Healthy Hearts Healthy Minds: A PPRN Demonstration Pragmatic Trial
Phase: NA
Conditions: Cardiovascular Diseases, Depression
Sponsor: Massachusetts General Hospital

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Healthy Hearts Healthy Minds: A PPRN Demonstration Pragmatic Trial 
ClinicalTrials.gov Identifier: NCT03373110 
 
 
 

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Healthy Hearts Healthy Minds: A PPRN Demonstration Pragmatic Trial 
Andrew Nierenberg, MD (Principal Investigator) 
Department of Psychiatry, Massachusetts General Hospital  
Harvard Medical School  
 
I. 
BACKGROUND AND SIGNIFICANCE                
 
Depression and cardiovascular disease (CVD) frequently occur together, exacerbate each 
other, and when combined, are among the leading causes of disability and death. Compared 
to people without depression, those with depression have two times the risk of 
myocardial infarction1, 2 and are four times more likely to die from coronary heart 
disease3, 4. Mostly because of cardiovascular comorbid conditions, people with major 
depressive disorder (lifetime prevalence of about 17%) 5-7, or bipolar disorder (prevalence 
of about 4.5%)7  die 8 to 25 years earlier than the general population 8, 9. Conversely, people 
with CVD (overall prevalence over 33% of adults10 ) have three to four times the rate 
of depression compared to the general population 11, 12, and  die at twice the rate if they 
have comorbid depression compared to those without depression 13-15.  Depression and CVD 
interact in a vicious cycle and are responsible for a large proportion of morbidity and 
mortality 16.  
Why Exercise may be the key to breaking the vicious cycle: The impact of 
exercise on CVD is clear and clinically meaningful. Exercise improves virtually all risk 
factors for CVD as well as the disease itself. For example, exercise positively benefits 
hypertension as well as risk of metabolic syndrome and diabetes17. A walking study of 8,436 
male and 33,586 female participants found that this physical activity remarkably lowered 
the risk of CVD mortality by 35%, ischemic heart disease mortality by 31%, diabetes 
mortality by 91%, and 34% for hypertensive diseases18. Recently, a 15-year study 
investigating the role of exercise in preventing and treating CVD in healthy adults 
(N=8,662) found that people exercising regularly were 0.35 (0.13–0.98) times less likely 
to die from CVD compared to those not exercising regularly19. Given these data the US 
Preventive Services Task Force (USPSTF) recently published a guideline recommending 
“referring adults who are overweight or obese and have additional CVD risk factors to 
intensive behavioral counseling interventions to promote a healthful diet and physical 
activity for CVD prevention.”  
The impact of exercise on depression is also clear and clinically meaningful. 
Two recent meta-analyses found that exercise for depression was superior to no treatment 
at all as well as to similarly efficacious psychotherapies20, 21. The treatment effect size for 
exercise across 11 well controlled trials was large (Hedge’s g = 1.39, for a random effects 
analyses), indicating that it has powerful antidepressant properties21. Exercising 3 
days/week for 45-min over four months is as effective in reducing depressive symptoms as 
an antidepressant (i.e., sertraline) for individuals with unipolar depression22, 23 24. Other studies 
have found that exercise improves bipolar depression25, 
26, one’s stress reactivity27 and 
cognition28. Similar to the risk for CVD, there is a dose-response relationship between 
exercise and depression highlighting the direct impact of exercise on one’s mental health28, 
29. Exercise may also address the underlying mechanisms for the vicious cycle of depression 
and CVD.  Recent evidence suggests that depression is linked to inflammatory processes 
(indicated by C-reactive protein and interleukins) 30 and inflammation is a key feature of 

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atherosclerosis and CVD.  The most robust way to combat inflammation is to exercise31-34. In 
sum, exercise is key to reducing the impact of these co-occurring conditions, which 
increases morbidity and mortality in the US population.  It is less clear, however, how to 
best help people make this important behavioral modification. 
 
The proposed study is particularly poised to further target high-risk 
populations as individuals with lived experience of depression and/or heart disease 
will co-design two online interventions with clinicians and researchers. We will also 
leverage existing knowledge about facilitating exercise amongst people with depression 
and individuals who are at risk for, or have, CVD online, through the positive role of 
others (e.g., online communities) and utilizing the rich experience of the field of online 
education to keep people engaged in the two chosen web-based, empirically-validated 
interventions to enhance exercise51-54. The proposed study also seeks to disseminate two 
targeted, empirically-based interventions for individuals with depression at risk for or 
with CVD. By bringing together MoodNetwork and Health eHeart (UCSF, CHR #12-
09993), we have the immediate opportunity to serve the participants currently enrolled in 
our two networks (>4100 in MoodNetwork and >80,000 in Health eHeart) across 50 
states, 5 territories, and 33 countries. Potential dissemination, however, is much wider. 
Thus, the impact of this study is increasing access to empirically-supported 
treatments that are specifically tailored by partnering with patients to enhance 
exercise in depressed individuals who are at risk for, or have, CVD. 
 
