Cognitive Training Video Game to Target Subclinical Depressive Symptoms in Youth
Phase: NA
Conditions: Depression, Subclinical Depressive Symptoms
Sponsor: University of Michigan

 
 
 
 
 
Cognitive Training Video Game to Target Subclinical  
Depressive Symptoms in Youth 
 
Protocol Number*: HUM00227345 
 
National Clinical Trial (NCT) Identified Number: NCT05697627  
 
Principal Investigator*: Hannah Becker, M.S. 
 
Sponsor: University of Michigan Medical School 
 
Grant Title: PsychTank Seeds of Change Award 
 
Grant Number*: G028070 
 
Funded by: Eisenberg Family Depression Center, University of Michigan 
 
Version Number:  v2.2 
 
8 October 2024 
 
 

 
 
NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
award terms.  
  
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345 
 
08 October 2024 
 
NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
Table of Contents 
STATEMENT OF COMPLIANCE .............................................................................................. 1 
INVESTIGATOR’S SIGNATURE ............................................................................................... 2 
1 
PROTOCOL SUMMARY .................................................................................................. 3 
1.1 
Synopsis ..................................................................................................................... 3 
1.2 
Schema ...................................................................................................................... 4 
1.3 
Schedule of Activities ............................................................................................... 5 
2 
INTRODUCTION ............................................................................................................... 6 
2.1 
Study Rationale ......................................................................................................... 6 
2.2 
Background ................................................................................................................ 6 
2.3 
Risk/Benefit Assessment ......................................................................................... 7 
2.3.1 
Known Potential Risks ............................................................................. 8 
2.3.2 
Known Potential Benefits ........................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ....................................... 9 
3 
OBJECTIVES AND ENDPOINTS ................................................................................... 9 
4 
STUDY DESIGN .............................................................................................................. 10 
4.1 
Overall Design ......................................................................................................... 10 
4.2 
Scientific Rationale for Study Design .................................................................. 10 
4.3 
Justification for Intervention .................................................................................. 11 
4.4 
End-of-Study Definition .......................................................................................... 11 
5 
STUDY POPULATION .................................................................................................... 12 
5.1 
Inclusion Criteria ..................................................................................................... 12 
5.2 
Exclusion Criteria .................................................................................................... 12 
5.3 
Lifestyle Considerations......................................................................................... 12 
5.4 
Screen Failures ....................................................................................................... 12 
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 
6.1.1 
Study Intervention or Experimental Manipulation Description ........ 14 
6.1.2 
Administration and/or Dosing ............................................................... 14 
6.2 
Fidelity ...................................................................................................................... 15 
6.2.1 
Interventionist Training and Tracking .................................................. 15 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................... 15 
6.4 
Study Intervention/Experimental Manipulation Adherence .............................. 15 
6.5 
Concomitant Therapy ............................................................................................. 16 
6.5.1 
Rescue Therapy ..................................................................................... 16 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL .......... 16 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation .................. 16 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................... 16 
7.3 
Lost to Follow-Up .................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 17 
8.1 
Endpoint and Other Non-Safety Assessments .................................................. 17 
8.2 
Safety Assessments ............................................................................................... 19 
8.3 
Adverse Events and Serious Adverse Events ................................................... 20 
8.3.1 
Definition of Adverse Events ................................................................ 20 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345 
 
08 October 2024 
 
NIH Protocol Template for Behavioral and Social Sciences Research Involving Humans 
8.3.2 
Definition of Serious Adverse Events .................................................. 20 
8.3.3 
Classification of an Adverse Event ...................................................... 20 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up
 
