Improving Outcomes for Care Partners of Persons With Traumatic Brain Injury
Phase: NA
Conditions: Caregivers
Sponsor: University of Michigan

Protocol 
 
Study Title: Improving Outcomes for Care Partners of Persons with Traumatic Brain Injury 
 
NCT #: NCT04570930 
 
IRB Approval Date: March 1, 2023 
 
Protocol Version Date:  February 15, 2023 

 
 
Improving Outcomes for Care Partners of Persons with 
Traumatic Brain Injury 
Protocol Number: HUM000181282 
National Clinical Trial (NCT) Identified Number:  NCT04570930 
Principal Investigator: Noelle E. Carlozzi, Ph.D. 
Sponsor: University of Michigan 
Grant Title: Improving Outcomes for Care Partners of Persons with Traumatic 
Brain Injury 
Grant Number: 2R01NR013658 
Funded by: National Institute of Nursing Research, National Institutes of Health 
Version Number:  v.4.0 
15 February 2023 

NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
ii 
 
Protocol Amendment History: 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
2/9/2021 
Added clinicaltrials.gov number on 
cover page and updated version date 
and number and table of contents 
page numbers. 
Administrative update 
2.0 
2/9/2021 
In sections 8.1, 8.1.5.3 and 8.1.5.4, 
noted that the monthly and follow-
up surveys could also be given in an 
interview format (in addition to the 
CareQOL app). 
Provides flexibility with 
administration 
3.0 
4/21/2022 
Updated version date and number 
and table of contents page numbers. 
Administrative update 
3.0 
4/21/2022 
Deleted confidentiality statement. 
Protocol will not be confidential 
(will be published and posted 
on clinicaltrials.gov). 
3.0 
4/21/2022 
In sections 1.1, 1.2 and 4.1, the 
number of participants was 
increased from 240 to up to 280. 
BCM participants were increased 
from 120 to 160. 
Enrollment was increased to 
allow BCM to enroll more 
participants and to replace 
participants who dropped out 
of the study before the end of 
the 6-month home monitoring 
period. 
4.0 
2/15/2023 
Updated version date and number 
and table of contents page numbers. 
Administrative update 
4.0 
2/15/2023 
Updated SOA (section 1.3) to include 
optional semi-structured interview. 
Added an optional semi-
structured interview for 
participants on study (e.g., 
haven’t completed the 12-
month assessment) at the time 
of IRB approval of protocol v4.0 
to learn more about participant 
experiences and perceptions of 
the main study, and particularly 
their experiences and 
perceptions of the CareQOL 
app. 
4.0 
2/15/2023 
Updated section 8.1.6 to include a 
description of the optional semi-
structured interview. 
Added optional semi-structured 
interview (see above). 
4.0 
2/15/2023 
Updated section 10.1.1.2 to describe 
consent procedure for optional 
semi-structured interview. 
Added optional semi-structured 
interview (see above). 
4.0 
2/15/2023 
Updated section 10.1.2 to provide 
information on confidentiality and 
Added optional semi-structured 
interview (see above). 

NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
iii 
privacy related to the optional semi-
structured interview. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Improving Outcomes for Care Partners of Persons w/ TBI  
Version 4.0 
Protocol HUM000181282 
 
15 Feb 2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
iv 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule of Activities .......................................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits .............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 10 
4 
STUDY DESIGN ........................................................................................................................................... 11 
4.1 
Overall Design .................................................................................................................................... 11 
4.2 
End-of-Study Definition ..................................................................................................................... 12 
5 
STUDY POPULATION ................................................................................................................................ 12 
5.1 
Inclusion Criteria ................................................................................................................................ 12 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 13 
5.4 
Screen Failures .................................................................................................................................. 13 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 13 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 14 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 14 
6.2 
Fidelity ................................................................................................................................................. 15 
6.3 
Concomitant Therapy ........................................................................................................................ 16 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 17 
7.1 
Participant Discontinuation/Withdrawal from the Study ............................................................... 17 
7.2 
Lost to Follow-Up ............................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 17 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 18 
8.2 
Adverse Events and Serious Adverse Events ............................................................................... 23 
8.2.1 
Definition of Adverse Events ........................................................................................ 23 
8.2.2 
Definition of Serious Adverse Events .......................................................................... 23 
8.2.3 
Classification of an Adverse Event .............................................................................. 23 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 25 
8.2.5 
MULTI-SITE Adverse Event Reporting ....................................................................... 25 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
9.1 
Statistical Hypotheses ....................................................................................................................... 25 
9.2 
Sample Size Determination .............................................................................................................. 26 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 27 
9.4.1 
General Approach .......................................................................................................... 27 
9.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 27 

Improving Outcomes for Care Partners of Persons w/ TBI  
Version 4.0 
Protocol HUM000181282 
 
15 Feb 2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
v 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 28 
9.4.4 
Baseline Descriptive Statistics ..................................................................................... 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 28 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 28 
10.1.1 
Informed Consent Process ........................................................................................... 29 
10.1.2 
Confidentiality and Privacy ........................................................................................... 29 
10.1.3 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.4 
Key Roles and Study Governance .............................................................................. 31 
10.1.5 
Safety Oversight ............................................................................................................. 31 
10.1.6 
Quality Assurance and Quality Control ....................................................................... 32 
10.1.7 
Data Handling and Record Keeping ............................................................................ 33 
10.1.8 
OTHER REPORTABLE INCIDENTS & OCCURRENCES (ORIOS) ..................... 34 
10.1.9 
Publication and Data Sharing Policy ........................................................................... 36 
11 
REFERENCES ............................................................................................................................................. 37 
12 
APPENDIX 1: MULTI-SITE RESEARCH REPORTING PLAN ............................................................. 40 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
1 
 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with the United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
CFR Part 812) and research best practices. The PI and all study team members who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials will complete Human Subjects 
Protection and best practices training. 
The protocol, informed consent document, and all participant materials will be submitted to IRBMED, 
which is serving as the IRB of record for both sites, for review and approval. Approval of both the 
protocol and the consent documents will be obtained before any participant is consented. Any 
amendment to the protocol will be submitted for review and approval by IRBMED before the changes 
are implemented to the study. All changes to the consent form(s) will be IRB approved; a determination 
will be made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
2 
 
INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances that 
this study will be conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local legal and regulatory requirements and applicable US federal 
regulations and research best practices. 
 
Principal Investigator and Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name: Noelle E. Carlozzi, Ph.D. 
 
Title: Associate Professor 
Affiliation: Department of Physical Medicine & Rehabilitation, University of Michigan 
Address: 2800 Plymouth Rd., NCRC Bldg. 14, Ann Arbor, MI 48109-2800 
Telephone: 734-763-8917 
Email: carlozzi@med.umich.edu 
 
 
 
Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name: Angelle Sander, Ph.D. 
 
Title: Associate Professor 
Affiliation: Baylor College of Medicine 
Address: 7200 Cambridge, Ste. 10C, Houston, TX 77030 
Telephone: 713-797-7161 
Email: asander@bcm.edu 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
3 
 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: Improving Outcomes for Care Partners of Persons with Traumatic Brain Injury 
 
Grant Number: 2R01NR013658 
 
Study Description: Informal family care partners of persons with traumatic brain injury (TBI) are often 
faced with considerable physical and emotional stress resulting from their caregiver role. Not 
surprisingly, this stress is associated with depression, anxiety, fatigue, isolation, sleep disturbance, and 
physical health problems for the care partner. This is especially problematic since these problems also 
inadvertently affect health and well-being (i.e., outcomes) of the person with TBI. Given this, there is a 
need for interventions to improve health-related quality of life (HRQOL) for these care partners. Yet, the 
time demands of caring for an individual with a TBI, as well as the associated physical and emotional toll, 
make it difficult for care partners to prioritize their own self-care. Therefore, it is critical that 
interventions are low burden, and easy to engage in, or else there is little hope that the intervention will 
improve care partner HRQOL. 
 
This study proposes using the TBI-CareQOL, a newly developed HRQOL measurement system specific to 
care partners of TBI, to evaluate the effectiveness of a personalized health management behavioral 
intervention aimed at improving the HRQOL of care partners. This personalized intervention, called the 
just-in-time adaptive intervention (JITAI), uses physical activity and sleep data collected using a wrist-
worn device (i.e., a Fitbit®) and real-time self-reports of HRQOL (caregiver strain, anxiety and 
depression) collected via a mobile app, to provide personalized feedback via app alert. 
 
Participants in this study will be randomized either to a control group, where they will wear the Fitbit® 
and provide daily reports of HRQOL over a six-month (180 day) period (without the personalized 
feedback), or the JITAI group, where they will wear the Fitbit®, provide daily reports of HRQOL and 
receive personalized pushes for 6 months. Up to 280 participants will be enrolled; 140 in the control 
group and 140 in the JITAI group. 
 
We hypothesize that the care partners who receive the intervention (JITAI group) will show 
improvements in caregiver strain and mental health (depression and anxiety) after the 6-month (180 
day) home monitoring period. 
 
Objectives:  
 
Primary Objective: Examine the efficacy of the JITAI to improve self-reported caregiver strain in care 
partners of persons with traumatic brain injury (TBI). 
Secondary Objectives: Examine the efficacy of the JITAI to improve self-reported mental health 
(depression and anxiety) in care partners of persons with traumatic brain injury (TBI). 
 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
4 
 
Endpoints:  
Primary Endpoint: Change from baseline in self-reported caregiver strain as measured by TBI-CareQOL 
Caregiver Strain at the end of the 6-month (180 day) intervention period. 
Secondary Endpoints: 1) Change from baseline in self-reported depression as measured by PROMIS 
Depression at the end of the 6-month (180 day) intervention period; and 2) Change from baseline in 
self-reported anxiety as measured by PROMIS Anxiety at the end of the 6-month (180 day) intervention 
period. 
 
Study Population: Up to 280 care partners of persons with TBI will participate in this study. Participant 
recruitment and enrollment will take place at two data collection sites – the University of Michigan and 
Baylor College of Medicine. Care partners must be at least 18 years old, be able to read and understand 
English and be caring for an adult (age 18 or above) with a medically documented TBI who is at least 1 
year post-injury who sustained their TBI at age 16 or older. They must be willing to use their personal 
mobile device (e.g., smartphone, tablet) for this study, be willing to download the study app (CareQOL) 
and Fitbit® app and be willing to complete all study assessments. 
 
Phase or Stage: Not applicable; behavioral intervention. 
 
Description of Sites Enrolling Participants: There are two data collection sites for this study: The 
University of Michigan in Ann Arbor, MI (n=120 care partners of persons with TBI) and Baylor College of 
Medicine in Houston, TX (n=160 care partners of persons with TBI). 
 
Description of Study Intervention: Just-in-time adaptive intervention (JITAI) is a mobile health behavior-
change approach that operationalizes the selection and delivery of personalized mobile device 
intervention strategies based on real-time data collection. In this study, a study-specific app (CareQOL 
app) will integrate sensor data from a Fitbit® (on physical activity and sleep) with real-time self-report 
ratings of HRQOL (caregiver strain, depression, anxiety) to inform the JITAI. The JITAI will deliver 
personalized messages via the app ~50% the days during the intervention period.  
 
Study Duration: Data collection is expected to take 4 years. 
 
Participant Duration: The participant duration in the study is ~375 days (a little over 1 year). 
 