 
This study will utilize the National Institutes of Health-funded Eureka 
mHealth Research Platform (UCSF, CHR #16-19397), a platform that enables 
investigators to conduct mobile, online, and wireless health research in a less costly, more 
streamlined manner, in order to recruit participants, collect and store study data, and 
manage study participants. The research platform will accelerate our ability to access a 
large cohort of volunteers who have agreed to participate in research, and provide a 
quick, affordable means for collecting their health data through mobile and wireless 
technologies. 
 
II. 
SPECIFIC AIMS 
The purpose of this research is to compare the effectiveness of web-based cognitive 
behavior therapy (CBT) and use of a fitbit device, web-based mindfulness-based cognitive 
therapy (MBCT) and use of a fitbit device, and use of a fitbit device with no adjunctive 
therapy for increasing physical activity in people with a history of depression and who have 
or are at risk of having cardiovascular disease.  
 
A. 
Primary Aims 
Aim 1: To determine if 1) web-based CBT or  web-based MBCT, supported by use 
of  Fitbit technology for self-tracking of activity, improves physical activity, and 2) 
How these two therapies compare to a Fitbit-only control group.  
Hypothesis 1a: Because CBT (compared to MBCT) is the more directive intervention, we 
hypothesize that CBT will be superior to MBCT in increasing daily steps over the course 
of 8-weeks of treatment and at follow-up.  
Hypothesis1b:  Both forms of therapy-based treatment will be superior to the Fitbit only 
control group in increasing daily steps over the course of 8-weeks of treatment and at 
follow-up.  

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Aim 2: Explore the heterogeneity of treatment effects (HTE) to both interventions. 
This aim will allow us to explore who will benefit from either CBT+ Fitbit, MBCT+ 
Fitbit, or Fitbit alone (predictors) and to determine the factors that can help match 
patients to each intervention (moderators or who will have better outcomes with 
CBT+Fitbit, MBCT+Fitbit, or Fitbit only).  
 
III. 
INTERVENTION MODULES AND OVERVIEW 
Participants in both therapy-based interventions will access materials (e.g., client 
vignettes, videos, activities) that illustrate ways to increase physical activity (e.g., walks, 
runs, climbing stairs, etc.). They will be guided to gradually increase their daily steps 
(physical activity) at their own pace. Both CBT and MBCT will be provided online and 
will guide participants through the elements of each treatment which are geared to 
address the barriers against exercise that individuals with mood disorders at risk for or 
with CVD face (fear of the physiological signs of exertion as they may mean a heart 
attack, etc.). Besides structured guidance towards exercise, the main focus of both 
treatments will be on addressing these obstacles that prevent individuals from engaging in 
exercise. Participants in both of these groups will receive Fitbit devices to measure their 
steps (main outcome) throughout the study. In addition to the two treatment-based 
intervention group there will also be a group of participants who serve as controls. This 
group will receive a Fitbit device, but no form of therapy and will not have access to the 
online therapy material. By including this control group, we will be able to ensure that 
any treatment effect is not due to wearing a Fitbit. 
 
Cognitive-behavioral therapy (CBT): CBT will be based on previous work using CBT 
to enhance exercise 53, 55-57 in individuals with mood disorders which includes the following 
elements: (1) identifying and setting realistic exercise-based goals and intermediate goals 
(to maximize success to increase motivation); (2) behavioral scheduling to optimize when 
to exercise, identify rewards for exercising, and problem solve obstacles to exercising; 
and (3) identify dysfunctional, maladaptive thoughts about exercise (which decrease 
motivation) and skills to identify more adaptive, positive thoughts (to overcome thoughts 
of being too tired or too stressed to exercise). These aspects follow the core components 
of CBT58, or to change dysfunctional thoughts and behaviors to change a problem 
behavior (i.e., sedentary behavior). Evidence shows that adjunctive CBT for exercise 
helps patients improve their planning to exercise, motivation to exercise, and self-
efficacy (or one’s belief in their ability) to exercise 56, 59, 60.  Two hundred participants will be 
randomized to this group. 
 
The CBT Program can be added to an individual’s regular course of treatment (such 
as medications), but should not replace ongoing treatment with his/her own doctor. 
Throughout participation in this study, the participant should continue any 
medications or treatments that his/her own doctor feels will best treat the symptoms 
of depression and/or cardiovascular disease.  
 
