The HOPE Trial: Helping Our Patients Excel, and The SMART Study: Symptom Management and Reporting
Phase: NA
Conditions: Gynecologic Cancer
Sponsor: Dana-Farber Cancer Institute

 
 
 
 
 
 
 
 
 
 
The HOPE Trial and SMART Study (NCT03022032) 
PI: Alexi A. Wright, MD, MPH 
Dana-Farber Cancer Institute 
IRB-Approved Protocol #16-477 (version 8.0) 
April 23, 2021 
 
 

 
 
Protocol Organization for DF/HCC Protocol 16-477 
The protocol document contains the study procedures for the HOPE Trial and the SMART Study. 
The SMART Study is a sub-study of the HOPE Trial. Both studies evaluate an almost identical 
intervention using a Fitbit device and smartphone app(s) with the goal of improving quality-of-life for 
women with gynecologic cancers. However, the studies are designed to assess different research 
questions, and there are slight variations in the interventions being administered: the HOPE Trial is a 
randomized controlled trial designed to test changes in health-related quality of life at an NCI-
designated Comprehensive Cancer Center (DFCI), while the SMART Study is a single-arm study 
designed to test the feasibility and acceptability of a combined intervention (Fitbit device and two 
smartphone apps) in NCORP community oncology sites.  
Because the interventions tested are similar and only minor variations exist in study procedures 
(e.g., in timings of outcomes assessments), the studies are being reviewed under one IRB protocol 
at Dana-Farber Cancer Institute.  
The HOPE Trial is being conducted only at Dana-Farber Cancer Institute. No outside sites are 
participating in the HOPE Trial. The HOPE Trial (Phase 2) is a four-arm randomized controlled trial 
testing Fitbits and a smartphone app. The primary endpoint of Phase 2 of the HOPE Trial is health-
related quality of life. 
The SMART Study is being conducted only at outside community oncology sites. Dana-Farber 
Cancer Institute is not enrolling patients in the SMART Study. The SMART Study is a single-arm 
study testing a Fitbit and two smartphone apps (Beiwe and SMART). Primary endpoints for this 
study are feasibility and acceptability of the intervention in the community oncology sites. 
To facilitate protocol implementation and regulatory review at both Dana-Farber and outside sites, 
this document is separated into two sections. Part 1 is the protocol for the HOPE Trial conducted at 
Dana-Farber only; Part 2 is the protocol for the SMART Study conducted at community oncology 
sites only. Lettered appendices (Appendices A-Z and AA) correspond with the HOPE Trial; 
numbered appendices (Appendices 1-24) correspond with the SMART Study.  
The HOPE Trial section begins on p.2 of this document. The SMART Study section begins on p. 41 
of the document. 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
Part 1 
The HOPE Trial 
 
 
 
 
 

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DAYS 
 
 
 
Study Timeline 
Intervention 
Instructional  
Session 
Data Collection: 
 
Participant Baseline Interview 
Data Collection: 
 
Participant Post-Baseline Interview 
Clinician Survey 
Debriefing Interviews 
Health/Tx Info 
Healthcare Utilization 
C ll L
Consent & 
Registration 
Post-
Baseline 
Visit 
Interventions:  
 
2 wearable accelerometers; 
App symptom management; 
Summary of app survey 
Data Collection:  
 
Daily symptom survey; 
Accelerometer data; 
Passive app data 
Data Collection: 
 
Clinician Survey 
Health/Tx Info
 
Baseline 
Visit 
0 
1 
30 
+/- 14 
SECTION 1: Protocol Schema  
First Phase: (n=10) 
Download and 
install the 
smartphone app 

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SECTION 2: Body of Protocol 
 
TABLE OF CONTENTS 
 
1.0 INTRODUCTION 
1.1 Overview ………………………………………………………………………………………………………….4 
1.2 Background and Rationale………………………………………………………………………………………5 
 
2.0 OBJECTIVES 
2.1 Phase 1……………………………………………………………………………………………………….......7 
2.2 Phase 2……………………………………………………………………………………………………….......7 
 
3.0 RESEARCH SUBJECT SELECTION 
3.1 Eligibility Criteria………………………………………………………………………………………………….8 
3.2 Exclusion Criteria………………………………………………………………………………………………...8 
 
4.0 RESEARCH SUBJECT ENTRY 
4.1 Subject Recruitment and Enrollment…………………………………………………………………………..8 
4.2 Subject Registration and Randomization……………………………………………………………………...9 
 
5.0 STUDY DESIGN AND METHODS 
5.1 Design/Study Type………………………………………………………………………………………………10 
5.2 Selection of Instruments………………………………………………………………………………………...11 
5.3 Description of Interventions……………………………………………………………………………………..18 
5.4 Data Collection…………………………………………………………………………………………………...22 
5.5 Description of Study Process…………………………………………………………………………………...23 
5.6 Adverse Reactions and Their Management…………………………………………………………………..28 
 
6.0 STATISTICAL ANALYSIS…………………………………………………………………………………………..29 
 
7.0 REFERENCES……………………………………………………………………………………………………….33 
 
8.0 APPENDICES………………………………………………………………………………………………………..38 
 

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1.0 INTRODUCTION 
1.1 Overview 
The goal of palliative chemotherapy is to reduce cancer patients’ symptoms and extend survival. Yet, 
oncologists’ methods of monitoring patients’ symptoms are underdeveloped. Studies show that clinicians 
consistently miss more than half of cancer patients’ symptoms, even in clinical trials that mandate collection of 
treatment toxicities.1-3 This may be because clinicians see patients at fixed time points (e.g., every 3 weeks 
linked to chemotherapy infusions) when patients have already recovered from their last treatment. Additionally, 
patients may underreport symptoms in clinical settings or have difficulty estimating their activity levels, 
hindering oncologists’ ability to accurately assess patients’ symptoms and/or performance statuses. The 
moments between visits—when patients are at the highest likelihood of experiencing toxicities—are more likely 
to contain meaningful information about patients’ symptoms and activity levels in the real world. Mobile health 
technologies (e.g., smartphones and accelerometers) offer novel methods for assessing patients’ symptoms 
and activity levels and opportunities to intervene to reduce suffering.  
The first goal of this study is to adapt and refine an existing smartphone app, paired with a wearable 
accelerometer, to assess patients’ symptoms in a population of patients with gynecologic cancers receiving 
palliative chemotherapy. An existing app will be customized to collect patient-reported toxicities using the 
Patient Reported Outcome (PRO) version of the Common Terminology Criteria for Adverse Events (PRO-
CTCAE) and offer patients feedback about how to manage their symptoms. Patient symptoms will be risk-
stratified. Patients with low-risk toxicities (grades 1 & 2) will receive tailored educational information, while 
patients with serious toxicities (grades 3 & 4) will receive alerts to call their clinician. Patients will also receive a 
graphical summary of their symptoms to share with clinicians during office visits. In first phase of the study we 
will conduct an initial assessment of the app with a diverse group of 10 patients to refine the app and test two 
different wearable accelerometers (i.e. Fitbit Zip and Fitbit Charge 2) before pilot testing. The wearable 
accelerometers will be used as a quantitative measure of patient performance status, and to detect severe 
symptoms that may impact patients’ average daily steps (e.g., abdominal pain, nausea, diarrhea).4 Patients will 
also be provided with a graphical summary of their average daily steps to share with clinicians. 
The second goal of this study is to conduct a pilot randomized controlled trial (RCT) of the smartphone app 
and/or wearable accelerometer (i.e. Fitbit Zip or Fitbit Charge 2) to assess the feasibility, acceptability, and 
preliminary efficacy of our intervention. During the second phase of the study, we will conduct a 4-arm pilot 
RCT in 100 patients with gynecologic cancers receiving palliative chemotherapy to establish preliminary effect 
sizes. Participants will be randomized to: 1) Fitbit+active app, 2) Fitbit+passive app, 3) Active app, or 4) 
Passive app. We hypothesize that the use of a Fitbit and an active app designed to assess PRO symptoms 
and deliver tailored advice to cancer patients receiving palliative chemotherapy will reduce the use of high-
intensity health care (i.e., unplanned infusion appointments, emergency room visits, and hospitalizations), 
compared with a Fitbit + passive app, Active app, or Passive app alone. We also hypothesize that patients 
randomized to the Fitbit + active app will have improved health-related quality of life (comparing the baseline 
and 6-month EuroQol EQ-5D), compared with other groups. Additionally, we expect that data collected from 
the wearable accelerometers and smartphone accelerometers (via passive app) will be significantly correlated 
with each other, and will provide quantitative measures that are correlated with patients’ performance status. 
We expect that the results of this pilot RCT, which is supported by the National Cancer Institute, National 
Palliative Care Research Center, and the Dana-Farber Cancer Institute Department of Medical Oncology, will 
provide a low-cost, scalable system to assess patients’ symptoms, address low-risk toxicities, and alert clinicians 
when patients have toxicities that require intervention with the goal of reducing patient suffering and the use of 
high-intensity, hospital-based health care. Upon completion of this project, we will be well positioned to test the 
efficacy of this intervention in a full scale RCT. 
 

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1.2 Background and Rationale 
There is substantial evidence that oncologists’ miss up to half of cancer patients’ symptoms, even within the 
context of clinical trials, which mandate structured reporting of symptoms and treatment toxicities.1-3 Evidence 
suggests that the integration of PROs into routine cancer care results in more efficient symptom assessment,5 
improved communication and continuity of care,6-8 better quality of life,3,9,10 lower health care utilization rates,10 
and superior quality-adjusted survival, compared with usual care.10,11 This is important because while prior 
studies have demonstrated that the early integration of palliative and oncologic care improves patients’ quality 
of life and survival,12-15 health systems are facing a serious workforce shortage of trained palliative care 
providers.16 Low-cost, scalable systems designed to assess patients’ symptoms, address low-risk toxicities, and 
alert clinicians when patients are in danger are urgently needed. 
Several studies have demonstrated that cancer patients with serious illnesses are willing to report their 
symptoms using technology, including tablets and web-based systems,10,17-19 even close to the end of life.20  
One large study of cancer patients found that nearly 70% of patients wanted to receive information and support 
about their disease through the internet.21 Another demonstrated that the use of a web-based system to 
assess PROs in patients with advanced cancer, combined with automated clinical alerts, resulted in better 
health-related quality of life, fewer emergency room visits and hospitalizations, and superior quality-adjusted 
survival, compared with usual care.22 Recently Denis et al. reported that the use of a web-based system to 
assess PROs weekly in patients with high-risk, non-small cell lung cancer resulted in earlier detection of 
symptomatic disease recurrences, earlier institution of supportive care, better patient quality of life, and 
improved overall survival, compared with routine clinical assessments.11 Researchers have not examined 
similar endpoints in patients with gynecologic malignancies, to our knowledge, but one small study found that 
chemotherapy toxicity reporting was feasible in women with gynecologic cancers using a web-based system, 
and that use of this system improved patient recall of symptoms at follow-up visits, communication with 
physicians and nurses, and patients’ self-efficacy.17 
To date, however, most studies have focused on collecting patient-reported symptoms during clinic visits 
that are frequently tied to chemotherapy infusions. Two key limitations to this approach are: 1) patients have 
often already recovered from many treatment-related toxicities and 2) it relies upon patients’ retrospective 
recall of events, which are often inaccurate. Few studies, to our knowledge, have performed real time and real 
world assessments of cancer patients’ symptoms and activity levels in daily life. 
Smartphone-based interventions are a low-cost, scalable tool for measuring and modifying health 
behaviors. In 2015, 64% of Americans owned a smartphone23 and more than 33% reported relying upon it as 
their sole tool for accessing the Internet, particularly among low-income and racial/ethnic minority 
populations.24 Mobile health interventions have demonstrated efficacy in assessing 
pain,25 monitoring psychiatric diseases,26,27 increasing medication adherence28 and 
improving other important clinical outcomes (e.g., systolic blood pressure, and 
body mass index).29 
Smartphones are capable of collecting two types of information:  1) “active 
data” which require patients’ involvement (e.g., taking surveys; please see Figure) 
and 2) “passive data” which are collected without the patients’ involvement (e.g., 
accelerometer data or spatial location).30 One of the advantages of using 
smartphones is that they can leverage sophisticated surveying techniques to 
generate personalized assessments, eliminating questions that have a high 
likelihood of being irrelevant and therefore reducing the survey burden upon 
participants.27 Smartphones can also be used to provide patients with real time 
active feedback for symptom management or to notify them that their symptoms are serious and require 
immediate attention. 
Figure 1 

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To date, few studies have examined the use of mobile phone-based interventions in patients with cancer. 
Similarly, few have collected quantitative measurements of cancer patients’ activity levels for extended time 
periods.31-34 This study is innovative because it will harness a validated app, which is being piloted in 
psychiatric, neurological, and surgical patients in the Partners HealthCare system, to collect passive data from 
patients (e.g. accelerometer, spatial location, and sleep data) and active data, including patients’ symptoms 
and treatment toxicities. The app has been tailored to categorize patient symptoms as low or high-risk, based 
upon clinical algorithms, and provide them with tailored advice to help manage their symptoms in real time in 
the real world. It is also innovative because it will enable clinicians to better understand patients’ symptoms in 
the time between visits. We expect this study will increase the frequency of discussions about patients’ 
symptoms between patients and providers. We also expect that this formative development work and early 
feasibility trial will set the stage for launching a broad portfolio of mobile-health intervention studies to improve 
seriously-ill cancer patients’ symptoms, performance statuses, and clinical outcomes.  
Like smartphones, wearable accelerometers (e.g. Fitbit Zip and Fitbit Charge 2) offer another novel means 
for collecting real world data to objectively measure patients’ performance statuses. Patients’ retrospective 
reports of activity levels are often inaccurate or imprecise. Without accurate information, oncologists may have 
difficulty objectively assessing patients’ performance statuses, and may underestimate patients’ symptom 
burdens and chemotherapy-related toxicities. Indeed, oncologist estimates of patients’ performance statuses 
are only moderately correlated with one another35,36 and weakly correlated with patient estimates,37-39 but 
improve when clinicians and patients participate in “shared” reporting of patients’ toxicities and performance 
statuses.40  
Wearable accelerometers are devices that track users’ energy expenditures, the amount and intensity of 
physical activity, and sedentary behavior. They offer cost-effective, user-friendly, and objective measurements 
of patients’ free living patterns. A few studies have piloted wearable accelerometers in adult cancer patients 
undergoing stem cell transplants (HCT) or treatment for colorectal, gastrointestinal, breast, and lung 
cancers.4,34,41,42 Results from one study of adult patients undergoing HCT who wore accelerometers over an 8 
week period found that patients’ reports of severe symptoms, impaired physical health, and restrictions in 
activities of daily living were associated with statistically significant decrements in objectively measured steps, 
suggesting that this may be an independent, quantitative measure of quality of life and patient performance 
status.4 In this study of 32 patients undergoing HCT over a 4 week period patients’ averaged 3,595 steps daily, 
and lower levels were significantly associated with an increased symptom burden.4 Although similar estimates 
are not available in patients with gynecologic cancers, to our knowledge, we expect that symptoms are likely to 
impact the amount of walking that patients can do and will therefore provide an independent measure of both 
patients’ performance status and symptom burden. 
In the second phase of this study all patients will have passive data collected via the app. We will compare 
the active version of the smartphone app (which collects passive data, surveys patients about their symptoms, 
and provides tailored symptom management advice) alone or paired with a wearable accelerometer against a 
wearable accelerometer or control in a four arm RCT (see study schema). This will enable us to examine 
whether the active smartphone app and wearable accelerometer improve patients’ quality of life, compared 
with active smartphone app or the wearable accelerometer, and determine whether their effects are 
independent or additive. In addition, it will help us determine whether wearable and smartphone-based 
accelerometers can provide valid and reliable measures of patient performance status and treatment toxicities. 
 
 
 
 

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2.0 OBJECTIVES 
2.1 Phase 1  
Objective: Adapt and refine an existing smartphone app to assess patients’ toxicities and activity levels in 10 
patients with metastatic gynecologic cancers receiving palliative chemotherapy and compare two wearable 
accelerometers (Fitbit Zip and Fitbit Charge 2) for use in the pilot RCT. 
• 
Hypothesis: Patients will be able to successfully recharge the Fitbit Charge 2 every 3-4 days, but will 
prefer the Fitbit Zip because it does not require recharging. 
• 
Hypothesis: The use of a wearable accelerometer will provide a quantitative measure that is correlated 
with patient performance status, and decrements of >25% in average daily steps will be associated with 
worse patient-reported quality of life and physical health (measured by the PROMIS Global-10 items 2 
and 3). 
 
2.2 Phase 2  
Objective: Conduct a four-arm pilot randomized controlled trial (RCT) comparing the Fitbit + active smartphone 
app, Fitbit + passive app, Active app, or passive app alone to assess the feasibility, acceptability, and 
preliminary efficacy of the intervention. 
• 
Hypothesis: Use of a monitored wearable accelerometer/passive smartphone app will improve patients’ 
health-related quality of life (comparing the baseline and 6-month EuroQol EQ-5D), compared with 
passive smartphone app alone. 
• 
Hypothesis: Use of both the active smartphone app and a monitored wearable accelerometer will 
improve patients’ health-related quality of life (comparing the baseline and 6-month EuroQol EQ-5D), 
more than the active smartphone app or wearable accelerometer/passive smartphone app alone. 
• 
Hypothesis: Use of the active smartphone app and a monitored wearable accelerometer will reduce the 
use of high-intensity health care (i.e., unplanned infusion appointments, emergency room visits, and 
hospitalizations), compared with a monitored wearable accelerometer/passive app, active smartphone 
app, or passive app alone. 
• 
Hypothesis: Use of the active smartphone app will decrease the number of patient phone calls and/or for 
symptoms, compared with a wearable accelerometer/passive app or passive app alone. 
• 
Hypothesis: Patients’ and oncologists’ estimates of a patient’s performance status will be more closely 
correlated in patients randomized to the monitored wearable accelerometers/passive app compared with 
the active smartphone app alone or the passive smartphone app alone. 
• 
Hypothesis: Data collected from the wearable accelerometers and smartphone accelerometers (via 
passive app) will be significantly correlated with each other, and will provide quantitative measures that 
are correlated with patients’ performance status and will be predictive of clinically significant events 
(hospitalizations, emergency department visits, and chemotherapy appointments) 
• 
Hypothesis: The correlation between the wearable accelerometers and smartphone accelerometers (via 
passive app) will be higher in patients randomized to be encouraged to wear their smartphone at all 
times, and the predictive ability of the smartphone accelerometers for patients’ performance status and 

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clinically significant events will be greater in in patients randomized to be encouraged to wear their 
smartphone at all times. 
• 
Hypothesis: Participants will express more negative affect and anxiety related to their cancer experience 
in the weeks preceding scans, compared with the weeks when scans are not performed. This 
association will be moderated by participants’ coping style (as measured by the brief COPE). 
 