21 
8.3.5 
Adverse Event Reporting ...................................................................... 22 
8.3.6 
Serious Adverse Event Reporting ....................................................... 22 
8.3.7 
Reporting Events to Participants ......................................................... 23 
8.3.8 
Events of Special Interest ..................................................................... 23 
8.3.9 
Reporting of Pregnancy......................................................................... 23 
8.4 
Unanticipated Problems......................................................................................... 23 
8.4.1 
Definition of Unanticipated Problems .................................................. 23 
8.4.2 
Unanticipated Problems Reporting ...................................................... 23 
8.4.3 
Reporting Unanticipated Problems to Participants ........................... 24 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 24 
9.1 
Statistical Hypotheses ............................................................................................ 24 
9.2 
Sample Size Determination................................................................................... 24 
9.3 
Populations for Analyses ....................................................................................... 25 
9.4 
Statistical Analyses................................................................................................. 25 
9.4.1 
General Approach .................................................................................. 25 
9.4.2 
Analysis of the Primary Endpoint(s) .................................................... 25 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................... 25 
9.4.4 
Safety Analyses ...................................................................................... 25 
9.4.5 
Baseline Descriptive Statistics ............................................................. 26 
9.4.6 
Planned Interim Analyses ..................................................................... 26 
9.4.7 
Sub-Group Analyses .............................................................................. 26 
9.4.8 
Tabulation of Individual Participant Data ............................................ 26 
9.4.9 
Exploratory Analyses ............................................................................. 26 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS . 26 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................... 26 
10.1.1 
Informed Consent Process ................................................................... 26 
10.1.2 
Study Discontinuation and Closure ..................................................... 27 
10.1.3 
Confidentiality and Privacy ................................................................... 28 
10.1.4 
Future Use of Stored Specimens and Data ....................................... 29 
10.1.5 
Key Roles and Study Governance ...................................................... 29 
10.1.6 
Safety Oversight ..................................................................................... 29 
10.1.7 
Clinical Monitoring .................................................................................. 30 
10.1.8 
Quality Assurance and Quality Control ............................................... 30 
10.1.9 
Data Handling and Record Keeping .................................................... 30 
10.1.10 
Protocol Deviations ................................................................................ 31 
10.1.11 
Publication and Data Sharing Policy ................................................... 32 
10.1.12 
Conflict of Interest Policy....................................................................... 32 
10.2 
Additional Considerations ...................................................................................... 32 
10.3 
Abbreviations and Special Terms ........................................................................ 32 
10.4 
Protocol Amendment History ................................................................................ 34 
11 
REFERENCES ................................................................................................................. 35 
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
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NIH Protocol Template for Behavioral and Social Sciences Research 
 
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 PIs and all study 
team members who are responsible for study conduct, management, or oversight will complete 
Human Subjects Protection and best practices training. 
 
The protocol, and informed consent and  recruitment materials will be submitted to the IRB for 
review and approval. Approval of both the protocol and the consent materials 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. 
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
        08 October 2024 
 
 
 
 
 
NIH Protocol Template for Behavioral and Social Sciences Research 
 
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, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
 
 
Signed: 
 
 
Date: 
12/1/2022 
 
Name:  Hannah Becker 
 
Title: 
Doctoral Candidate in Clinical Science 
 
Investigator Contact Information 
Affiliation: Department of Psychology, University of Michigan 
Address: 530 Church St. Ann Arbor, MI 48109 
Telephone: 734-764-2580 
Email: hcbecker@umich.edu 
 
 
 
 
 
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Cognitive Training Video Game to Target Subclinical  
Depressive Symptoms in Youth 
Grant Number: 
G028070 
Study Description: 
Youth with subclinical depressive symptoms (9-17) will be recruited to 
complete a cognitive training, video game-based, preventative 
intervention (CCT). Multilevel data (clinical measures of depression and 
anxiety symptoms and behavioral indexes of cognitive control capacity) 
will be collected before and after the intervention, to examine the extent 
to which CCT may reduce symptoms of depression and/or enhance 
cognitive control related behaviors.  
 