 

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Mindfulness-based Cognitive Therapy (MBCT): MBCT will be based on previous 
work with individuals with mood disorders 62-66. A central aspect of MBCT is the concept of 
awareness. Participants practice a variety of meditation types (e.g. breath awareness) and 
learn to bring mindfulness to everyday situations. Awareness will be directed to elements 
in participants' lives that interfere with living a more productive, physically active life 
(e.g. thoughts and feelings that interfere with becoming more physically active; stressful 
situations and circumstances that prevent them from engaging in exercise). The program 
guides participants to a mindful consideration about how to "respond" to factors that 
interfere with a healthy lifestyle. In addition participants bring mindfulness to actual 
physical activity and the pleasant after effects (to enhance motivation). Compared to 
CBT, mindfulness, takes a more explorative, self-guided approach of raising awareness 
rather than a more directive and prescriptive approach adopted by CBT. The fundamental 
difference between CBT and MBCT is that CBT focuses on goal setting, planning, 
behavioral contingencies and re-conceptualizing of dysfunctional thoughts that interfere 
with goal achievement, whereas MBCT strives for gradually increasing awareness 
towards personal and situational factors that interfere with a healthy, more physically 
active lifestyle, and developing personalized ways to respond to these factors as well as 
changing the experience of exercise itself. Although participants cannot choose the 
intervention, we will explore treatment preferences as a potential source of heterogeneity 
effects. Two hundred participants will be randomized to this group. 
 
The MBCT Program can be added to an individual’s regular course of treatment 
(such as medications), but should not replace ongoing treatment with his/her own 
doctor. Throughout participation in this study, the participant should continue any 
medications or treatments that his/her own doctor feels will best treat the symptoms 
of depression and/or cardiovascular disease.  
 
 
Fitbit-Only Control Group: 
Participants assigned to the Fitbit-only control study group you will not be receiving 
therapy. However, they will receive a Fitbit, which they will be asked to wear over 
the course of 16 weeks as well as to complete the same schedule of assessments as the 
therapy arms. One hundred participants will be randomized into this group. 
 
Participation in this study can be added to an individual’s regular course of treatment 
(such as medications) but should not replace ongoing treatment with his/her own 
doctor. Throughout participation in this study, the participant should continue any 
medications or treatments that his/her own doctor feels will best treat the symptoms 
of depression and/or cardiovascular disease.  
 
 
IV. 
RESEARCH DESIGN AND METHODS 
 
Overview  
Given that majority of participants screened will not be eligible, we plan to screen 5000 
individuals with the expectation that 10% will be eligible. We propose to recruit 500 eligible 

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patients from the ongoing MoodNetwork and the Health eHeart Alliance studies who self-report 
a history of depression and are at elevated risk for cardiovascular events. 40% of participants 
(2000) will be recruited from MoodNetwork, while 60% (3000) will be will be recruited from 
Health-eHeart.  Participation will take a total of 16 weeks. During the first 8 weeks, participants 
will receive online CBT and a fitbit device to track activity, online MBCT and a fitbit device to 
track activity, or a fitbit device to track activity but no adjunctive therapy.  The second 8 weeks 
are a follow-up period where participants will be asked to continue wearing their fitbit device, 
but receive no other form of treatment, regardless of which group they were initially randomized 
to. Participants will use desktop computers, laptops, tablet devices, or phones to participate in 
this study. These procedures are described in detail below.  
Accessed through a links managed by MoodNetwork.org and Health-eHeart.org, interested 
participants will sign an online consent form waiver, found in a web portal hosted by the Eureka 
mHealth Research Platform. Eureka is a multi-tenant system (architecture in which a single 
instance of a software application serves multiple customers), which is housed on a HIPAA 
compliant Amazon cloud database. Once the participant has read and electronically signed the 
waiver of consent form, participants will register for Eureka and then complete a short battery of 
assessments to determine eligibility. The assessments will consist of 3 standard psychological 
assessments (The Patient Health Questionnaire [PHQ-9], the Altman Self-Rating Mania Scale 
[ASRM], and the Mini International Neuropsychiatric Interview [MINI], and 2 cardiac health 
assessments (The Duke Activity Status Index [DASI], and the International Physical Activity 
Questionnaire [IPAQ]). They will also be asked to complete a standard demographic form, and 
their medical and psychiatric histories. If they are not eligible, they will be thanked for their 
interest and informed that unfortunately, they are not eligible. If found eligible, they will provide 
their mailing address information so that we can ship them a Fitbit device.  Once they receive 
their Fitbit device, they will return to the study portal to sync their fitbit with our system so that 
we can collect their step data complete a series of questionnaires, including the World Health 
Organization Composite International Diagnostic Interview for Bipolar Spectrum Disorders 
(CIDI), The Patient Health Questionnaire (PHQ-9), The Altman Self-Rating Mania Scale 
(ASRM), The Sheehan Disability Scale (SDS), The World Health Organization-5 Well-Being 
Index (WHO-5), the Self Efficacy for Exercise (SEE),  the International Physical Activity 
Questionnaire (IPAQ), the Seattle Angina Questionnaire-7 (SAQ-7) and the Perceived Stress 
Scale (PSS). Once completed, participants will be randomized to CBT + Fitbit, MBCT + Fitbit, 
or the Fitbit-only control group. Those who are randomized to one of the two therapy-based 
treatment groups will be sent to a portal on MoodNetwork.org to access the interventions. Those 
randomized to the Fitbit-only treatment group will be brought to a page thanking them for their 
participation, reminding them to wear their fitbit for the next 16 weeks, and informing them that 
they will be emailed reminders when they need to return to the portal to complete surveys. All 
participants, regardless of study group, will be asked to return to Eureka in weeks 2, 4, 6, 8, and 
16 to complete a battery of assessments and asked questions about adverse events that may have 
occurred since beginning the study (detailed in Table 1 below).  