 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
5 
 
 
1.2 
SCHEMA  
 
 
 
 
Assessed for Eligibility
Randomized
Day -10
JITAI; N=140
HRQOL / Baseline Survey / Home Monitoring
Control: N=140
HRQOL / Baseline Survey / Home Monitoring
HRQOL
HRQOL
Pre-enrollment
Enrollment
Allocation
Analysis
Consented
Day -10
HRQOL / Home Monitoring
HRQOL / Home Monitoring
HRQOL
HRQOL
Day 270 +/- 30 days
(3-months post home monitoring)
Run-In: Day -10 to Day -1
On Study: Day 0 to Day 180 +/- 7 days
(6-month home monitoring)
Day 360 +/- 30 days
(6-months post home monitoring)

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
6 
 
1.3 
SCHEDULE OF ACTIVITIES  
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Pre-
enrollment 
Enrollment    
Day -10 
~ 12 months1 
Run-in2      
Days -10 to -1 
End of months 1-5 assessments    
30, 60, 90, 120, 150 (+/- 7 days) 
End of 6 month assessment3  
180  (+/- 7 days) 
+3m F/U Assessment    
270  (+/- 30 days) 
+6m F/U Assessment   
360  (+/- 30 days) 
TBI Documentation 
X 
 
 
 
 
 
 
 
 
 
 
Caregiver Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Demographics/Baseline Survey 
 
X 
 
 
 
 
 
 
 
 
 
Caregiver Appraisal Scale 
 
X 
 
 
 
 
 
 
 
 
 
MPAI-4 
 
X 
 
 
 
 
 
 
 
 
 
PCL-5 
 
X 
 
 
 
 
 
 
 
 
 
SRS 
 
X 
 
 
 
 
 
 
 
 
 
TBI Medical Record Confirmation CRF 
 
X 
 
 
 
 
 
 
 
 
 
HRQOL Outcome Measures 
 
X 
 
X X X X X 
X 
X 
X 
Fitbit® & CareQOL app Instructions 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
JITIA4,5 or Control Home Monitoring5 
 
 
 
 
 
Daily EMA6 
 
 
 
 
 
Feasibility/acceptability questionnaire 
 
 
 
     
X 
 
 
Medications/Therapies/Med 
History/COVID 
 
X 
 
  x   
X 
X 
X 
Adverse Events Reporting 
 
 
 
  x   
X 
X 
X 
OPTIONAL Semi-structured Interview 
 
 
 
     
X 
1 – Individual participant duration may vary depending on when they complete their HRQOL assessments; 2 – Approximately 10 days in 
duration, to include time for shipping and at least 3-4 days of data collection; 3 – Primary outcome assessment time point; 4 – Active 
intervention, includes personalized push notifications; 5 – Includes daily wearing the Fitbit® for sleep and physical activity monitoring for 
both groups; 6 – for both active and control groups;  7 - Optional semi-structured interview (for participants who have not completed the 
study [e.g., 12 month visit] at the time of IRB approval of v4.0 of the protocol); separate consent required 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
7 
 
SIGNIFICANCE 
Illness impacts the entire family, and the complete picture of human disease is a collage of the 
experiences of both the affected patient and family care partner(s).1 As a society, responsibility for 
addressing these needs has always been placed on family care partners, who face an enormous and 
growing burden providing care to a loved one while trying to maintain their own health and well-being 
(e.g., HRQOL).2  
Traumatic brain injury (TBI) is a particularly challenging condition for family care partners due to the 
unexpected burden of providing prolonged supportive care at home once the survivor has been 
discharged from the hospital or rehabilitation facility. Care partners of persons with TBI must not only 
learn to cope with dramatic changes in their loved one’s health and functional abilities, but they also 
may feel ill-equipped to provide the requisite level of care. 
Care partners of persons with TBI commonly experience problems with physical and mental HRQOL as a 
result of the caregiver role. While interventions exist to help improve these care partners’ HRQOL, they 
are typically time-intensive and expensive, and have limited success at improving HRQOL in these 
individuals. Despite clear advantages in terms of convenience, reach and scalability with using mobile 
technologies (including JITAIs) to support healthy behavior change, their clinical utility in care partners 
of persons with TBI remains untested. We will address this critical gap in the literature by using passive 
data (i.e., physical activity and sleep data derived from the Fitbit®) and real-time assessments of HRQOL 
to identify and provide support to care partners of persons with TBI at the greatest risk for negative 
outcomes. We will also assess the effectiveness of a low-cost, low-burden intervention (the JITAI) 
designed to improve HRQOL outcomes in these care partners.  
2.2 
BACKGROUND  
 
Preliminary Studies (Care Partners of Persons with TBI). 
Under the leadership of Noelle Carlozzi (PI), the first funding period of this R01 (NINR/NIH R01NR013658 
(09/27/12 – 06/30/18) resulted in the publication of over 27 papers.3-28 In addition, data have been 
presented to institutional, national, international, and community audiences (29 presentations have 
been conducted to date). The overall purpose of the initial R01 was to identify important HRQOL 
domains that are relevant for care partners of persons with TBI (Aim 1), as well as to develop (Aim 2) 
and validate (Aim 3) a PRO measurement system that captures both the generic and more unique 
aspects of HRQOL in care partners of persons with TBI, with the goal of being able to use this 
measurement system to inform the development and assess the efficacy of clinical interventions 
designed to improve care partner HRQOL. Findings indicated the pervasive negative impact that caring 
for an individual with a TBI can have across mental, physical and social HRQOL; the new measurement 
system, the TBI-CareQOL,7 includes 24 different measures of HRQOL and is now ready to be used in 
clinical trials designed to improve care partner HRQOL. 
Preliminary Studies (JITAI Feasibility and Efficacy).  
The proposed JITAI study methodology is modeled after and informed by the current findings from the 
Intern Health Study (R01MH101459; PI Srijan Sen). To date, the Intern Health study includes three 
separate cohorts. In the first cohort, physical activity and sleep were assessed using Fitbit® trackers, and 
daily ratings of mood were completed via text for N=38 medical interns. In this study, 92% of 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
8 
 
participants provided sleep, activity, and mood data on at least 80% of days. Data showed an expected 
strong association between sleep and mood, but found that sleep predicted mood the following day 
substantially more strongly than 
mood predicted subsequent sleep 
(SleepMood b=0.12; p<0.001; 
MoodSleep b=0.05; p=0.04; 
Figure). They also found that, on a 
given night, the farther an 
individual’s sleep midpoint was from 
their pre-internship baseline 
midpoint, the lower their mood 
(p<0.001).29 Most recently, Sen and 
colleagues extended this work to a 
larger randomized controlled trial 
comparing a JITAI with usual care 
(n=2053). This trial employed 
microrandomization (which involved 
repeatedly randomizing each 
individual to receive various intervention feedback in order to determine the efficacy of different classes 
and types of mobile data feedback, and assess the moderating influence of location and timing on the 
effectiveness of the feedback). Findings from this work indicated that the optimal study design involved 
participants receiving feedback on ~50% of the days during the six-month intervention period (thus we 
have elected to implement this feedback strategy in this protocol). Further, they found that receptivity 
to mobile health interventions was moderated by participants’ current state related to the target of the 
intervention. For instance, interventions around increasing sleep duration were most effective when 
participants had low sleep the night before, adding further conceptual backing for the JITAI approach. 
Study findings also indicated that medical interns who were randomized to the JITAI intervention 
demonstrated significant improvements in depression.  
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The risks associated with the proposed study are minor and infrequent and include risks to: i) 
confidentiality; ii) frustration, stress and/or anxiety; iii) and skin irritation: 
 
i. 
Confidentiality. Confidentiality is a concern in this study. Every possible effort will be made 
to keep the research information in the strictest confidence, but we cannot absolutely 
guarantee that accidental disclosure will not happen. We remind participants that the 
responsibility of confidentiality rests with everyone: they should think carefully before 
discussing their role in this study with anyone since the effects of disclosure are unknown. 
Additionally, during the 6-month home monitoring period, participants may receive alerts 
when the participant is not in a private area. Participants will be informed that it is up to 
them where they complete the daily assessments, and if it is inconvenient/uncomfortable 
Figure  

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
9 
 
for them to complete the assessments when prompted they can wait and do it when it is 
more convenient/private or skip that assessment. 
 
To reduce the risk to confidentiality, no personal identifying information will appear on or 
with the participant data, where possible. Each participant will be assigned a participant ID 
by the study team to maintain confidentiality. The participant’s self-report data and CRF 
data will be identified with the participant ID. Additionally, an access code will be assigned 
to each participant which they will use to enroll in the CareQOL app. Participants will 
register their study Fitbit® on the Fitbit® app using a username and email address of their 
choice. The study team will help the participant configure the Fitbit® app for minimal 
sharing; however, participants may opt to change those settings on their own (without 
study team knowledge). The data collected on the Fitbit® will be linked to the CareQOL app 
by user authentication token, which is comprised of a random series of characters that is 
used to securely query for user activity data; no identifying information (including email 
address or Fitbit® user ID) is saved in the CareQOL app. 
 
Each site will keep a master list of their site’s participant names and matching participant 
IDs. This master list will not be shared with the other site, and will be kept by site personnel 
in a password-protected file on a secure server or in a secure environment (e.g., locked 
cabinet, restricted access). No one other than the study team at the study site will have 
access to their site’s master list (except when needed for study monitoring). Informed 
consents will be stored in a study-specific database which contains only the informed 
consents and the informed consents for each site will only be available to their site’s study 
team members (except when needed for study monitoring). The electronic data collection 
and storage systems used (e.g., CareQOL app, REDCap, Qualtrics, Fitbit®) are secure, web-
based systems, with access to the study data limited to authorized individuals.  
 
Additionally, participants in this study are covered under a NIH Certificate of Confidentiality 
(CoC). The CoC limits the disclosure of identifiable, sensitive information to a few instances: 
1) if required by Federal, State, or local laws (e.g., as required by the Federal Food, Drug, 
and Cosmetic Act, or state laws requiring the reporting of communicable diseases to State 
and local health departments), excluding instances of disclosure in any Federal, State, or 
local civil, criminal, administrative, legislative, or other proceeding; 2) if necessary for the 
medical treatment of the individual to whom the information, document, or biospecimen 
pertains and made with the consent of such individual; 3) if made with the consent of the 
individual to whom the information, document, or biospecimen pertains; or 4) if made for 
the purposes of other scientific research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. Participants will be 
notified in the informed consent that this study is covered by a CoC and will be informed of 
the protections and limitations to protections provided by the CoC. Lastly, the identities of 
all participants will be held in strict confidence to the extent provided by law. If findings 
from the study are published and/or presented at a professional meeting, no participant will 
be identified by name. 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
10 
 
ii. 
Fatigue, Frustration, Stress and/or Anxiety.  It is possible that participants may experience 
fatigue, frustration or feel inconvenienced when completing the self-report surveys, when 
receiving the personalized interventions from the CareQOL app or from wearing the Fitbit®. 
Participants may also feel fatigue, stress and/or anxiety related to completing the study 
activities. Participants will be instructed that they can skip any questions that make them 
feel uncomfortable, and if they receive an app alert when it isn’t convenient for them, they 
can wait and open the app when it is more convenient. 
 
iii. 
Skin Irritation.  Some participants may get skin irritation from wearing the Fitbit®. 
Participants will be instructed to remove the device if this occurs and to contact the study 
team. Their band may be swapped out for a different type of wristband if they experience 
irritation. We offer a wide variety of wristbands to help make the Fitbit® as comfortable as 
possible. 
 
To minimize the potential for risks, participants will be briefed in detail as to what they will experience 
throughout the study. All participants are informed that they may terminate participation from the 
study at any time without penalty. 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The proposed study aims to investigate the effectiveness of the JITAI to promote mental and physical 
health self-management in care partners of persons with TBI, as well as assess care partners at the 
greatest risk of negative mental and physical HRQOL outcomes. While there may not be any direct 
benefits to participants, it is possible that participants may find that the JITAI improves their mood, 
stress levels, and/or overall quality of life. Additionally, some participants may also have a positive 
benefit from wearing the Fitbit®, as it may make them more aware of their activity levels and sleep. 
Overall, we expect that the findings from this study will help researchers further develop a personalized, 
easy to deploy, clinical intervention for care partners of persons with TBI.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
As described above, there are minimal risks for the study participants and several potential benefits. 
Thus, the risk/benefit ratio is highly favorable.  
3 
OBJECTIVES AND ENDPOINTS  
 
Objectives 
Endpoints 
Primary 
Examine the efficacy of the JITAI to improve self-
reported caregiver strain in care partners of 
persons with traumatic brain injury (TBI) 
Change from baseline in self-reported caregiver 
strain as measured by TBI-CareQOL Caregiver 
Strain at the end of the 6-month (180 day) 
intervention period 
Secondary 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
11 
 
Examine the efficacy of the JITAI to improve self-
reported mental health (depression and anxiety) 
in care partners of persons with traumatic brain 
injury (TBI) 
Change from baseline in self-reported depression 
as measured by PROMIS Depression at the end of 
the 6-month (180 day) intervention period 
Change from baseline in self-reported anxiety as 
measured by PROMIS Anxiety at the end of the 6-
month (180 day) intervention period 
Tertiary/Exploratory/Other 
All other objectives and endpoints (e.g. sleep and physical activity variables, other mental and 
physical health domains, etc.) are considered tertiary 
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
Study Design: This behavioral trial will use a two-arm randomized controlled design. Each of the up to 
280 care partner participants will be randomized to an active “JITAI” arm or to a control arm. The 
random allocation of participants to the treatment arm or control arm establishes the basis for testing 
the statistical significance or difference between the groups in HRQOL (caregiver strain, depression and 
anxiety).  
 