3.0 RESEARCH SUBJECT SELECTION 
 
3.1 Eligibility Criteria  
Eligible patients include women >20 years of age who plan to receive chemotherapy at DFCI to treat 
recurrent, incurable gynecologic cancers (i.e., ovarian, uterine, and cervical that has recurred despite ≥1 prior 
treatments), own a smart-phone (Android or iOS), are capable of downloading and running the study app, can 
read and provide informed consent in English, and do not have cognitive or visual impairments that would 
preclude use of the app.  
 
3.2 Exclusion Criteria 
Patients will be ineligible if they are participating in an investigational drug treatment trial that requires 
structured symptom or toxicity reporting at the time of enrollment. Patients with severe cognitive impairments 
or who appear too weak, emotionally distraught, agitated or ill to participate, as judged by either the research 
study staff or an oncology provider, will be excluded. Patients who are unable to provide informed consent in 
English will be excluded because the smartphone app intervention is only available in English at this time. 
Children and young adults up to age 20 will be excluded because the diagnosis of metastatic gynecologic 
cancers in this age group is rare and the proposed instruments are not designed for people of those ages. In 
addition, patients with a life expectancy of ≤6 months, as determined by their oncology providers, will be 
excluded since they cannot participate in all of the required data collection. Patients who are currently actively 
tracking their steps using wearable technology or smartphone apps will also be excluded.  
 
4.0 RESEARCH SUBJECT ENTRY 
 
4.1 Subject Recruitment and Enrollment 
We will enroll patients from the DFCI Gynecologic Oncology Program. Study staff, gynecologic oncology 
providers, and members of the Gynecologic Medical Oncology Team will identify patients who may be eligible 
for the study. Prior to initiating recruitment, we will meet with the clinical staff, including oncologists, embedded 
palliative care physicians, nurse practitioners, program nurses, clinical research study staff, and social workers, 
to discuss and solicit feedback on the recruitment and enrollment procedures. 
 
4.11 Screening & Recruitment 
Prior to obtaining informed consent, study staff will review the electronic medical records of patients 
listed on the gynecologic oncology providers’ clinic schedules to identify patients with metastatic, recurrent 
gynecologic cancers undergoing chemotherapy. These patients’ medical records will only be reviewed to 
confirm this protected health information (PHI), and it will only be shared with gynecologic oncology 
providers in the context of patients’ eligibility for the study.  
When an eligible patient is identified, study staff will contact the patient’s oncology provider to confirm 
she meets the eligibility criteria and to request permission to approach the patient at an upcoming clinic 
visit. If the patient is approved to approach for enrollment, the research assistant (RA) will coordinate with 
the oncology provider to meet with the patient to discuss the study at the time of her clinic visit. If the 

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oncology provider deems the patient ineligible or too distressed to participate in a clinical study at this time, 
the patient will not be approached for inclusion. 
PHI will not be shared with anyone outside of the study team and patients’ oncology providers. All 
emails will be sent within the Partner's firewall. A HIPAA waiver requesting permission to review the PHI of 
these select patients prior to consent during screening and recruitment has been submitted to justify this 
process. 
 
4.12 Informed Consent 
If a patient agrees to learn more about the study, the RA will meet with the patient to describe the 
study, review the consent form, answer any questions, and provide her contact information. The RA will 
encourage patients to take their time in deciding whether they want to participate in the study or not.  
If a patient is interested in participating, the RA will obtain written informed consent, which will include 
explaining how and why the current research study is being conducted, the study risks and benefits, the 
potential time commitment involved, and the option to give permission to be contacted for future research 
studies. The RA will explain in explicit detail what type of information will be collected from the smartphone 
application and wearable accelerometers and how these data are monitored. The RA will reiterate that the 
data collected are not a part of the patient’s standard treatment and will underscore the importance placed 
upon maintaining patient confidentiality and a patient’s rights while involved in the study, including the right 
to withdraw participation at any time for any reason during the study because participation is completely 
voluntary.  
The informed consent form will contain a section dedicated to explaining what constitutes PHI and how 
this information will be protected as confidential per HIPAA guidelines. The consent form will also provide 
contact information for both the Principal Investigator (PI) as well as the Office for the Protection of 
Research Subjects. All informed consent processes will adhere to the policies set forth by the Institutional 
Review Board. Signed informed consent forms will be stored in a locked file cabinet to maintain the privacy 
of all study participants.   
If a patient is unsure if she would like to participate in the study, she will be offered the consent form to 
review and a postage paid opt-out card (Appendix A) to notify study staff that she is not interested. If no 
contact is made after a few days, the RA will call the patient. If the patient decides to participate, the RA will 
meet her at a subsequent appointment to obtain informed consent. If a patient is not interested, the RA will 
thank her for considering, reassure the patient that the process will have no impact on her care. No further 
interactions will occur with patients who either decline or prove ineligible for the study. Patients will not be 
contacted after three unreturned voicemails. 
 
4.2 Subject Registration and Randomization 
During both phase I and phase II of the study, the RA will register eligible participants in the Clinical 
Trials Management System (CTMS) OnCore. Registrations will occur prior to beginning study interventions. 
Any participant not registered to the protocol before study interventions have begun will be considered 
ineligible and registration will be denied. An investigator will confirm eligibility criteria and a member of the 
study team will complete the protocol-specific eligibility checklist. 
Following registration, participants may begin study interventions. Issues that would cause delays in 
interventions should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive study interventions following registration, the participant’s registration on the study will be canceled. 
Registration cancellations will be made in OnCore as soon as possible. After obtaining informed consent, 
participants will be assigned a unique study ID and registered to the study in Redcap.  
The following information will be recorded for each participant in the Registration Form (Appendix B):  

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• 
Name and telephone number of RA enrolling the participant 
• 
Date participant signed consent and RA who obtained consent 
• 
Participant’s study ID and first and last initials  
• 
Participant’s date of birth 
• 
Participant’s primary oncology providers 
• 
Confirmation that participant meets eligibility criteria  
• 
Name of oncology provider who approved participant’s eligibility and date of approval  
• 
Participant’s contact preferences (phone call, text, or e-mail; collected post-consent) 
• 
Participant’s study arm (to be completed after randomization)  
In the second phase, the study team will randomize enrolled participants to one of the four arms: 1) 
Fitbit+active app, 2) Fitbit+passive app, 3) Active app, or 4) Passive app —using a 1:1:1:1 ratio using a 
computer-generated random allocation sequence with blocks of 8 in order to maintain balance between study 
arms over time. Study staff will generate group assignments in sequentially numbered and sealed opaque 
envelopes. Please refer to the protocol schema for details. 
 
5.0 STUDY DESIGN AND METHODS 
 
5.1 Design/Study Type 
 
5.11 First Phase: 
Ten patients will be purposively sampled to enroll a diverse group based upon guidelines for the Phase 
Ia and Ib of the Obesity-Related Behavioral Intervention Trials (ORBIT) model for behavioral treatment 
development (Figure 2).43 In the first phase, we will enroll at least 3 patients who are ≥65 years of age, 3 
patients from racial/ethnic minority groups, and 2 patients who do not use text messages to 
communicate >1x/week based upon evidence that patients with computer experience are more receptive to 
electronic self-reporting than those without experience.44 
 
 
 
 
 
 
 
 
 
 
 
 
We anticipate enrolling 10 patients to refine the HOPE App intervention and determine which 
accelerometer (Fitbit Zip and Fitbit Charge 2) will be used in phase II of the study. In this phase of the study all 
participants will receive the smartphone app, the Fitbit Zip, and the Fitbit Charge 2 so that we can: 1) identify 
which wearable accelerometer to use in the second phase, and 2) compare step counts between the 
accelerometers (the smartphone, a hip-worn device, and a device worn on the non-dominant arm). 
 
 
Figure 2 

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5.12 Second Phase 
A feasibility and acceptability study will employ convenience sampling from 100 consecutive patients 
who meet inclusion criteria in a pilot randomized trial of: 
Arm 1: Fitbit + active app 
Arm 2: Fitbit + passive app 
Arm 3: Active app 
Arm 4: Passive app 
 
 
There are two versions of the HOPE smartphone app—“active” and “passive.” The “active” smartphone 
app refers to the version of the smartphone app in which active symptom collection is occurring (e.g, 
patients are receiving surveys and receiving tailored symptom management advice) in addition to passive 
data collection (accelerometer, GPS. Incoming calls and texts, etc.) The “passive” smartphone app refers 
to the version of the smartphone app in which only passive data collection is occurring, and no surveys or 
active data collection are being sent to participants. In the passive app, participant interaction with the 
smartphone app consists of installing the app and keeping it running in the background of their phone; all 
data is collected in the background. The active and passive apps are built on the same underlying platform 
and the security protections for the active and passive smartphone apps are identical, detailed in Appendix 
L, HOPE App Data Privacy and Security. 
 
All patients will be assigned to a separate, secondary randomization either to be encouraged to wear 
their smartphone on them at all times, or not to be encouraged to wear their smartphone at all times (refer 
to study schema for details.) We have no reason to believe that encouragement to wear a smartphone will 
impact  patients’ health-related quality of life, performance status, and use of high-intensity health 
care/phone calls; thus, the secondary randomization will not impact the comparison of the 4 study arms for 
these outcomes.  
 
With a total sample size of 100 patients (25 patients per arm), this study design will yield 70% power to 
detect a 6-point change in EQ-5D and 80% power to detect a 7-point change in patients’ health-related 
quality of life (measured with the EQ-5D; see section 6.0). Our analyses will also provide preliminary 
estimates of feasibility, acceptability, safety outcomes, scale scores, missing data, and participant and 
physician feedback.  
5.2 Selection of Instruments 
 
5.21 Interviews and Surveys 
The following measures will be used in the study interviews and surveys, including the Participant 
Baseline Interview (Appendix C), Participant Post-Baseline Interview (Appendix D), Clinician Survey 
(Appendix E), and Symptom Survey (Appendix F). Table 1 outlines their distribution across the study 
instruments. 
 
5.21a Global Health Status: EQ-5D-5L 
The EQ-5D is a standardized measurement of health status that has been used in a wide range of 
health conditions and treatments, including cancer patient populations.45 The EQ-5D-5L is the most 
recent 5-level version that has proven validity and reliability in a range of patient groups with chronic 
diseases46 and cancer.47 It is a 5-item questionnaire (measuring mobility, self-care, usual activities,  

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pain/discomfort, and anxiety/depression. Each dimension has three levels of perceived problems: 1) no 
problems, 2) slight problems, 3) moderate problems 4) severe problems, and 5) extreme problems. 
Patients check the statement level that best describes their current health status in each dimension, 
which are then scored to generate a patient’s unique health state. In the EQ-VAS, patients report a 
single index value of how good or bad their current health state is on a visual scale that ranges from 
worst imaginable at zero to best imaginable at one hundred. The EQ-5D-5L can be administered with 
little to no guidance and takes only a few minutes to complete. Upon scoring, the EQ-5D produces a 
composite score between 0-1 (multiplied by 100 to generate a number between 0-100), which 
represents general health status, normalized for the US population.48 Lower scores represent worse 
quality of life, and a change of ≥6 is clinically significant in US cancer populations.49 
 
5.21b PROMIS Global-10 and PROMIS Physical Function short form 6b 
The PROMIS Global-10 is a brief measure of patient health status that is not disease specific.50,51 It 
consists of 10 questions; e.g. “In general, how would you rate your physical health?” Items are scored 
on a Likert scale of 1-5, where higher scores indicate better health, except for pain which is measured 
on a 10 point scale. Standardized T-scores (range 0-100) are calculated for the global physical and 
mental health scales, and higher scores indicate better health. The full scale takes approximately 2-3 
minutes to complete and will be used at baseline, post-baseline survey and the single-item global 
quality of life and physical health questions will be used daily among those randomized to the 
smartphone app. 
The PROMIS Physical function (PF) 6b is a brief, 6 item measure used to characterize patients’ 
overall health, level of physical disability, and general well-being. The PROMIS PF 6b has been 
validated in 4,840 cancer patients across a range of ages, racial/ethnicity groups, stages and cancer 
types, and normalized for the US population. It has high reliability, minimal floor effects, and can 
precisely measure meaningful differences in functional status, disease burden, and comorbidities. 
 
5.21c Performance Status: ECOG PS 
The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) assessment is a 
standard measurement that oncologists often use to assess a patient’s current functional level and 
eligibility for clinical trials. The scale ranges from 0 to 5 and the criteria for each grade is as follows: 0 = 
Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically 
strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light 
house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours; 3 = Capable of only limited self-care; confined 
to bed or chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on any self-care; 
totally confined to bed or chair; 5 = Dead.52  
The ECOG PS will allow clinicians and participants to provide a standard evaluation of the 
participant’s performance status over time and with minimal burden. Participants will use the patient 
self-report version that has been used successfully in a study with cancer patients. We expect that it will 
take 1-2 minutes to answer the question.53 
 
5.21d Depression: PHQ-9 
The Patient Health Questionnaire-9 (PHQ-9) is a validated self-report measure that assesses nine 
depressive symptoms using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
(DSM-IV) diagnostic criteria for major depressive disorder. It is used to screen, diagnose, and monitor 
depressive symptoms54 and has been administered/demonstrated validity in cancer patients,55,56 as well 
as smartphone apps.27 Respondents report if each symptom has bothered them “not at all,” “several 

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days,” “more than half the days,” or “nearly every day” during the previous two weeks.57 We expect that 
it will take participants no more than 3-5 minutes to complete.  
 
5.21e Symptoms Assessment: CTCAE and PRO-CTCAE  
The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) is a patient-centered, standardized self-report measure that enables patients to report 
symptoms and AEs. Clinicians will use the standard CTCAE items (used to rate and report toxicities in 
therapeutic drug trials) while participants will use the PRO-CTCAE items. Dr. Schrag, one of the study’s 
investigators, was one of the first researchers to identify, develop, test, refine and validate methods for 
collecting PROs.17-19,22 She was instrumental in the development of the primary study measure, the 
PRO-CTCAE, which demonstrated favorable validity, reliability, and responsiveness in a large 
heterogeneous United States sample of cancer patients undergoing treatment.19 Ten PRO-CTCAE 
items that are salient to gynecologic cancers will be collected, including: abdominal pain, nausea, 
vomiting, constipation, diarrhea, peripheral neuropathy, anxiety, depression, dizziness and fatigue.  
The PRO-CTCAE items use conditional branching for AEs that contain multiple attributes. For 
example, if a participant reports a symptom, she is asked to quantify the severity and the extent to 
which the symptom interfered with her daily activities; if she does not report a symptom, these items are 
skipped. We anticipate that participants and oncology providers will complete their respective versions 
of the measure in about 3-5 minutes. Participants enrolled in phase I, and intervention arms 3 and 4 in 
the second phase RCT will also report their symptoms weekly in the HOPE app intervention. 
 
5.21f Anxiety: GAD-7 
The Generalized Anxiety Disorder 7-Item (GAD-7) is a reliable and validated self-report measure 
that assesses GAD. Respondents rate how often they have been bothered by 7 anxiety symptoms over 
the past two weeks using the following scale: 0 = Not at all; 1 = Several Days; 2 = Over half the days; 
and 3 = Nearly every day. Respondents also answer a question to assess the duration of their anxiety 
symptoms. Responses are tallied and the total score indicates the presence and severity of GAD.58  
The measure has since been validated in the general population59 and was the recommended 
evaluative measure for anxiety in adult cancer patients in the 2014 American Society of Clinical 
Oncology (ASCO) Guideline Adaptation.60 We anticipate that it will take participants approximately 3-5 
minutes to complete. 
 
5.21j Overall Quality of Life and Physical Health:  FACIT-PAL 
Patients’ quality of life (QoL) will be assessed with Functional Assessment of Chronic Illness 
Therapy – Palliative Care, which has demonstrated internal consistency, reliability and validity.68 The 
measure is divided into four primary QoL domains: physical well-being (7-items), social/family well-
being (7-items), emotional well-being (6-items), and functional well-being (7-items). It also includes 12 
additional items that are specific to palliative care priorities for patients with chronic illnesses such as 
cancer.  Participants will rate each symptom over the past 7 days as: 0) Not at all; 1) A little bit; 2) 
Somewhat, 3) Quite a bit, and 4) Very much. Subscales can be analyzed separately or aggregated to 
produce a total score.  
 
5.21k Literacy Measures: Health Literacy and Numeracy & Mobile Communication Competence 
Health literacy69 and numeracy70 and mobile communication competence71 will be collected for all 
participants at baseline. The “comfort with technology” and “mobile preference” subscales of the Mobile 
Communication Competence scale will be used because they assess factors directly impacting patients 
in our study, who will be asked to acclimate to and consistently use an accelerometer and/or 

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smartphone app. The mobile communication preference and comfort with technology subscales 
individually demonstrated internal reliability, consistency and validity. We estimate that it will take 
participants approximately 5 minutes to complete all of the literacy measures. 
 
5.21l Demographic Information 
Basic demographic information will be collected for all participants, including: age, marital status, 
race/ethnicity, education, household structure, income, and employment. The questions will only take a 
few minutes to complete.  
 