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Participants in the two therapy-based intervention groups will receive either online CBT or 
online MBCT through a portal in MoodNetwork for 8 weeks. The therapy will consist of 25-40 
minutes of weekly material. After this 8-week period, they will enter an 8-week follow-up phase 
during which no new treatment material will be administered, but they can access the material 
already presented during the treatment phase. If randomized to the control group, participants 
will wear the Fitbit device for an 8-week period and follow the same schedule of assessments as 
the treatment groups. Throughout the 16-week study, Fitbit data will be pulled into the Eureka 
mHealth Research Platform database, which is housed on a HIPAA compliant Amazon cloud 
database, using Fitbit’s secure application programming interface (API). Coordinated and 
approved of by the Partner’s Clinical Trial Office, Fitbit and MGH have agreed to a 
collaboration wherein Fitbit will share data (heart rate variability data and sleep data) with the 
study team that is collected with the devices, which is not available through their public API. 
Additionally, Fitbit will donate half of the devices needed for the study (275).  In return, the 
study team will share de-identified assessment and summary data with Fitbit. Data will be 
transferred in a secure file sharing area (S3 Bucket) in Amazon cloud services. This has been 
documented in a donation agreement and a data use agreement.  
 
Participant Selection and Recruitment 
Participants (N = 5000) will be recruited from MoodNetwork.org and health-
eheartstudy.org. Participation will take 16 weeks and will involve (1) 8 weeks of receiving 
online CBT and use of a fitbit, MBCT and use of a fitbit, or use of a fitbit with no adjunctive 
therapy and (2) 8 weeks of follow-up. Participants will use desktop computers, laptops, 
tablet devices, or phones to participate in this study. An IRB approved electronic alteration 
of a written Informed Consent will be obtained from all patients before protocol-specified 
procedures are carried out. Patients will be recruited according to the following criteria: 
 
a. Inclusion Criteria 
 
• 
Ability to give informed consent 
• 
Fluent in English 
• 
Between the ages of 18-65 
• 
Lives in the United States 
• 
Self-report of having experienced depression as assessed by the Mini International 
Neuropsychiatric Interview (MINI) 
• 
Self report an elevated risk for or of having cardiovascular disease ( < 150 minutes 
of physical activity a week) 
• 
Registered a personal account with Fitbit prior to enrollment in the study 
 
b. Exclusion Criteria 
• 
Unwilling/unable to comply with study procedures 
• 
Pregnant 

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• 
Responds to item 9 (Suicidal ideation) on the PHQ-9 with a 3 (i.e., “Thoughts that 
you would be better off dead or of hurting yourself in some way nearly every day  
”) 
• 
Contraindications to exercise or diet interventions as assessed by the DASI  
• 
Already uses a fitbit device or other activity monitor 
• 
Suffers from repeated episodes of “blacking out” or “fainting”  
• 
Survived a cardiac arrest 
• 
Has recurrent chest discomfort with activity that goes away within 10 minutes of 
rest or with nitroglycerin  
• 
Has heart failure  
• 
Has been hospitalized recently (within past 6 weeks) for a cardiovascular problem 
 
c. Diagnostic and Clinical Assessments 
 
Diagnostic and Clinical Assessments:  
The Mini International Neuropsychiatric Interview (MINI) The MINI can assess for current 
17 Axis I diagnoses, exploring lifetime diagnoses where clinically relevant (i.e., previous manic 
episode for a diagnosis of bipolar disorder). Diagnoses can be ruled out by answering no to one or 
two screening questions. Positive responses to screening questions are followed by further 
exploration of other diagnostic criteria. The MINI shows good specificity and sensitivity for most 
psychiatric diagnoses and concordance with other structured diagnostic interviews. 
The World Health Organization Composite International Diagnostic Interview for Bipolar 
Spectrum Disorders (CIDI) is a 12-item fully-structured lay-administered diagnostic interview 
that was validated as being capable of generating conservative diagnoses of both threshold and 
sub-threshold bipolar disorder. 
The Duke Activity Status Index (DASI) is a 12- item self-administered questionnaire that utilizes 
self-reported physical work capacity to estimate peak metabolic equivalents and has been show to 
be a valid measurement of functional capacity. 
The Patient Health Questionnaire-9 (PHQ-9) is a brief self-report instrument used to screen, 
diagnose, monitor, and measure the severity of depression. The first 8 questions incorporate DSM-
IV diagnostic criteria as well as other major depressive symptoms, and Question 9 assesses for the 
presence and duration of suicidal ideation. 
The Altman Self-Rating Mania Scale (ASRM) is a brief (5-item) self-report questionnaire that 
helps measure the severity or intensity of manic or hypomanic symptoms. 
The Sheehan Disability Scale (SDS) measures functional impairment resulting from depressive, 
panic, anxiety, or phobic symptoms. Patients rate the extent to which their work/school work, 
social life/leisure activities, and family responsibilities/home life are affected on a 10-point scale. 
Patients also indicate the number of days lost and number of days underproductive due to 
symptoms. 
The World Health Organization-5 Well-Being Index (WHO-5) is a brief self-report (5-item) 
of positively-worded statements related to positive mood (good spirits, relaxation), vitality (being 
active and waking up fresh and rested), and general interests (being interested in things) over the 
prior two weeks.  