Randomization: Blocked randomization will be used to limit bias and achieve an equal distribution of 
participants to the control and treatment arms. A randomization list will be generated for each site and 
the study statistician will oversee randomization. The participant will be randomized once he/she is 
deemed eligible and has provided informed consent (i.e. at Enrollment prior to baseline data collection). 
The study coordinator/research assistant who consented the participant will use their site’s 
randomization list to assign the participant to the correct study arm. 
 
Duration of Study Participation: Study participation for both arms of the study (control and JITAI) 
involves a baseline assessment, followed by an approximate 10-day run-in period then a 6-month (180 
day) home monitoring period (in which the intervention will be administered to the JITAI group). After 
the completion of the 6-month (180 day) home monitoring period, post-intervention surveys will be 
administered at 3 months (90 days) and 6 months (180 days) after the end of the 6-month (180 day) 
home monitoring period. Thus, the total duration of the study is ~375 days.  
 
Study Sites: This is a multi-site study involving two sites: University of Michigan and Baylor College of 
Medicine. University of Michigan is the lead site and their IRBMED will serve as the single IRB for this 
study. 
 
Study Intervention: The just in time adaptive intervention (JITAI) uses sensor data derived from the 
Fitbit® (e.g., accelerometer-based estimates of physical activity and sleep) and real-time self-report 
ratings (assessed once daily) of HRQOL (caregiver strain, depression, anxiety) to deliver personalized 
“pushes” to participants via a study specific app (CareQOL app). The personalized pushes will be 
delivered on ~50% of the days over the 6-month intervention period. 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
12 
 
4.2 
END-OF-STUDY DEFINITION 
 
While the primary outcome assessment is at the end of the 6-month (180 day) home monitoring period, 
the end of the study is defined as completion of the final follow-up survey administered 6 months (180 
days) after end of the home monitoring period shown in the Schedule of Activities (SoA), Section 1.3.] 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provide informed consent 
2. Be at least 18 years of age 
3. Be able to read and understand English 
4. Be caring for an adult (age 18 or above) with a medically documented TBI that is ≥1-year post-
injury and meets the TBI Model Systems (TBIMS) criteria* for complicated mild, moderate or 
severe TBI and who sustained their TBI at age 16 or older 
5. Provide emotional, physical, and/or financial support/assistance to the individual with the TBI, 
indicating a response ≥1 to the following question: “On a scale of 0-10, where 0 is “no 
assistance” and 10 is “assistance with all activities”, how much assistance does the person you 
care for require from you to complete activities of daily living due to problems resulting from 
his/her TBI? Activities could consist of personal hygiene, dressing and undressing, housework, 
taking medications, managing money, running errands, shopping for groceries or clothing, 
transportation, meal preparation and cleanup, remembering things, etc.” 
6. Have access to necessary resources for participating in a technology-based intervention 
(smartphone/tablet and internet access) and be willing to use their personal 
equipment/internet for this study, including downloading the study app and the Fitbit® app on 
their mobile device 
7. Is able and willing to complete all study assessments for the duration of their study participation 
(approximately 375 days) 
 
*TBIMS Criteria: TBI is defined as having had damage to brain tissue caused by external mechanical 
force. Complicated mild TBI is defined as an emergency room GCS score of 13-15 with positive 
findings on neuroimaging. Moderate to severe TBI is defined by at least one of the following: 1) post 
traumatic amnesia greater than 24 hours, 2) trauma related intracranial neuroimaging 
abnormalities, 3) loss of consciousness greater than 30 minutes not due to sedation or intoxication, 
4) Glasgow Coma Scale in the emergency room of less than 13, not due to intubation, sedation or 
intoxication. 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets the following criteria will be excluded from participation in this study: 
1. Is a professional, paid caregiver (e.g., home health aide) 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
13 
 
2. Anything that would preclude safe or meaningful participation in the study 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
• 
Wear a Fitbit® 24 hours/day, except when charging during the 10-day run-in period and 6-
month (180 day) home monitoring period. 
• 
Install the CareQOL app and Fitbit® app on their personal mobile device, and keep these apps 
installed for the duration of the study (~375 days). 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Screen failures are unlikely in 
this study because eligibility assessment occurs pre-informed consent. However, if during the 10-day 
run-in period before the 6-month home monitoring period starts the study team is made aware of 
something that would change their eligibility, the participant will be noted as a screen failure. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment: Two sites (University of Michigan [U-M] – Ann Arbor, MI; and Baylor College of Medicine 
[BCM] - Houston, TX) will be used to recruit participants (care partners of persons with TBI) for this 
study. Sites will recruit participants primarily through their established medical and TBI clinics, 
participant registries (both TBI- and care partner-specific registries), and clinical databases. Study 
participants will also be recruited through local TBI and care partner support groups, from organizations 
like the Brain Injury Association, and through targeted Facebook ads.  
 
Recruitment and retention methods used in this study will be approved by the Institutional Review 
Board at U-M (U-M IRBMED; serving as the single IRB for this study for BCM and U-M) and are detailed 
in the IRBMED submission. Potential participants will be recruited directly or through the person they 
are caring for. Individuals who are interested in participating will be encouraged to ask questions about 
the study and their participation, and if they opt to enroll, they will provide informed consent prior to 
completing any study assessments. 
 
In order to ensure that recruitment targets are being met, teleconference calls with the study 
recruitment teams by the project manager will be conducted to review progress, discuss problems, and 
guide additional recruitment efforts to meet stratification goals. Stratification goals (e.g., race, ethnicity, 
gender, etc.) can be found in the manual of procedures for this study. 
 
Retention: Given the intensive nature of this study, we expect that participants will miss some daily 
assessments and have times when they do not wear the Fitbit®; our retention plan is focused on 
minimizing these missed assessments and engaging participants throughout the study. 
 
Retention will be facilitated by several strategies: 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
14 
 
• 
App development will consider factors known to increase participant engagement including 
strategies to target engagement and minimize fatigue (easy to navigate platform, app tailoring 
based on Fitbit® sensor feedback, etc.).30 The app will also include a study team dashboard that 
we will use to monitor participant engagement.  
• 
User guides and contact information for the study team (phone and email) will be supplied to 
participants and they will be encouraged to contact the study team with any questions or 
concerns. 
• 
When enrolling participants, we will offer participants a choice of wristbands; they can select 
the wristband that is most comfortable and visually appealing to them. If they are not happy 
with their selection, we will provide an alternate wristband. 
• 
Study staff will maintain regular contact with the study participants. All study participants will be 
contacted at least once during the study run-in period, at least once during the first week of the 
6-month home monitoring period and at least once each month during the remaining months of 
the 6-month home monitoring period.  
• 
Participants who do not complete any study assessments (e.g., uploading Fitbit® data or 
answering EMAs) for several days will receive a reminder from the study team. 
• 
In case of lost equipment/equipment failure during the run-in and home monitoring periods, we 
will send replacements as supplies allow. 
 
Participant Incentives: We will compensate participants for their time and inconvenience, as follows: 
o Baseline assessment, final 6-month home monitoring assessment, 3-month post-
monitoring assessment, 6-month post-home monitoring assessment: Participants will 
receive $20 for completing each survey ($80 total possible). 
o Monthly HRQOL surveys during the home monitoring period: Participants will complete 
end of month surveys during the home monitoring period. Participants will receive $10 
for completing each end of month survey for months 1-5 ($50 total possible).  
o Daily EMA assessments and Fitbit® data during the 6-month home monitoring period: 
Participants will receive $1 per day for each day that they have EMA and/or Fitbit® data 
during the six-month (180 day) home monitoring period ($180 total possible). 
o Participants who complete the study will be allowed to keep the Fitbit® that they use in 
the study. 
• 
Compensation will occur monthly to encourage prompt responding. 
• 
We may send out nominal value items (e.g., notepads, pens) throughout the duration of study 
participation to encourage engagement. 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
All participants will receive a Fitbit ® for the collection of sleep and activity (steps) data, and will 
download the Fitbit® app and study app, CareQOL, on their personal mobile device (iOS or Android). The 
CareQOL app will deliver ecological momentary assessments (EMAs) once per day, compile and display 
data (including that collected on the Fitbit®), and deliver study notifications, including messages for the 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
15 
 
participant to complete the daily EMA and other study surveys as well as delivering the personalized 
study intervention prompts to the intervention group (Just-in-time adaptive intervention [JITAI] group).  
 
All study participants will complete 3 EMA questions daily on the CareQOL app. Each participant will be 
prompted by a push notification in a five-hour window (based on participant preference) from the app 
to answer the questions. The EMA questions are comprised of: 1 question on caregiver strain (taken 
from the TBI-CareQOL Caregiver Strain item bank), 1 question on anxiety (taken from the PROMIS 
Anxiety item bank) and 1 question on depression (taken from the PROMIS Depression item bank). 
Questions are on a five-point scale, with higher scores indicating more of the named construct. 
 
In addition to the collection of the EMA data, the app complies and displays a graphical summary of 
historical data for caregiver stress (strain), worry (anxiety), sadness (depression), steps (collected by the 
Fitbit®) and hours of sleep (collected by the Fitbit®) on a participant dashboard. Participants can view 
this information for the past week, past month or past year. This is available to all participants as a pull – 
that is, it is available at all times but is accessed only if the user chooses to access it.  
 
In this study, half of the participants will be randomized to receive the intervention (JITAI; described 
below); the remaining participants will be in the control group, who will not receive the JITAI but will 
complete the activities already described in this section. Participants who are randomized to receive the 
JITAI will have a 50/50 chance of receiving the intervention each day.  
 
The JITAI aims to promote behavioral change through motivational messages that are delivered through 
the CareQOL app as push notifications. These notifications provide a trigger for participants to initiate or 
continue behavior change and/or monitor behaviors (through engagement with the with the app). The 
push notifications are low burden: participants can personalize the administration time (in a 5-hour 
window) and notifications can be viewed quickly on their phone’s lock screen. Participants can also 
choose not to engage with the notification at the time it is sent if it is inconvenient – they can return to 
it later if needed. 
 
The JITAI push notifications are aimed at promoting healthy behaviors (physical activity and good sleep 
hygiene) and improving mood (anxiety, depression, caregiver strain). If receiving a notification, the 
message will be randomly drawn from this pool of messages. Some messages will use participants’ data 
directly in the messages (e.g., You walked an average of 8,120 steps this week), and most of messages 
will be personalized based on data (e.g., someone with low steps will get a different message than 
someone with medium steps than someone with high steps; high-medium-low). Messages are 
comprised of one or more of the following different types: 1) Data feedback; 2) Facts; 3) Tips; and 4) 
Support. Randomization of the days the participants receive messages and the message the participant 
receives from the pool will be done through the CareQOL app. 
 
The study intervention period is 180 days (6 months); in addition, there is an ~10-day run-in period 
where participants will install/adjust/troubleshoot the study technology and the app will gather baseline 
data to use to tailor messages once the intervention period begins.  
6.2 
FIDELITY 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
16 
 
For this study, the intervention will be administered via the CareQOL app. The study team will conduct 
training during the baseline visit with each participant which will include: 
• 
Helping the participant download and register for the CareQOL and Fitbit® apps on their 
personal device 
• 
Helping the participant set any relevant app settings (e.g., make sure alerts are turned on/off, 
privacy settings, etc.) 
• 
Demonstrating the CareQOL app features to the participant (e.g., participant dashboard, etc.) 
• 
Ensuring that the participant understands the importance of entering the daily ratings and 
wearing the Fitbit® 
• 
Explaining the relationship between the daily ratings and Fitbit® data and the intervention 
prompts (JITAI group only)  
• 
Demonstrating how to sync the Fitbit® (including using the Fitbit® app) and how to enter the 
daily ratings in the CareQOL app 
 
During the 10-day run-in period between the baseline visit and the start of the intervention, study team 
members will assist participants to make sure that participants can:  
• 
Successfully wear and sync the Fitbit®  
• 
Successfully respond to the EMA prompts 
 
Participants who are unable to successfully complete the run-in period will be terminated from the 
study and noted as a screen failure. 
 