5.21m Smartphone Usage Questions  
Data on smartphone-specific usage habits will be collected for all participants. Participants will be 
asked a total of four questions: average daily time spent using smartphone, purpose of using 
smartphone, comfort using smartphone apps, and frequency of using smartphone apps. We estimate 
that it will take participants approximately 2 minutes to complete these questions. 
 
5.21n Cancer Experience Question 
 
About the cancer experience question 
On a weekly basis, participants will be asked one qualitative question about their cancer 
experience. We hope that this open-ended question will give patients an opportunity within the study to 
express additional concerns, emotions and experiences regarding their cancer that may not be 
adequately reflected in other study instruments.  A large body of previous work has successfully asked 
cancer patients to share open-ended, qualitative measures of their emotional experiences (i.e. by 
writing in response to a prompt).87-91 However, to our knowledge, our study will be the first to examine 
whether these qualitative measures correspond with clinical outcomes measured in real time in the real 
world.  
  
Using a question adapted from Stanton and colleagues’ emotional expression study with breast 
cancer survivors,72 participants will be asked to describe their experience with cancer over the course of 
the previous week. Participants will be presented with the cancer experience question as an audio 
survey within the HOPE App once a week (see Appendix F for question text) and will record their 
answers into the microphone of their smartphone. The app reminds the participant to make a voice 
recording in the same way that it reminds the participant to take any other survey in the HOPE app: by 
making a notification appear in the phone. The participant does not need to make a voice recording 
immediately and may wait until she is in private to do so.  The participant can make the audio recording 
in the app at any time after the notification appears, until the next audio recording reminder replaces it. 
Participants will spend up to 5 minutes on this question, depending on how much they wish to share. 
This question will be answered within the smartphone app at the baseline interview and symptom 
survey (once weekly). 
 
Audio recording data security 
Patients will be informed about the audio recording questions in the study in the consent form 
and during the informed consent process and will be encouraged to ask any questions they may have 
about the audio recording.  
In the weekly audio recording questions, the participant’s voice is recorded as an MP4 audio file 
so that researchers can analyze the audio file. The app’s voice recording feature does not ask for any 
identifiable information, but it is conceivable that, in the course of describing his/her day, a participant 

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could speak his/her own name or reveal other identifying details. As such, the voice recording data is 
encrypted. 
For all data except voice recording data, the app encrypts the data line-by-line as it writes data 
to the device’s disk. This means that the app never writes unencrypted data to disk for these files. For 
the voice recording file, it is not feasible to do on-the-fly asymmetric encryption (since most of the 
established stream ciphers use symmetric encryption), so the voice recording file is encrypted once the 
recording is complete.  Because the phone cannot decrypt any of its own data, when the participant 
views his/her survey answers, the participant is actually logging in to the server, downloading the 
answers via an SSL connection, and effectively viewing them through an HTTPS site, not decrypting 
any data on the phone. 
The HOPE App will employ the same data privacy and security processes used in six IRB 
approved protocols across three Partners Institutions (BIDMC Protocol #: 2015P-000240; McLean 
Hospital Protocol #s: 2015P001303, 2015P001538, 2012P000890, 2015P002189; MGH Protocol #: 
2015P000666). This list includes IRB-approved research studies that have also used the voice 
recording component of the app with patients as research participants. Although the app collects a 
large amount of data, it was custom built to be used in a health care setting and includes robust 
security and privacy features to safeguard all data and protect participants’ privacy, including data 
anonymity, participant authentication, and data encryption. 
Recordings will be tied only to a study ID number, and the only document linking the patient’s 
study ID to identifiable information is in a restricted-access, password-protected file stored securely on 
Dana-Farber servers. Audio recordings from the HOPE App will be transcribed for further analysis 
using a DFCI-approved, HIPAA-compliant transcription vendor. All patient identifiable information will 
be removed when the audio recordings are transcribed. Audio recordings will be destroyed when 
analyses are complete. 
 
Cancer experience question analysis plan 
We plan to analyze qualitative data from the cancer experience question using the Linguistic 
Inquiry and Word Count (LIWC) program,92 developed by James Pennebaker and colleagues and used 
widely in emotional expression literature with cancer patients and other populations.87-90, 93 LIWC reads 
text and identifies which words are associated with psychologically-relevant categories, i.e. affect, 
cognitive processes, content dimensions, etc.94 Because the holistic nature of the responses may not 
be adequately captured by the word count approach of LIWC analyses, we also plan to perform a 
content analysis93, 96-97 of the output from the cancer experience question with trained independent 
raters, examining categories of psychologically relevant content in the recordings.  For Phase I, due to 
the limited sample size, analyses will be descriptive in nature. For Phase II, we plan to use multivariate 
analyses of covariance (MANCOVA) as primary statistical procedures, controlling for baseline values, 
on conceptually related groups of variables including physical health-related outcomes (i.e., symptoms 
and healthcare utilization),  psychological adjustment as measured by other study instruments (i.e., 
quality of life and emotional acceptance), and psychological properties of participants’ responses to the 
cancer experience question (i.e. positive and negative affect). We also plan to conduct preliminary 
multivariate analyses of variance for continuous variables and chi-squared analyses for categorical 
variables, on demographic variables, cancer-related parameters, and other relevant variables (e.g 
quality of life) at baseline. If relevant, we will use the baseline values on these measures as covariates 
to control for nonsignificant chance variation between groups at baseline.72 
 
 

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5.21o Brief COPE 
The Brief COPE is a 28-item measure developed to assess a broad range of coping 
responses.91 The Brief COPE has been validated in several populations including breast cancer 
patients and community samples.91 Subscales of the Brief COPE include use of emotional support, 
religion, and self-distraction, and individual subscales can be used independently. We will use the 
denial, behavioral disengagement, self-distraction, active coping, use of emotional support, use of 
instrumental support, positive reframing, planning, acceptance, and religion subscales of the Brief 
COPE. The Brief COPE will be administered to patients during the participant baseline interview 
(Appendix C). 
5.21p Note on Smartphone Surveys 
The PHQ-9 is not administered through the smartphone application—only during baseline and 
post-baseline surveys, which are administered by a research assistant—so the study team will become 
aware of any concerning responses to PHQ-9 items immediately. We will review the symptom surveys 
administered over Beiwe daily and have developed an automated internal reporting tool for this 
purpose. The audio recordings will be reviewed at the end of the study, and patients will be notified that 
the recordings will not be reviewed in real-time by a clinician when they are taught how to use the 
smartphone app. Additionally, after each symptom survey, patients are automatically reminded that a 
clinician will not see their responses in real-time and that they must contact their clinicians with 
concerns. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1. Distribution of measures during Phase 1 and Phase 2 
 
 
INSTRUMENTS1 
 
 
Participant Baseline 
Interview 
Participant Post-
Baseline 
Interview  
Clinician 
Survey  
Symptom 
Survey 
 
 
 
Phase 1 
Phase 2 
Phase 
1 
Phase 
2 
MEASURE 
PRO-CTCAE 
✓ 
✓ 
✓ 
✓ 
 
✓  
PROMIS Global-10 and 
Physical Function 6b 
✓ 
✓ 
✓ 
✓ 
 
✓ 
CTCAE 
 
 
 
 
✓ 
 
ECOG PS 
✓ 
✓ 
✓ 
✓ 
✓ 
 
PHQ-9 
✓ 
✓ 
✓ 
✓ 
 
 
GAD-7 
✓ 
✓ 
✓ 
✓ 
 
 
EQ-5D-5L 
✓ 
✓ 
✓ 
✓ 
✓ 
 
FACIT-PAL 
✓ 
✓ 
✓ 
✓ 
 
 
Brief COPE 
 
✓ 
 
 
 
 
Health Literacy & 
Numeracy 
✓ 
✓ 
 
 
 
 
Cancer Experience 
Question 
 
✓ 
 
 
 
✓ 
Mobile Communication 
Competence 
✓ 
✓ 
 
 
 
 
Smartphone Usage 
Questions 
✓ 
✓ 
 
 
 
 
Demographic Info 
✓ 
✓ 
 
 
 
 
1 Measures were refined during phase I, resulting in the addition or omission of instruments in response to 
patient or physician feedback 
 
5.22 Medical Chart Abstractions and Patient-Reported Medical Resource Utilization 
 
5.22a Health/Treatment Information 
Participants’ medical charts will be reviewed to abstract health and treatment related information, 
including disease site, comorbid health conditions,73 number of prior chemotherapy regimens, and time 
since diagnosis. Data will be recorded in the Health/Tx Info form (Appendix G). 
 
5.22b Health Care Utilization 
Participants’ medical charts will be reviewed to abstract health care utilization data during 
enrollment, including chemotherapy regimen and treatments, palliative care visits, emergency 
department visits, hospitalizations, and hospice referrals. If a participant dies while enrolled in the 
study, the date of death will also be recorded. Data will be recorded in the Health Care Utilization form 

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(Appendix H). Participants will also be given a patient diary to record all health care utilization that 
occurs during the study period, including hospitalizations, admissions to an intensive care unit, 
emergency room and urgent care visits, and oncology visits. This form was developed by the NRG 
Cancer Care Delivery Research Group because of a recognition that participants often receive care at 
outside hospitals that cannot be captured by abstracting the medical record. Clinical research 
coordinators will be asked to verify medical care that happened within a site-affiliated medical center. 
Participants’ medical charts will be reviewed to abstract health care utilization data during enrollment, 
including chemotherapy regimen and treatments, palliative care visits, emergency department visits, 
hospitalizations, and hospice referrals. If a participant dies while enrolled in the study, the date of death 
will also be recorded. Data will be recorded in the Medical Resource Utilization Form (Appendix Z). 
Additionally, participants will be asked about whether they (or their informal caregiver) needed to take 
time off from work, how far they traveled for treatment, and for a rough estimate of their out-of-pocket 
expenditures to capture some of the burden associated with cancer care. 
 
5.22c Call Log  
Per usual care, program nurses in the Division of Gynecologic Oncology will document participants’ 
phone calls with clinical staff in participants’ electronic medical health records. Study staff will abstract 
information about these phone calls during a participant’s enrollment and record data in the Call Log 
(Appendix I). Data collected for each call will include: date/time, incoming/outgoing, left message, 
duration in minutes, reason for the call, symptoms documented, and the outcome. 
 
5.23 Debriefing Interviews 
Debriefing interviews will be conducted with participants enrolled in the first phase and their oncology 
providers. The purpose of these interviews is to obtain information about the acceptability of the 
interventions and recommendations for modifications to improve any aspect of recruitment, enrollment, 
education, timing of study assessments, and the graphical display of information, the wearable 
accelerometers, and the smartphone app. We will also conduct debriefing interviews with a purposively 
sampled subset of patients enrolled in Phase II (see Appendix J: Debriefing Interviews for Phase 2). We 
will administer interviews to 5 patients enrolled in each arm of the study. We will aim to sample a subset of 
patients with varying backgrounds and experiences with the study in order to better understand how the 
HOPE trial interventions work across a diverse patient population.  
Additionally, debriefing interviews will be audiotaped in order to ensure that the interviewer adequately 
captures all feedback from patients and caregivers. The consent forms for the study include information 
that the debriefing interview will be audiotaped, and we will verbally request permission from patients to 
audiotape the debriefing interview before beginning the interview. Verbal permission will be documented on 
RedCap in Appendix J: Debriefing Interviews for Phase 2. We will not administer a debriefing interview to 
any patient who does not consent to being audiotaped during the debriefing interview. All audio recordings 
of study sessions will be stored in secure locations in restricted-access, locked filing cabinets on Dana 10 
and 11, and in password-protected folders on Partners servers. Recordings will be tied only to a study ID 
number, and the only document linking the patient’s study ID to identifiable information is in a restricted-
access, password-protected file stored securely on Dana-Farber servers. Audiotapes of debriefing 
interviews will be transcribed for further analysis using a DFCI-approved, HIPAA-compliant transcription 
vendor. All patient identifiable information will be removed when the audio recordings are transcribed. 
Audio recordings of debriefing interviews will be destroyed when analyses are complete. 
 
5.3 Description of Interventions 

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Per the protocol schema, the first phase of the study will test the HOPE app with the Fitbit Zip or the Fitbit 
Charge 2. Based on the usability and acceptability data, the larger pilot RCT will test the HOPE app and the 
Fitbit model selected based upon user feedback. Based upon participant feedback (70% preferred Charge 2) 
from the first phase of the study, Phase II will test the HOPE app with the Fitbit Charge 2.  
 
5.31 Monitored Wearable Accelerometer: Fitbit 
The Fitbit Zip is a commercially available accelerometer that is worn on the hip and tracks users’ steps, 
distance, calories burned, and active minutes. The accuracy of the step counts reported by Fitbit’s hip-worn 
accelerometers have been validated against treadmill walking,74 other accelerometers,75, 76 and an indirect 
calorimetry device.77 In addition, the Fitbit Zip was found to be the most valid device in a study that 
examined the validity and reliability of ten commercially available accelerometers for measuring step count 
against the gold standard devices used in laboratory and free-living conditions.78  One of the advantages of 
the Fitbit Zip is it runs off of a watch battery which only needs replacing every 2-3 months. One of the 
disadvantages to using the device in free-living conditions is it may be difficult to distinguish between low 
activity levels and low adherence to the device. 
 
The Fitbit Charge 2 is an accelerometer that is worn on the wrist and tracks users’ heart rate 
continuously in addition to steps, distance, calories, and active minutes. The addition of an optimal heart 
rate sensor enables monitoring of the time that the tracker is being worn (e.g., adherence).79, 80 Wrist-worn 
activity trackers have been shown to accurately measure heart rate when compared with 
electrocardiography,81, 82 have good test-retest reliability (intraclass correlations of 0.75-0.95)78 but over 
count steps compared with the gold standard ActivPAL in free-living conditions due to the variability in limb-
specific activities.83 One of the advantages of the Fitbit Charge 2 is it allows for close monitoring of 
adherence to the device over time because of its continuous measurement of heart rate. The 
disadvantages include: it is not as accurate as a hip-worn device, is dependent upon the user to recharge it 
every 3 days, and may be less accurate if the participant is dependent upon a device for ambulating (e.g., 
cane or walker) or wears the device on her non-dominant arm. 
Fitbit data will be stored with Fitabase, (Small Steps Labs LLC), a third-party research platform 
designed to collect data from the Fitbit (https://www.fitabase.com). It provides minute-by-minute measures 
(e.g. steps, heart rate) for data monitoring and analysis.82 All data will be anonymized with the use of 
participant codes, and the data will be stored a in high security data center. 82, 84  
 
5.32 Smartphone Application: HOPE App 
The other intervention is an iOS and Android smartphone application that runs on participants’ 
personal smartphones and collects information about their health and behaviors. Originally named “Beiwe,” 
the app was conceived and designed by one of the co-investigators, Dr. Jukka-Pekka Onnela, at the 
Harvard T.H. Chan School of Public Health. Zagaran, Inc., located in Cambridge, Massachusetts, built the 
software.  
In a prior pilot study, Dr. Onnela tested the app in 13 patients with major depressive disorder. 
Participants installed the app on their personal smartphones and completed a self-report survey of PHQ-9 
items 3 times per day with >75% adherence to the app over a 30-day period27. Participants scores were 
strongly correlated with paper-based surveys administered in clinic (Pearson linear correlation coefficient 
0.84) but were 3.0 points higher on average (i.e. indicating more distress), and participants were much 
more likely to report significant suicidal ideation.  
Since this publication, Dr. Onnela’s lab has developed a more sophisticated system that features a 
web-based research study portal, a customizable Android and iOS smartphone app, Amazon Web 
Services S3 database, and data modeling and analysis tools. The app collects many different types of 
sensor data and administers surveys. Although this platform has not yet been used in cancer patients, 

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there are currently 8 IRB approved protocols across local centers that are utilizing the Beiwe application in 
research, including Beth Israel Deaconess Medical Center, Harvard University (Faculty of Arts and 
Sciences), McLean Hospital, and Massachusetts General Hospital. Three studies have begun enrolling 
patients or healthy controls, and the user experience has been overwhelmingly positive. In addition, there 
are no signs that adherence is condition-specific to date. 
In this study, the active smartphone app is named the “Helping Our Patients Excel (HOPE)” app.   
 
5.32a. App Versions (Active vs. Passive) 
The HOPE Trial will employ two different versions of the customized smartphone app: an “active” app 
and a “passive” app. 
 
Active app: The “active” app collects both active and passive data from the participant’s phone 
usage. Active data is collected while a patient is using the app (e.g. responding to survey questions). 
Passive data is collected continuously without patient input. Patients using the active app will be asked 
to actively respond to survey questions including the symptom survey and cancer experience question. 
  
Passive app: The “passive” app collects passive data only from the participant’s phone usage. It does 
NOT collect active data (e.g, the participant will not be asked to respond to any survey questions.) The 
passive data collection will occur in the background of the phone. 
 
As noted above, both the active app and passive app collect passive data from the participant’s phone. 
Specifically, as detailed in the HOPE App Data Privacy and Security (Appendix L), passive data 
includes: mobility traces, consisting of flights (linear segments of movement) and pauses (times of no 
movement) which are constructed from GPS data; and summary statistics of phone communication 
(calls and text messages) patterns, simple examples being the total number of communication events 
in a time period (e.g., 1 week), the total number of communication partners, reciprocity of 
communication (defined as the difference between outgoing communication volume and incoming 
communication volume).  
 
The active and passive app are built on the same underlying platform (Beiwe). As such, the active and 
passive app have identical data security protections, which are detailed in Appendix L, HOPE App Data 
Privacy and Security. 
 
5.32b Software and Data Collection Features  
The smartphone apps employ the original features and data collection methods used in the 
aforementioned studies and protocols. Consult HOPE App Features and Screenshots (Appendix K) for 
descriptions of the app’s features, including: log-in screen, “Call My Clinician” button, “Forgot 
Password” button, notifications, surveys, “Call Research Assistant” button, and main menu.  
 