Objectives: 
 
Primary Objective: To examine the efficacy of CCT in reducing 
depressive symptoms and improve cognitive control. 
Secondary Objectives: To examine the durability of change in 
depressive symptoms and (if applicable) cognitive control 3-months 
after the CCT intervention. Feasibility Objectives: 1) To assess whether 
participants engage in the intervention as instructed. 2) To assess 
whether participants enjoy engaging in the intervention. 3) To examine 
whether the effects of CBT in the Parent study have been maintained at 
a 2-year follow-up. 
  
Endpoints: 
Primary Endpoints: Depressive symptoms and cognitive control 
behavioral performance after the intervention. Secondary Endpoints: 
Depressive symptoms and cognitive control behavioral performance 3-
months after the intervention. The secondary endpoint was discontinued 
as of protocol version 2.1 (02 April 2024). Feasibility Endpoints: 1) 
Game-play metrics provided by Akili software; 2) ESS scores from each 
assessment; 3) Depressive symptoms at Assessment #1 of current study.   
 
Study Population: 
Anxious youth (AY) with subclinical depressive symptoms between the 
ages of 9 to 17.99 
Phase or Stage: 
N/A  
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Michigan   
Description of Study 
Intervention/Experimental 
Manipulation: 
Participants will be recruited to complete the CCT intervention. 
Participants will be offered a 4-week, web-based cognitive control 
intervention (CCT), which is ~25 minutes a day x 5 days per week.  
Study Duration: 
24 months 
Participant Duration: 
Up to 6 months 
 
 
 
 
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
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NIH Protocol Template for Behavioral and Social Sciences Research 
 
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1.2 
SCHEMA  
 
 
Pre-Screening 
Day -75 to  
Day 1 
 
 
 
Assessment 1  
(Day 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 2 
Day 60±30 
 
 
 
 
 
Assessment 3* 
Day 150±20 
 
 
Total N: 150 
Pre-screen potential participants. Determine list of participants to contact. 
Contact participants and schedule first visit. Participant contact will be 
paused if > 30 participants pass pre-screening and have first visits 
scheduled. After pre-screening is completed, participants will complete the 
informed consent process.  
Perform baseline assessments. If eligible to continue participation in the 
study, participants will continue to the study intervention (enrollment). If 
clinical exclusionary criteria are detected and additional care is requested by 
the participant, a referral for treatment outside of the study will be provided.  
Refer to Section 1.3, Schedule of Activities 
Administer study intervention (5x/week, for ~25 minutes, for 4 weeks)  
Assessment 3* 
Refer to Section 1.3, 
Schedule of Activities 
 EndeavorRx 
N = 20  
Assessment 2: re-assess symptoms and behavior 
*Assessment 3 was optional to participants and then discontinued in protocol version 2.1 (02 April 
2024).  

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
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NIH Protocol Template for Behavioral and Social Sciences Research 
 
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1.3 
SCHEDULE OF ACTIVITIES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*These assessments may be administered more than once if >14 days pass before the cognitive battery 
and cognitive training can be administered. See Section 6.4 for additional details.  
 
**Assessment 3 was optional to participants and then discontinued in protocol version 2.1 (02 April 
2024).  
 
***Provided iPads will be re-collected after Assessment 2. If participants do not have access to a personal 
tablet from which they can complete the tasks from, then they will not complete the Cognitive Battery at 
Assessment 3 (if applicable).   
 
 
 
 
Pre-
screening 
(Pre-consent) 
 
Assessment 
1 
Day 1 
Assessment  
2 
Day 60±30 
Assessment  
3** 
150±20 
Review eligibility with phone screen  
X 
 
 
 
Informed Consent 
 
X 
 
 
Demographics 
 
X 
 
 
Clinical assessment 
 
 
 
 
CBCL 
 
X 
 
 
MASC 
 
X 
X 
X 
CDI  
 
X* 
X 
X 
K-SADS (Clinical report) 
 