Training and training materials will be provided to all study team members. New study members will 
undergo training before the study is started. Training will be documented in the electronic regulatory 
binder. 
 
Participant adherence to the protocol will be assessed throughout the study. Study staff will have access 
to the CareQOL app dashboard which can be used to monitor participant engagement and adherence 
with the app. Specifically, study staff will monitor: 
• 
Adherence to EMA entry 
• 
Adherence to Fitbit® use/syncing 
• 
Adherence to completing the end of month surveys (~30, 60, 90, 120, 150, 180 day)  
• 
Adherence to completing the 3-month (~270 days) and 6-month (~360 days) post-intervention 
surveys 
 
Adherence will be calculated as a percentage for each of these areas for all participants who are not 
withdrawn or lost to follow-up. 
6.3 
CONCOMITANT THERAPY 
 
There are no concomitant treatment or management strategy restrictions for this study. Information 
about current treatments (medications and non-medications) will be collected at baseline. Changes in 
treatments will be captured at the end of month 3 (~90 days) and month 6 (~180 days) during the home 
monitoring period, and 3-months (~270 days) and 6-months (~360 days) post-home monitoring period.  

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
17 
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue a participant from the study for the following reasons: 
• 
Lost-to-follow up; unable to contact participant (see Section 7.2, Lost to Follow-Up) 
• 
Any event or medical condition/situation that occurs that would indicate that continued 
collection of follow-up study data would not be in the best interest of the participant or might 
require treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
The participant is non-compliant with the study protocol 
 
The reason for participant discontinuation or withdrawal from the study will be recorded. Participants 
who sign the informed consent form and are randomized but do not complete the 10-day run-in period 
will be replaced. Participants who withdraw or are discontinued before the end of the 6-month (~180 
day) home monitoring period will be replaced. 
7.2 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if: 1) he or she does not complete the end of month 
survey at the end of the 6-month (~180 day) home monitoring period and 2) study staff are unable to 
contact the participant after a minimum of 3 attempts.  
 
The following actions must be taken if a participant fails to complete the end of the month survey at the 
end of the 6-month (~180 day) intervention period: 
• 
The site will attempt to contact the participant and counsel the participant on the importance of 
completing the survey and ascertain if the participant wishes to and/or should continue in the 
study 
• 
The site will make every effort to regain contact with the participant (where possible, 3 
telephone calls/emails/texts and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods) before a participant is deemed lost to follow-up. 
These contact attempts will be documented in the participant’s study file.  
• 
Participants that continue to be unreachable will be considered to have withdrawn from the study 
(with a primary reason recorded as lost to follow-up). 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
18 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Participants will complete a baseline assessment, daily and monthly assessments during a 6-month 
(~180 day) home monitoring period, and two follow-up assessments.  Study data will be collected via 
self-report into web or app-based surveys and a consumer wearable (Fitbit®). 
 
Eligibility and baseline procedures and assessments can be conducted either virtually via 
teleconference/webinar or in-person. Daily, monthly and follow-up assessments will be conducted 
virtually through the CareQOL app; monthly or follow-up assessments may also be conducted by 
interview.  
 
8.1.1 TBI DOCUMENTATION 
We will verify and document TBI status and injury severity of the care recipient for all participants. Data 
must conform to the TBI Model Systems classification, and be obtained from official medical 
documentation (e.g. medical records). 
 
8.1.2 CARE PARTNER ELIGIBILITY 
Confirmation of care partner eligibility according to criteria listed in Section 5, above, will be 
documented on the Eligibility CRF. It will occur prior to informed consent being obtained and before any 
study procedures associated with baseline assessment. Eligible individuals will then participate in the 
consent process, followed by randomization and baseline data collection. 
 
8.1.3 DEMOGRAPHICS & CHARACTERIZATION 
All participants will complete a series of surveys designed to characterize the sample with respect to 
demographics, caregiving experiences, and usual coping or management strategies. 
• 
Participant Demographics. A study-designed form will be used to capture demographic data 
including age, gender, race, ethnicity, education, marital status, work status, COVID 
history/status, care partner data, care recipient data, etc. Administration time for this 
assessment is ~5-10 minutes.  
• 
Medical History, Medications, Treatments, COVID Questionnaire. Study designed forms will be 
used to capture medical history and current treatments/management strategies (medication 
and non-medication – e.g., exercise, mindfulness) and COVID history. Administration time for 
this assessment is 10 minutes. 
• 
Caregiver Appraisal Scale (CAS). The CAS assesses positive and negative aspects of the caregiving 
role. Four separate subdomain scores (perceived burden, caregiver relationship satisfaction, 
caregiving ideology, and caregiving mastery) can be calculated; higher scores indicating better 
functioning. Administration time for this 47-item measure is ~5-10 minutes.  
• 
Mayo-Portland Adaptability Inventory- Fourth Edition (MPAI-4). The MPAI-4 is a 35-item proxy-
report measure designed to assess functional ability for persons with TBI. Higher scores indicate 
poorer functional ability. The administration time for this measure is ~5-10 minutes. 
• 
Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5). This version of the PCL-5 has been 
adapted for the proxy (in this study, the care partner is the proxy) assessment of posttraumatic 
stress disorder (PTSD) symptoms in the person with TBI. The PCL-5 is a 20-item measure that 
assesses the 20 symptoms of PTSD defined by the Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition (DSM–5). A total symptom severity score, as well as 5 cluster scores can be 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
19 
 
obtained from this measure; higher scores indicate more PTSD symptomatology. Administration 
time for this 20-item measure is ~5-10 minutes.  
• 
Supervision Rating Scale (SRS). This is a single rating that the caregiver provides about the 
overall amount of “supervision” that the person with TBI receives.  Ratings range from 1-13; 
higher ratings indicate greater levels of required supervision. Administration time is ~2 minutes. 
• 
Care Recipient Medical Record Information. Study staff will complete a CRF with information 
about the person with TBI for whom the care partner is providing care (e.g., time since 
diagnosis, details of diagnosis, disease stage/severity, imaging findings etc.). This data will be 
entered into the study database by study staff.  
 
8.1.4 FITBIT® AND CAREQOL APP 
Participants will be taught how to install both the Fitbit® and CareQOL apps onto their personal mobile 
devices. Participants will also to be taught how to create and login to the necessary accounts. See 
section 6.2 for details regarding participant education. 
• 
The study team will provide an access code for login to the CareQOL app. 
• 
Participants will use a user id and personal email address of their choosing for their Fitbit® 
account. 
• 
Data collected from the Fitbit® will be securely transmitted to the CareQOL app by user 
authentication token, which is comprised of a random series of characters that is used to 
securely query for user activity data. 
• 
Participants will view their Fitbit® sleep and step-count data through the CareQOL app, though 
there are not restrictions on them also viewing the information in the Fitbit® app. 
 
8.1.4.1 FITBIT® 
All participants will don a wrist-worn Fitbit® with heart rate recording capabilities for the duration of the 
10-day run-in period and 6-month (180 day) home monitoring period to monitor activity and sleep. 
While we intend to use the Fitbit Inspire HR®, we reserve the option to adopt a comparable device in the 
event of supply limitations or changes to the product line as long as there is minimal impact on the 
intervention delivery or primary outcome data integrity. 
• 
Participants may use a personal Fitbit® if it has comparable features. 
• 
Participants are expected to wear the Fitbit® continuously except for when charging and 
uploading data. 
• 
Participants are expected to sync the Fitbit® daily.  
 
8.1.4.2 CAREQOL APP 
The study app (CareQOL) is the participant-facing platform for all daily, monthly and follow-up 
assessments, for viewing sleep and step count data from the Fitbit®, and for intervention delivery. After 
the home monitoring period is over (e.g. after the 6-month [180 day] assessment), the app will go into 
an “assessment only” mode during which only the +3 month (270 day) and +6-month (360 day) follow-
up assessments will be activated. The daily and monthly assessments, the link with the Fitbit®, and 
intervention delivery will cease after the home monitoring period has elapsed. 
 
8.1.4.3 RUN-IN HOME MONITORING PERIOD 
A 10-day run-in period will follow the baseline assessment. This period is to allow shipping time of the 
Fitbit® and provide the participant time to familiarize themselves with the study technology (Fitbit®, 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
20 
 
CareQOL app) and procedures. This period will also allow the study team to troubleshoot any potential 
barriers or issues that arise before the official start of the 6-month (180 day) home monitoring period. It 
also allows for data collection that can be used to inform the intervention messages once the home 
monitoring period begins. 
 
8.1.5 HRQOL ASSSESSMENT 
Participants will complete a battery of HRQOL surveys; some will be administered daily and be used to 
drive the intervention, and others will be administered at baseline, monthly and during follow-up.  The 
individual survey administration schedule is shown in the Table, and descriptions are provided below. 
Table: HRQOL Assessment Schedule 
 
Baseline 
Daily* 
1m-
5m 
(30, 
60, 
90, 
120, 
150d) 
6m 
(180d) 
+3m 
(270d) 
F/U 
+6m 
(360d) 
F/U 
Caregiver Strain SF 
X 
 
X 
X 
X 
X 
Caregiver-Specific Anxiety SF 
X 
 
X 
X 
X 
X 
Sleep-Related Impairment SF 
X 
 
X 
X 
X 
X 
Fatigue SF 
X 
 
X 
X 
X 
X 
Anxiety SF 
X 
 
X 
X 
X 
X 
Depression SF 
X 
 
X 
X 
X 
X 
Anger SF 
X 
 
X 
X 
X 
X 
Self-Efficacy SF 
X 
 
X 
X 
X 
X 
Positive Affect & Well-Being SF 
X 
 
X 
X 
X 
X 
Perceived Stress 
X 
 
X 
X 
X 
X 
Ability to Participate in Social Roles & 
Activities SF 
X 
 
X 
X 
X 
X 
Global Health 
X 
 
X 
X 
X 
X 
COVID HRQOL 
X 
 
X 
X 
X 
X 
Single-item Caregiver Strain 
 
X 
 
 
 
 
Single-item Anxiety 
 
X 
 
 
 
 
Single-item Depression 
 
X 
 
 
 
 
MedHistory/Medications/Treatment/COVID 
X 
 
3m 
(90d) 
X 
X 
X 
AE/Status Update 
 
 
3m 
(90d) 
X 
X 
X 
Feasibility 
 
 
 
X 
 
 
*Daily surveys will be administered through the Run-in and 6-month home monitoring periods. 
 