5.32c Symptom Management 
The active smartphone app is designed to collect and assess participants’ toxicities and symptoms 
on chemotherapy treatment in between visits with their clinician. Participants report the severity of their 
symptoms via a brief in-app survey of PRO-CTCAE items. The app then determines a symptom’s risk 
level and necessary response, which is either to provide no intervention, tailored symptom 
management advice, or an alert to call the clinician. Figure 3 provides a more detailed overview of this 
process. 

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The symptom response criteria and the Symptom Management Content (Appendix M) were 
developed by research staff in cooperation with the gynecologic oncology providers and staff nurses at 
Dana-Farber. The study PI, who is also a practicing gynecologic oncologist on the gynecologic 
oncology team, collated reputable and trusted sources, such as ASCO, the National Cancer Institute, 
and Dana-Farber, to create the content for each symptom, which includes: symptom management 
advice and questions to ask the clinical team. The content and response criteria were then reviewed 
and refined by study investigators, research staff, and gynecologic oncology clinicians to produce the 
final versions.  
 
5.33 HOPE Symptom Education Website 
In Phase II of the study, participants randomized to receive the Fitbit+active app, or active app 
arms will have access to a website (www.hopetrial.org) which will contain static patient education 
materials about the symptoms that are targeted in the HOPE app. This website will present evidence-
based information on symptom education and symptom management. Some of the content on the 
website will mirror the content in the symptom management app, while other information will be housed 
only on the website. The purpose of the website is to provide a centralized location for patients to find 
symptom education and symptom management information at any time they might be experiencing low-
level symptoms. Content will be created by the study PI (a practicing gynecologic oncologist at DFCI) 
and the study team, and will include information from trusted sources such as the NCI and ASCO.   
 
 
5.34 Encouragement to Wear Smartphone 
 
In Phase II of the study, participants will be randomized both to a main study arm and a 
secondary randomization. The secondary randomization will randomize patients either to be 
encouraged to wear the smartphone at all times during the study (n=50), or not encouraged to wear the 
smartphone at all times during the study (n=50). Participants who are randomized to the “encouraged” 
arm will receive an appliance (e.g belt clip/arm band) which will allow them to carry their smartphone 
with them throughout the day, including while they would not ordinarily carry their smartphones with 
them (such as when walking around inside the home.)  Participants who are randomized to the “not 
encouraged” arm will not receive any instructions about keeping their smartphone with them, and will 
not be provided with an appliance to carry their phone throughout the day.

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Figure 3. Symptom classification and response in the active smartphone app intervention 
 
 
The participant reports the severity of her symptoms 
using PRO-CTCAE items with conditional branching  
No intervention 
No information is given 
Symptom management 
Presents advice on how to manage 
the symptom at home; includes links 
to questions to ask the clinical team 
and additional diet recommendations 
when appropriate 
Alert to call clinician 
Notifies the patient that her symptom 
is severe and requires further 
management from her clinical team; 
Alert instructs the patient to hit the 
“Call My Clinician” button 
The patient hits the button 
and is directed to the staff 
nurses for triage 
The app displays a custom survey completion screen 
using the symptoms’ intervention classification 
The active HOPE app 
The app prompts participants to complete daily surveys. 
For each symptom, the app classifies the intervention 
needed based upon the reported severity:  
a) No intervention 
b) Symptom management 
c) Alert to call clinician 
The patient reports her symptoms for all PRO-CTCAE 
survey items and clicks “submit” 
 In  
In Phase II, participants 
randomized to receive the 
active HOPE app will have 
access to a website with 
static symptom education 

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5.4 Data Collection 
Tables 2 and 3 specify the instrument and intervention data collection timelines during each study 
phase. Intervention data will be collected continuously during enrollment; all synch automatically over Wi-Fi. 
Table 2. First phase instrument data collection 
 
 
 
 
 
 
 
 
 
Table 3. Second phase RCT instrument data collection per study arm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DAY 
Visit 
0 
1-29 
Visit 
30 
INSTRUMENT 
Participant Baseline Interview 
✓ 
 
 
Participant Post-Baseline 
Interview 
 
 
✓ 
Clinician Survey 
✓ 
 
✓ 
Debriefing Interviews 
 
 
✓ 
Accelerometer Data 
 
✓ 
✓ 
Daily QoL,PF, and Symptom 
Questions 
 
✓ 
 
Weekly Symptom Survey 
 
✓ 
 
Passive App Data 
 
✓ 
✓ 
 
 
DAY 
 
Visit 
0 
1-29 
Visit 
30 
31-89 
Visit 
90 
91-179 
Visit 
180 
INSTRUMENT 
Participant Baseline 
Interview 
1,2,3,
4 
 
 
 
 
 
 
Participant Post-
Baseline Interview 
 
 
1,2,3,4 
 
1,2,3,4 
 
1,2,3,4 
Clinician Survey 
1,2,3,
4 
 
1,2,3,4 
 
1,2,3,4 
 
1,2,3,4 
Health/Tx Info 
1,2,3,
4 
 
1,2,3,4 
 
1,2,3,4 
 
1,2,3,4 
Healthcare 
Utilization 
 
 
1,2,3,4 
 
1,2,3,4 
 
1,2,3,4 
Call Log 
 
 
1,2,3,4 
 
1,2,3,4 
 
1,2,3,4 
Accelerometer Data 
 
1,2 
1,2 
1,2 
1,2 
1,2 
1,2 
Daily Quality of Life, 
Physical Function, 
and Symptom 
Questions 
 
1,3 
1,3 
1,3 
1,3 
1,3 
1,3 
Weekly Cancer 
Experience 
Question 
1,3 
1,3 
 
1,3 
 
1,3 
 
Weekly Physical 
Function Survey 
 
1,3 
1,3 
1,3 
1,3 
1,3 
1,3 
1. Fitbit + active app 
2. Fitbit + passive app 
3. Active app 
4. Passive app 

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Data obtained via interviews, surveys and chart abstractions will be stored on the Harvard REDCap server. 
HOPE App will employ the same data privacy and security processes used in six IRB approved protocols 
across three Partners Institutions (BIDMC Protocol #: 2015P-000240; McLean Hospital Protocol #s: 
2015P001303, 2015P001538, 2012P000890, 2015P002189; MGH Protocol #: 2015P000666). Although the 
app collects a large amount of data, it was custom built to be used in a health care setting and includes robust 
security and privacy features to safeguard all data and protect participants’ privacy, including data anonymity, 
participant authentication, and data encryption. Hope App Data Privacy and Security describes the processes 
in detail. 
Fitbit data will be stored with Fitabase, a research platform that collects and stores data from Internet 
connected devices, like Fitbit, for monitoring and analysis. It provides minute-by-minute measures (e.g. steps, 
heart rate) for data monitoring and analysis.82 All data will be anonymized with the use of participant codes, 
and the data will be stored a in high security data center., 82,84 
 
5.5 Description of Study Process 
Study procedures for the first phase are outlined below. Prior to opening the second phase, the study protocol 
and procedures will be amended based upon participant and clinician feedback. The RA will be primarily 
responsible for carrying out the following procedures; study staff will be trained accordingly so they can 
perform procedures as needed. 
 
Based on the study team’s experience conducting pilot studies, we understand that piloting minimal-risk 
interventions must be flexible in order to ensure that they can quickly adapt to patient needs as we learn more 
about them over the course of the study. The study activities currently outlined in the protocol therefore may be 
adapted without the submission of an amendment in cases where these modifications would pose no 
additional risk to patients, as determined by the study PI.  
5.51 Instrument Administration  
 
Participant Baseline Interview: 
• 
The RA will administer the survey to participants via an in-person interview on Day 0 before or after the 
participant’s visit with her oncology provider (Baseline Visit). 
• 
Participants will complete the interview on the same day informed consent is obtained; if this is not 
possible, the RA and participant will plan to complete it at a subsequent visit. 
• 
Participants will not be asked to come to Dana-Farber outside of their regularly scheduled visits.  
• 
Estimated time to completion: 45 minutes.  
 
Participant Post-Baseline Interview: 
• 
The RA will administer the interview to participants via an in-person interview before or after a regularly 
scheduled visit that falls as close to the projected assessment date as possible (Post-Baseline Visit).  
• 
Every effort will be made to administer the interview in-person and on the date of the Post-Baseline 
Visit. If this is not feasible, participants will complete it over the phone as close to the visit date as 
possible. 
• 
To encourage participation and reduce the number of incomplete interviews, participants will be 
contacted prior to their visit to confirm the date of their upcoming visit and interview. 
• 
Estimated time to completion: 30 minutes.  

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Clinician Surveys: 
• 
The oncology provider(s) who met with the participant during the Baseline and Post-Baseline Visit will 
complete the survey. 
• 
To help ensure surveys are completed in a timely manner, study staff will highlight their importance 
during study training and elicit clinicians’ preferences for receiving and completing surveys, which will 
include: a HIPAA-compliant email, Redcap survey, hard copy, or in-person interview. 
• 
The RA will administer the survey according to the provider’s personal preferences within 24 hours of 
the visit. If not completed within 48 hours of receipt, she will leave a hard copy in the clinician’s office or 
administer the survey during the weekly GYN research meeting. 
• 
Estimated time to completion: 5 minutes. 
Symptom Survey: 
• 
Participants will be prompted by the HOPE app to complete the survey. 
• 
The surveys will consist of single item measures of global quality of life and physical health, 
administered daily; the PROMIS PF 6b (6-item questionnaire about physical function) administered 
weekly; PRO-CTCAE questions for 10 symptoms, administered weekly (2 symptoms per day over 5 
days); and a cancer experience question (audio recording), administered weekly. 
• 
Survey items will not interfere with participants’ use of their phone, but they will remain present until 
they are completed.  
• 
Estimated time to completion: 3-5 minutes. 
• 
At each subsequent visit, participants and their oncology providers will be given a summary of their 
survey responses since the last visit.  
 
Debriefing Interview: 
• 
The RA will conduct debriefing interviews with participants enrolled in the first phase and a subset of 
the patients enrolled in the second phase immediately following their completion of the final post-
baseline survey (either in-person or over the phone). 
• 
Study staff will discuss the debriefing interviews to identify opportunities for protocol improvement. 
• 
Estimated time to completion: 5-10 minutes 
 
Health/Treatment Chart Abstraction: 
• 
The RA will review participants’ medical charts to complete the Health/Tx Information form at the time 
of participants’ baseline and post-baseline visits.  
• 
Chart abstractions will be completed within 10 days of participants’ study visits. 
Health Care Utilization Chart Abstraction: 
• 
The RA will review participants’ medical charts to complete the Health Care Utilization form at the time 
of participants’ baseline and post-baseline visits. 
• 
Chart abstractions will be completed within 10 days of participants’ study visits. 
 
 
 
 

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5.52 Intervention Administration  
 
5.52a Smartphone App 
Instructional Session (passive and active app): 
• 
Following the completion of the Participant Baseline Survey on Day 0, study staff will help 
participants download, install, and run the HOPE App on their personal smartphones. 
• 
Participants will be prompted by Android or iOS to agree install the app and the software will review 
what the app will have access to on the phone (see the participant guide). This language is part of 
the Android and iOS operating systems and cannot be changed. There is no way to prevent this 
message, which is a basic security feature in Android and reflects the broadest possible access 
granted to an application.  
• 
To ensure that subjects are not misinformed, the study staff member will explain the app’s privacy 
and data security in the HOPE App Required Reading & Discussion document (Appendix N). It 
should be noted that the discussion related to access on page 3 is specific to Android phones only. 
• 
When the app opens, participants will register using a unique User ID and temporary password and 
then choose a new password. The subject will be assigned a unique 8-character Participant ID 
which consists of mixture of numbers and letters. The app does not ask the subject to enter any 
personal information (name, date of birth, phone number, etc.) and cannot be directly linked to their 
DFCI health records. 
• 
Participants will enter their oncology providers’ phone numbers for the “Call my Clinician” button 
and enter the RA’s contact number for the “Call Research Assistant” button.  
• 
At the end of the registration process, the participant will click a button to acknowledge she has 
reviewed the information with the RA and provide in-app consent.  
• 
The RA will then review how to use the app and participants will be given a copy of the HOPE App 
Participant Guide-Active App (Appendix O) or the HOPE App Participant Guide—Passive App 
(Appendix W) which describes the app and provides directions on how to use its features, 
frequently asked questions, as well a review of the data that is collected and privacy measures.  
 
Symptom Management (Active app only): 
• 
Participants will be prompted to answer single item global measures of their quality of life and 
physical health daily; answer 6 questions about their physical function weekly; answer one question 
about their cancer experience weekly; and answer questions about 2 symptoms daily in between 
study visits via the HOPE App in the Symptom Survey (details in section 5.52).  
• 
If a participant reports one or more low-risk toxicities, the app will present tailored advice on how 
she can manage each symptom at home. If participants report high-risk toxicities, they will be 
instructed that they have reported a toxicity that requires further management from their clinical 
team and to hit the “Call My Clinical Team” button. Please refer to the figure in section 5.53 for an 
overview of this process. 
• 
After completing each survey, the app will remind participants that the results will not be reviewed 
by a clinician, so the survey cannot be used to communicate with study staff or to request help. The 
reminder will also note that if the participant feels unsafe, she should contact the treating clinician 
directly. 

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• 
At each clinic visit, participants and their oncology providers will be given a graphical summary of 
the symptoms participants reported, and/or the steps walked by participants (depending on study 
arm) in-between visits. The study team will provide a summary of symptoms and/or steps either by 
providing a hard copy during clinic or through email, depending on feasibility and provider 
preference. If the patient is randomized to the active app-only study arm, she and her provider will 
only receive symptom reporting; if the patient is randomized to the accelerometer+passive app 
study arm, she and her provider will only receive “step count” reporting; if the patient is randomized 
to the active app+accelerometer arm, she and her provider will receive both symptom and step 
count reporting; and if the patient is randomized to the passive app only study arm, she and her 
provider will not receive a symptom summary. This is dependent on patient adherence –e.g if a 
patient is not wearing her Fitbit or using the smartphone application and we are unable to receive 
step or symptom data, we will not have data to share with patients or their clinicians and no 
summary sheet will be provided. See Appendix V: Sample Summary Sheet for an example of what 
the summary data will look like. We will not monitor whether clinicians use the summary sheets, 
since it is difficult to reliably capture what providers read and absorb during clinic visits. 
 
 
App Use and Compliance (Active and passive app):  
• 
Participants will be instructed to avoid adjusting the app settings to ensure data is collected. We will 
contact patients when we do not receive data from the app and/or Fitbit and aim to do so according 
to their contact preferences stated in the registration form. 
• 
If the app is not synching properly, the RA will contact patients via text/phone/email to help resolve 
the issue remotely. If this is not possible, the RA will meet participants at a regularly scheduled 
clinic visit to download the data manually or help resolve the issue.  
 
5.52b Wearable Accelerometers:  
All participants will also receive a Fitbit Zip and Fitbit Charge 2. Participants in the Fitbit and 
Fitbit+HOPE App arms of Phase II of the study will receive only the Fitbit Charge 2.  
 
Instructional Session:  
• 
Following the completion of the Participant Baseline Survey on Day 0, the RA will help participants’ 
download the Fitbit software and smartphone app, demonstrate how to use the Fitbit app and 
device, and teach patients how to synch the device to their smartphone. Participants will be 
assigned a unique study email that will be used to synch the device with the Fitbit app, as well as 
register the device in Fitabase (i.e., study’s data collection platform). 
• 
To reduce missing data, the RA will highlight the importance of wearing the accelerometer and 
review how they will be contacted by the study team, ideally through their preferred method of 
communication (phone/text/email), to encourage compliance. In addition to the accelerometer, 
participants will receive a wireless sync connector, and the Fitbit Participant Guide (Appendix Q), 
which describes proper wear and care, charging and battery life, troubleshooting instructions, 
uploading data, and compliance. 
• 
The RA will encourage participants to contact study staff at any time with questions or issues to 
help ensure proper wear and use of the Fitbit.  

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Wear Time, Compliance, and Monitoring Average Daily Steps:  
• 
Participants will be asked to wear the Fitbit Charge 2 on their non-dominant wrist. Study staff will 
continuously monitor participants wear time and data via Fitabase. We may contact patients when 
we do not receive data from the app and/or Fitbit and aim to contact patients according to their 
preferences stated in the registration form. If a Fitbit is not synching properly, the RA will contact 
patients via text/phone/email to help resolve the issue remotely. If this is not possible, the RA will 
meet the participants in person at a regularly scheduled clinic visit to download the data manually.  
 
Tracking Devices:  
• 
The accelerometers assigned to each participant will be tracked according to the product serial 
number and assigned unique ID number.  
• 
Participants will be allowed to keep the accelerometers as a token of appreciation for their 
participation in the study, and to minimize potential transmission of skin infections (e.g. methicillin-
resistant Staphylococcus aureus) between participants. 
 
5.53 Special Concerns 
 
5.53a Troubleshooting the HOPE App 
The intervention’s participant guides outline common troubleshooting issues and how to solve them. 
Participants will be instructed to call study staff as soon as possible to report if they are having trouble 
using the app. 
 
5.53b Lost Accelerometers 
If a participant reports to study staff that she lost the accelerometer, study staff will provide a 
replacement, either in person or via mail, as soon as possible. 
 
5.53c Surveys 
Study staff will contact participants to complete their upcoming study survey. After three unreturned 
voicemails, participants will not be contacted again for additional surveys.  
 
5.53d Subsequent Enrollment in a Therapeutic Drug Trial 
Participants in this study may enroll in a therapeutic drug trial at any point after signing consent to 
participate in this study. However, if a patient enrolls in a therapeutic drug trial that requires structured 
symptom or toxicity reporting we will record this and perform a sensitivity analysis, excluding any 
patients who participated in a therapeutic trial after enrollment, to determine whether this impacts our 
findings. Since this is a feasibility and acceptability trial, we do not want to censor participants.  
 