X 
 
 
SCARED-P 
 
X 
 
X 
CDSRS 
 
X* 
X 
X 
C-SSRS 
 
X 
 
 
ERQ-CA 
 
X 
X 
X 
Behavioral assessment 
 
 
 
 
Millisecond Inquisit Web Cognitive 
Battery 
 
X 
X 
X*** 
Other assessments 
 
 
 
 
ESS 
 
 
X 
X 
Adherence Metrics from Akili 
 
 
X 
X 
Debrief 
 
 
 
X 
Adverse Events Reporting 
 
X 
X 
X 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
        08 October 2024 
 
 
 
 
 
NIH Protocol Template for Behavioral and Social Sciences Research 
 
6 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Rates of depression in children and adolescents are substantial (Basta et al., 2022), and prevalence is 
steadily increasing (Hawes et al., 2021). Challenges to the treatment of depressive disorders in youth 
include a dearth of trained providers, treatment cost, and imperfect treatment response with ~30%-60% 
failing to respond to gold standard treatments (TADS, 2004). These daunting challenges necessitate the 
development of preventative interventions to reduce subclinical depressive symptoms in children and 
adolescents before full-blown, clinical depression develops. Given links between depressive symptoms 
and low levels of cognitive control, video-game-based cognitive control training may serve as a low-cost, 
accessible, and suitable strategy for improving emotion regulation, lessening subclinical symptoms, and 
thereby reducing risk for developing clinical depression. The video-game intervention assessed in the 
current study is called EndeavorRx. Cognitive control training through EndeavorRx will target cognitive 
and affective domains, with the goal of improving cognitive control/emotion regulation and thus reducing 
depressive symptoms.  
 
2.2 
BACKGROUND  
2.2.1 SUBCLINICAL DEPRESSION IS PREVALENT IN YOUTH, INCREASES RISK 
FOR FULL DEPRESSIVE DISORDER AND LONG-TERM IMPAIRMENT; 
BETTER INTERVENTIONS ARE NEEDED.  
 
Depressive disorders are extremely common, beginning at peripuberty, with youth who experienced 
anxiety disorders at younger ages at especially high risk for depression in adolescence (Kessler et al., 2001; 
Basta et al., 2022). Despite the large number of youth experiencing these disorders a decade ago (~10% for 
depression and ~30% for anxiety; Merikangas et al., 2010), rates of depression and anxiety have continued 
to rise during the course of the COVID-19 pandemic (Hawes et al., 2021). Depression symptoms are often 
evident at young ages, and if left untreated, can lead to significant impairment in social, educational, and 
familial domains (e.g., school dropout, unemployment, social isolation, and suicide; Rapaport et al., 2005). 
Further, having symptoms of these disorders increases risk for developing additional psychopathology later 
in life. Despite treatments that exist to reduce symptoms of depression in youth, such as CBT, many children 
are left without care. Hospitals and clinics are overwhelmed with demand, and treatments like CBT are 
resource-intensive, putting a significant time-burden on patients, their families, and the clinicians (Rasing 
et al., 2017). There are not enough providers or resources to reach all the children and adolescents with 
depression and/or anxiety, even when considering that many youth and their families will not to seek 
treatment in the first place (Planey et al., 2019; Reinert et al., 2021). Moreover, once a depressive disorder 
sets in, full remission following treatment is difficult to achieve, and as many as ~30-60% continue to 
experience clinically significant symptoms even after receiving treatment (TADS, 2004).  
Prior research on youth depression has focused mostly on patients with diagnosed, clinical depression. 
However, depressive symptoms also exist at the subclinical level. For instance, estimates indicate that more 
than 20% of adolescents experience subclinical depressive symptoms (Wickrama et al., 2009); these youth 
have symptoms of depression but do not meet the diagnostic criteria that would indicate a full clinical 
diagnosis. Although youth who are suffering from subclinical symptoms are often absent from published 
prevalence estimates of depression, their impact on society and the healthcare system is hardly invisible. A 
recent study in Dutch youth found that the associated costs of subclinical depressive symptoms in 
adolescents in the Netherlands was equivalent to about $235 million annually (Bodden et al., 2022). In 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
        08 October 2024 
 