• 
TBI-CareQOL Caregiver Strain Short Form (SF). TBI-CareQOL Caregiver Strain assesses 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
21 
 
perceived feelings of feeling overwhelmed, stressed and “beat-down” related to the care 
partner role. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more strain. The administration time for this measure is ~1 minute. 
• 
TBI-CareQOL Caregiver-Specific Anxiety SF. TBI-CareQOL Caregiver-Specific Anxiety assesses 
perceived feelings of worry and anxiety specific to the safety, health, and future well-being 
of the person with TBI. This measure is scored on a T metric (M = 50; SD = 10). Higher scores 
indicate more anxiety. The administration time for this measure is ~1 minute. 
• 
PROMIS Sleep-Related Impairment SF. PROMIS Sleep-Related Impairment evaluates the 
effect of poor sleep on daytime functioning. This measure is scored on a T metric (M = 50; 
SD = 10). Higher scores indicate more sleep-related impairment. Administration time for this 
measure is ~1 minute. 
• 
PROMIS Fatigue SF. PROMIS Fatigue evaluates self-reported symptoms of fatigue, ranging 
from mild subjective feelings of tiredness to overwhelming exhaustion that may decrease 
one’s ability to perform activities of daily living. This measure is scored on a T metric (M = 
50; SD = 10). Higher scores indicate more fatigue. Administration time for this measure is ~1 
minute. 
• 
PROMIS Anxiety SF. PROMIS Anxiety assesses self-reported feelings of fear, anxiety and 
hyperarousal. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more anxiety. Administration time for this measure is ~1 minute. 
• 
PROMIS Depression SF. PROMIS Depression assesses self-reported feelings of sadness and 
worthlessness. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more depression. Administration time for this measure is ~1 minute. 
• 
PROMIS Anger SF. PROMIS Anger assesses self-reported feelings of irritability and 
frustration. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more anger. Administration time for this measure is ~1 minute. 
• 
NIH Toolbox Self-Efficacy.  NIH Toolbox Self-Efficacy assesses self-reported confidence in the 
ability to successfully perform specific tasks or behaviors related to one’s overall 
functioning. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more self-efficacy. Administration time for this measure is ~1 minute. 
• 
Neuro-QoL Positive Affect & Well-Being SF. Neuro-QoL Positive Affect and Well-Being 
assesses parts of an individual’s life that are related to overall life meaning and purpose, 
well-being and satisfaction. This measure is scored on a T metric (M = 50; SD = 10). Higher 
scores indicate greater satisfaction. Administration time is ~1 minute. 
• 
NIH Toolbox Perceived Stress SF. NIH Toolbox Perceived Stress is a self-report measure 
designed to assess an individual’s feelings about the nature of events and individual coping 
resources. This measure is scored on a T metric (M = 50; SD = 10). Higher scores indicate 
more perceived stress. Administration time is ~1 minute. 
• 
PROMIS Ability to Participate in Social Roles and Activities SF. PROMIS Ability to Participate 
in Social Roles and Activities assesses involvement in one’s ability to participate in usual 
social roles and activities. This measure is scored on a T metric (M = 50; SD = 10). Higher 
scores indicate more ability to participate. Administration time is ~1 minute. 
• 
PROMIS Global Health v1.2. This 10-item patient-reported outcome measure assesses 
overall physical, mental, and social health. This measure is scored on a T metric (M = 50; SD 
= 10); separate scores are generated for physical and mental health. Higher scores indicate 
better health. The administration time for this measure is ~3 minutes. 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
22 
 
• 
COVID HRQOL. This 1-item patient-reported outcome measure asks how concerned the 
participant is about COVID-19 from 0 – 10. The administration time for this measure is less 
than 1 minute. 
 
8.1.5.1 BASELINE ASSESSMENTS 
Participants will be prompted by the CareQOL after registration to complete the baseline HRQOL 
assessments. Administration time is 10-15 minutes. 
 
8.1.5.2 DAILY ASSESSMENTS 
Participants will be prompted by the CareQOL app to complete a brief 3-item assessment once per day 
during the run-in and six-month (180 day) home monitoring periods. These questions will be answered 
directly on the app and involve <1 minute administration time in total. The daily assessments will 
include: 
• 
TBI-CareQOL Caregiver Strain – single-item assessment to evaluate self-reported caregiver 
strain. The individual items that are administered each day will vary. 
• 
PROMIS Anxiety – single item assessment to evaluate self-reported anxiety. The individual 
items that are administered each day will vary. 
• 
PROMIS Depression – single item assessment to evaluate self-reported depression. The 
individual items that are administered each day will vary. 
 
8.1.5.3 MONTHLY ASSESSMENTS 
Participants will be prompted by the CareQOL app to complete a series of self-report surveys at the end 
of each month (day 30, 60, 90, 120, 150, 180) during the 6-month (180 day) home monitoring period. 
They will also complete a post-intervention/app feasibility survey at the end of month 6 (day 180).  
These surveys will be answered directly on the CareQOL app and/or by interview, and should take ~10-
15 minutes to complete. 
• 
Study Feasibility: At the 6-month (180 day) assessment only, participants will complete a Study 
Feasibility survey to assess the experience of the participant with the study methodology and 
technology, including the CareQOL app, Fitbit®, and the JITAI. Administration time is 5 minutes. 
Additionally, participants will update their medical history, medications, therapies, and COVID history 
and be queried about AEs at the end of month 3 (day 90) and month 6 (day 180).  
• 
Medical History, Medications, Treatments, COVID Questionnaire. Participants will update their 
medical history and current treatments/management strategies (medication and non-
medication – e.g., exercise, mindfulness) and COVID history. Administration time for this 
assessment is 10 minutes 
• 
Adverse Events. Participants will be asked about any changes in mental or physical health. 
Administration time is 5 minutes. 
 
8.1.5.4 FOLLOW-UP ASSESSMENTS 
Participants will be prompted by the CareQOL app to complete a series of self-report surveys at +3-
months (270 days) and +6-months (360 days) follow-up. As with the monthly surveys, responses will be 
directly entered into the CareQOL app and/or by interview and should take ~10-15 minutes to complete. 
Additionally, participants will update their medical history, medications, treatments and COVID history 
and be queried about AEs at these time points.  
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
23 
 
8.1.6 OPTIONAL SEMI-STRUCTURED INTERVIEW (Added in protocol version 4.0) 
Participants who have not completed the main caregiver study at the time of protocol version 4.0 IRB 
approval (~March 2023) may be invited to complete an optional, in-depth semi-structured interview 
that will assess participants’ experiences and perceptions of the caregiver study, particularly their 
experiences and perceptions of the CareQOL app. Additionally, participants that are in the intervention 
group will also be asked about the intervention messages that they received from the CareQOL app. The 
interview will be conducted via Zoom, audio-recorded and last for 45-60 minutes. The interview will be 
conducted after the 6-month home monitoring period is completed. The data collected from this 
interview will be used to improve the CareQOL app and inform study design for future studies. 
 
Participants who choose to complete this optional interview will be required to provide separate 
informed consent for this portion of the study, and participants will receive $30 for completing the 
interview. The audio-recording of the interview will be transcribed and analyzed using qualitative 
analysis software (e.g., NVivo). 
 
8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.2.1 DEFINITION OF ADVERSE EVENTS 
 
The U-M IRBMED definition of an adverse event will be used for this study. The definition can be found 
at https://az.research.umich.edu/medschool/glossary and is below:  
 
An adverse event (AE) is any experience or abnormal finding that has taken place during the course of a 
research project and was harmful to the subject participating in the research, or increased the risks of 
harm from the research, or had an unfavorable impact on the risk/benefit ratio. The event may or may 
not be caused by an intervention. Adverse events also include psychological, social, emotional or 
financial harms. 
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
The U-M IRBMED definition of a serious adverse event (SAE) will be used for this study. The definition 
can be found at https://az.research.umich.edu/medschool/glossary and is below:  
 
A serious adverse event (SAE) is any adverse experience occurring at any dose or level of participation 
that results in any of the following outcomes: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
8.2.3 CLASSIFICATION OF AN ADVERSE EVENT 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
24 
 
8.2.3.1 SEVERITY OF EVENT 
 
All AEs will be assessed by the principal investigator, and/or if necessary, a study co-investigator or the 
study’s independent safety monitor. 
 
The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
8.2.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained investigator based on temporal relationship and his/her clinical 
judgment. All AEs will be categorized according to the likelihood that they are related or not related to 
the study intervention. 
 
• 
Related (Possible, Probable, Definite) 
o The event is a known or suspected effect of the intervention or research procedures 
(e.g., listed in the protocol documents including, consent, publications, etc.) 
o There is at least a reasonable temporal relationship between the intervention or 
procedure and the event onset 
o The event abates when the intervention is discontinued 
o The event reappears upon a re-challenge with the intervention 
o The event includes data that was collected solely for research purposes 
o The event included disturbing or upsetting questions asked solely for research purposes  
 
• 
Not Related (Unlikely, Not Related) 
o The event is NOT a known or suspected effect of the study intervention or procedures 
o The event is readily explained by characteristics of the study population  
o There is no temporal relationship between the intervention and event onset 
o An alternate etiology has been established 
8.2.3.3 EXPECTEDNESS  
 
An investigator with appropriate expertise will be responsible for determining whether an adverse event 
(AE) is expected or unexpected. An event that is expected has been addressed or described in one or 
more of the following: Informed consent document for this study, IRB application for this study, grant 
application or study agreement, protocol or procedures for this study, ISR Reports, published literature, 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
25 
 
other documentation, or characteristics of a study population. An AE will be considered unexpected if 
the nature, severity, or frequency of the event is not consistent with the risk information described. 
8.2.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of the study team via spontaneous report or 
formal assessment, where participants will be asked to describe any physical or mental health 
worries/concerns since the last check-in (see SOA for time points). Regardless of the reporting 
mechanism, the study team will probe any concerns to get additional information and determine if it is 
an adverse event. Details will be documented in the participant study record. 
 
Any side effects that are determined to be adverse events related to study participation will be 
documented on the study adverse event form in the study REDCap database and followed until 
resolution.  
 
8.2.5 MULTI-SITE ADVERSE EVENT REPORTING  
 
For this study, only related adverse events will be reported. Adverse events will be reported to U-M 
IRBMED and NINR using the standard IRBMED reporting schedule: 
(https://az.research.umich.edu/medschool/guidance/adverse-event-reporting). The U-M IRBMED 
reporting schedule is dependent on the severity of the event, and whether such adverse events were 
expected. Any serious adverse events will be reported to the ISM, U-M IRBMED and NINR as soon as 
possible but not later than 7 days of learning of the event. Non-threatening potentially serious adverse 
events that are causally related to the research will be reported within 14 days of learning of the event 
to the ISM, U-M IRBMED and NINR. 
 
Sites will report study-related adverse events using the adverse event form in the REDCap study 
database promptly. In the case of a serious adverse event, the project PI and project manager should be 
notified by email or phone as soon as possible but not later than 7 days of learning of the event. Adverse 
events will be discussed at investigator and project staff meetings. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
Primary Endpoint:  
1) We hypothesize greater decreases in caregiver strain will be observed among participants in 
the JITAI group (relative to the control group) at the end of the 6-month home monitoring 
period.  
 
Secondary Endpoints: 
1) We hypothesize greater decreases in anxiety will be observed among participants in the JITAI 
group (relative to the control group) at the end of the 6-month home monitoring period.  
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
26 
 
2) We hypothesize greater decreases in depression will be observed among participants in the 
JITAI group (relative to the control group) at the end of the 6-month home monitoring period.  
9.2 
SAMPLE SIZE DETERMINATION 
 
Our initial power calculations were based on the expected difference in change in self-reported TBI-
CareQOL Caregiver Strain (from baseline to 6-month follow-up) between the JITAI intervention group 
and the control group. Using self-reported TBI-CareQOL Caregiver Strain, we expect using a normative T-
score, with a standardized mean set at 50 and a standard deviation of 9.66, the minimum detectable 
difference (MID) for caregiver strain to be in the range of 4-6 points. A sample size of 92 in each group 
will have 80% power to detect a difference in means of 4.0 assuming that the common standard 
deviation is 9.66 using a two group t-test with a 0.05 two-sided significance level.  
 
Similar results would be expected for the expected difference in change in self-reported PROMIS 
Depression (from baseline to 6-month follow-up) between the JITAI intervention group and the control 
group. Using self-
reported PROMIS 
Depression, we expect 
using a normative T-
score, with a 
standardized mean set 
at 52.03 and a 
standard deviation of 
9.79, the minimum 
detectable difference 
(MID) for depression 
to be in the range of 
4-6 points. A sample 
size of 95 in each 
group will have 80% 
power to detect a 
difference in means of 4.0 assuming that the common standard deviation is 9.79 using a two group t-
test with a 0.05 two-sided significance level.  
 
Similar results would also be expected for the expected difference in change in self-reported PROMIS 
Anxiety (from baseline to 6-month follow-up) between the JITAI intervention group and the control 
group. Using self-reported PROMIS Anxiety, we expect using a normative T-score, with a standardized 
mean set at 54.8 and a standard deviation of 9.53, the minimum detectable difference (MID) for 
depression to be in the range of 4-6 points. A sample size of 90 in each group will have 80% power to 
detect a difference in means of 4.0 assuming that the common standard deviation is 9.53 using a two 
group t-test with a 0.05 two-sided significance level.  
 