5.54 Compensation 
In the first phase, there will be no compensation for participants in this study. However, participants will 
be allowed to keep the wearable accelerometers (approximately $200 value) and will be provided with 
phone chargers to compensate for battery drainage that may be caused by installing the HOPE App 
(approximately $15 value). In the second phase, participants who are randomized to the corresponding 
arms will be allowed to keep the wearable accelerometer and/or receive a phone charger if requested. All 

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patients will be provided with a gift-card after the 1-month, 3-month, 6-month interviews to minimize attrition 
and prevent differential drop-out by study arm. The incentives will be $20 at 1 month, $30 at 3 months, and 
$50 at 6 months. Subjects who are randomized to arm 4 (passive app) will also receive a $20 gift card after 
the first study interview at baseline.  
In addition, if subjects incur additional costs related to their phones’ data plan use as a result of 
participating in the study, subjects will be asked to provide the study team with receipts, and study-related 
expenses will be reimbursed. Subjects will be provided with an information sheet (Appendix AA: Patient 
Reimbursement Info Sheet) describing the reimbursement process. 
 
5.6 Adverse Reactions and Their Management 
 
5.61 Reporting Adverse or Unanticipated Events 
Potential adverse events (AE) for this project are expected to be all non-medical in nature. There is 
small risk of physical injury. Participants could experience discomfort while wearing the Fitbit Charge 2 on 
their wrist.  There is also a chance participants could worsen repetitive use injuries (e.g., carpal tunnel 
syndrome) while using the smartphone app. Subjects may experience mild anxiety when answering survey 
questions about emotional issues or questions about coping challenges or difficulties related to discussing 
the subject matter. The PI will report unanticipated and serious adverse events to the IRB in a timely 
manner on an ongoing basis. For the purpose of this study a Serious Adverse Event (SAE) is defined as an 
event that, as a direct result of the study, causes serious harm to the subject (e.g., hospitalization).  
 
5.62 Anticipated Reactions & Reaction Management 
Should participants become exceedingly upset, disoriented or fatigued or need to attend to matters of 
personal care during the surveys, study staff will ask the subject if they would like to take a break or 
reschedule the survey for another time. In the event that participants experience distress while completing 
surveys, we will follow standard procedures used in our behavioral health intervention studies for 
counseling and referral. The PI will be notified immediately, and participants will be provided with the pager 
numbers for both the study PI and the study psychiatrist included in the consent form. Dr. Ilana Braun, a 
DFCI psychiatrist, has agreed to serve as a psychiatrist on the study. Dr. Braun will evaluate any 
participants who are distressed for risk of imminent danger and refer them to appropriate services if they 
are needed. 
As noted in the study procedures, all clinical staff will be trained in the study protocol. A participants’ 
clinical care team will be notified of every incoming call to the triage nurses, per standard practice, and her 
physician will be paged in the case of an emergency.  
 

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6.0 STATISTICAL ANALYSIS 
 
6.1 Primary and Secondary Endpoints 
 
Primary Endpoints: First Phase 
1) To assess the feasibility and acceptability of the HOPE app and the two wearable accelerometers 
2) To compare two wearable accelerometers (Fitbit Zip and Fitbit Charge 2) with respect to correlations 
with clinical outcomes (ECOG PS and patient-reported quality of life and physical health as measured 
by the PROMIS Global-10 items 2 and 3), for use in pilot RCT. 
 
Secondary Endpoints: First Phase 
1) To describe correlations between data collected from the HOPE app and the wearable accelerometers 
with additional clinical outcomes: PRO-CTCAE, CTCAE, and EQ-5D-5L. 
   
Primary Endpoint: Second Phase 
1) Health-related quality of life, comparing the patient-reported baseline and 6-month EuroQol EQ-5D.  
 
Secondary Outcomes: Second Phase 
1) Health care utilization (i.e. emergency room visits, hospitalizations, unplanned infusion appointments, 
and number of patient phone calls)  
2) Correlation between patient and physician estimates of performance status 
3) Additional clinical outcomes (e.g. anxiety and depression). 
4) Correlation between data collected from the wearable and smartphone accelerometers 
5) Predictive ability of wearable and smartphone accelerometers for patient’s performance status and 
clinically significant events 
6) Difference in correlation between data collected from the wearable and smartphone accelerometers, 
and difference in predictive ability of smartphone accelerometers for patient’s performance status and 
clinically significant events, by whether patients are encouraged to wear their smartphones 
 
6.2 Sample Size and Statistical Power or Precisions 
 
 
A convenience sample of 10 patients will be enrolled to the first phase of the study. Due to the limited 
sample size, statistical analysis will be descriptive in nature.  
100 patients will be enrolled to the second phase of this study, which will employ a 2x2 factorial design as 
depicted in the table below. Patients will be randomized 1:1:1:1 to one of the four arms.  
 
 
 
 

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Fitbit 
App 
Arm 
Sample size 
+ 
Active 
1 (Fitbit + active app) 
25 
+ 
Passive 
2 (Fitbit + passive app) 
25 
- 
Active 
3 (Active app) 
25 
- 
Passive 
4 (Passive app) 
25 
 
 
Total 
100 
 
For the outcome of change in EQ-5D, we will use a one-sided type I error rate of 5% to conclude that an 
intervention is promising for further study. Based on prior literature,22 the standard deviation of the change in 
EQ-5D at 6 months compared to baseline is approximately 14 points. With a total sample size of 100 patients 
(25 patients per arm), the table below summarizes the power to conclude that the either or both of the 
interventions are promising for further study based on a variety of effect sizes.  
 
Difference in EQ-5D versus Usual Care 
Power to conclude that 
intervention is promising for 
further study 
HOPE 
App 
Wearable 
accelerometer 
HOPE App + 
Wearable 
accelerometer 
HOPE App 
Wearable 
accelerometer 
6 
0 
6 
70% 
-- 
7 
0 
7 
80% 
-- 
6 
3 
9 
70% 
28% 
7 
3 
10 
80% 
28% 
6 
3 
8 
62% 
23% 
7 
3 
8 
68% 
17% 
 
   
 
6.3 Intervention Allocation Plan  
In the second phase, enrolled participants will be randomized to one of the four arms: 1) Fitbit + active app, 
2) Fitbit + passive app, 3) Active app, 4) Passive app—using a 1:1:1:1 ratio. Enrolled participants will undergo 
a secondary randomization to being encouraged to use a smartphone, or not encouraged to use a 
smartphone. Randomization to the main study arms will occur using a computer-generated random allocation 
sequence with blocks of 8 in order to maintain balance between study arms over time. Study staff will generate 
group assignments in sequentially numbered and sealed opaque envelopes. 
 

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6.4 Analysis Plan 
 
First phase: 
 
Due to the limited sample size, statistical analysis will be descriptive in nature. Refinement of the HOPE 
App and selection of the wearable accelerometer to use in the second phase will be based on a descriptive 
assessment of feasibility, acceptability, and correlations with clinical outcomes. 
 
Feasibility: We will record the proportion of eligible patients who enroll in the study and basic reasons for 
refusal [i.e. “too busy,” “not interested,” “other (specify)”]. Among those who enroll, we will plot the 
proportion who complete daily (quality of life, self-rated health, and PRO-CTCAE questions) and weekly 
(Promis PF 6b)  surveys from the HOPE App over time, and the average steps per day obtained from each 
of the accelerometers. We will also descriptively summarize the proportion of clinicians complete the 
CTCAE and performance status data for enrolled patients at baseline and post-baseline. 
 
Acceptability: Upon completion of the study, participants will be asked several questions, including: 1) 
“Participating in this study placed a substantial burden on me” and 2) “I wish I had not agreed to participate 
in this study.” Responses to these items will be summarized descriptively. 
Refinement of the HOPE App: 
Participants will be asked about their experiences using the HOPE app, including: “Was the app helpful for 
managing your symptoms?” Participants will be asked about the frequency, format, and content of the app-
based surveys, and whether there were symptoms that were missing from the app. Participants will also be 
asked open-ended questions, including: “What did you like about the app?” “What was most frustrating 
[about the HOPE app]?”, “How could it [the HOPE app] have better met your needs?”, and “Would you 
recommend this to a friend going through treatment? Why?” Responses to these items will be summarized 
descriptively. 
 
Comparison between two wearable accelerometers: 
Participants will also be asked several questions about their experience using the Fitbit, including: “Which 
Fitbit did you like better?” Response options will include: “Fitbit Zip (worn on your waistband),” Fitbit Charge 
2 (worn on your wrist),” “No preference,” and “Neither.” Participants will be asked an open-ended question: 
“Why did you like the [FitbitZip/Fitbit Charge 2] better?” Participants will also be asked to what extent they 
agree with the following questions: “The Fitbit Charge 2 was easy to use” and “The Fitbit Zip was easy to 
use.” We will also ask participants how many waking hours they wore each device daily (i.e. % waking 
hours), and how many times they forgot to wear the device or forgot to recharge it. Responses to these 
items will be summarized descriptively. 
Correlations with clinical outcomes: 
We will descriptively summarize correlations between data collected from the HOPE app (quality of life and 
physical function) and the wearable accelerometers (average daily steps) with clinical outcomes collected at 
baseline and post-baseline (i.e. performance status, quality of life, and symptoms assessment as obtained 
from the PRO-CTCAE and CTCAE).  
 

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Second phase: 
In addition to descriptive analyses and estimating correlations between passive smartphone data and 
clinical outcomes, passive data may contain information that allows for the prediction of future clinically-
relevant events, such as visits to the emergency department, urgent clinic encounter, or hospitalization. By 
testing for changes in activity, mobility, and social patterns over time as measured through smartphone use 
may be able to identify significant anomalies in patient behavior in the days prior to relapse. In a study in a 
cohort with schizophrenia, behavioral anomalies detected in the two weeks prior to clinical relapse occurred at 
a rate 71% higher than anomalies detected on other days.92 The method is based on a modification of the 
Hotelling’s T test to detect changes in the distribution of previous passively-measured activity. In our proposed 
study, this method might be used to query patients in real time to detect if an unscheduled clinical event might 
occur in the near future. Analyses will be repeated within secondary randomization arm to explore whether 
correlations and predictive ability of information from smartphone accelerometers are lower when participants 
are not encouraged to wear their smartphones. 
 
For the primary analysis, the EQ-5D index scores will be calculated in each study arm at both baseline and 
6 months and compared. The effect of the Fitbit on EQ-5D will be obtained by comparing the mean change in 
EQ-5D among all arms that consist of the Fitbit (i.e. arms 1 and 2) versus that obtained among all arms that do 
not consist of the Fitbit (i.e. arms 3 and 4). Similarly, the effect of the HOPE app on EQ-5D will be obtained by 
comparing the mean change in EQ-5D among all arms that consist of the HOPE app (i.e. arms 1 and 3) versus 
that obtained among all arms that do not consist of the HOPE app (i.e. arms 2 and 4). Additionally, pair-wise 
comparisons will be conducted of arms 2, 3, and 4 to arm 1 to examine which arms are driving or diluting any 
differences observed. Mean score changes from baseline will be compared using t tests and multivariable 
linear regression. The multivariable linear regression model will consist of change score as the dependent 
variable, and will adjust for baseline covariates (age, sex, cancer type, race, education, and literacy and 
numeracy). Additional analyses will use Fisher’s exact test to compare the proportion of patients in each study 
arm who experience an improvement, no change, or a decrement in quality of life. This will be conducted both 
for any level of change from baseline and for a 6-point change from baseline (the threshold for a clinically 
meaningful difference). Similar analyses will be conducted for the secondary outcomes, including anxiety, 
depression, and number of patient phone calls, using the appropriate regression model (e.g. negative binomial 
regression may be used for the outcome of the number of patient phone calls).   
For the health care utilization endpoints of unplanned infusion appointments, emergency room visits, and 
hospitalizations, cumulative incidence functions will be calculated with death treated as a competing event. 
Competing risk regressions will be used to model risk with and without adjustment for baseline covariates. 
Agreement between patient-oncologist estimates of performance status will be estimated by Cohen’s 
Kappa statistic, and differences in agreement between the study groups will be tested by bootstrapping.   
6.5 Handling of Missing Data 
For the primary quality-of-life analysis, we will exclude from our analyses any patients who do not complete 
any post-baseline EQ-5D questionnaires and carry forward the last post-baseline observation available for 
patients without 6-month data. If >10% of participants have missing data from the 6-month survey, we will 
perform sensitivity imputation analyses including: 1) no observations carried forward, 2) minimum observation 
values carried forward, 3) average observation values carried forward, and 4) last observation carried forward, 
but with an EQ-5D value of 0 if death occurred before 6 months. 

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7.0 REFERENCES 
 
1. 
Di Maio M, Gallo C, Leighl NB, et al: Symptomatic toxicities experienced during anticancer 
treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol 33:910-
5, 2015 
 
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Phenotyping: A Pilot Study. Journal of the American Medical Informatics Association. Submitted. 
 
 

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8.0 APPENDICES 
 
Recruitment/Enrollment: 
Appendix A: Opt-out card 
Appendix B: Registration Form  
Appendix AA: Reimbursement Sheet 
 
Instruments: 
Appendix C: Participant Baseline Survey 
Appendix D: Participant Post-Baseline Survey 
Appendix E: Clinician Survey 
Appendix F: Symptom Survey  
Appendix G: Health/Tx Information 
Appendix H: Health Care Utilization 
Appendix I: Call Log 
Appendix J: Debriefing Interviews  
Appendix Z: Medical Resource Utilization Form 
 
Interventions: 
Appendix K: HOPE App Features and Screenshots  
Appendix L: HOPE App Data Privacy and Security  
Appendix M: Symptom Management Content 
Appendix N: HOPE App Required Reading & Discussion 
Appendix O: HOPE App Participant Guide for Active App 
Appendix P: Summary Sheet for Participants  
Appendix Q: Fitbit Participant Guide 
Appendix R: Summary Sheet for Participants, Fitbit + passive app 
Appendix S: Summary Sheet for Participants, Active app 
Appendix T: Summary Sheet for Participants, Fitbit + active app 
Appendix U: Common Fitbit problems 
Appendix V: Sample Summary Sheet 
Appendix W: HOPE App Participant Guide for Passive App 
Appendix X: Summary Sheet for Participants, Passive App 
Appendix Y: Encouraged to Wear Smartphone Reminder Sheet 
 
 
 
 
 
 
 
 

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Part 2 
The SMART Study 
 
 

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SECTION 1: Study Schema for SMART (n=30) 
 

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SECTION 2: Body of Protocol 
 
TABLE OF CONTENTS 
 
1.0 Introduction, Background and Rationale………………….........…………………………………….….….….45 
2.0 Objectives………………….........……………………………………………….…………………….……….….46 
2.1 Primary Objectives………………….........…………………………….…………………….……….….46 
2.2 Secondary Objectives………………….........……………………………………………….…………..46 
3.0 Research Subject Selection………………….........………………………………………………….………….46 
3.1 Eligibility Criteria………………….........………………………………………………………….………46 
3.2 Exclusion Criteria………………….........…………………………………………………….…………..47 
4.0 Research Subject Entry………………….........………………………………………………………….………47 
4.1 Subject Recruitment and Enrollment………………….........……………………………….………….47 
4.2 Subject Registration………………….........…………………………………………………….….…....48 
5.0 Study Design and Methods………………….........…………………………………………….………………..48 
5.1 Design/Study Type………………….........………………………………………….…………………...48 
5.2 Selection of Instruments………………….........……………………………….………………………..48 
5.3 Description of Interventions………………………………….........…….………………………………53 
5.4 Data Collection………………….........……………………………….………………………………….58 
5.5 Description of Study Process………………….........……………….………………………………….59 
5.6 Adverse Reactions and Management…………………........……….………………………………...62 
6.0 Statistical Analysis………………….........……………………………………….……………………………....64 
6.1 Primary and Secondary Endpoints………………….........……………….……………………………64 
6.2 Sample Size and Statistical Power………………….........……………….……………………………64 
6.3 Analysis Plan……..........................................................................................................................64 
7.0 References................................................................................................................................................66 
8.0 Appendices................................................................................................................................................69 
 

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1.0 INTRODUCTION, BACKGROUND AND RATIONALE 
The goal of chemotherapy is to reduce symptoms and extend survival. Yet, oncologists’ methods of 
monitoring patients’ symptoms are underdeveloped. Studies show that clinicians consistently miss more than 
half of cancer patients’ symptoms, even in clinical trials that mandate collection of treatment toxicities.1,3  
Similarly, oncologists’ estimates of patients’ performance statuses are highly subjective, yet key determinants of 
patients’ eligibility for clinical trials, chemotherapy, and hospice. Oncologists’ performance status assessments 
are only moderately correlated with one another4,5 and are even less reliable when compared with patients’ 
estimates.6-8 This may be because clinicians see patients at fixed time points that are frequently tied to 
chemotherapy infusions, when patients have often already recovered from their last treatment. The moments 
between visits—when patients are at the highest likelihood of experiencing treatment toxicities—are far more 
likely to contain more meaningful data about patients’ symptoms and activity levels. 
Integration of patient-reported outcomes (PROs) into clinical practice is an increasingly promising strategy 
for improving patients’ symptoms, communication, and clinical outcomes.9,10 Basch et al. recently demonstrated 
that for patients with metastatic cancers, the use of a web-based system to assess PROs, combined with 
automated clinical alerts, resulted in better health-related quality of life, fewer emergency room visits and 
hospitalizations, and superior quality-adjusted survival, compared with usual care.10 However, this study and 
others have predominantly assessed patients during clinic visits.11 A key limitation to this approach is that it 
relies upon a patient’s retrospective recall of events. Our research will be among the first to produce real time 
and real world assessments of cancer patients’ symptoms and activity levels within their daily lives.  
Smartphones offer an accessible, low-cost method for conducting real time and real world assessments of 
patients' symptoms and activity levels. A study conducted by members of our team demonstrated that patients 
with major depressive disorder used a smartphone app to answer questions from the Patient Health 
Questionnaire-9 (PHQ-9) 3 times per day over a 30-day period with >75% adherence.12 Patients’ scores were 
strongly correlated with standard paper-based surveys, but 3 points higher on average (reflecting more 
distress), and patients reported higher rates of suicidal ideation. We subsequently adapted this platform to 
assess symptoms using the PRO-CTCAE; risk-stratify patient responses; provide tailored feedback to patients 
with low-risk symptoms; and notify patients and clinicians of high-risk symptoms.13 Preliminary data from a pilot 
in patients with gynecologic cancers at Dana-Farber Cancer Institute suggests that patients are able to use the 
app, have favorable impressions of it, and high adherence rates. Moreover, we have detected several clinically 
significant symptoms (e.g. severe vomiting, abdominal pain) which were not captured in routine clinical practice, 
and prevented emergency department visits by addressing them real-time.14 Smartphones offer new strategies 
for assessing patients’ symptoms, identifying toxicities, and intervening to reduce suffering.  
Additionally, smartphones have the functionality to monitor social and behavioral markers of health and 
illness remotely using passively collected data (without patient involvement) to detect temporal changes and 
behavioral anomalies that can indicate the onset of clinically significant symptoms. Recently, a study conducted 
by Barnett and Onnela demonstrated the use of a smartphone platform, Beiwe, to detect relapses in patients 
with schizophrenia by identifying anomalies in their pre-relapse behaviors, including changes in their mobility 
and phone use patterns. This approach did not require active patient participation or the introduction of new 
technologies. Data were collected from participants’ personal smartphones, making these devices an ideal and 
scalable technology for long-term remote monitoring with minimal participant burden.  
Like smartphones, wearable accelerometers offer another novel means for collecting real world data to 
objectively measure patients’ performance statuses. Patients’ retrospective reports of activity levels are often 
inaccurate or imprecise. Without accurate information, oncologists may have difficulty objectively assessing 
patients’ performance statuses, and may underestimate patients’ symptom burdens and chemotherapy-related 
toxicities. Indeed, oncologist estimates of patients’ performance statuses are only moderately correlated with 