 
 
 
 
NIH Protocol Template for Behavioral and Social Sciences Research 
 
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addition to the impairment associated with subclinical depressive symptoms on their own, research has 
noted that subclinical depressive symptoms predict the onset of clinical depression (Cuijpers et al., 2014; 
Garber & Weersing, 2010). Having an anxiety disorder diagnosis is also a risk factor for developing clinical 
depression; these disorders are highly comorbid, though anxiety typically occurs prior to the development 
of depression (Kalin, 2021). To prevent the development of clinical depression in children and adolescents, 
depressive symptoms should be intervened upon at the subclinical level. However, in order to be effective, 
the preventative intervention needs to be accessible, low-cost, and feasible without the use of clinician 
resources.   
2.2.2 SYMPTOMS OF DEPRESISON AND ANXIETY ARE ASSOCIATED WITH 
DEFICITS IN COGNITIVE CONTROL.  
 
Cognitive control involves the ability to direct attention towards regulating emotions and behaviors, 
and can be measured by tasks with a high cognitive demand (Joorman & Vanderlind, 2014; Muris et al., 
2008). Accumulating evidence indicates that are there cognitive control behavioral deficits in youth with 
depression and anxiety (Han et al., 2016; Keller et al., 2019; Kertz et al., 2016), a dysfunction that is 
observed at the neurobiological level as well. For example, cognitive control is facilitated by a network of 
regions across superior parietal, lateral, and medial prefrontal cortex, sometimes referred to as the 
frontoparietal network (FPN; Zanto & Gazzaley, 2013). In youth with anxiety, as compared to healthy 
youth, there is hypo-activity of the FPN during cognitive control demanding tasks (Fitzgerald et al., 2013). 
Additionally, a meta-analysis of studies assessing major depressive disorder identified hypo-connectivity 
of the FPN as compared to healthy individuals (Kaiser et al., 2015). One model of depression in youth 
postulates that lower cognitive control capacity confers risk for developing depression; when challenging 
life events occur, those with lower cognitive control capacity are less able to implement effective emotional 
regulation, leading to worse symptoms (Joorman & Vanderlind, 2014; Tajik-Parvinchi et al., 2020). Despite 
evidence that targeting cognitive control might improve outcomes for youth with depression (Han et al., 
2016), no preventative interventions for subclinical depression have been developed  that specifically target 
cognitive control. The current project will assess a novel, low-cost and accessible preventative intervention 
that trains cognitive control, with the goal of reducing subclinical depression symptoms.   
2.2.3 A VIDEO GAME (ENDEAVORRX) MIGHT IMPROVE COGNITIVE CONTROL 
AND THEREFORE REDUCE DEPRESSIVE SYMPTOMS 
 
The intervention used in the current study is EndeavorRx, a video game that has been demonstrated to 
improve cognitive control in youth (Kollins et al., 2020). EndeavorRx is designed specifically to improve 
attention and cognitive control and is FDA approved to support the treatment of Attention-
Deficit/Hyperactivity Disorder (ADHD; Davis et al., 2018; Kollins et al., 2020). In studies of ADHD-
affected youth, the benefits of EndeavorRx on cognitive control appear to be maintained over time. 
Specifically, following EndeavorRx training, ADHD symptom reduction is maintained over a three year 
span (Jurigova et al., 2021). Though untested in youth with subclinical depressive symptoms, a recent study 
found that EndeavorRx led to improvements in cognitive control in adults with clinical depression (Keefe 
et al., 2022). Based on this convergence of evidence, we hypothesize that EndeavorRx will increase 
cognitive control and thereby reduce depressive symptoms in subclinically-affected youth. This hypothesis 
is further supported by preliminary work from our research group which demonstrated that an interactive-
play cognitive training intervention in anxious preschoolers improved cognitive control and reduced anxiety 
symptoms (Schroder et al., 2022), which commonly precede depressive symptoms at later ages. 
 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
        08 October 2024 
 
