Modeling Mood Course to Detect Markers for Effective Adaptive Interventions- Aim 3
Phase: PHASE1
Conditions: Bipolar Disorder, Psychosocial Intervention
Sponsor: University of Wisconsin, Madison

Protocol for Aim 3 
Modeling Mood Course to Detect Markers for Effective Adaptive Interventions 
 
ClinicalTrials.gov  
NCT04098497 
 
Date: 
03/15/19 
Version: 
1 
Principal Investigator: 
Melvin McInnis 
Contact:  
Heinz C. Prechter Bipolar Research Fund 
University of Michigan Depression Center 
Rachel Upjohn Building 
4250 Plymouth Road 
Ann Arbor, MI 48109-2700 
bpresearch@umich.edu 
1-877-864-3637 
Institute: 
University of Michigan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Contents 
Introduction ........................................................................................................................................................... 3 
A. Type of Research ......................................................................................................................................... 3 
B. Purpose/Objective of the Study .................................................................................................................... 3 
C. Background of the Study .............................................................................................................................. 3 
Participant Selection ............................................................................................................................................. 4 
A. Inclusion and exclusion criteria ..................................................................................................................... 4 
B. Gender .......................................................................................................................................................... 4 
C. Racial/Ethnic Origin ...................................................................................................................................... 4 
D. Vulnerable Populations ................................................................................................................................. 5 
E. Age ............................................................................................................................................................... 5 
F. Total Number of Participants to be Enrolled ................................................................................................. 5 
Study Design / Method / Procedures .................................................................................................................... 5 
A. Summary of the Research Design ................................................................................................................ 5 
B. Analysis of Study Results ............................................................................................................................. 6 
C. Monitoring ..................................................................................................................................................... 7 
D. Storage and Confidentiality of Data .............................................................................................................. 7 
Participant Recruitment and Informed Consent .................................................................................................... 7 
A. Recruiting ...................................................................................................................................................... 7 
B. Informed Consent / Assent ........................................................................................................................... 7 
 
 
 
 