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The Perceived Stress Scale (PSS) is the most widely used psychological instrument for assessing 
perception of stress.  This scale measures the extent to which situations in one’s life are labeled as 
stressful. 
Self Efficacy for Exercise (SEE) is a 13-item instrument that focuses on self-
efficacy expectations related to the ability to continue exercising in the face of barriers to exercise. 
International Physical Activity Questionnaire (IPAQ) The IPAQ was developed to assess 
cross-national monitoring of physical activity and inactivity. It is validated in 12 countries and is 
available in both a long and a short form.  
Cardiac Events (CE) is a two - question survey designed to monitor participants who may develop 
contraindications to exercise or who are at elevated risk for a cardiac event over the course of the 
study. 
Seattle Angina Questionnaire – 7 (SAQ-7) is a well-validated and widely used 19-item 
instrument that measures patient-reported symptoms, function and quality of life for patients with 
coronary artery disease. 
Adverse Event Questions (AEQ) two-question survey designed to assess if participant has 
experienced any adverse events, related to the study, since starting to participate. 
 
Table 1. Schedule of Assessments  
Weeks 
0 1 2 
4 
6 
8 
16 
Pre 
Mid Post 
Follow-
Up 
Demographics 
X  
 
 
 
 
 
 
Medical/Psych Hx 
X 
 
 
 
 
 
 
Mini International Neuropsychiatric Interview (MINI)    
X 
World Health Organization Composite International 
Diagnostic Interview for Bipolar Spectrum Disorders 
(CIDI) 
X 
Duke Activity Status Index (DASI) 
X 
The Patient Health Questionnaire (PHQ-9) 
X X X X 
X 
X 
X 
Altman Self-Rating Mania Scale (ASRM) 
X X X X X 
X 
X 
Sheehan Disability Scale (SDS) 
X 
X 
X 
X 
Well-Being Index (WHO-5) 
X X X 
X 
X 
X 
Perceived Stress Scale (PSS) 
 
X 
 
X 
 
X 
X 
Self Efficacy for Exercise (SEE) 
X 

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International Physical Activity Questionnaire (IPAQ) 
short form 
X X 
 
 
 
 
 
Cardiac Events 
X X X X 
X 
X 
X 
Seattle Angina Questionnaire – 7 (SAQ-7)* 
 X  
 
 
X 
X 
Adverse Event Questions 
 
 X X 
X 
X 
X 
 
*The SAQ-7 will only be re-administered to those who respond affirmatively to having angina 
(coronary artery disease), heart attack, coronary bypass surgery coronary stent or angioplasty procedure 
or if participant has recurrent chest discomfort with activity that goes away within 10 minutes of rest 
or with nitroglycerin 
 
d. Targeted Enrollment 
We expect to recruit a representative sample of the US. We expect that our sample will 
resemble the general population given the recruitment sites, or MoodNetwork and Health 
eHeart. 
 
Table 2. Expected Enrollment by Race, Ethnicity and Gender 
Race 
Male (N) Female (N) 
Total (N) 
American Indian/Alaska Native 
6 
7 
13 (2.5%) 
Asian 
12 
13 
25 (5%) 
Black/African American 
87 
88 
175 (35%) 
Hawaiian/Pacific Islander 
2 
3 
5 (1%) 
White 
137 
138 
275 (55%) 
Multiracial 
3 
4 
7 (1.5%) 
Ethnicity 
Male (N) Female (N) 
Total (N) 
Hispanic (Latino/Latina) 
 50 
 50 
100 (20%)  
Non-Hispanic 
 200   
 200  
400 (80%) 
Age 
Male (N) Female (N) 
Total (N) 
17 years or younger*  
 ---- 
----  
0% 
18 to 44 years 
125 
 125 
250 (50%)  
45 to 64 years 
125 
125  
250 (50%)  
65 years or older* 
 --- 
--- 
0% 
 
V. 
POTENTIAL BENEFITS 
The proposed research study involves an intervention that holds the potential for direct 
individual benefit such as weight loss, increased healthy lifestyle choices and habits, and 
decreased medical burden. This research will further our knowledge about medical 

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burden in depression and the feasibility of psychosocial treatment to reduce this burden. 
Risks of discomfort associated with the treatment should be offset by the potential 
physical and mental health benefits. Thus, this study has the potential to not only improve 
the treatment of depressed patients, but also advance the field by developing a treatment 
that can be used in future treatment studies of depression. 
 