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one another4,5 and weakly correlated with patient estimates,6-8 but improve when clinicians and patients 
participate in “shared” reporting of patients’ toxicities and performance statuses.15 
Wearable accelerometers are devices that track users’ energy expenditures, the amount and intensity of 
physical activity, and sedentary behavior. They offer cost-effective, user-friendly, and objective measurements 
of patients’ free living patterns. A few studies have piloted wearable accelerometers in adult cancer patients 
undergoing stem cell transplants (HCT) or treatment for colorectal, gastrointestinal, breast, and lung cancers.16-
19 Results from one study of adult patients undergoing HCT who wore accelerometers over an 8 week period 
found that patients’ reports of severe symptoms, impaired physical health, and restrictions in activities of daily 
living were associated with statistically significant decrements in objectively measured steps, suggesting that 
this may be an independent, quantitative measure of quality of life and patient performance status.16 In this 
study of 32 patients undergoing HCT over a 4-week period patients’ steps were significantly associated with an 
increased symptom burden.16 Similar results were observed in a population of patients receiving concurrent 
chemoradiation.20 We expect that symptoms are likely to impact the amount of walking that patients can do and 
will therefore provide an independent measure of both patients’ performance status and symptom burden. 
The overall goals of this study are to test the combination of two smartphone research platforms, the 
SMART app and the Beiwe app, and a wearable accelerometer for use in NCI Community Oncology Research 
Program (NCORP) sites to improve cancer patients’ quality of life and symptom management. The SMART 
Study (Symptom Management and Reporting Toxicities) has a single-arm research design and aims to assess 
feasibility, acceptability and perceived efficacy of a wearable accelerometer and two smartphone apps in 30 
patients receiving chemotherapy to treat recurrent gynecologic cancers. The SMART intervention refers to the 
combination of both smartphone apps (SMART app and Beiwe app) and the accelerometer (Fitbit). The SMART 
app is the technology that is actively collecting symptom reporting information from patients (e.g. patients are 
receiving surveys, recording their symptoms daily, and receiving tailored symptom management materials on 
their phone in response). The Beiwe app is the technology involved in the passive data collection of 
participants’ symptoms (GPS and accelerometer data) without their involvement. 
 
2.0 OBJECTIVES 
2.1 Primary Objectives 
To conduct a single-arm study to assess feasibility and acceptability of two smartphone apps and a wearable 
accelerometer in 30 patients with gynecologic cancers receiving chemotherapy. 
• Feasibility will be defined as: 1) ≥50% approach to enroll rate, and 2) ≥50% 3-month adherence rates to 
both smartphone apps and the wearable accelerometer. 
• Acceptability will be defined as: ≥60% of study participants would recommend the intervention to other 
patients; and <30% of patients rate the study as burdensome or wish they had not participated. 
 
2.2 Secondary Objectives: 
Assess the perceived efficacy of the smartphone apps and wearable accelerometer and estimate outcome 
parameters for this population 
• Perceived efficacy will be measured by qualitative analysis: We will conduct debriefing interviews with a 
subset of participants and clinicians to obtain information about the acceptability of the intervention and 
recommendations for any modifications to improve any aspects of recruitment, enrollment, education, the 
timing of study assessments, graphical displays of information, fitness tracker use, and the apps that could 
be improved. 
• Outcome parameters will be estimated by quantitative analysis: We will descriptively summarize the 
distribution of toxicities and clinical outcomes at baseline and at 3-month follow-up.  
 

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3.0 RESEARCH SUBJECT SELECTION 
 
3.1 Eligibility Criteria  
• 
Women ≥18 years of age who plan to receive chemotherapy to treat recurrent, incurable gynecologic 
cancer (i.e., ovarian, fallopian, primary peritoneal, uterine, or cervical cancer) that has recurred despite 
≥1 prior treatment. 
• 
Own a smart phone (Android or iOS). 
• 
Capable of downloading and running the study apps.  
• 
Can read and provide informed consent in English. 
• 
Does not have cognitive or visual impairments that would preclude use of the apps.  
 
 
3.2 Exclusion Criteria 
• 
Patients will be ineligible if they are participating in an investigational drug treatment trial that requires 
structured symptom or toxicity reporting at the time of enrollment.  
• 
Patients with severe cognitive impairments or who appear too weak, emotionally distraught, agitated or 
ill to participate, as judged by either the research study staff or an oncology provider, will be excluded. 
• 
Patients who are unable to provide informed consent in English will be excluded because the 
smartphone apps are only available in English at this time.  
• 
Children and young adults up to age 17 will be excluded because the diagnosis of metastatic 
gynecologic cancers in this age group is rare and the proposed instruments are not designed for people 
of those ages.  
• 
Patients with a life expectancy of ≤3 months, as determined by their oncology providers, will be 
excluded since they cannot participate in all of the required data collection.  
 
4.0 RESEARCH SUBJECT ENTRY 
 
4.1 Subject Recruitment and Enrollment 
We will enroll patients from community oncology sites. Study staff, oncology providers, and clinic staff will 
identify patients who may be eligible for the study. Prior to initiating recruitment at each site, we will use a 
rigorous, stakeholder-driven process21 to ensure that the apps and fitness tracker can be integrated into 
practice without disrupting the workflow or causing patient distress. For example, for a similar study using the 
adapted smartphone app and wearable accelerometers in women with gynecologic cancers at DFCI, our 
recruitment protocol includes: 1) reviewing clinicians’ weekly schedules to identify potentially eligible patients 
for study enrollment, 2) contacting clinicians for permission to approach potentially eligible patients, and 3) 
introducing the study to the patient at the next clinic visit (e.g., describing the study, reviewing the consent 
form, answering questions, and obtaining written informed consent) before we enroll each patient. While this 
protocol has been successful at DFCI, we recognize that each clinical practice setting is unique and will work 
with practices to develop site-specific study recruitment and enrollment protocols. 
4.11 Screening & Recruitment 
Prior to obtaining informed consent, study staff will determine whether patients are eligible for the study. 
Study staff will identify patients with recurrent gynecologic cancers that have progressed through one or 
more treatments and who are planning to receive chemotherapy. Site-specific procedures will be 
developed to identify eligible patients, which may involve review of medical records and/or discussion with 
a patient’s oncology providers. A HIPAA waiver requesting permission to review the PHI of potentially 

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eligible patients has been submitted to justify this process. If a patient’s oncology provider deems the 
patient ineligible or too distressed to participate in a clinical study at this time, the patient will not be 
approached for inclusion. PHI obtained in the context of study recruitment will not be shared with anyone 
outside the study team and patients’ oncology providers. For all enrolled participants, sites will document 
confirmation of participant eligibility by their providers.  
 
 
 
4.12 Informed Consent 
If a patient agrees to learn more about the study, study staff will describe the study, review the consent 
form, answer any questions, and provide contact information for the study team. The staff member will 
encourage patients to take their time in deciding whether they want to participate in the study or not.  
If a patient is interested in participating, she will enter the informed consent process, which will include 
explaining how and why the current research study is being conducted, the study risks and benefits, the 
potential time commitment involved, and the option to give permission to be contacted for future research 
studies. The patient will learn what type of information will be collected from the smartphone applications 
and accelerometer and how these data are monitored. The staff member will reiterate that the data 
collected are not a part of the patient’s standard treatment and will underscore the importance placed upon 
maintaining patient confidentiality and a patient’s rights while involved in the study, including the right to 
withdraw participation at any time for any reason during the study because participation is completely 
voluntary.  
The informed consent form will contain a section dedicated to explaining what constitutes PHI and how 
this information will be protected as confidential per HIPAA guidelines. The consent form will also provide 
contact information for both the Principal Investigator (PI) as well as the Office for the Protection of 
Research Subjects (or analogous body at local sites). All informed consent processes will adhere to the 
policies set forth by the Institutional Review Board. Signed informed consent forms will be stored in locked 
file cabinets to maintain the privacy of all study participants.   
If a patient is unsure if she would like to participate in the study, she will be offered the consent form to 
review and the contact information of study staff. If the patient does not contact staff after a few days and 
further contact is appropriate, study staff will contact the patient. If the patient decides to participate, a staff 
member will engage in the informed consent process with the patient. If a patient is not interested, the staff 
member will thank her for considering, and reassure the patient that the process will have no impact on her 
clinical care. No further interactions will occur with patients who either decline or prove ineligible for the 
study.  
 
4.2 Subject Registration 
After informed consent is obtained, participants will be assigned a unique study ID and registered to the study 
in RedCap. Participants will be retrospectively registered in OnCore, the Clinical Trial Management System for 
Dana-Farber in a de-centralized fashion. Registrations may occur up to 30 days after consent is signed per 
REGIST-101.  
5.0 STUDY DESIGN AND METHODS 
 
5.1 Design/Study Type 
In a single-arm study of patients at community oncology sites in the United States, we will employ convenience 
sampling from 30 patients who meet inclusion criteria. Our analyses involve estimations of feasibility, 
acceptability, and preliminary efficacy. In addition, we will assess safety outcomes, toxicity scale scores, 

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missing data, and patient/physician feedback. We will not conduct formal hypothesis testing in this small 
sample. 
5.2 Selection of Instruments 
 
5.21 Interviews and Surveys 
The following measures will be used in the study interviews and surveys, including the Participant 
Baseline Interview (Appendix 14), Participant Post-Baseline Interview (Appendix 15), and SMART App 
Surveys (Appendix 16). Table 1 outlines their distribution across the study instruments. 
 
5.21a Global Health Status: EQ-5D-5L 
The EQ-5D is a standardized measurement of health status that has been used in a wide range of 
health conditions and treatments, including cancer patient populations.23 The EQ-5D-5L is the most 
recent 5-level version that has proven validity and reliability in a range of patient groups with chronic 
diseases24 and cancer.25 It is a 5-item questionnaire (measuring mobility, self-care, usual activities,  
pain/discomfort, and anxiety/depression. Each dimension has three levels of perceived problems: 1) no 
problems, 2) slight problems, 3) moderate problems 4) severe problems, and 5) extreme problems. 
Patients check the statement level that best describes their current health status in each dimension, 
which are then scored to generate a patient’s unique health state. In the EQ-VAS, patients report a 
single index value of how good or bad their current health state is on a visual scale that ranges from 
worst imaginable at zero to best imaginable at one hundred. The EQ-5D-5L can be administered with 
little to no guidance and takes only a few minutes to complete. Upon scoring, the EQ-5D produces a 
composite score between 0-1 (multiplied by 100 to generate a number between 0-100), which 
represents general health status, normalized for the US population.26 Lower scores represent worse 
quality of life, and a change of ≥6 is clinically significant in US cancer populations.27 
 
5.21b PROMIS Global-10 and PROMIS Physical Function short form 6b 
The PROMIS Global-10 is a brief measure of patient health status that is not disease specific.28,29 It 
consists of 10 questions; e.g. “In general, how would you rate your physical health?” Items are scored 
on a Likert scale of 1-5, where higher scores indicate better health, except for pain which is measured 
on a 10-point scale. Standardized T-scores (range 0-100) are calculated for the global physical and 
mental health scales, and higher scores indicate better health. The full scale takes approximately 2-3 
minutes to complete and will be used in the baseline and post-baseline surveys, and in the SMART 
app. 
The PROMIS Physical function (PF) 6b is a brief, 6-item measure used to characterize patients’ 
overall health, level of physical disability, and general well-being. The PROMIS PF 6b has been 
validated in 4,840 cancer patients across a range of ages, racial/ethnicity groups, stages and cancer 
types, and normalized for the US population. It has high reliability, minimal floor effects, and can 
precisely measure meaningful differences in functional status, disease burden, and comorbidities. The 
full scale takes approximately 1-2 minutes to complete and will be used in the baseline and post-
baseline surveys, and in the SMART app. 
 
5.21c Performance Status: ECOG PS 
The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) assessment is a 
standard measurement that oncologists often use to assess a patient’s current functional level and 
eligibility for clinical trials. The scale ranges from 0 to 5 and the criteria for each grade is as follows: 0 = 
Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically 

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strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light 
house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours; 3 = Capable of only limited self-care; confined 
to bed or chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on any self-care; 
totally confined to bed or chair; 5 = Dead.30  
The ECOG PS will allow clinicians and participants to provide a standard evaluation of the 
participant’s performance status over time and with minimal burden. Participants will use the patient 
self-report version that has been used successfully in a study with cancer patients. We expect that it will 
take 1-2 minutes to answer the question.31 
 
5.21d Depression: modified PHQ-9 
The Patient Health Questionnaire-9 (PHQ-9) is a validated self-report measure that assesses nine 
depressive symptoms using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
(DSM-IV) diagnostic criteria for major depressive disorder. It is used to screen, diagnose, and monitor 
depressive symptoms32 and has been administered/demonstrated validity in cancer patients,33,34 as well 
as smartphone apps.12 Respondents report if each symptom has bothered them “not at all,” “several 
days,” “more than half the days,” or “nearly every day” during the previous two weeks.35 We will not 
include question 9, which assesses suicidal ideation, since access to 24-hour psychiatry services may 
not be available at all sites. We expect that it will take participants no more than 3-5 minutes to 
complete the 8 questions.  
 
5.21e Symptoms Assessment: PRO-CTCAE  
The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) is a patient-centered, standardized self-report measure that enables patients to report 
symptoms and AEs.10,11,36,37 The PRO-CTCAE has demonstrated validity, reliability, and 
responsiveness in a large heterogeneous United States sample of cancer patients undergoing 
treatment.37 Ten PRO-CTCAE items that are salient to gynecologic cancers will be collected, including: 
abdominal pain, nausea, vomiting, constipation, diarrhea, peripheral neuropathy, anxiety, depression, 
dizziness and fatigue.  
The PRO-CTCAE items use conditional branching for AEs that contain multiple attributes. For 
example, if a participant reports a symptom, she is asked to quantify the severity and the extent to 
which the symptom interfered with her daily activities; if she does not report a symptom, these items are 
skipped. We anticipate that participants will complete this measure in about 3-5 minutes at baseline and 
the end of the study. Patients will also report their symptoms daily through the SMART app. 
 
5.21f Anxiety: GAD-7 
The Generalized Anxiety Disorder 7-Item (GAD-7) is a reliable and validated self-report measure 
that assesses GAD. Respondents rate how often they have been bothered by 7 anxiety symptoms over 
the past two weeks using the following scale: 0 = Not at all; 1 = Several Days; 2 = Over half the days; 
and 3 = Nearly every day. Respondents also answer a question to assess the duration of their anxiety 
symptoms. Responses are tallied and the total score indicates the presence and severity of GAD.38  
The measure has since been validated in the general population39 and was the recommended 
evaluative measure for anxiety in adult cancer patients in the 2014 American Society of Clinical 
Oncology (ASCO) Guideline Adaptation.40 We anticipate that it will take participants approximately 3-5 
minutes to complete. 
 

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5.21g Overall Quality of Life and Physical Health:  FACIT-PAL 
Patients’ quality of life (QoL) will be assessed with Functional Assessment of Chronic Illness 
Therapy – Palliative Care, which has demonstrated internal consistency, reliability and validity.41 The 
measure is divided into four primary QoL domains: physical well-being (7-items), social/family well-
being (7-items), emotional well-being (6-items), and functional well-being (7-items). It also includes 12 
additional items that are specific to palliative care priorities for patients with chronic illnesses such as 
cancer.  Participants will rate each symptom over the past 7 days as: 0) Not at all; 1) A little bit; 2) 
Somewhat, 3) Quite a bit, and 4) Very much. Subscales can be analyzed separately or aggregated to 
produce a total score. Patients will complete this at baseline and the end of the study. Through the 
SMART app, patients will also answer a brief weekly survey, Functional Assessment of Cancer 
Therapy-General (FACT-G7), which serves as a rapid assessment of patients’ top-rated symptoms and 
concerns regarding cancer treatment. This measure allows physicians to quickly identify and address a 
broad range of issues that may affect a patient’s quality of life.  
 