With regard to the exploratory analyses, sample size estimates used the following inputs:31 1) type I 
error rate (α) = 0.05; 2) the smallest meaningful difference to be detected = (δ); 3) power (γ) = 0.8; 4) we 
assumed outcome marginal variance (σ2) is constant over time and 102 (according to the T-metric used 
to score each HRQOL domain); 5) the number of repeated measurements per person (n) = 1 baseline, 8 
post-baseline for a total of n=9 repeated assessments; and 6) with regard to the correlation structure 
among the repeated measurements we assumed an exchangeable correlation (ρ) = a range of values 
0.4, 0.5, 0.6, 0.7, 0.8. The sample size formula is: 
N =
4ቊ𝑍𝑍1−𝛼𝛼
2
+𝑍𝑍1−𝛾𝛾ቋ
2
𝜎𝜎𝐶𝐶
2
𝛿𝛿2
, where 𝜎𝜎𝐶𝐶
2 = 𝑉𝑉𝑉𝑉𝑉𝑉(𝐶𝐶𝑖𝑖)[1 −{𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶(𝑌𝑌𝑖𝑖0, 𝐶𝐶𝑖𝑖)}2] = 
(1−𝜌𝜌){1+(𝑛𝑛−1)𝜌𝜌}𝜎𝜎2
𝑛𝑛−1
 
The Table provides the sample sizes needed for different effect sizes (δ) and correlations (ρ) when 
comparing post-baseline averaged outcomes between JITAI and control groups using an ANCOVA 
Table. Estimated Sample Sizes 
Effect sizes  
(T-metric) 
Correlation (ρ) 
0.40 
0.50 
0.60 
0.70 
0.80 
5 
234 
230 
198 
146 
82 
10 
60 
58 
50 
38 
22 
15 
26 
26 
22 
16 
10 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
27 
 
method (assumed 15% attrition rate32-34). Thus, the proposed sample size of N=240 care partners is 
sufficient to detect small, but meaningful effects. 
 
Thus, the proposed sample size comfortably exceeds those required to address the primary and 
secondary endpoint analyses, and is sufficient to examine the tertiary and exploratory endpoints. 
9.3 
POPULATIONS FOR ANALYSES 
 
The primary and secondary endpoints will compare the JITAI group with the control group.  Tertiary 
analyses may also compare important subgroups (e.g., caregiver groups that differ by relationship type 
[parent vs. spousal caregivers], caregiver groups that differ by sex [male vs. female caregivers], caregiver 
groups that differ according to the functional status of the person with TBI (e.g., complicated mild vs. 
moderate vs. severe TBI or perceived functional status based on Mayo Portland Adaptability Index 
scores). 
 
The analyses will be an intention-to-treat approach where the participant will contribute data to the arm 
he/she was randomized to regardless of the amount of data contributed (i.e. the duration of 
participation).  
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
Continuous measures will be described using means and standard deviations (or medians and ranges if 
non-normality is detected), while categorical measures will be summarized with frequencies and 
percentages.  
 
For inferential tests, a two group t-test with a 0.05 two-sided significance level will be used. 
 
Analyses for primary, secondary, and tertiary endpoints are described individually, below. 
 
The distribution of the data will be examined to ensure that parametric testing is appropriate. In cases 
where data distributions are not normal, nonparametric tests will be used to analyze the data. 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Primary Endpoint: TBI-CareQOL Caregiver Strain Short Form (SF). TBI-CareQOL Caregiver Strain assesses 
perceived feelings of feeling overwhelmed, stressed and “beat-down” related to the care partner role. 
Self-reported responses are on a Likert scale. This measure is scored on a T metric (M = 50; SD = 10). 
Higher scores indicate more strain.  
 
Self-reported TBI-CareQOL Caregiver Strain (T score) will be used to test the effectiveness of the JITAI. 
Change from baseline to 6-months post-intervention will be compared between the two arms. Means 
and standard deviations of the within-person changes will be calculated. In addition, we will model the 
dependent variable (Caregiver Strain) using linear mixed effect model, where a random intercept will be 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
28 
 
included to account for repeated measurements from the same subject. We include in the model the 
following independent variables: the randomization arm, time and interaction between randomization 
arm and time, and baseline Caregiver Strain T scores. Key biologic variables such as age, sex, TBI 
severity, and co-morbidities will be among some of the factors explored as potential confounders.  
Differences between treatment arms can then be obtained by estimating and testing the corresponding 
parameters in the linear mixed effect model.  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary Endpoints: 
• 
PROMIS Anxiety SF. PROMIS Anxiety assesses self-reported feelings of fear, anxiety and 
hyperarousal. Self-reported responses are on a Likert scale. This measure is scored on a T 
metric (M = 50; SD = 10). Higher scores indicate more anxiety. Administration time for this 
measure is ~1 minute. 
• 
PROMIS Depression SF. PROMIS Depression assesses self-reported feelings of sadness and 
worthlessness. Self-reported responses are on a Likert scale. This measure is scored on a T 
metric (M = 50; SD = 10). Higher scores indicate more depression. Administration time for 
this measure is ~1 minute. 
 
Self-reported PROMIS Anxiety (T score) or PROMIS Depression (T score) will be used to test the 
effectiveness of the JITAI. Change from baseline to 6-months post-intervention will be compared 
between the two arms. Means and standard deviations of the within-person changes will be calculated. 
In addition, we will model the dependent variable (Anxiety or Depression, respectively) using linear 
mixed effect model, where a random intercept will be included to account for repeated measurements 
from the same subject. We include in the model the following independent variables: the randomization 
arm, time and interaction between randomization arm and time, and baseline PROMIS Anxiety or 
PROMIS Depression T scores. Key biologic variables such as age, sex, TBI severity, and co-morbidities will 
be among some of the factors explored as potential confounders.  Differences between treatment arms 
can then be obtained by estimating and testing the corresponding parameters in the linear mixed effect 
model.  
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
Care partners in each study group (JITAI and control) will be compared descriptively according to 
Consolidated Standards of Reporting Trials Guidelines.35  
 
T tests/ANOVA will be used to examine group differences for continuous variables (e.g., age, HRQOL 
outcomes, time since injury, functional status of person with TBI).  Chi-squared/Fisher exact tests will be 
used to examine group differences for categorical variables (e.g., sex, ethnicity, race, education, marital 
status, relationship to person with TBI, TBI severity). 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
29 
 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
The participant will be provided with a PDF of their certified consent form approved by the U-M IRBMED 
describing in detail the study intervention, study procedures, and risks. Informed consent will be 
obtained prior to the participant completing any study-related assessments. An example can be found in 
the U-M IRBMED application for this study. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
All consent procedures will be approved by the U-M IRBMED. Because participants do not need to come 
to a study site to participate in this study, informed consent may be conducted virtually (e.g., Zoom, 
Bluejeans, telephone, etc.) or in-person. Consent will be documented using the REDCap consent 
platform for all participants; participants will indicate their consent by entering their name and the date 
into the REDCap consent document. All individuals who are interested in participating in the study will 
be encouraged to ask questions about the study and their participation, and will be given as much time 
as needed to make a decision about participating. Participants will receive a pdf copy of their ‘signed’ 
consent. 
 
Participants completing the optional semi-structured interview portion of the study (see section 8.1.6) 
will consent for this portion of the study using a separate consent form, following the same procedures 
above. 
 
A waiver of informed consent and HIPAA waiver is requested for eligibility screening for this study and 
for collection of medical record data for the individual with TBI that the participant (care partner) is 
caring for. The medical record data is needed to accurately capture injury severity, time since injury, etc. 
10.1.2 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, the independent safety monitor and funding agency. This confidentiality is extended to the data 
being collected as part of this study. Data that could be used to identify a specific study participant will 
be held in strict confidence within the research team.  
 
All research activities will be conducted in as private a setting as possible.  The study participant’s 
contact information will be securely stored at each site for internal use during the study. Each site will 
keep a master list of their site’s participant names and matching participant IDs. This master list will not 
be shared with the other site, and will be kept by site personnel in a password-protected file on a secure 
server or in a secure environment (e.g., locked cabinet, restricted access). No one other than the study 
team at the study site will have access to their site’s master list (except when needed for study 
monitoring). Informed consents will be stored in a study-specific database which contains only the 
informed consents and the informed consents for each site will only be available to their site’s study 
team members (except when needed for study monitoring). At the end of the study, all records will 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
30 
 
continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, 
Institutional policies, or funding agency requirements.  
 
No personal identifying information will appear on or with the participant data, where possible. Each 
participant will be assigned a participant ID by the study team to maintain confidentiality. The primary 
unique identifier is the study-assigned participant ID. The participant’s self-report data and CRF data will 
be identified with the participant ID. Additionally, an access code will be assigned to each participant 
which they will use to enroll in the CareQOL app. Participants will register their study Fitbit® on the 
Fitbit® app using a username and email address of their choice. The data collected on the Fitbit® will be 
linked to the CareQOL app by user authentication token, which is comprised of a random series of 
characters that is used to securely query for user activity data; no identifying information (including 
email address or Fitbit® user ID) is saved in the CareQOL app.  
 
For participants completing the optional semi-structured interview portion of the study (see section 
8.1.6), no personal identifiers will be kept with the transcription of the interview. Only audio will be 
recorded during the interview (no video), and the participant will be instructed and reminded (if 
needed) to avoid using names, other identifiers, etc. during the interview. Audio-recordings and 
transcripts will be stored securely (e.g., password protected server, study-specific M-Box). 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and managed by the University of Michigan. Individual participants and their research 
data will be identified by a unique study identification number, where possible. The study data entry and 
study management systems (e.g., CareQOL app, REDCap, Qualtrics, M-Box, Fitbit®, etc.) used by clinical 
sites and by University of Michigan research staff are secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the University of Michigan. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made 
available to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms 
used to share data will include proper plans and safeguards for the protection of privacy, confidentiality, 
and security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not 
be traceable to a specific study participant).  
 
Certificate of Confidentiality  
Participants in this study are covered under a NIH Certificate of Confidentiality (CoC). The CoC limits the 
disclosure of identifiable, sensitive information to a few instances: 1) if required by Federal, State, or 
local laws (e.g., as required by the Federal Food, Drug, and Cosmetic Act, or state laws requiring the 
reporting of communicable diseases to State and local health departments), excluding instances of 
disclosure in any Federal, State, or local civil, criminal, administrative, legislative, or other proceeding; 2) 
if necessary for the medical treatment of the individual to whom the information or document pertains 
and made with the consent of such individual; 3) if made with the consent of the individual to whom the 
information or document pertains; or 4) if made for the purposes of other scientific research that is in 
compliance with applicable Federal regulations governing the protection of human subjects in research. 
Participants will be notified in the informed consent that this study is covered by a CoC and will be 
informed of the protections and limitations to protections provided by the CoC.  

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
31 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data Retention 
Research data and information will be retained for both study record-keeping purposes and for future 
research use. Any materials with identifiers (e.g., informed consents) will be stored in locked filing 
cabinet or on a secure server separate from coded study information.  
 
Data from participants who withdraw from the study will be retained in the study database. 
 
Study Record Keeping 
During the study, we will maintain identifiable data to facilitate day-to-day study operations such as 
follow-up contact, distribution of study incentives, etc. These records may be destroyed after 7 years 
per U-M record keeping guidelines (https://az.research.umich.edu/medschool/guidance/record-keeping-
guidelines).   
 