Subjects will not receive monetary compensation. Subjects will, however, receive the 
online therapy modules at no cost (if randomized to one of the two therapy-based 
intervention groups). All participants, regardless of which group they are randomized to, 
will receive a fitbit device at no cost. For completing the bi-weekly assessments, 
participants can earn up to $60 worth of Amazon gift cards.  Lastly, participants will have 
the opportunity to be part of the cutting edge of clinical research.  
 
VI. 
RISKS AND DISCOMFORT  
The risks that this trial poses to participants are reasonable in relation to the anticipated 
benefits because bipolar disorder is associated with a disproportionately high medical 
burden as well as chaotic mood swings and a high rate of functional impairment.  
 
The risk of loss of privacy in our study hosted by the Eureka Research Platform and the 
MoodNetwork will be present for all persons participating. Loss of privacy could occur 
by compromise of either of the technical systems, or if either are required by law to 
disclose data to authorities, e.g. to prevent serious harm to the participant or others.  
 
Potential Risks to Subjects 
Participants may experience some discomfort or anxiety from discussing personal material 
and completing self-report questionnaires. If a subject feels uncomfortable responding to a 
question, he or she will not be required to give a response.  
 
As with any type of physical activity, there is a small risk of physical injury. In order to 
minimize this risk, we take several steps. First, we ask individuals to participate only if 
they are healthy enough for mild to moderate physical activity. We ask that if they are not 
sure, that they check with a physician before continuing with this study. Second, we ask 
that they do not engage in any exercise practices that cause any physical discomfort or 
place them at risk of falling. If, for some reason, they do experience an injury while 
participating in this study, we ask that they contact their primary care physician or visit 
their local emergency room.  
 
A further risk is a breach of confidentiality. This breach could occur when PII is 
accidentally made visible to other researchers or to the public. The potential harm from 
this risk is psychological or social harm from having personal data made public. 
 
Protection Against Risks 
We will implement the following procedures to protect participants against risks: 
 

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1. Screening procedures will exclude any individuals who are not clinically suitable for 
the study protocol. For example, individuals will be excluded if they endorse a 3 on 
item 9 (Suicidal ideation) of the PHQ-9 (i.e., “Thoughts that you would be better off 
dead or of hurting yourself in some way p nearly every day”) during study 
intake.   Lastly, to protect participants against risks, we will exclude individuals who 
have any contraindication to exercise or who are at elevated risk for a cardiac event as 
assessed by the DASI and Cardiac Events questionnaire. 
 
2. Throughout the study, participants will be closely monitored for exacerbation of 
mental health conditions with the Patient Health Questionnaire (PHQ-9) and Altman 
Self-Rating Mania Scale (ASRM). Participants who score greater than a total score of 
a 20 on the PHQ-9 (indicative of “very severe” depression) and/or a total score of a 
16 on the ASRM (or indicative of “very severe” mania) will be sent an automated 
message stating that their response on these assessments suggests that follow-up care 
with a local provider is warranted. If item 9 (Suicidal ideation) on the PHQ-9 is a 2 or 
higher (i.e., “Thoughts that you would be better off dead or of hurting yourself in 
some way on more than half the days”), then an automatic message will also be 
generated alerting the individual that their response warrants follow-up care with a 
local provider. Specifically, via embedded web links, we will refer participants to the 
MoodNetwork resource page and the DBSA “Find a Pro” link, and will encourage 
people to contact the National Suicide Prevention lifeline number (1-800-273-TALK) 
and/or online chat service if needed. When automated messages are sent, a flagged 
email will be sent to the PI, Dr. Nierenberg. Based off the patient responses from the 
assessments, Dr. Nierenberg and his fellow study clinicians will determine if it is safe 
for the participant to continue participating in the study.  
 
3. Patients will complete the brief, bi-weekly survey of potential cardiovascular 
symptoms (CE) to monitor participants throughout the study. The survey will ask 
patients whether they have been hospitalized for any of a variety of cardiac 
conditions. Patients who respond affirmatively to any of the components of the CE 
(specifically any of the choices 1-7 in question 1) will be automatically prompted to 
stop engaging in any excessive physical activity (including activity related to study) 
and to seek medical attention from their primary provider before proceeding. Study 
staff will be alerted in these situations and may follow-up directly with the 
participant. 
 
4.   Subjects may be withdrawn from the study for any of the following: 1; 1) Elevated 
risk for a cardiac event as confirmed by Cardiac Events assessment 2) Clinically 
significant or serious adverse event not consistent with continuation in study, as 
determined by subject or study clinicians; 43 Subject's decision to withdraw. Any 
subjects that are withdrawn for the study will be asked to contact their treating 
physician for any follow up care. 
 