5.21h Literacy Measures: Health Literacy and Numeracy & Mobile Communication Competence 
Health literacy42 and numeracy and mobile communication competence43 will be collected for all 
participants at baseline. The “comfort with technology” and “mobile preference” subscales of the Mobile 
Communication Competence scale will be used because they assess factors directly impacting patients 
in our study, who will be asked to acclimate to and consistently use an accelerometer and/or 
smartphone apps. The mobile communication preference and comfort with technology subscales 
individually demonstrated internal reliability, consistency and validity. We estimate that it will take 
participants approximately 5 minutes to complete all of the literacy measures. 
 
5.21i Demographic Information 
Basic demographic information will be collected for all participants, including: age, marital status, 
race/ethnicity, education, household structure, income, and employment. The questions will only take a 
few minutes to complete.  
 
5.21j Smartphone Usage Questions  
Data on smartphone-specific usage habits will be collected for all participants. Participants will be 
asked a total of four questions: average daily time spent using smartphone, purpose of using 
smartphone, comfort using smartphone apps, and frequency of using smartphone apps. We estimate 
that it will take participants approximately 2 minutes to complete these questions. 
 
5.21k Brief COPE 
The Brief COPE is a 28-item measure developed to assess a broad range of coping 
responses.46 The Brief COPE has been validated in several populations including breast cancer 
patients and community samples.46 Subscales of the Brief COPE include use of emotional support, 
religion, and self-distraction, and individual subscales can be used independently. We will use the 
denial, behavioral disengagement, self-distraction, active coping, use of emotional support, use of 
instrumental support, positive reframing, planning, acceptance, and religion subscales of the Brief 
COPE. The Brief COPE will be administered to patients during the participant baseline interview 
 
 

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Table 1. Distribution of measures during Baseline and Post-Baseline Interviews.  
 
 
 
Baseline 
Interview 
Post-
baseline 
Interview 
SMART App 
Surveys 
MEASURE 
PRO-CTCAE 
 
 
  
PROMIS Global-10 and 
Physical Function 6b 
 
 
 
ECOG PS 
 
 
 
PHQ-9 
 
 
 
GAD-7 
 
 
 
EQ-5D-5L 
 
 
 
FACIT-PAL 
 
 
 
Brief COPE 
 
 
 
Health Literacy & Numeracy 
 
 
 
Mobile Communication 
Competence 
 
 
 
Smartphone Usage Questions 
 
 
 
Demographic Info 
 
 
 
Healthcare Utilization  
 
 
 
 
5.22 Medical Chart Abstractions and Patient-Reported Medical Resource Utilization 
 
5.22a Health/Treatment Information 
Participants’ medical charts will be reviewed to abstract health and treatment related information, 
including disease site, comorbid health conditions,47 number of prior chemotherapy regimens, and time 
since diagnosis. Data will be recorded in the Health/Tx Info form (Appendix 17). 
 
5.22b Health Care Utilization 
At baseline participants will be given a patient diary to record all health care utilization that occurs 
during the study period, including hospitalizations, admissions to an intensive care unit, emergency 
room and urgent care visits, and oncology visits. This form was developed by the NRG Cancer Care 
Delivery Research Group because of recognition that participants often receive care outside of NRG 
sites that cannot be captured by the medical record. Clinical research coordinators will be asked to 
verify medical care that happened within a site-affiliated medical center. Participants’ medical charts will 
be reviewed to abstract health care utilization data during enrollment, including chemotherapy regimen 
and treatments, palliative care visits, emergency department visits, hospitalizations, and hospice 
referrals. If a participant dies while enrolled in the study, the date of death will also be recorded. Data 
will be recorded in the Health Care Utilization form (Appendix 18). Additionally, participants will be 
asked about whether they (or their informal caregiver) needed to take time off from work, how far they 
traveled for treatment, and for a rough estimate of their out-of-pocket expenditures to capture some of 
the burden associated with cancer care. 
 

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5.22c Call Log  
If the data is available, study staff will abstract information about phone calls to their providers 
during a participant’s enrollment and record data in the Call Log (Appendix 19). Data collected for each 
call will include: date/time, incoming/outgoing, left message, duration in minutes, reason for the call, 
symptoms documented, and the outcome. 
 
5.23 Debriefing Interviews 
Debriefing Interviews will be conducted with a purposively sampled subset of participants, 
approximately 15 across all sites. The purpose of these interviews is to obtain information about the 
acceptability of the interventions and recommendations for modifications to improve any aspect of 
recruitment, enrollment, education, timing of study assessments, the graphical display of information, and 
the smartphone apps. The interview guide can be found in Appendix 20. In accordance with qualitative 
interviewing procedures, additional themes and topics that arise over the course of the study may be 
explored further in the debriefing interview, in addition to the list of questions in the interview guide. Study 
staff will aim to administer debriefing interviews to the first few patients enrolled at each site and an 
additional purposively sampled subset of patients; debriefing interviews will be conducted for approximately 
15 patients total. Study staff will also solicit debriefing feedback from clinicians who are serving as co-
investigators on the study and site research staff who are managing the clinician dashboard. If site policy 
permits, participating co-investigators and site staff will receive gift cards in appreciation of the time they 
have dedicated to study debriefing. The feedback provided by co-investigators and site staff will be used to 
further refine integration of the study into clinical workflow and improve the effectiveness of the study. 
Additionally, debriefing interviews will be audiotaped in order to ensure that the interviewer adequately 
captures all feedback from patients, co-investigators, and site staff. The consent forms for the study include 
information that the debriefing interview will be audiotaped, and we will verbally request permission from 
patients, co-investigators, and site staff to audiotape the debriefing interview before beginning the 
interview. Verbal permission will be documented on RedCap. We will not administer a debriefing interview 
to any person who does not consent to being audiotaped during the debriefing interview. All audio 
recordings of study sessions will be stored in secure, restricted-access locations. Recordings will be tied 
only to a study ID number, and the only documents linking the patient’s study ID to identifiable information 
are in a restricted-access file stored securely on restricted-access folders. Audiotapes of debriefing 
interviews will be transcribed for further analysis using a DFCI-approved, HIPAA-compliant transcription 
vendor or locally at Dana-Farber. All patient identifiable information will be removed when the audio 
recordings are transcribed. Audio recordings of debriefing interviews will be destroyed when analyses are 
complete. 
 
5.3 Description of Interventions 
The SMART intervention is a mobile health intervention that consists of two smartphone apps, and a 
wearable accelerometer. For this study, the smartphone apps are named the “SMART app” and “Beiwe 
app” and the accelerometer is the Fitbit Charge 3.  
 
5.31 Smartphone apps 
The SMART study intervention is based on two iOS and Android smartphone applications, the SMART 
app and Beiwe app, which run on participants’ personal smartphones and collect information about their 
health and behaviors. The SMART app employs “active” data which require direct participant 

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involvement—for example survey responses. The Beiwe app collects “passive” data, which are generated 
without any direct participant involvement—for example, GPS or accelerometry. 
 The “Beiwe,” app was conceived and designed by one of the co-investigators, Dr. Jukka-Pekka 
Onnela, at the Harvard T.H. Chan School of Public Health. Zagaran, Inc., located in Cambridge, 
Massachusetts, built the software. One of the advantages of the Beiwe app is that it protects identifying 
data through hashing, and all data are encrypted while on the device, in transit, and stored on the server. 
Once collected by the phone, raw data are encrypted and securely transmitted to an instance of Amazon 
S3 for storage and later retrieval for analysis. 
In a prior pilot study, Dr. Onnela tested the app in 13 patients with major depressive disorder. 
Participants installed the app on their personal smartphones and completed a self-report survey of PHQ-9 
items 3 times per day with >75% adherence to the app over a 30-day period.12 Participants scores were 
strongly correlated with paper-based surveys administered in clinic (Pearson linear correlation coefficient 
0.84) but were 3.0 points higher on average (i.e. indicating more distress), and participants were much 
more likely to report significant suicidal ideation.  
Since this publication, Dr. Onnela’s lab has developed a more sophisticated system that features a 
web-based research study portal, a customizable Android and iOS smartphone app, Amazon Web 
Services S3 database, and data modeling and analysis tools. The app collects many different types of 
sensor data and administers surveys. There are currently several IRB approved protocols across local 
centers that are utilizing the Beiwe application in research, including Dana-Farber Cancer Institute, Beth 
Israel Deaconess Medical Center, Harvard University (Faculty of Arts and Sciences), McLean Hospital, and 
Massachusetts General Hospital. Several studies have begun enrolling patients or healthy controls, and 
the user experience has been overwhelmingly positive. In addition, there are no signs that adherence is 
condition-specific to date. 
We subsequently adapted this platform to assess symptoms using the PRO-CTCAE; risk-stratify patient 
responses; provide tailored feedback to patients with low-risk symptoms; and notify patients and clinicians 
of high-risk symptoms. Preliminary data from a pilot in patients with gynecologic cancers at Dana-Farber 
Cancer Institute suggests that patients are able to use the app, have favorable impressions of it, and high 
adherence rates. Moreover, using this app we detected several clinically significant symptoms (e.g. severe 
vomiting, abdominal pain) which were not captured in routine clinical practice, and prevented emergency 
department visits by addressing them real-time.14 
The Beiwe platform has the functionality to evaluate patients’ health behaviors and activities by 
collecting either active or passive data, or both concurrently. Through previous research, we discovered the 
research platform did not have a clinician-facing interface to enable tracking of individual symptoms in real-
time, or a clinician dashboard to enable study staff to monitor a population of patients simultaneously. This 
meant that study participants’ symptoms could be downloaded once daily into a pdf for the full population, 
and this was format was infeasible for a multi-site study. Moreover, patients reported that the surveys were 
“not engaging,” and Beiwe would not be easily adapted to a more engaging format. 
  Based upon these experiences, the study team at Dana-Farber concluded that there was a significant 
need to develop a better patient- and clinician facing interface for engagement and population 
management before launching a multi-site trial. As a result, the decision was made to seek out a different 
technology platform that could meet these needs. Once an appropriate platform was identified, the decision 
was made to turn off the “active” data collection features of the Beiwe app, with a plan to continue using 
Beiwe for “passive” data collection. We then partnered with a different company to design a new 
smartphone app on a different platform for active data collection. For the SMART app redesign, we 
partnered with RMDY Health, an established commercial digital health provider that creates mobile health 

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and web programs, including interventions for medication management, weight loss, prevention, 
adherence, and lifestyle modification programs.  
In collaboration with RMDY, Dana-Farber study staff were able to design a custom “white-label” digital 
health platform catered specifically to the patient population involved in this research study. The RMDY 
platform is comprised of three main components: 1) an app where patients can answer surveys (i.e. NCI 
PRO-CTCAE survey items) and receive symptom management advice tailored to symptom severity, 2) a 
web-based clinician dashboard where staff track patients’ symptoms and steps, and communicate with 
patients, and 3) an administrative website where program content can be managed and generated.   
Through the SMART app, patients track their symptoms daily through surveys and then receive tailored 
symptom management advice based on their reported symptoms. Patients can also track their steps, sleep 
and heart rate, and communicate with their study team directly through the app. The SMART platform also 
includes a clinician dashboard and admin site where nurses, providers, and other study team members can 
login to view and manage patients enrolled to the study. The console also allows study staff to monitor the 
severity and frequency of symptoms patients are reporting throughout the day, view patient steps, collect 
patient survey response data, send reminders to patients, and assign program content.  
The Beiwe app will be used to passively collect information about participants. Passive data collection 
is essential because mobile health interventions that require significant patient involvement tend to have 
higher rates of attrition, and patients’ illness may interfere with their ability to report their symptoms. It is 
essential to develop an intervention that can be utilized to detect patients’ symptoms or anomalies in their 
behaviors with minimal involvement. Rapid identification and management of symptoms can improve 
patients’ quality of life and other disease related outcomes. We anticipate the remote monitoring of patient 
symptoms using both the SMART app and Beiwe app will allow us to better understand cancer patients' 
behaviors and relate them to clinically significant patient symptoms and outcomes. The intervention 
combination may also provide a method for better identifying clinically meaningful anomalies in cancer 
patients' behaviors.  
 
5.31a Software and Data Collection Features  
The SMART app employs similar features and data collection methods used in the aforementioned 
studies and protocols. Please see SMART App Features and Screenshots: Patient Guide (Appendix 5) 
for descriptions of the app’s features, including: log-in screen, symptom management advice, 
connecting to Fitbit device/Apple Health/Google Fit, notifications, surveys, the “Call My Clinician” 
function so that patients can contact their clinical teams without searching for numbers, and general 
app navigation.  
As noted above, the SMART app collects active data from participants’ survey responses and 
wearable accelerometer, connected to the platform with patient permission. Active data are collected 
while a patient is using the app (e.g. responding to survey questions). Information regarding data 
collection and privacy measures for the SMART app is located in SMART App Data Privacy and 
Security (Appendix 7). The Beiwe smartphone app collects passive data from participants’ phone 
usage, with participant consent, continuously without patient input. Participant interaction with the 
Beiwe app consists of installing the app and keeping it running in the background of their phone; all 
data is collected in the background. Specifically, as noted in the Beiwe App Data Privacy and Security 
(Appendix 10) the app collects passive data, including: mobility traces, consisting of flights (linear 
segments of movement) and pauses (times of no movement) which are constructed from GPS data; 
and summary statistics of phone communication (calls and text messages) patterns, simple examples 
being the total number of communication events in a time period (e.g., 1 week), the total number of 

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communication partners, and reciprocity of communication (defined as the difference between outgoing 
communication volume and incoming communication volume).  
Since passive data collection does not require participant input, the study team has put a safeguard 
in place for the Beiwe app to ensure participants log into their app at least once a week. Participants 
will receive bi-weekly push notifications from the Beiwe app containing a positive affirmation. The brief 
quote will serve as a reminder for participants to log in to the Beiwe app and make sure that it is still 
running properly on their phone.  
 
5.31b Symptom Management 
The SMART app is designed to collect and assess participants’ toxicities and symptoms on 
chemotherapy treatment in between visits with their clinician. Participants report the severity of their 
symptoms via a brief in-app survey of PRO-CTCAE items. The app then determines a symptom’s risk 
level and necessary response, which is either to provide no intervention, tailored symptom 
management advice, or an alert to call the clinician. Figure 3 provides a more detailed overview of this 
process. 
The symptom response criteria and the Symptom Management Content (Appendix 2) were 
developed by research staff in cooperation with the oncology providers at Dana-Farber. The study PI, 
who is also a practicing gynecologic oncologist, collated reputable and trusted sources, such as ASCO, 
the National Cancer Institute, the American Cancer Society, Cancer Care Ontario, and the Dana-Farber 
Cancer Institute, to create the content for each symptom, which includes: symptom management 
advice, questions to ask the clinical team, and multimedia content for participants to actively engage in 
symptom management practices. The content and response criteria were then reviewed and refined by 
study investigators, research staff, and gynecologic oncology clinicians to produce the final versions. 
If, over the course of the study, participants identify a need to access static versions of the patient 
education materials outside of the smartphone app, the study team will create a website which will 
contain static patient education materials about the symptoms that are targeted in the SMART App. 
This website will present evidence-based information on symptom education and symptom 
management. Some of the content on the website will mirror the content in the symptom management 
app, while other information will be housed only on the website. The purpose of the website would be to 
provide a centralized location for patients to find symptom education and symptom management 
information at any time they might be experiencing low-level symptoms. Content will be created by the 
study PI (a practicing medical oncologist at Dana-Farber Cancer Institute) and the study team, and will 
include information from trusted sources listed above.  
 
5.32 Wearable Fitness Tracker 
 
The Fitbit Charge 3 is an accelerometer that is worn on the wrist and tracks users’ heart rate 
continuously in addition to steps, distance, and calories. The addition of an optimal heart rate sensor 

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enables monitoring of the time that the tracker is being worn (i.e. adherence).48,49 Wrist-worn activity 
trackers have been shown to accurately measure heart rate when compared with 
electrocardiography,50,51 have good test-retest reliability (intraclass correlations of 0.75-0.95)52 but over 
count steps compared with the gold standard ActivPAL in free-living conditions due to the variability in 
limb-specific activities.53 One of the advantages of the Fitbit Charge 3 is it allows for close monitoring of 
adherence to the device over time because of its continuous measurement of heart rate. Additionally, 
the device has a long battery life and looks like a traditional wristwatch which may make participants 
more likely to adhere to the device when compared with other wearable fitness trackers. The 
disadvantages include: it may be less accurate if the participant is dependent upon a device for 
ambulating (e.g., cane or walker) or wears the device on her non-dominant arm. 51, 54 The Fitbit data will 
be stored on participants’ devices and smartphones, consistent with the commercially available 
devices, and also uploaded to the RMDY SMART site.,  

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Figure 3. Symptom classification and response in the SMART app intervention 
Participants report the severity of symptoms using PRO-
CTCAE items with conditional branching  
No symptoms reported 
No information is given 
Symptom management 
Presents advice on how to manage 
the symptom at home; includes links 
to questions to ask the clinical team 
at the next visit 
Alert to call clinician 
Notifies the participant that the 
symptom is severe and requires 
immediate medical management; 
alert instructs the participant to hit the 
“Call My Clinician” button 
 
The SMART app prompts participants to complete quality 
of life, physical health, and symptom questions  
For each symptom, the app classifies the intervention 
needed based upon the reported severity:  
a) No intervention 
b) Symptom management 
c) Alert to call clinician 

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5.4 Data Collection 
Table 2 specifies the instrument and intervention data collection timelines during each study phase. 
Intervention data will be collected continuously during enrollment. 
 