Data for Future Research Use 
We will archive de-identified data for future research use. These data may be used for additional 
analyses related to the main study, new analyses, and in grant proposals for new research.   
• 
The data will be stored on Michigan Medicine servers in a HIPAA-compliant electronic data 
capture system and/or statistical datasets that are stripped of identifiers. 
• 
Access to the data will be at the discretion of the PI. 
• 
Any data shared with collaborators and other researchers will be transferred using secure 
methods (e.g. MiShare, encryption, etc.) 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Independent Safety Monitor 
Noelle Carlozzi, PhD, Associate 
Professor, Dept. of Physical 
Medicine & Rehabilitation, 
Medical School 
Mary Janevic, MPH, PHD, 
Associate Research Scientist, 
Health Behavior/Health 
Education, School of Public 
Health 
University of Michigan  
University of Michigan  
2800 Plymouth Rd., NCRC Building 
14, Ann Arbor, MI 48109-2800 
2817 SPH 1 
Ann Arbor, MI 48109-2029 
734-763-8917 
734-647-3194 
Carlozzi@med.umich.edu 
mjanevic@umich.edu 
10.1.5 SAFETY OVERSIGHT 
 
Mary Janevic, MPH, PhD, will serve as the Independent Safety Monitor (ISM) for this study. Dr. Janevic is 
an Associate Research Scientist in Health Behavior/Health Education at the U-M School of Public Health 
and is a faculty member of the University of Michigan’s Center for Managing Chronic Disease. She is not 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
32 
 
a member of the study team and is available to review and recommend appropriate action over the 
duration of this five-year study. Her ISM responsibilities include: 
• 
Reviewing the research protocol, informed consent documents and plans for data safety and 
monitoring. 
• 
Recommending subject recruitment be initiated after the receipt of a satisfactory protocol. 
• 
Evaluating the progress of the trial, including annual assessments of data quality and 
timeliness, recruitment, accrual and retention, participant risk versus benefit, overall 
performance of the trial and other factors that can affect outcomes. 
• 
Protecting the safety of study participants. 
• 
Considering factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the trial. 
• 
Reviewing study performance, making recommendations and assisting in the resolution of 
problems reported by the PI. 
• 
Ensuring the confidentiality of study data. 
• 
Reporting on the safety and progress of the trial annually. 
• 
Making recommendations to the PI and IRB about the continuation, termination or 
modifications of the trial based on the observed beneficial or adverse effects of the 
treatment. 
 
The PI will meet with the ISM prior to the start of participant recruitment and annually throughout the 
duration of the study, coinciding with the IRB scheduled continuing review. Additionally, the ISM will be 
available and consulted if greater than expected safety concerns or other issues arise. The ISM will 
prepare an annual report for the PI. The PI will be responsible for submitting this annual report to the U-
M IRBMED and NINR.   
10.1.6 QUALITY ASSURANCE AND QUALITY CONTROL 
 
QA and QC practices will be the responsibility of all team members.  Training and regular meetings (held 
remotely or in-person) will be conducted to monitor and facilitate quality data collection. 
 
Training: 
All site investigators and study staff will be trained on the project protocol, project data collection 
systems and other study-related topics by the principal investigator and the project manager prior to 
beginning data collection. The standardized training will be conducted at all sites prior to them enrolling 
participants in the study. Additionally, the project manager, in cooperation with the PI and the data 
manager, will develop a detailed manual of procedures, case report forms and other related study 
materials. The manual of procedures will provide step-by-step instructions on the conduct of the trial, 
including how to use and troubleshoot all of the data collection platforms. The manual of procedures 
and other study documents will be reviewed in detail with the data collectors at each site as part of the 
training, and all materials will be available on the study-specific shared MBox site for access at any time. 
Study staff will be encouraged to use the step-by-step instructions when conducting participant visits to 
ensure that they are adhering to the study protocol. Ongoing training will occur via regular conference 
calls and during site visits. Additionally, any staff who join the team after the project starts will be 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
33 
 
required to complete the standardized training prior to enrolling participants. Training will be 
documented in the electronic regulatory binder. 
 
Meetings: 
• 
Full Team (U-M and BCM): Full team meetings will be held prior to enrolling participants (study 
launch) and yearly thereafter to focus/re-focus the project goals, summarize challenges and 
successes, and participate in applicable trainings 
• 
Investigator Meetings – Meetings (remote or in-person) with the study investigators will be held 
monthly to discuss study activities, progress and troubleshoot any issues. Other project staff will 
attend as needed. 
• 
Project Staff Meetings – The Project Manager will hold monthly meetings after data collection 
begins with the project staff. These meetings will be focused on tracking recruitment efforts, 
data collection (including data management and clearing of queries), and discussion of protocol 
deviations or adverse events. Investigators may attend as needed. 
• 
Data Management Team – The PI, study statistician, and Data & Project Managers will meet 
regularly throughout the project; these meetings will occur more often as the study launches, 
and then less frequently thereafter to develop and uphold the data management plan (from 
collection through analysis). Other attendees (e.g. investigators, U-M/BCM staff, etc.) may be 
included as needed 
• 
Site Visits: Annual visits (virtual or in-person) by the PI and the Project Manager will be 
conducted at both data collection sites to review study regulatory materials, informed consents, 
data, procedures and compliance to the study protocol. 
10.1.7 DATA HANDLING AND RECORD KEEPING  
10.1.7.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
This project uses multiple electronic data capture and management platforms (e.g., REDCap, CareQOL, 
Qualtrics, Fitbit®, U-M server, Google Cloud, AWS Cloud). All platforms are designed for human subjects 
research and comply with federal and local data and information security practices. Each site will use 
the same platforms. 
 
Data collection is the responsibility of the site study staff under the direction of the Project Manager and 
site PI. All data are entered or captured on the platforms by study staff or directly by participants (e.g. 
sleep/activity data, daily EMAs etc.). Any study documents completed on paper will be completed legibly 
and in ink. 
 
The Project and Data Manager and the PI will directly oversee the QA/QC activities using standard 
operating procedures, checklists, and built-in and study-specific data validation rules to uphold data 
integrity. Routine data backups will be part of this process.  
 
Annual site visits will be made by the U-M PI and project manager will be conducted at U-M and BCM 
and are described below:   
• 
Auditing Selected Cases for Compliance with IRB Requirements. These annual audits will include 
a random review of 20% of the cases that have been collected since the previous review. 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
34 
 
• 
Conformance with Informed Consent Requirements. As part of these annual assessments, the 
project manager and PI will also review all consent forms for participants that have been seen 
since the previous review. 
• 
Verification of Source Documents. These annual audits will also include a verification of all 
source documents at both sites. 
• 
Investigator Compliance. We will review the site regulatory binder to ensure that all study 
investigators have updated CVs and documentation of human subjects’ training. 
 
To document adherence to this plan we will maintain a monitoring log and create accompanying 
monitoring reports for each review. The monitoring log will be kept in the electronic regulatory binder. 
 
The data manager will be responsible for setting up, monitoring and maintaining the data collection 
systems for both sites, and collaborating with the Project Manager on the initial implementation checks 
of data quality. Initially, data from the mobile app will be reviewed following the run-in period from the 
first 5 participants to ensure that daily data is being appropriately collected. We will continue to monitor 
the same 5 participants throughout the completion of the study (including the end of month surveys 
during the home monitoring period and the post-home monitoring surveys). We will evaluate 
procedures to ensure that data transfers at all points are accurate. Review of the data quality will be 
conducted by the data manager and reviewed by the study statistician and PI. Irregularities or problems 
detected will be discussed with the study team and addressed. Following any needed adjustments or 
corrections to study procedures, subsequent data quality as described above will be monitored for the 
next 5 participants and then by random inspection of the data independently by the data manager, 
statistician and PI. Quarterly audits will confirm proper data transfers and downloads, and include 
checks for missing and/or out-of-range data, logic errors, etc.  Quality control and reliability of the data 
will be discussed at regular team meetings. 
 
10.1.7.2 STUDY RECORDS RETENTION  
 
Study records will be retained according to University of Michigan guidance for research records 
retention involving health-related data (https://az.research.umich.edu/medschool/guidance/record-
keeping-guidelines).   
10.1.8 OTHER REPORTABLE INCIDENTS & OCCURRENCES (ORIOS) 
 
Both sites will adhere to IRBMED’s Multi-Site Research Reporting Plan (see Appendix 1) for ORIOs, 
including UaPs and Protocol Deviations.  Briefly, this plan requires reporting of events to IRBMED within 
7 days of the study team’s awareness of said event. Refer to Appendix 1 for list of reportable events. 
 
Unanticipated Problems: 
An Unanticipated Problem Involving Risks to Subjects or Others (UaP) is an actual incident, experience or 
outcome that warrants consideration of substantive changes in the research protocol or informed 
consent process/document or other corrective actions in order to protect the safety, welfare or rights of 
subjects or others. The following criteria must be met: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board (IRB)-

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
35 
 
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places subject(s) or other at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Unanticipated problems will be reported by the principal investigator to the U-M IRBMED per their 
standard reporting timeline. See: https://az.research.umich.edu/medschool/guidance/unanticipated-
problems-involving-risks-subjects-or-others 
 
Sites will report study-related unanticipated problems using the unanticipated problem form in the 
REDCap study database. Unanticipated problems will be discussed at investigator and project staff 
meetings. 
 
The study ISM will review all UaPs at least annually throughout the course of the study. They will be 
summarized in the ISM report that is submitted to the U-M IRBMED and NINR at annual review and in 
other ISM reports (if applicable). 
 
Protocol Deviations: 
This protocol uses the University of Michigan definition of a protocol deviation 
(https://az.research.umich.edu/medschool/glossary/deviation) which defines a protocol deviation as 
“an incident involving non-compliance with the protocol, but one that does not have a significant effect 
on the subject’s rights, safety or welfare, and/or on the integrity of the data. Deviations may result from 
the action of the participant, researcher or staff.” 
 
We will follow the U-M IRBMED reporting guidance for protocol deviations found here  
https://az.research.umich.edu/medschool/guidance/other-reportable-information-or-occurrence-orio. 
 
Reportable protocol deviations will be reported and tracked in the REDCap database and will be 
discussed at investigator and project staff meetings. 
 
The following events will not be reported as protocol deviations: 
• 
A protocol deviation will not be reported for participants who skip/do not complete study 
survey questions or entire surveys (like end of month assessments or post-intervention surveys). 
Participants can decline to answer any survey question for any reason. We expect in an 
intensive, long duration protocol like this that participants may miss some assessments. 
• 
A protocol deviation will not be reported for out-of-window assessments. Use of this data will 
be assessed by the study investigators for each study analysis; some analyses may need tighter 
compliance to the assessment window while others will not. 
• 
A protocol deviation will not be reported for participants who miss/do not complete the EMA 
assessments or do not wear/miss uploading Fitbit® data during the home-monitoring period. For 
example, we expect that there may be instances where participants are unable to complete the 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
36 
 
EMA assessments (for example, they are somewhere where it is inconvenient for them to 
answer) or forget to put on or sync the Fitbit®.  
• 
A protocol deviation will not be reported for participants who decline the participant payment. 
It has been our experience that some research participants do not wish to receive payment for 
their participation in research studies.  
 
Reportable protocol deviations will be reviewed at the project staff and investigator meetings, and 
summarized in the ISM report that it submitted to the U-M IRBMED and NINR at annual review 
(coinciding with the scheduled continuing review) and in other ISM reports (if applicable). 
10.1.9 PUBLICATION AND DATA SHARING POLICY  
 
The University of Michigan (U-M) is committed to the Data Sharing Policies specified by the study 
funder. The Principal Investigator and her collaborators will make unique research resources readily 
available for research purposes to individuals within the scientific community after publication. U-M has 
previously used a variety of means as appropriate and expeditious to share data resulting from 
sponsored projects with research colleagues, such as depositing data into secure web-accessible data 
warehouses or arranging distribution of data, and protocols to other researchers using established 
mechanisms and repositories.  
 
U-M will assure the timely release and sharing of data no later than the acceptance for publication of 
the main findings from the final dataset and will protect the rights and privacy of human subjects who 
participate in research by redacting all identifiers, and adopting other strategies to minimize risks of 
unauthorized disclosure of personal identifiers in accordance with authorization and consent 
documents. U-M agrees that data sharing is essential for expedited translation of research results into 
knowledge, products, and procedures to improve human health. To enable efficient data sharing, the U-
M Project Manager will coordinate requests for data and maintain documentation for requests and 
distributions. The University has an established Institutional Data Use Agreement that can easily be 
adapted and deployed.  
 