Introduction 
A. Type of Research 
The research to be conducted under this protocol falls under the general heading of a micro-
randomized trial. It investigates feasibility of a study on how to tailor an intervention based on acceptance and 
commitment therapy (ACT) when delivered via a smartphone app. 
B. Purpose/Objective of the Study 
Our long-term objective is to develop a mobile health platform for the translation of a psychosocial 
intervention for bipolar disorder (BP) into an effective adaptive intervention. In this particular part of the study, 
we investigate the feasibility of a mobile health and wearable device platform for the translation of a BP 
psychosocial therapy into an evidenced-based adaptive intervention. To answer this question, we will 
study how individuals with BP respond to a microintervention delivered via a mobile app. Our primary 
outcome is to evaluate the feasibility of a micro-randomized trial in ACT in terms of completion of assessments 
(interview and self-report), wearing of Fitbit, and completion of microintervention questions. Our secondary 
outcome is to detect a linear effect in time of the microintervention on symptom levels of mania and depression 
in individuals with bipolar disorder. The estimated linear effect would be used to power a larger study. 
C. Background of the Study 
Bipolar (BP) disorder is a chronic illness of profound shifts in mood ranging from mania to depression. BP 
is successfully treated by combining medication with psychosocial therapy, but care can prove inadequate in 
practice. With gaps in coverage and medication, along with imprecise guidelines on when, where, and how to 
intervene, promising psychosocial therapies require adaptive strategies to better address the specific needs of 
individuals in a timely manner (NIMH Strategy 2). To accomplish this, however, requires evidence-based 
practices for adapting a psychosocial therapy. This project aims to address this knowledge gap by establishing 
a mobile health platform for translating a psychosocial therapy in BP into an effective adaptive intervention. 
To adapt a psychosocial therapy to information in the moment, the symptoms should be monitored 
frequently over extended periods. Frequent observations (multiple times a day) are needed to capture the 
diurnal patterns (Wirz-Justice 2008) and rapid mood shifts (Kramlinger and Post 1996) associated with BP. 
Extended observation (weeks to years) captures full length episodes (Solomon, Leon et al. 2010) and certain 
medication effects (Goodwin, Jamison et al. 2007).     
Mood is commonly charted with self-reports, often on a one-dimensional scale such as the Mood 24/7 
scale (April C. Foreman 2011) and the NIMH Life Chart Method (Denicoff, Leverich et al. 2000). However, 
mood in BP may not be one-dimensional. NIMH’s RDoC, for example, defines both a negative valence and 
positive valence domain (Cuthbert and Insel 2013). Accuracy of self-reports may also depend on an 
individual’s mood (Born, Amann et al. 2014) and time of day (Wirz-Justice 2008). They also require individuals 
to actively record symptoms, a burden that leads to disengagement (Nahum-Shani, Smith et al. 2014). In sum, 
self-reports are subjective and time-intensive and lose information that limit its utility in charting BP.  
BP can also be charted passively through sensors on smart-phones and wearable devices (Depp, 
Mausbach et al. 2010). Smart-phone platforms MONARCA (MONitoring, treAtment and pRediCtion of bipolAr 
Disorder Episodes) and PRIORI (Predicting Individual Outcomes for Rapid Intervention; McInnis, PI, 
R34MH100404) aim to predict mood from patterns of speech and behavior from recorded calls, number of 
phone calls, and phone call duration.  However, smart-phones do not monitor circadian and sleep rhythms, a 
primary target of therapies such as sleep deprivation (Wu, Kelsoe et al. 2009) and interpersonal and social 
rhythm therapy (Frank, Kupfer et al. 2005). Disrupted circadian rhythms are thought to be central to BP 
etiology, with connections to risk genes, animal models, and pharmacological therapy (McClung 2013). 
Actigraphy is a promising alternative that can evaluate sleep and circadian rhythms. Pagani, Clair et al. 
(2015) have linked actigraphic variables to genetic differences between BP-I and non-BP-I individuals that 
include later wake times, longer sleep durations, and lower activity levels in BP-I subjects during euthymia. In a 
current study with the investigators, actigraphy data revealed that BP individuals wake up significantly later 
than non BP individuals, while reporting they are less rested, drink more caffeine, and use more sleep 
medication. Lower activity is also found to be significantly associated with an increase in depressive 
symptoms, whereas higher activity is associated with an increase in manic symptoms. A validated 
mathematical model of circadian rhythms were developed by Dr. Daniel Forger (Forger, Jewett et al. 1999). 

With these models and statistics, Dr. Forger, his student Olivia Walch, and a co-investigator of the current 
study, Amy Cochran, analyzed sleep habits from over 5000 users from over 100 countries collected with a 
smartphone app ENTRAIN (Walch, Cochran et al. 2016). This work has been published in Science Advances 
and featured in over 100 media outlets across the globe that include Huffington Post, BBC, Wired, and TIME. 
With mobile health, psychosocial therapy can be tailored to the needs of a patient when they arise. The 
NIMH highlights the need for such adaptive interventions in its Strategic Objective 2: “Chart Mental Illness 
Trajectories to Determine When, Where, and How to Intervene”. Moving towards effective adaptive 
interventions, however, requires getting at the heart of why a particular intervention works. Although effective 
psychosocial therapies share common goals, such as awareness of symptoms and regular sleep schedules, 
they still lack clear mechanisms (Miklowitz and Scott 2009). Psychosocial therapies are also unequal in their 
ability to generalize to all BP individuals, cost-effectiveness, and ease of translation to real-world practice, as 
reported by the Candidate’s co-mentor Dr. Amy Kilbourne and colleagues (Bauer, McBride et al. 2006).  
Micro-randomized trials are a relatively new adaptive trial, designed by the Candidate’s co-mentor Dr. 
Murphy and colleagues for mobile health adaptive interventions (Liao, Klasnja et al. 2015). In a 
microrandomized trial, patients are repeatedly randomized to one of multiple intervention options over time. 
Microrandomized trials contrasts a traditional two-arm study, in that the intervention group to which a patient 
belongs changes over time. Consequently, the collected data can not only compare two interventions, but also 
be used to optimize decisions on “when, where, and how” to intervene. Dr. Murphy and colleagues have 
developed sample size calculators for these trials and are using the design in the HeartSteps study 
(R01HL125440). 
Participant Selection 
A. Inclusion and exclusion criteria 
We will recruit 30 individuals from the Prechter Longitudinal study of Bipolar Disorder who (i) have agreed to be 
contacted for future research, (ii) have a smart-phone, and (iii) have a diagnosis of bipolar disorder.  
B. Gender  
Participation is open to men and women. For the six-week study, we will recruit 15 women and 15 men to 
balance gender in the 30 individuals.  
C. Racial/Ethnic Origin 
Participation is open to all ethnic and racial groups. The research team’s capacity to enroll a study sample with 
adequate representation of minorities is enhanced by the diversity of Washtenaw and surrounding Counties, in 
which the majority of the clinic patients live. According to the U.S. Census’ American Fact Finder 2010 
Demographic Profile Data, the demographics of the population of Washtenaw County are estimated as follows: 
 