 
 
 
 
NIH Protocol Template for Behavioral and Social Sciences Research 
 
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2.3 
RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
 
1)  Risk of boredom or fatigue (likely). Participants may become tired or bored during the intervention, 
assessments, and computerized cognitive testing. 
To minimize risk: Participants will be allowed breaks in between testing sections and game-play is 
completed for no more than 25 minutes/day. 
2) Loss of confidentiality around sensitive information (rare). 
To minimize risk: All subjects are assigned research numbers, and all research information collected 
is linked to the subject only by this number. Great care is taken to remove all identifying information 
from research records. A single tracking file contains links to the research records and subject codes. 
Recruitment tracking files are kept only for the duration of recruitment. Any paper records are kept 
in locked file drawers in a locked room, to which only authorized research personnel have access. 
Any paper records with identifying information (consent form, payment records) are kept in locked 
file cabinets, physically separate from the research records. Computer records with identifying 
information are kept on secure, password protected servers. Staff members are trained to 
scrupulously protect the confidentiality of sensitive information, and take care to limit the printing of 
documents with identifying information and to avoid unnecessary discussion of subject names. 
Screening forms for subjects who do not qualify for the study will be destroyed, except for 
anonymous information unlinkable to the subjects (such as age, gender, and education). 
However, if a subject may become eligible in the near future, e.g. they need to wait 1 month after a 
recent medication change, we will retain certain records so as not to repeat the assessments, with the 
assent of the potential participant. 
3)  Worsening of depressive symptoms, including suicidal thoughts plans, intentions or behaviors. 
Depressive symptoms may worsen during the course of the participation in the study, including the 
emergence of suicidality. During the screening period in Assessment 1, suicidal thoughts, plans, 
intentions and behaviors will be assessed with the Columbia-Suicide Severity Rating Scale – Screen 
Version (C-SSRS). If assessment uncovers suicidal plans or intentions or recent behaviors, 
emergency evaluation will occur, and an appropriate plan of action will be followed, e.g. safety plan 
will be created and referral to psychiatric emergency room. Subjects will not continue to be enrolled 
in the study if any items on the C-SSRS are endorsed during the screening period of Assessment 1. 
Therefore, any potential participant with suicidal thoughts or behaviors will be excluded from the 
study. Suicidal thoughts will also be assessed after the 4-week intervention and (if applicable) at a 3-
month follow up through items on the CDI and CDSRS. If these items are endorsed, then evaluation 
will occur, followed by an appropriate plan of action (as stated above). If symptoms worsen during 
the course of participation, but not to the level of suicidal thoughts, plans, intentions or behaviors, 
the participant may be withdrawn (see 7.1 below). 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
For all participants, there is a potential benefit from the CCT intervention. For those who may have 
previously received CBT, there is an added potential benefit from the effect of combined therapy and 
cognitive control training (CCT). It is also possible that participants may not derive any direct benefit from 
participating in the study. Please refer to section 2.2.3 for additional information about potential benefit 
from the CCT intervention.  

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
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NIH Protocol Template for Behavioral and Social Sciences Research 
 
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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The risks associated with this study are no greater than those associated with usual clinical management of 
subclinical depression and anxiety in children and adolescents. The proposed experiment could reveal 
important information about the nature of mental processes involved in the pathophysiology of subclinical 
depression and anxiety. It is expected that this information may indirectly lead to the development of better 
forms of preventative intervention for depression and for treatment for anxiety and/or depression. There is 
no other, safer or less-invasive means of answering the questions posed by the experiment described above. 
Strategy has been made to minimize each risk, respectively.  
 
