controls for baseline ISI values. We will analyze the treatment effect using the 
intent-to-treat principle.  Descriptive statistics will examine differences in baseline 
variables between completers and dropouts.  If important differences are observed 
(suggesting the data are missing under a “Not Missing at Random” mechanism) or the 
loss to follow-up rate exceeds 10%, the primary analysis will be tested through multiple 
imputation of the ANCOVA model, where potential predictors of dropout will be included 
in the imputation model, e.g., response to a baseline question asking about the degree 
of motivation of the participants to stay in the study.  

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Additional analyses will describe mean changes within groups and test change using 
paired t-tests. We will also analyze whether we met the clinically relevant target for 
success of sub-threshold or better scores (≤14) among >80% of the intervention 
participants. Group differences at post-intervention will be assessed by logistic 
regression, controlling for baseline ISI score. 
 
Analysis of the Secondary Endpoint(s) 
We also plan to calculate differences between study arms for the following CSD metrics: 
sleep efficiency, wake after sleep onset, sleep onset latency, total sleep time and sleep 
quality. We will calculate descriptive statistics (means and standard deviations) to 
examine differences between groups. 
 
Exploratory outcomes: 
 
1) Differences in ISI score by engagement. We will conduct sub-analyses of change 
in ISI between high engagers (based on frequency of skill utilization) and low 
engagers (separated by median value).  
2) Differences in ISI score by participant satisfaction. Participant satisfaction will be 
graded on a Likert scale, as well as whether participants would recommend the 
sleep program to friends or family. 
3) We will also explore differences in fatigue and depression (common co-occurring 
symptoms) as measured on the PROMIS 29, by arm. 
 
 
Safety Analyses 
N/A 
 
Baseline Descriptive Statistics 
 
We will compare intervention and control arms on baseline characteristics using means 
for continuous variables (age) and frequencies for categorical variables (e.g. stage, 
education, race/ethnicity, marriage status, employment). Variables such as time since 
diagnosis or level of physical activity may be analyzed as continuous or categorical 
depending on the distribution of the data. As recommended by CONSORT guidelines, we 
will not calculate baseline statistically significant differences by study arm. 
 
Planned Interim Analyses  
N/A 
 
Sub-Group Analyses 
 
We will explore data by participant age, race, and recruitment site, if we have appropriate 
numbers. These analyses will be exploratory in nature. 
 
Tabulation of Individual Participant Data 
 
Individual participant data will not be listed by measure and time point. Rather, it will be 
presented in the aggregate. 

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17.1  
Data collection will be the responsibility of the MHRI trial staff at the site under Dr. Arem’s 
supervision. All data will be stored within MHRI’s secure REDCap system. Dr. Arem will 
be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported, as well as for storing all informed consent documents and for managing 
any other identifiable information, including any audio recordings or transcripts. 
 
All study data will be collected in REDCap and non-PHI will be downloaded into a SAS 
dataset. Study documents will be retained for a minimum of 3 years after the last annual 
Federal Financial Report (FFR) is submitted. Data will be stored behind the MedStar 
Health firewall in Box. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) will be entered into REDCap, a 21 CFR Part 11-compliant data 
capture system provided by the Medstar Health Research Institute. The data system 
includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. While 
participants will be recruited from multiple sites, all records will be collected and stored by 
MHRI and only MHRI research staff who have a need will be able to see identifiable 
information. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
N/A. This research involves only Minimal Risk to subjects. 
 
Dr. Arem will have primary responsibility for monitoring the data and safety of this project 
and complying with the reporting requirements of the funding agency and the IRB of record 
(MHRI IRB). As part of the annual progress report to the NIH sponsor, the PI will provide 
an update of project activities to date, summary of the characteristics of participants, 
expected versus actual enrollment, and any changes to the protocol.  The PI will work 
closely with members of the study team to ensure that a quality assurance plan and the 
data and safety monitoring plan are thoroughly followed.  
 
Adverse events and Serious Adverse Events 
 
Definition of Adverse Events 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward 
medical occurrence associated with the use of an intervention in humans, whether or 
not considered intervention-related.  
 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening. Any adverse experience that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred (i.e., it does 
not include a reaction that, had it occurred in a more serious form, might have 
caused death). 

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• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
An event that requires intervention to prevent permanent impairment or damage.  
• 
Important medical events that do not result in death, are not life-threatening, or do 
not require hospitalization may be considered serious adverse events when, based 
upon appropriate medical judgment, they might jeopardize the subject and might 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 
Classification of an Adverse Event 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the 
following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”. 
 