• 
72.1% White alone, not Hispanic or Latino 
• 
12.7% Black or African American 
• 
7.9% Asian 
• 
4.0% Latino or Hispanic 
• 
3.4% Two or more races 
• 
0.3% American Indian or Alaskan Native 
• 
0.0% Native Hawaiian or Other Pacific Islander 
 
Recruitment milestones have been submitted to the National Institute of Health (see table below). Actual 
recruitment will be reported to the NIH every four months.  
 
Total 
Racial Minority 
Hispanic 
April 1, 2019 
3 
0 
0 
August 1, 2019 
15 
3 
1 
December 1, 2019 27 
6 
2 
April 1, 2020 
30 
7 
2 

 
D. Vulnerable Populations 
The study is limited to a subgroup of the population which does not specifically target pregnant women and/or 
fetuses; lactating women; women of child-bearing potential; prisoners; cognitively impaired adults; college 
students; economically or educationally disadvantaged persons; patients of the study team; employees, 
students or trainees of the study team; or family members of the study team.  
E. Age 
Participation is open to adults (18 years of age or older).  
F. Total Number of Participants to be Enrolled 
A total of 30 individuals will participate in the six-week study.  
Study Design / Method / Procedures 
A. Summary of the Research Design 
Recruitment. Thirty individuals with BP will be recruited from the Prechter Longitudinal Study of Bipolar 
Disorder (PI: Melvin McInnis; HUM606) to participate in a six-week study. They have already completed a 
Diagnostic Interview for Genetic Studies (DIGS) about their health and mental illness history. We will access 
the diagnostic information and other data from the longitudinal study so not to repeat the interview process. 
The study is necessarily not blinded.  
Randomization.  Randomization will occur at the level of the microintervention twice a day (once in 
the morning and once in the evening) for each participant on each day of the study. Participants will have 
a 50/50 chance of being prompted with a microintervention question from the smartphone app each 
morning and each evening. Randomization will be embedded in the smartphone app.  
Entrance interview. A summary of participation in the study is given in the table below. First, we 
will mail each participant an activity tracker like a FitBit or an Apple Watch, along with a return box with 
postage paid.  Once they receive the activity tracker, we will schedule a time to talk to them over the phone to 
assess their mood and functioning and to explain how to set-up and use the study smartphone application and 
activity tracker, including how to report and review your information and set preferences for notifications.  
Activity tracker and smart-phone application. We will ask each participant to wear the activity 
tracker at all times, except to charge the tracker or to shower. Automatic messages will be sent to the 
participant to remind them to wear the tracker. The tracker will automatically collect information about physical 
activity and sleep. The smart-phone application will automatically prompt the user twice-a-day (once in the 
morning and once in the evening) on questions about their mood, stress, bed and wake times, and medication 
adherence.  These questions will be prompted automatically by the smart-phone app.  The smart-phone app 
will also allow the participant to review their information provided to the study team, including information 
collected from the activity tracker and processed offline by computational algorithms. Finally, each morning and 
each evening (two times per day) there will be a 50/50 chance of the smart-phone app delivering a 
microintervention question to each participant. 
Exit interview. At the end of the study, we will interview each participant to assess functioning, mood, 
and engagement/preference with smart-phone application and activity tracker.  This assessment will take 
about one hour. The participant will then be asked to mail any study equipment (e.g., activity tracker) using the 
return box.  
Table 1. Summary of participation in study.  
Name 
Instruments 
Time per 
event 
(min) 
Event time 
Entrance Phone 
Interview 
• 
Young Mania Rating Scale (YMRS) 
60 
Day 0 