Ensuring Confidentiality 

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To minimize risk of loss of privacy, MoodNetwork and the Eureka mHealth Research 
Platform takes the following steps: 
For MoodNetwork, the database and the web portal will be housed on the Partners 
Research Computing Cloud Infrastructure (DIPR and RFA). The Discovery Information 
Platform for Research (DIPR) provides a set of virtual services within the Partners secure 
data center and within the Partners network which consist of virtual servers for web or 
application hosting, file storage and database management.  All systems are secured 
behind the Partners firewall and follow Partners Healthcare Information Security policies 
for authenticated, minimum access.  All systems are patched, monitored and scanned 
routinely for vulnerabilities and intrusions by the systems administrator and PHS 
Information Security. The web server and database server are hosted within the Partners 
Firewall. The web server makes use of standard 128-bit Secure Socket Layer (SSL) 
encryption to protect data in transit. 
 
Unique identifiers (UIDs), or strings of letters and numbers continuing no PHI, will be 
used to de-identify the data. MGH will securely store a linking list document, which 
allows the UIDs from this project to be linked to the UIDs used by the MoodNetwork and 
Eureka, allowing access to historical medical data stored in these databases. However, no 
data generated by this project will be inserted into MGH or Partners Healthcare medical 
records.  
 
The Eureka mHealth Research Platform is hosted on Amazon Web Services (AWS), a 
cloud-based server system and computing services, similar to those that protect websites 
used by banks and electronic health record systems. The platform is HIPAA compliant 
and Eureka follows security guidelines of the U.S. Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Specifically, all research data are stored behind a 
secure firewall, guarded by intrusion detection software, and encrypted at rest and in 
transit in our Amazon Virtual Private Cloud. Identifying information (name and email 
address) will be stored in separate (but linked) data tables so that health-related data can 
be viewed by approved staff as needed without inadvertent association with identifiers 
when such linkage is not required. In summary, data are coded, the data key is kept 
separately and securely; electronic data are protected with a password, and all data are 
stored on a secure network. 
 
We will include the MoodNetwork and Eureka Privacy Policy and Data Security 
Measures that will be referenced in study onboarding and viewable at any time (please 
see attached documents to this submission).  The statement will inform patients of the 
risks of loss of privacy, including via technical compromise or legal requirements.  We 
will also make them aware that they are responsible for keeping their login credentials 
secure. 
 
VII. 
DATA COLLECTION 
All data collection will adhere to HIPAA regulations. Data will be obtained specifically for 
research purposes and managed using a secure and HIPAA compliant Amazon cloud 
database managed by the Eureka mHealth Research Platform. All data will be managed 

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and shared between MGH and USCF per the subcontract agreement. Both teams have 
separate statistical analysis and engineering teams. Teams can work both together and 
individually to manage the needs of data gathering, quality assurance, and data 
management. 
 
These data will be used to evaluate treatment feasibility and acceptability, treatment 
integrity, efficacy, and possible mechanisms of change.  
 
All data will be managed and shared between the study team and Fitbit per the data-use 
agreement.   
 
 
a. Safety and Monitoring 
The PI (Dr. Nierenberg) and the study staff will discuss participant safety in person or via 
conference call on a regular basis. They will discuss and resolve any safety issues, as such 
issues arise - for example, the occurrence of adverse events, possible participant 
withdrawal from the study, or a score of full depression, hypomania/mania or suicidal 
ideation. Dr. Nierenberg will be responsible for preparing a written report that summarizes 
these discussions and any decisions that are made pertaining to participant disposition. He 
will also be responsible for determining whether the research should be altered or stopped. 
 
In addition, there will be a Data Safety and Monitoring Board (DSMB) for this study 
composed of (1) three Massachusetts General Hospital clinical researchers experienced in 
conducting randomized clinical trials for depression (2) an expert in assessing and 
treating cardiovascular disease; (3) an expert in biostatistics; and (4) a patient stakeholder 
with cardiovascular disease.  This DSMB will monitor safety issues, including the review 
of adverse events, the PI’s quarterly report of the study’s progress, all IRB amendments, 
and the adequacy and integrity of accumulating data. The purpose of this process is to 
assess scientific integrity and patient safety issues, and ensure the ethical conduct of the 
trials. The DSMB will approve the initiation of the study and subject enrollment, and 
determine if study procedures should be altered or stopped due to evidence of benefit or 
harm to trial subjects that may be attributable to the study or reasons related to scientific 
integrity. The PI will submit quarterly reports to the DSMB detailing any study changes, 
adverse events, subject recruitment and retention, reasons for early termination, and 
ongoing data reports. The PI will also respond to all DSMB issues and queries. 
 
b. Adverse Events 
Researchers will follow all ethical and professional reporting requirements for adverse 
events. Reporting of adverse events will occur as follows (procedures below are 
consistent with requirements of the Partners IRB): 
 
1) Serious adverse events that are reportable according to the guidelines of the Office for 
Human 
 
Research Protections (OHRP) and FDA (e.g., death, suicide attempt, inpatient 
hospitalization) will be reported by telephone within 2 business days to the IRB of MGH. 