Table 2. Instrument data collection across study timeline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data obtained via interviews, surveys and chart abstractions will be stored on the Harvard REDCap server 
and hard copies will be stored in secure, restricted-access locations. Data obtained via the smartphone apps 
and Fitbit will be stored on the RMDY and Beiwe research platforms.  
RMDY follows industry-adopted best practices and regulatory requirements for digital therapeutics 
applications. The RMDY platform is fully compliant with HIPAA and GDPR. All applications are hosted in 
Microsoft Azure datacenters, offering enterprise-level security, availability, scalability, and compliance. All data 
hosted in the RMDY platform is encrypted “at rest” using AES256 encryption, and “in transit” using TLS 1.2. 
The organization is also currently undergoing a third-party assessment for HiTrust certification, which 
demonstrates compliance with, and adherence to, globally-recognized standards, regulations, and business 
requirements – including ISO, NIST, PCI, GDPR, HIPAA and various state laws. 
The Beiwe App will employ the same data privacy and security processes used in IRB approved protocols 
across four Partners Institutions (DFCI Protocol # 16-477; BIDMC Protocol #: 2015P-000240; McLean Hospital 
Protocol #s: 2015P001303, 2015P001538, 2012P000890, 2015P002189; MGH Protocol #: 2015P000666). 
Although the app collects a large amount of data, it was custom-built to be used in a health care setting and 
includes robust security and privacy features to safeguard all data and protect participants’ privacy, including 
data anonymity, participant authentication, and data encryption. SMART App Data Privacy and Security 
(Appendix 7) and Beiwe App Data Privacy and Security (Appendix 10) describe these processes in detail.  
 
 
 
 
DAY 
Visit 
0 
1-89 
Visit 
90 
INSTRUMENT 
Participant Baseline Interview 
 
 
 
Participant Post-Baseline Interview 
 
 
 
Health/Tx Info 
 
 
 
Healthcare Utilization & Call Log 
 
 
 
Debriefing Interviews 
 
 
 
QoL, PF, and Symptom Questions 
 
 
 
Physical Function Survey 
 
 
 
Medical Care Resource Form 
 
 
 
Passive App Data 
 
 
 
Accelerometer Data 
 
 
 

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5.5 Description of Study Process 
Study procedures are outlined below. Based on the study team’s experience conducting pilot studies, we 
understand that piloting minimal-risk interventions across sites with varying institutional policies and patient 
populations must be flexible in order to ensure that the study can quickly adapt to patient needs as we learn 
more about them over the course of the study. The study activities currently outlined in the protocol therefore 
may be adapted without the submission of an amendment in cases where these modifications would pose no 
additional risk to patients, as determined by the overall PI of the study.  
5.51 Instrument Administration  
 
Participant Baseline Survey: 
• 
Participants will complete a baseline survey when they begin study interventions (Appendix 14). 
• 
All data from the interview will be stored in RedCap; if paper copies are used, they will be stored in 
restricted-access locations.  
• 
Estimated time to completion: 45 minutes.  
 
Participant Post-Baseline Survey: 
• 
Participants will complete a post-baseline survey approximately three months after the intervention was 
administered, as close to the 3-month projected assessment date as possible (Appendix 15). 
• 
All data from the interview will be stored in RedCap; if paper copies are used, they will be stored in 
restricted-access locations. 
• 
Estimated time to completion: 30 minutes.  
 
App-Based Surveys: 
• 
Participants will be prompted by the SMART app to complete the survey. 
• 
The surveys will consist of measures of global quality of life, physical health, PRO-CTCAE questions for 
10 symptoms, and an additional question designed to query severe symptoms. 
• 
Survey items will not interfere with participants’ use of their phone.  
• 
Symptom surveys are administered daily, and the participant cannot take the symptom survey more 
than once per day. Quality of life surveys will be given over the weekend. Patients can also submit 
responses less frequently. Once the participant completes the survey it is removed from their action list. 
Missed surveys do not remain on the patient’s action list and can be completed at the next survey 
timepoint, as applicable. 
• 
Estimated time to completion: 2-3 minutes. 
• 
Participants and their oncology providers will be given summaries of their survey responses throughout 
the study through HIPAA-compliant secure email. Patients and clinicians may also choose to have their 
survey responses mailed to them via priority mail or to receive hard copies. 
 
Debriefing Interview: 
• 
Study staff will aim to conduct debriefing interviews with the first few participants enrolled at each site 
and a purposively sample a subset of patients who enroll later (up to 15 total). 
• 
Debriefing interviews will be administered by study staff following participants’ completion of the final 
post-baseline survey. 
• 
Study staff will discuss the debriefing interviews to identify opportunities for protocol improvement. 

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• 
Estimated time to completion: 20 minutes 
 
Health/Treatment Chart Abstraction:  
• 
Study staff will review participants’ medical charts to complete the Health/Tx Information form for the 
time-points of participants’ baseline and post-baseline visits.  
 
Health Care Utilization Chart Abstraction:  
• 
Study staff will review participants’ medical charts to complete the Health Care Utilization form after 
participants’ post-baseline visit. 
• 
Patients will complete the Medical Care Resource Form to capture all health care utilization during the 
study, including care outside of affiliated sites that may not be captured in site medical records. 
 
5.52 Intervention Administration  
 
5.52a Smartphone Apps 
Instructional Session: 
• 
On Day 0, participants will download, install, and run the SMART and Beiwe apps on their personal 
smartphones, with assistance from study staff as needed. Participants will receive step-by-step 
instructions and login information for the apps (SMART App Installation Information is included in 
SMART App Features and Screenshots (Appendix 5); Appendix 12: Beiwe App Installation Guide 
iOS and/or Appendix 13: Beiwe App Installation Instructions for Android). 
• 
Participants are registered to the SMART App by a study team member that has access to the 
clinician dashboard and admin site. Study staff will create an account for the participant by using 
their mobile phone number. When the participant opens the SMART App, they will be required to 
login using two-step verification. First, participants will be promoted to enter their mobile number. 
Next, they will have to enter a 4-digit personal validation code that will be automatically sent to their 
smartphone via SMS. The app does not ask the subject to enter any personal information (name, 
date of birth, etc.) and cannot be directly linked to their health records. 
• 
Participants will register in the Beiwe App by using a unique User ID and temporary password and 
then choose a new password. The subject will be assigned a unique 8-character Participant ID 
which consists of mixture of numbers and letters. The app does not ask the subject to enter any 
personal information (name, date of birth, phone number, etc.) and cannot be directly linked to their 
health records. 
• 
Participants will enter their oncology providers’ phone numbers for the “Call my Clinician” button 
and enter study staff’s contact number for the “Call Research Assistant” button.  
• 
At the end of the registration process for Beiwe, the participant will click a button to acknowledge 
that she has reviewed the privacy information with the RA and provide in-app consent.  
• 
The RA will then review how to use the apps and participants will be given a copy of the SMART 
App Participant Guide (Appendix 5) and the Beiwe App Participant Guide (Appendix 8) and 
Summary Sheet for Participants (Appendix 3) which describes the apps and provides directions on 
how to use its features, frequently asked questions, information regarding Beiwe positive affirmation 
push notifications, as well a review of the data that is collected and privacy measures.  
 

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Symptom Management: 
• 
Participants will be prompted daily to answer questions about 10 unique symptoms via the SMART 
App in the Symptom Survey. If a participant is not experiencing any symptoms that day, they can 
select “not-applicable”. Over the weekend participants will be administered quality of life surveys 
(the FACT-G7 and PROMIS Physical Function short form 6b).  
• 
If a participant reports one or more low-risk toxicities, the app will present tailored advice on how 
she can manage each symptom at home. If participants report high-risk toxicities, they will be 
instructed that they have reported a toxicity that requires further management from their clinical 
team and  are given the instruction to call their clinician. Their clinician’s phone number will be listed 
within the SMART app so that it is easily accessible for participants’ use. Please refer to Figure 3 
for an overview of this process. 
• 
In order to ensure participant safety, the RAs and apps will emphasize to participants that survey 
results will not be reviewed by a clinician in real-time. Thus, surveys cannot be used in place of 
communicating with clinicians to request help. The reminder will also note that if the participant 
feels unsafe, she should contact the treating clinician directly. 
• 
Participants and their oncology providers will be given a graphical summary of the symptoms 
participants reported by participants in-between visits. This is dependent on patient adherence –e.g. 
if a patient is not using the smartphone application and we are unable to receive symptom data, we 
will not have data to share with patients or their clinicians and no summary sheet will be provided. 
See Appendix 4: Sample Clinical Summary Sheet for an example of what the summary data will 
look like. We will not monitor whether clinicians use the summary sheets, since it is difficult to 
reliably capture what providers read and absorb.  
 
5.52b Troubleshooting the SMART App 
The intervention’s participant guides outline common troubleshooting issues and how to solve them. 
Participants will be instructed to call study staff as soon as possible to report if they are having trouble 
using the app. 
 
5.52c Fitness Tracker 
All participants will also receive a Fitbit Charge 3 wearable fitness tracker.  
 
Instructional Session:  
• 
Following the completion of the Participant Baseline Survey on Day 0, participants will set up their 
fitness tracker, with assistance from study staff as needed. Participants will learn how to use the 
fitness tracker; download the Fitbit smartphone app; learn how to synchronize their device to their 
smartphone; and work with study staff to synchronize their accelerometer data to the research 
database.  
• 
In addition to the accelerometer, participants will receive the Fitbit Participant Guide (Appendix 11), 
which describes proper wear and care, charging and battery life, troubleshooting instructions, 
uploading data, and compliance. 
• 
Participants will be encouraged to contact study staff at any time with questions or issues to help 
ensure proper wear and use of the fitness tracker.  
 
Tracking Devices:  

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• 
The accelerometer assigned to each participant will be tracked according to the product serial 
number and assigned unique ID number.  
• 
Participants will be allowed to keep the accelerometer as a token of appreciation for their 
participation in the study, and to minimize potential transmission of skin infections (e.g. methicillin-
resistant Staphylococcus aureus) between participants. 
 
Monitoring 
• 
If patients are wearing their accelerometer continuously throughout the day and experience a 
severe drop in steps (e.g. ≤1,000 steps in a 24-hour period) that is unlikely to be attributable to 
external factors (e.g., severe snowstorm or rain), study staff will contact the patient to ask if she is 
experiencing severe symptoms.  
 
 
5.52d Apps and Fitness Tracker Use and Compliance 
Participants will be instructed to avoid adjusting app settings (for Fitbit, SMART, and Beiwe Apps), to 
ensure data is collected. If the study team does not receive data from the SMART or Beiwe Apps or 
fitness tracker, study staff will attempt to contact patients to help resolve the issue remotely or during an 
upcoming clinic/study visit. 
5.52e Subsequent Enrollment in a Therapeutic Drug Trial 
Participants in this study may enroll in a therapeutic drug trial at any point after signing consent to 
participate in this study. However, if a patient enrolls in a therapeutic drug trial that requires structured 
symptom or toxicity reporting we will record this and perform a sensitivity analysis, excluding any 
patients who participated in a therapeutic trial after enrollment, to determine whether this impacts our 
findings. Since this is a feasibility and acceptability trial, we do not want to censor participants.  
 
5.53 Compensation 
If site policies permit, patients will be provided with a gift-card, Clincard or equivalent valued at $50 
after completing the baseline and post-baseline interviews, to thank patients for their time participating in 
the study and to minimize attrition. Additionally, participants may be reimbursed for significant study-related 
expenses (e.g., expenses >$25 directly attributable to the cost of uploading data from the smartphone app 
over a cellular data plan) if site policies allow. 
 
5.6 Adverse Reactions and Management 
 
5.61 Reporting Adverse or Unanticipated Events 
Potential adverse events (AE) for this project are expected to be all non-medical in nature. There is a 
small chance that participants could worsen repetitive use injuries (e.g., carpal tunnel syndrome) while 
using the smartphone app. Subjects may experience mild anxiety when answering survey questions about 
emotional issues or questions about coping challenges or difficulties related to discussing the subject 
matter. The PI will report unanticipated and serious adverse events to the IRB in a timely manner on an 
ongoing basis. For the purpose of this study a Serious Adverse Event (SAE) is defined as an event that, as 
a direct result of the study, causes serious harm to the subject (e.g., hospitalization).  
 
5.62 Anticipated Reactions & Reaction Management 

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Should participants become exceedingly upset, disoriented or fatigued or need to attend to matters of 
personal care during the surveys, study staff will ask the subject if they would like to take a break or 
reschedule the survey for another time. In the event that participants experience distress while completing 
surveys, we will follow standard procedures used in our behavioral health intervention studies for 
counseling and referral. The PI will be notified immediately, and participants will be provided with the pager 
numbers for both the study PI and a clinician at the primary site, who will evaluate any participants who are 
distressed for risk of imminent danger and refer them to appropriate services if they are needed. 
 

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6.0 STATISTICAL ANALYSIS 
 
6.1 Primary and Secondary Endpoints 
 
Primary Endpoints 
 
1) Feasibility of the SMART intervention 
2) Acceptability of the SMART intervention 
 
Secondary Endpoints 
 
2) Perceived efficacy 
3) Additional patient outcomes, including: health-related quality of life, anxiety and depression, symptom 
burden, and health care utilization 
4) Agreement between patient and physician estimates of performance status 
5) Correlation between data collected from the wearable and smartphone accelerometers 
6) Predictive ability of wearable accelerometer and smartphone data for patient’s performance status and 
clinically significant events 
 
6.2. Sample Size  
The primary objective of this study is to assess the feasibility and acceptability rates of the SMART 
intervention. A convenience sample of 30 patients will be enrolled to the study, with expected accrual of 
approximately 15 patients each at a maximum of 2 community oncology sites.   
6.3 Analysis Plan 
Statistical analysis will be descriptive in nature and will access feasibility, acceptability, and perceived efficacy, 
as well as estimate outcomes parameters. 
Feasibility: Feasibility will be defined as ≥50% approach-to-enrollment rate among eligible participants, and 2) 
≥50% 3-month adherence rates to the smartphone app and wearable accelerometer (based upon attrition rates 
from prior trials of PROs).10 Patients who complete daily surveys ≥4 days per week over the three-month study 
period will be considered as adherent to the smartphone app. Patients who wear the wearable accelerometer 
≥4 days per week over the three-month study period will be considered as adherent to the wearable 
accelerometer. 
Acceptability: Acceptability will be defined as ≥60% of participants “agree” or “strongly agree” that they “would 
recommend the SMART Study to other patients with cancer receiving chemotherapy;” and <30% of 
participants answering agree or strongly agree to either question:  1) “Participating in this study placed a 
substantial burden on me” and 2) “I wish I had not agreed to participate in this study.” 
Perceived efficacy: Perceived efficacy will be measured by qualitative analysis. We will conduct debriefing 
interviews with approximately 30 participants and their clinicians (evenly distributed among the community 
oncology sites) to obtain information about the acceptability of the intervention and recommendations for any 
modifications to improve any aspects of recruitment, enrollment, education, the timing of study assessments, 
graphical display of information, and the app that could be improved. 

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Patient outcomes: We will collect baseline and 3-month outcome data from patient interviews and clinician 
surveys. At each time point clinicians and participants will be asked to rate the participant’s ECOG 
performance status and EuroQoL EQ-5D index; patients will also be asked to rate their symptoms using the 
PRO-CTCAE. We will also collect health care utilization data (e.g. nursing calls, emergency department visits, 
hospitalizations, and hospice referrals) from the medical chart and healthcare utilization logs provided by 
patients. For purposes of estimating outcomes parameters, the distributions of these patient outcomes will be 
summarized using descriptive statistics such as means, standard deviations, and proportions, and, where 
appropriate, cumulative incidence functions. Additional demographic information that will be summarized 
include age, marital status, race/ethnicity, education, household structure, income, employment, health literacy 
and numeracy, and cancer treatment associated burden. We will abstract information from the medical chart; 
e.g., comorbid health conditions, prior chemotherapy regimens, and time since diagnosis. 
Correlative analyses: 
Agreement between patient-oncologist estimates of performance status will be estimated by Cohen’s 
Kappa statistic. We will descriptively summarize correlations between active (e.g. quality of life and symptoms) 
and passive (e.g. time spent away from home) data collected from the SMART and Beiwe apps and the 
wearable accelerometer (average daily steps) with clinical outcomes collected at baseline and post-baseline 
(i.e. performance status, quality of life, and symptoms assessment as obtained from the PRO-CTCAE and 
CTCAE). In addition to descriptive analyses and estimating correlations between passive smartphone data and 
clinical outcomes, passive data may contain information that allows for the prediction of future clinically-
relevant events, such as visits to the emergency department, urgent clinic encounter, or hospitalization. By 
testing for changes in activity, mobility, and social patterns over time as measured through smartphone use 
may be able to identify significant anomalies in patient behavior in the days prior to relapse. In a study in a 
cohort with schizophrenia, behavioral anomalies detected in the two weeks prior to clinical relapse occurred at 
a rate 71% higher than anomalies detected on other days.55 The method is based on a modification of the 
Hotelling’s T test to detect changes in the distribution of previous passively-measured activity. In our proposed 
study, this method might be used to query patients in real time to detect if an unscheduled clinical event might 
occur in the near future. 
 

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DF/HCC Protocol 16-477: The SMART Study 
 
April 23, 2021 | v8 
72 
 
 
8.0 APPENDICES 
 
Recruitment/Enrollment: 
Appendix 1: Registration Form  
 
Interventions: 
Appendix 2: Symptom Management Content 
Appendix 3: Summary Sheet for Participants 
Appendix 4: Sample Clinical Summary Sheet 
Appendix 5: SMART App Features and Screenshots: Patient Guide 
Appendix 6: SMART Study Clinician Dashboard  
Appendix 7: SMART App Data Privacy and Security  
Appendix 8: Beiwe App Participant Guide  
Appendix 9: Beiwe App Info for Study Team 
Appendix 10: Beiwe App Data Privacy and Security  
Appendix 11: Fitbit Participant Guide  
Appendix 12: Beiwe App Installation Guide: iOS 
Appendix 13: Beiwe App Installation Guide: Android 
 
Instruments: 
Appendix 14: Participant Baseline Interview 
Appendix 15: Participant Post-Baseline Interview 
Appendix 16: SMART App Survey  
Appendix 17: Health/Tx Information 
Appendix 18: Health Care Utilization 
Appendix 19: Call Log 
Appendix 20: Patient Debriefing Interview 
Appendix 21: Clinician and Site Staff Debriefing Interview 
 
Other: 
Appendix 22: Data and Safety Monitoring Plan 
 
Appendix 23: Reimbursement Sheet  
Appendix 24: Beiwe Positive Affirmation Push Notifications  
Appendix 25: Consent Form Template