Investigator provided 
data 
• 
Structured Interview Guide for the 
Hamilton Depression Rating Scale (SIGH-
D) 
• 
36-Item Short Form Survey (SF-36) 
• 
Set-up 
o 
Subject ID 
o 
Prechter ID 
 
App setup 
o 
Typical wake and bed time 
o 
ACT video 
1 
Day 0 
Daily Self-Report 
through App 
User provided data 
o 
Activity questions (toward vs away 
behavior) 
o 
Brief inventory of symptoms and 
medication adherence: 
o 
Shortened YMRS 
o 
Shortened SIGH-D 
o 
Medication adherence (at most once 
daily; depends on medication routine) 
 
5 
Days 1-42; 
Morning and Evening 
Morning (Evening) = first 
(last) quarter of subjects 
"typical" wake period 
Activity Tracker 
Automated 
• 
Uploaded daily activity data  
 
0 
Days 1-42;  
Mid-Night 
Mid-Night = middle of 
subjects "typical" sleep 
period 
Daily Computed 
Variables 
Automated 
• 
Computed variables: 
o 
Circadian phase 
o 
Physical and sedentary behavior 
o 
Sleep duration 
o 
Longitudinal patterns of sleep, mood, 
and stress 
0 
Days 1-42;  
Mid-Night 
Daily 
Microinterventions 
Automated 
 
• 
Brief acceptance and commitment therapy 
(ACT) based questions about participants’ 
well-being 
o 
Engagement 
o 
Openness 
o 
Awareness 
 
0-10 
Days 1-42 
Morning and Evening 
(50-50 chance of being 
delivered at each time point) 
Exit Phone Interview 
Investigator provided 
data 
• 
YMRS 
• 
SIGH-D 
• 
SF-36 
60 
Day 42 
 
    
Study termination. The study team may decide to end participation of any person in the study if (i) the 
team believes it is not in the person’s best interest to stay in the study; (ii) the person becomes ineligible; (iii) 
the person’s condition changes or needs treatment that is not allowed while taking part in the study; (iv) the 
person does not follow instructions from the study team; or (v) the study has been suspended or cancelled.   
Suicidality. We will ask about questions about suicide (e.g., attempts, ideation) as part of the 
Structured Interview Guide for the Hamilton Rating Scale for Depression. The outpatient psychiatry department 
at the University of Michigan has standard procedures that are followed when there is a concern for patient 
safety and the University of Michigan psychiatric emergency room is available 24/7. In instances when the 
study team anticipates a threat of self-harm, or harm to others due to the individuals worsening psychiatric 
condition, we will take all clinically indicated appropriate actions to protect the individual, which may include 
hospitalization. We may need to breach confidentiality in these instances, but will limit the sharing of 
knowledge to the bare minimum required for safety. 
B. Analysis of Study Results 
Our primary outcome is to evaluate the feasibility of a micro-randomized trial in ACT by measuring 
completion of assessments (interview and self-report), wearing of Fitbit, and completion of microintervention 
questions. Our secondary outcome is to detect a linear effect in time of the microintervention on symptom 