Relationship to Study INTERVENTION/Experimental Manipulation 
All adverse events (AEs) will have their relationship to study procedures, including the 
intervention, assessed by an appropriately-trained clinician based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be 
graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to study 
procedures administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study procedures should 
be 
clinically 
plausible. 
The 
event 
must 
be 
pharmacologically 
or 
phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study procedures, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of study 
procedures). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 

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• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study procedures administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study procedures) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures 
administration, and/or evidence exists that the event is definitely related to another 
etiology. A clinician will document the alternative, definitive etiology. 
 
Expectedness  
A clinician with appropriate expertise in breast cancer and/or CBT-I will be responsible for 
determining whether an adverse event (AE) is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study procedures. 
Time Period and Frequency for Event Assessment and Follow-Up 
We do not anticipate adverse event (AE) or serious adverse event (SAE) during the 
course of this study. However, the principal investigator will be responsible for following 
adverse event reporting requirements as outlined below.  These responsibilities include: 
a. Reviewing the accuracy and completeness of all adverse events reported 
b. Compliance with IRB policies for reporting adverse events and/or serious 
adverse events 
c. Closely monitoring research participants at each point of contact for any new 
Adverse Events (AEs) or Serious Adverse Events (SAEs). 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case 
report form (CRF). Information to be collected includes event description, time of onset, 
assessment 
of 
severity, 
relationship 
to 
study 
procedures, 
and 
time 
of 
resolution/stabilization of the event. All AEs occurring while on study will be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an 
AE. Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed.  
 
Adverse Event Reporting  
 
Any mild to moderate event on the above scale will be reported by the MHRI PI to the IRB 
within 5 business days. 
Serious Adverse Event Reporting  
 
1. The study is of low to moderate risk.  No serious adverse events are expected. 
 

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2. We will attempt to report serious unanticipated events within 24 hours to the 
GU/MHRI IRB, but no longer than 3 business days. Adverse events will be 
considered serious if graded 3 or higher on the scale outlined above.  
 
3. An adverse event report including a description of the event, when the event 
occurred, and when and how the event was reported, will be generated for each 
event. Any documentation related to the event or its attribution will be included in 
the report. 
 
4. The study PI point of contact with the IRB (Dr. Arem) will conduct a review of all 
adverse events upon completion of every study subject. She will evaluate the 
frequency and severity of the adverse event(s) and, in conjunction with the IRB at 
GU/MHRI, will determine if modifications to the protocol or consent forms are 
required.  
 
 
The IRB will evaluate whether the study should continue unchanged, require modification, 
continue, or close to enrollment. If increased frequency of serious adverse events is 
detected and reported, an ad hoc safety review will be convened to determine whether 
and how to modify, continue, or terminate enrollment.  
 
19.0 Provisions to Protect the Privacy Interests of Subjects 
 
All participant data recorded by the Alexa Echo Dot device or sent to the Alexa Echo during 
the course of the testing is encrypted for patient privacy. All participant data collected by 
the Alexa Echo system is held on Amazon’s servers in a de-identified form. All participant 
data to and from the smartphone app will likewise be encrypted and will not reside on 
patient smartphones, but will only be held on protected servers in a de-identified format. 
Media Rez will make this de-identified data available to MHRI for data analysis. GW MHRI 
holds the keys to participant data identification, but at no time will any identified or 
identifiable participant data be sent to or stored at Media Rez. All participants will use 
Alexa accounts created by Media Rez to prevent Amazon from gaining access to patient 
names or privacy data.       
 
All staff will be trained on MedStar Health standards of confidentiality prior to being given 
access to any data using the CITI training certification. Staff training is comprehensive and 
will entail not only confidentiality but also respect for persons, safety, the intervention, 
testing, and all related components of the study. The PI will oversee and ensure ongoing 
respect for participants and their data throughout the study. 
 
Study staff will be trained on confidentiality standards and proper interviewing technique. 
This will include the following points: 
 
• 
Always protect participant data and confidentiality of persons. 
• 
Participant names should not be included in any data collection instruments or 
systems. The only numbers used to label and identify data from the participant are 
the Survey ID or the Recruiter ID. 

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• 
Questionnaires and any digital recordings are to be linked using the Survey ID 
number and the interview date. No personal identifiers should be written or affixed to 
the survey results. 
• 
Protect the electronic security of all databases. 
• 
Computers that can access electronic data should be physically secured and should 
be protected by coded passwords. Networks must be demonstrated to be secure by 
the IT department prior to use. 
• 
Only authorized persons are to have access to electronic databases.  
• 
Project staff must shred documents containing sensitive information before disposing 
of them. 
 