This study will comply with the National Institutes of Health (NIH) Public Access Policy, which ensures 
that the public has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
This study will also comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission 
rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will 
be submitted to ClinicalTrials.gov. 
 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
37 
 
11 REFERENCES  
1. 
Rothing M, Malterud K, Frich JC. Caregiver roles in families affected by Huntington's disease: a 
qualitative interview study. Scand J Caring Sci. 2013. 
2. 
Verhaeghe S, Defloor T, Grypdonck M. Stress and coping among families of patients with 
traumatic brain injury: a review of the literature. J Clin Nurs. 2005;14(8):1004-1012. 
3. 
Carlozzi NE, Brickell TA, French LM, et al. Caring for our wounded warriors: A qualitative 
examination of health-related quality of life in caregivers of individuals with military-related 
traumatic brain injury. Journal of Rehabilitation Research & Development. 2016;53(6):669-680. 
4. 
Carlozzi NE, Hanks R, Lange RT, et al. Understanding Health-related Quality of Life in Caregivers 
of Civilians and Service Members/Veterans With Traumatic Brain Injury: Establishing the 
Reliability and Validity of PROMIS Mental Health Measures. Arch Phys Med Rehabil. 2018. 
5. 
Carlozzi NE, Ianni PA, Lange RT, et al. Understanding health-related quality of life of caregivers of 
civilians and service members/veterans with Traumatic Brain Injury: Establishing the reliability 
and validity of PROMIS social health measures. Arch Phys Med Rehabil. 2018. 
6. 
Carlozzi NE, Ianni PA, Tulsky DS, et al. Understanding Health-Related Quality of Life in Caregivers 
of Civilians and Service Members/Veterans With Traumatic Brain Injury: Establishing the 
Reliability and Validity of PROMIS Fatigue and Sleep Disturbance Item Banks. Arch Phys Med 
Rehabil. 2018. 
7. 
Carlozzi NE, Kallen MA, Hanks R, et al. The TBI-CareQOL Measurement System: Development 
and Preliminary Validation of Health-Related Quality of Life Measures for Caregivers of Civilians 
and Service Members/Veterans With Traumatic Brain Injury. Arch Phys Med Rehabil. 2018. 
8. 
Carlozzi NE, Kallen MA, Hanks R, et al. The development of a new computer adaptive test to 
evaluate feelings of being trapped in caregivers of individuals with traumatic brain injury: TBI-
CareQOL Feeling Trapped Item Bank. Arch Phys Med Rehab. 2018. 
9. 
Carlozzi NE, Kallen MA, Ianni PA, et al. The Development of a New Computer-Adaptive Test to 
Evaluate Strain in Caregivers of Individuals With TBI: TBI-CareQOL Caregiver Strain. Arch Phys 
Med Rehabil. 2018. 
10. 
Carlozzi NE, Kallen MA, Ianni PA, et al. The development of a two new computer adaptive tests 
to evaluate feelings of loss in caregivers of individuals with traumatic brain injury: TBI-CareQOL 
Feelings of Loss-Self and Feelings of Loss-Person with Traumatic Brain Injury. Arch Phys Med 
Rehabil. 2018. 
11. 
Carlozzi NE, Kallen MA, Sander AM, et al. The development of a new computer adaptive test to 
evaluate anxiety in caregivers of individuals with traumatic brain injury: TBI-CareQOL Caregiver-
Specific Anxiety. Arch Phys Med Rehabil. 2018. 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
38 
 
12. 
Carlozzi NE, Kratz AL, Sander AM, et al. Health-related quality of life in caregivers of individuals 
with traumatic brain injury: development of a conceptual model. Archives of Physical Medicine 
& Rehabilitation. 2015;96(1):105-113. 
13. 
Carlozzi NE, Lange RT, French LM, Sander AM, Freedman J, Brickell TA. A Latent Content Analysis 
of Barriers and Supports to Healthcare: Perspectives From Caregivers of Service Members and 
Veterans With Military-Related Traumatic Brain Injury. J Head Trauma Rehabil. 2018. 
14. 
Carlozzi NE, Lange RT, French LM, et al. Understanding Health-Related Quality of Life in 
Caregivers of Civilians and Service Members/Veterans With TBI: Reliability and Validity Data for 
the TBI-CareQOL Measurement System. Arch Phys Med Rehabil. 2018. 
15. 
Song Y, Keatley LR, Middleton PG. Methicillin-resistant Staphylococcus aureus in health-care 
workers with cystic fibrosis in Sydney. Respirol Case Rep. 2018;6(9):e00378. 
16. 
Kratz AL, Sander AM, Brickell TA, Lange RT, Carlozzi NE. Traumatic brain injury caregivers: A 
qualitative analysis of spouse and parent perspectives on quality of life. Neuropsychol Rehabil. 
2017;27(1):16-37. 
17. 
Sander AM, Hanks RA, Ianni PA, et al. Sociocultural factors influencing caregiver appraisals 
following traumatic brain injury. Arch Phys Med Rehab. 2018. 
18. 
Carlozzi NE, Kallen MA, Brickell TA, et al. Measuring emotional suppression in caregivers of 
adults with traumatic brain injury. Rehabil Psychol. 2019. 
19. 
Sander AM, Boileau NR, Hanks RA, Tulsky DS, Carlozzi NE. Emotional Suppression and 
Hypervigilance in Military Caregivers: Relationship to Negative and Positive Affect. J Head 
Trauma Rehabil. 2020;35(1):E10-E20. 
20. 
Carlozzi NE, Lange RT, Kallen MA, et al. Assessing vigilance in caregivers after traumatic brain 
injury: TBI-CareQOL Caregiver Vigilance. Rehabil Psychol. 2020. 
21. 
Carlozzi NE, Lange RT, French LM, et al. TBI-CareQOL military health care frustration in 
caregivers of service members/veterans with traumatic brain injury. Rehabil Psychol. 2020. 
22. 
Carlozzi NE, Lange RT, Boileau NR, et al. TBI-CareQOL family disruption: Family disruption in 
caregivers of persons with TBI. Rehabil Psychol. 2019. 
23. 
Carlozzi NE, Boileau NR, Kallen MA, et al. Reliability and validity data to support the clinical 
utility of the Traumatic Brain Injury Caregiver Quality of Life (TBI-CareQOL). Rehabil Psychol. 
2019. 
24. 
Hanks RA, Boileau NR, Norman AL, Nakase-Richardson R, Mariouw KH, Carlozzi NE. Spirituality 
and outcomes in caregivers of persons with traumatic brain injury (TBI). Rehabil Psychol. 2020. 
25. 
Brickell TA, Cotner BA, French LM, et al. Severity of military traumatic brain injury influences 
caregiver health-related quality of life. Rehabil Psychol. 2020. 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
39 
 
26. 
Kratz AL, Boileau NR, Sander AM, et al. Do emotional distress and functional problems in 
persons with traumatic brain injury contribute to perceived sleep-related impairment in 
caregivers? Rehabil Psychol. 2020. 
27. 
Raad JH, Tulsky D, Lange RT, et al. Establishing the Factor Structure of a Health-Related Quality 
of Life Measurement System for Caregivers of Persons Living with Traumatic Brain Injury. Arch 
Phys Med Rehabil. 2020. 
28. 
Carlozzi NE, Boileau NR, Hanks RA, Sander AM, Nakase-Richardson R, Massengale JP. Sleep 
impairment is related to health-related quality of life among caregivers of lower-functioning 
traumatic brain injury survivors. Rehabil Psychol. In Press. 
29. 
Kalmbach DA, Fang Y, Arbedt JT, et al. Effects of Sleep, Physical Activity, and Shift Work on Daily 
Mood: a Prospective Mobile Monitoring Study of Medical Interns. J Gen Intern Med. 
2018;33(6):914-920. 
30. 
Nahum-Shani I, Smith SN, Spring BJ, et al. Just-in-Time Adaptive Interventions (JITAIs) in Mobile 
Health: Key Components and Design Principles for Ongoing Health Behavior Support. Ann Behav 
Med. 2018;52(6):446-462. 
31. 
Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis. Vol 998. Boston, MA: John 
Wiley & Sons; 2012. 
32. 
Powell JM, Fraser R, Brockway JA, Temkin N, Bell KR. A Telehealth Approach to Caregiver Self-
Management Following Traumatic Brain Injury: A Randomized Controlled Trial. J Head Trauma 
Rehabil. 2016;31(3):180-190. 
33. 
Holmen H, Torbjornsen A, Wahl AK, et al. A Mobile Health Intervention for Self-Management 
and Lifestyle Change for Persons With Type 2 Diabetes, Part 2: One-Year Results From the 
Norwegian Randomized Controlled Trial RENEWING HEALTH. JMIR Mhealth Uhealth. 
2014;2(4):e57. 
34. 
Whitehead L, Seaton P. The Effectiveness of Self-Management Mobile Phone and Tablet Apps in 
Long-term Condition Management: A Systematic Review. Journal of medical Internet research. 
2016;18(5):e97. 
35. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: Updated guidelines for reporting 
parallel group randomised trials. J Pharmacol Pharmacother. 2010;1(2):100-107. 
 
 
 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
40 
 
12 APPENDIX 1: MULTI-SITE RESEARCH REPORTING PLAN 
 
REPORTABLE WITHIN 7 DAYS 
The following types of events must be reported to the lead site (University of Michigan) study team 
within 7 calendar days of becoming aware of the event. 
 
Unanticipated Problems Involving Risks to Human Subjects or Others: an actual incident, experience, 
or outcome that warrant consideration of substantive changes in the research protocol or informed 
consent process/document or other corrective actions in order to protect the safety, welfare, or rights 
of subjects or others. The following criteria must be met: 
 
1. 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied 
2. 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); 
3. 
Suggests that the research places subject(s) or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Non-compliance: The failure of a person or organization to act in accordance with the requirements of a 
law, regulation, policy, or the requirements and/or determination of an IRB. Major protocol deviations 
that may adversely impact safety of participants, or impact integrity/validity of the data are considered 
non-compliance (such as dosage errors/intervention errors, consent process deviations, deliberate 
procedural deviations, and accidental procedural deviations) 
 
Continuing non-compliance: Noncompliance that recurs after an investigator has been notified of a 
similar or related noncompliance concern pertaining to one or more protocols. 
 
Serious non-compliance: Non-compliance that, in the judgment of the IRB, materially increases the risks 
or causes substantive harm to research participants or materially compromises the rights or welfare of 
participants including consideration of the following: 
 
1. 
Harm to participants; 
2. 
Exposure of participants to a significant risk of substantive harm; 
3. 
Compromised privacy and confidentiality of participants; 
4. 
Willful or knowing research misconduct on the part of the investigator; 
5. 
A violation of ethical principles for human research; or 
6. 
Damage caused to the scientific integrity of the data collected. 
 
Complaints: Complaints from any individual related to participant safety, study conduct, or study 
related materials. 
 
Accident/Incident: Accidents/Incidents involving participants, their data, biospecimens or facilities 
associated with the research (e.g., breach of confidentiality, loss of research data or biospecimens). 

Improving Outcomes for Care Partners with Persons w/ TBI 
 
Version 4.0  
Protocol HUM000181282 
 
15 Feb2023 
NIH Behavioral and Social Intervention Clinical Trial Protocol Template v3.0 - 20180827 
 
 
41 
 
 
Subject Incarceration: Incarceration of a participant when the research was not previously approved for 
the enrollment of prisoners under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
 
Oversight Reports: Reports of internal or external audits; study holds or suspensions that are not built 
into the study design and affect the local site only. Reports of monitoring (such as Data Safety 
Monitoring) outcomes that have concerns of subject safety or suggested revision of study materials. 
 
Subject Withdrawal: Withdrawal due to safety reasons. 
 
Pertinent publication/public announcement: Information affecting the risk/benefit ration of the study 
or information affecting subjects’ willingness to participate in the research. 
 
IRB Approval Lapse: Report of any study activity during the lapse in approval (this can happen if a site 
does not get information to lead site in time for the submission of the continuing review). 
 
REPORTABLE AT CONTINUING REVIEW 
The following types of events must be reported to the lead site (University of Michigan) study team at 
the next scheduled continuing review. 
 
Site Status Reports: Site enrollment closed and/or completed interaction/intervention notifications 
without safety or regulatory concerns. 
 
Subject Withdrawal: Withdrawal of a subject due to PI discretion, subject discretion/request or other 
reasons, such as meeting protocol stopping rules.