levels of mania and depression in individuals with bipolar disorder. An estimate of this linear effect would be 
used as a power analysis to justify a larger study. For this secondary outcome, we would measure manic,  
depressive, and activity levels using the ten symptoms self-reported via the smartphone app twice daily. The 
linear effect would be estimated using the procedure outlined in Liao, Klasnja et al. 2015 based on estimating 
equations. Significance will be considered an alpha level of 0.05. 
C. Monitoring 
Monitoring safety of the study will be the responsibility of the research team and principal investigator. 
On a monthly basis, the candidate with a research assistant of the Prechter study will review any serious 
adverse events; drop-outs and non-serious adverse events; proposed amendments to the study protocol 
including those for reasons related to the safety of study subjects; completeness and validity of data to be used 
for analyses; progress towards Recruitment Milestone Report (RMR) for all subjects and for minority 
recruitment; and any violation/deviations in protocol including breach in subject privacy and confidentiality. 
Immediately upon review, reports will be relayed to the Prechter study team and Dr. Melvin McInnis and any 
adverse events including violation/deviations in protocol will be reported to the IRBs. Each adverse event will 
also be assessed according to its relatedness to the proposed study and expectedness as specified by the 
IRB, informed consent, and protocols.  As in any research study, it is not possible to anticipate all possible 
adverse events. The Prechter team has substantial experience in monitoring, interviewing, and treating 
individuals with bipolar disorder. They do extensive training with our staff on ascertaining, monitoring, and 
documenting adverse events. Established procedures are in place at the site for rendering first aid and life 
threatening emergencies. In the case of this study, all investigators and study staff will be trained in monitoring 
and documenting adverse events. 
D. Storage and Confidentiality of Data 
We will the secure, HIPAA-compliant web-based application known as REDCap, as well as fully 
automated encryption technology and secure websites (https) for data capture. Study records that contain 
patient names will have access limited to the Principal Investigator and the immediate study team that is 
collecting the data. Confidentiality will be preserved by coding all study data with a unique identifying research 
number, and referring to this number in all analyses. Data from REDCap will be downloaded through secure 
internet connections and stored in secure, restricted access servers which are behind a firewall, under 
intrusion monitoring; will be made accessible only to the members of the study team; and will have all 
personally-identifiable information (e.g., participants’ names, email addresses) removed and will be coded with 
a participant ID. Data will be backed up regularly on secure, restricted access servers that are administered by 
the University of Michigan School of Information’s highly trained information technology department. Coded 
data will be stored separately from the link between the participant’s personally-identifiable information and 
participant ID. In addition, the smart-phone application will use fully automated encryption technology and 
secure websites for data capture to minimize the risk of security breach to the files. 
Participant Recruitment and Informed Consent 
A. Recruiting 
Participants will be recruited through email or phone from the Prechter Longitudinal Study of Bipolar 
Disorder (HUM606) who have agreed to be contacted for future studies. 
B. Informed Consent / Assent 
The following steps will be taken to consent participants for the study:  
1) Participants will be emailed a pdf version of the consent form prior to the start of the study. The form 
will provide important information about the study, including the purpose of the study, and the risks and 
possible benefits of participating in the study.  
2) A member of the study team will phone each participant, provide a complete description of the study to 
the participants, answer any questions, and give them enough time to participate.  

3) At the end of the phone call, the participant will be emailed from REDCap an electronic version of the 
consent form that is designed as a REDCap survey.   
4) If the participant decides to participate, the electronic version can be completed and will be identical to 
the pdf version of the consent form in content and order. Each of the 12 sections of the consent form 
will be contained on separate pages of the electronic consent that the participant will click through. At 
the 12th section, the participant will be asked to provide an electronic version of their signature through 
the use of a mouse or touch-screen device and then submit the consent form.   
5) The study member receiving the consent form will print the signed consent form and then sign and date 
the form. Each participant will be emailed a copy of his or her signed informed consent form and the 
printed form will be placed in a secure filing location within a locked cabinet behind locked doors.