Other concerns and resolutions to specific to using the Amazon Alexa device: 
Delete Voice Recordings: One risk is that every time the participant says the wake word 
“Alexa,” the participant’s voice is recorded and sent to Amazon’s servers, where Amazon 
could potentially misuse the voice recordings because these recordings are potentially 
identifiable. While these voice recordings are not available to anyone outside of Amazon, 
there is a small chance that they will be somehow misused by Amazon. To mitigate this 
small but real risk, Media Rez will delete these voice recordings on a daily basis. Further, 
Media Rez will delete them via Amazon’s content management tools without hearing them. 
Because Alexa accounts are controlled by Media Rez, participants will not have to sign up 
with Amazon or provide Amazon with any identifiable data.    
 
Disable Calling: Another risk posed by using an Alexa Echo Dot is the chance of being 
overheard by other Echo owners by accidently connecting to them via calling and 
messaging. To prevent this (which has happened to at least one Echo owner who 
inadvertently sent voice recordings to people in their contracts list), Media Rez will disable 
these calling and messaging features for the duration of the testing.  
 
Disable Voice Purchasing: Likewise, voice-based purchasing will be turned off (and will 
not be linked to the participant or their credit cards or their Amazon account). 
Mute Mode: We will also inform participants about how they can mute the Echo Dot by 
pressing the mute button. 
 
We believe that these risks are minimal and are outweighed by the potential benefit of 
improved sleep. 
 
20.0 Compensation for Research-Related Injury 
20.1 We believe that this study involves only Minimal Risk to subjects. 
We will not provide any compensation in the event of research-
related injury. 
21.0 Economic Burden to Subjects 
21.1 Subjects will be responsible for all regular care, but not for any 
expenses related to the study. We will mail study devices to 
participants and will provide return shipping labels.  
22.0 Consent Process 
 

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Informed Consent Process 
 
All informed consent will be conducted in compliance with NIH Human Research 
Protections Program policies and procedures. A study team member trained in 
human subjects research will conduct informed consent as described below:  
Consent/assent and Other Informational Documents Provided to participants 
 
We will have 2 separate consent forms: a) for screening and b) for the RCT. 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks will 
be given to the participant and written documentation of informed consent will be 
completed prior to starting the study intervention.   
 
Consent Procedures and Documentation 
 
Informed consent will be conducted by phone. Anyone called will first be read the consent 
for screening form, which requires only a verbal consent so as to minimize the potential to 
link PHI. Individuals will be asked a series of questions by a MHRI research assistant or 
clinical research coordinator to determine eligibility (including the Insomnia Severity 
Index), and will be notified of whether they are eligible within 3 business days.  
 
If deemed eligible, participants will receive a copy of the full consent form by email. The 
CRC will then set up a phone call where study staff will review the full consent form and 
ask individuals if they have any questions or concerns. Once informed consent has been 
completed, participants will receive a subject ID, which will be linked to a personalized 
survey administered via REDCap. Participants will also be able to view a written version 
of the informed consent on a landing page in REDCap, which they must agree to before 
continuing to complete baseline forms. The landing page will include a single page 
summary of the research, with an option to download the full informed consent again 
(although they will have previously received the full form by email). Both the text that will 
be on the landing page and the full informed consent are included in this application.  
Confidentiality and Privacy  
 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, the safety and oversight monitor(s), and the sponsor(s) and 
funding agency. This confidentiality is extended to the data being collected as part of this 
study. Data that could be used to identify a specific study participant will be held in strict 
confidence within the research team. No personally-identifiable information from the study 
will be released to any unauthorized third party without prior written approval of the 
sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or 
representatives from companies or organizations supplying the product, may inspect all 
documents and records required to be maintained by the investigator, including but not 

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limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
In this study, Media Rez provides Amazon Alexa Echo Dot devices to individuals who 
have met eligibility criteria and agreed to participate. All participant data recorded by the 
Alexa Echo Dot device or sent to the Alexa Echo during the course of the testing is 
encrypted for patient privacy. All participant data collected by the Alexa Echo system is 
held on Amazon’s servers in a de-identified form. All participant data to and from the 
smartphone app will likewise be encrypted and will not reside on patient smartphones, but 
will only be held on protected servers in a de-identified format. Furthermore, Media Rez 
provides both the phone and the hotspot so that the individual does not have to link the 
device to her personal wifi. Media Rez will make this de-identified data available to MHRI 
for data analysis. MHRI maintains participant data identification. At no time will any 
identified or identifiable participant data be sent to or stored at Media Rez.     
 
The study participant’s contact information will be securely stored at MHRI for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor/funding agency requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at MHRI. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems 
used by clinical sites and by MHRI research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at MHRI. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing 
Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should 
be made available to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will 
ensure all mechanisms used to share data will include proper plans and safeguards for 
the protection of privacy, confidentiality, and security for data dissemination and reuse 
(e.g., all data will be thoroughly de-identified and will not be traceable to a specific study 
participant). Plans for archiving and long-term preservation of the data will be 
implemented, as appropriate.  
 