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15 
 
A full written report of the event will be sent to the MGH IRB within 1 week of the 
event's occurrence. 
 
2) Any other unanticipated problems occurring will be reported to the IRB within 2 
weeks, in 
accordance with guidelines of the Office for Human Research Protections (OHRP) and 
FDA. 
 
3) All adverse events will be summarized in the PCORI and IRB annual progress reports. 
 
VIII. DATA ANALYSIS 
Baseline demographic and clinical characteristics will be examined by the PI in 
collaboration with Steve Faraone, Ph.D., Professor of Biostatistics. Measures of 
central tendency and variability will be estimated on each continuous measure; 
proportions estimated for categorical variables. Transformations will be used when 
distributional assumptions are not fulfilled for inferential tests. Dropouts and 
completers will be compared on baseline variables using Mann-Whitney or chi-square 
tests. Following FDA guidance for clinical trials, we will not correct our single 
primary outcome for multiple comparisons.  We have 61 additional 
secondary/exploratory analyses.  These will be corrected for multiple comparisons 
using the Bonferroni method, which yields an alpha level of 0.0008.  
 
A. 
Data Management: Amazon Cloud 
Using 128 bit RSA Secure Socket Layer (SSL) encryption, approved users will be logged-
in to machines using secured browsers behind the Partners Healthcare Systems IS corporate 
firewall or the RIH firewall. Staff will have a unique identifying key that will link them to 
the electronic study forms. This unique ID will be used in addition to a randomly generated 
secure password that only the staff person will have. Additional confidentiality procedures 
are detailed in the Human Subjects section.  
 
B. 
Statistical Analyses Plan for Research Aims 
Each of the statistical tests below will use a two-tailed alpha-level of 0.05. 
Aim 1: Hypothesis 1a and 1b: CBT will be superior to MBCT in increasing daily steps 
over the course of 8-weeks of treatment and after 8 additional weeks of follow-up, and both 
forms of treatment will be superior to the Fitbit-only, control group.   The primary 
hypothesis, or Hypothesis 1a, is that the CBT group will do better than the MBCT group 
at increasing the number of daily steps. A secondary hypothesis, or Hypothesis 1b,  is that 
the CBT and MBCT groups will do better at increasing the number of steps as measured 
by the FitBit over the 16-week study compared to the FitBit-only group.  Since the data for 
Hypotheses 1a and 1b both use repeated measures on subjects, we will conduct analyses 
for both hypothesis using general linear mixed models that account for the covariance of 
observations within subjects. For both hypotheses, we will model a random intercept and 
slope for subjects and site and fixed effects for treatment, time, and potentially confounding 
covariates. The treatment by time interaction for both hypotheses will be used to assert the 
statistical significance of treatment effects. Canonical links will be used to correctly model 
the distribution of dependent variables: for count data (e.g. steps) Poisson regression 

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16 
 
models will be fit with the Poisson family and the log link and for normally distributed data 
linear regression models will be fit with the Gaussian distribution and identity link. To 
choose the correct model for the hypotheses, we will use the Shapiro-Wilk test to assess 
for normality as well as the deviance statistic, the Akaike information criterion and the 
Bayesian information criterion to assess the best fitting model. We will compare nested 
models with the likelihood ratio chi-square statistics for both hypotheses. When a treatment 
effect is significant for either Hypothesis 1a or 1b, we will clarify its clinical significance 
by computing, for each time point, effect size statistics that convey the magnitude of 
treatment group differences. For effect size of both hypotheses, we will use the 
standardized mean difference for continuous variables. Our primary analyses for 
Hypotheses 1a and 1b will use daily steps as measured by Fitbit (primary outcome), and 
then self-reported physical activity, weight, perceived stress, PHQ-9, Altman Mania Scale 
Scores, and Sheehan disability scores as secondary outcome measures  
Aim 2: Exploratory Aims (Phase II). Hypotheses: Between treatment group effects sizes 
(and 95% CI) will be calculated. To supplement this, Mann-Whitney tests will compare 
treatment groups on medical burden (as measured by FRS) (Hypothesis 2a) and on 
improvement in symptoms (PHQ-9, ASRM) and functioning (SDS) (Hypothesis 2b) based 
on change from baseline.  
 
C. Rate of Attrition 
Some attrition (i.e., 20%) is expected and this can result in bias and reduce power, precision 
and generalizability70. Consistent with the Intent to Treat principle71, we will continue with 
the assessments for the study duration, even among those who fail to comply with the 
treatment72.  
 
D. Power Analysis 
Following FDA guidance for clinical trials, we will not correct our single primary outcome 
for multiple comparisons.  We have 61 additional secondary/exploratory analyses.  These 
will be corrected for multiple comparisons using the Bonferroni method, which yields an 
alpha level of 0.0008. 
 
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