▪ 
Future Use of Data  
Data collected for this study will be analyzed and stored at MHRI for five years after trial 
completion. We will make de-identified relevant data and associated documentation 
available to users who request access to the data one year after study completion only 
under a data sharing agreement that provides for: (1) a commitment to using the data only 
for research purposes and not to seek to identify any individual participant; (2) a 
commitment to securing the data using appropriate computer technology; and (3) a 
commitment to destroying or returning the data after analyses are completed.  
 
23.0 Process to Document Consent in Writing 
 

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Any in-person consenting will include written consent as follows: A study team 
member who has completed human subjects training will read through informed 
consent with patient participants and will answer any questions about the study. The 
patient will then be asked if he or she would like more time to consider the study or 
if he or she would prefer to go ahead and complete the informed consent. If the 
informed consent is signed in person, the individual obtaining consent will sign as 
well. In the case that the individual is consented remotely (due to pandemic 
conditions, his/her preferences, the location of the participant, or scheduling), we 
will first email (or mail if preferred) a copy of the informed consent to the participant. 
We will then schedule a time to read through the consent by phone or Microsoft 
Teams to give them a chance to ask any questions about the study. We will verbally 
confirm whether they want to proceed. If they agree, we will send them an 
individualized REDCap link with baseline forms. The REDCap landing page will 
have the summary of the informed consent (the brief version), with a link to the 
detailed ICF document, and will ask the participant to write their name to proceed. 
REDCap has an e-consent module where participants type their name and certify 
consent before being allowed to proceed with data collection. REDCap’s e-consent 
process has two steps: 1) Before a participant completes the survey, an extra 
certification page is added to the end of the survey that displays an in-line PDF copy 
of the document in which they will be asked to confirm that personal information 
(name) in the document is correct. This survey will not be considered complete until 
they fulfill the certification step. 2. Upon completion of the survey, a static copy of 
their responses in the form of a consent-specific PDF will be stored in the project’s 
File Repository. 
 
24.0 Setting 
 
Participants will be recruited from MedStar Washington Hospital Center and 
Georgetown’s Lombardi Comprehensive Cancer Center from the breast oncology 
clinics. The clinical research coordinator (CRC) will use MedConnect and will 
work with the breast oncology and survivorship care clinics as needed to identify 
potentially eligible subjects and to flag these participants for the oncologist. With 
oncologist approval, the CRC will reach out to patients by phone to describe the 
trial and if the patient is interested, to conduct informed consent and baseline 
forms. All forms can be completed online by the participant, or conducted by 
phone with the CRC, or if preferred by participants, can be mailed in hard copy to 
the individual. 
 
The intervention delivery and data collection will be conducted remotely. Primary settings 
for recruitment include the Medstar Washington Hospital Center, Georgetown’s Lombardi 
Comprehensive Cancer Center, and the Dana-Farber Cancer Institute (DFCI)/Harvard 
Cancer Center. Each will abide by site-specific preferences around recruitment, and will 
work with physicians on site to lower the burden on physicians. If recruitment is slow, we 
will submit a modification to expand to other MedStar facilities including MedStar Franklin 
Square Hospital, and/or MedStar Union Memorial Hospital. 
 
25.0 Resources Available 
 

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The research team (Dr. Arem, Claire Starling, and collaborators) will meet weekly to 
discuss ongoing research progress. Internally at MHRI, we will conduct additional weekly 
meetings to discuss participant recruitment and any updates to research protocol or duties 
and functions. Dr. Arem is dedicating 20% effort to the project, and Claire Starling, 
research coordinator will dedicate 50-100% effort as needed. Andrea Lopez will contribute 
as clinical research coordinator. We will also include breast medical oncologist Dr. 
Christopher Gallagher at 2% effort and an oncology nurse at 5% effort to support 
recruitment efforts. Collaborators at Media Rez (prime) and Harvard/DFCI also have 
dedicated effort towards developing this project. 
 
Data from the WHC Medical Records indicate that 275 women per year on average are 
treated at WHC for breast cancer; numbers are similar for GU. We anticipate that ~30% 
of these women will have insomnia after treatment completion. Given that we are including 
women who are survivors, women who return for adjuvant therapy for 5-10 years post-
curative treatment will be eligible for screening, increasing our sample size. 
 
We do not anticipate medical or psychological resources needed for patients, but will refer 
them to their primary care physician for these issues- no services will be provided through 
our research study. 
 
26.0 Multi-Site Research* 
 
While we are recruiting from multiple sites, all data will be collected and stored at MHRI. 
Thus, no data will be held by other sites.