3 
OBJECTIVES AND ENDPOINTS  
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary 
 
 
 
To examine the efficacy of 
CCT in reducing depressive 
and anxiety symptoms and 
improve cognitive control. 
 
Depressive 
symptoms and 
cognitive control 
behavioral 
performance after 
the intervention.  
We anticipate that CCT 
will result in increased 
cognitive control 
capacity, which will also 
relate to reductions in 
depressive symptoms.  
Enhanced cognitive 
control ability (as 
trained with CCT) will 
improve the ability to 
regulate symptoms, 
thus lowering 
symptoms and 
reducing risk of 
developing full 
disorder.  
Secondary* 
 
 
 
 To examine the durability of 
change in depressive 
symptoms and cognitive 
control 3-months after the 
CCT intervention. 
 
 
 
 
 
 
*Secondary endpoint was optional to 
participants and then discontinued after 
protocol version 2.1 (02 April 2024).  
 
Depressive 
symptoms and 
cognitive control 
capacity 3-months 
post-intervention. 
We anticipate that 
depressive symptoms 
will be reduced, and 
cognitive control 
enhanced, to a greater 
extent 3-months post-
intervention as compared 
to immediately post-
intervention. 
 
 
Changes in cognitive 
control that may also 
support a reduction in 
depressive symptoms 
may have solidified 
over 3-months and 
therefore become 
detectible in self-report 
and clinician-
administered 
assessments.  
 
 
Feasibility/Acceptability and 
Experimental Outcomes 
 
 
 
1) To assess whether 
participants engage in the 
intervention as instructed. 
1) Game-play 
metrics provided 
by Akili software; 
2) ESS scores from 
1) We anticipate that 
participants will play the 
game as instructed, 2) 
that they will have 
Prior studies of 
EndeavorRx have 
demonstrated the 
feasibility and 

Video Game to Target Subclinical Depressive Symptoms in Youth                            Version 2.2  
Protocol #: HUM00227345  
 
 
 
 
 
        08 October 2024 
 
 
 
 
 
NIH Protocol Template for Behavioral and Social Sciences Research 
 
10 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
2) To assess whether 
participants enjoy engaging in 
the intervention. 
3) To examine whether the 
effects of CBT in the Parent 
study have been maintained 
at a 2-year follow-up. 
each post-
intervention 
assessment;  
3) Depressive 
symptoms at 
Assessment #1 of 
current study   
favorable emotions 
associated with game 
play and, 3) that 
depressive symptoms 
will still be reduced from 
the original baseline 
assessment, but that they 
will be greater than they 
were immediately after 
intervention in the Parent 
study. 
acceptability of the 
intervention. Also, that 
treatment for anxiety 
disorders in the Parent 
study should also 
reduce co-morbid 
depressive symptoms, 
and that this reduction 
should be maintained 
over time.  
 
 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
We hypothesized that cognitive training EndeavorRx may augment cognitive control and reduce 
depressive symptoms. In this study, youth with subclinical depressive symptoms (ages 9 to 17) will be 
recruited to complete the CCT intervention for 4-weeks. Before and after the intervention, all participants 
will complete semi-structured clinical assessment of depressive symptoms and a computerized evaluation 
of cognitive control capacity (e.g., Millisecond Inquisit Web Cognitive Battery; Zelazo, Anderson, Richler, 
Wallner-Allen, and Beaumont, 2013) 
Recruitment will leverage a well-characterized sample from a recently completed study (“Parent 
study”; HUM00118950) of clinically significant anxiety, a known risk factor for emergence of later 
depressive symptoms in the subclinical-to-clinical range. In the Parent study, 148 youths (7-17 years) 
with impairing anxiety were recruited and randomized 2:1 to receive 12-week CBT or a non-active 
control therapy, “relaxation and mentorship therapy” (RMT); behavioral, neurobiological (fMRI), and 
clinical measures were collected before and after treatment. Additional participants may need to be 
recruited beyond the “Parent study” sample (for reasons such as: slow recruitment from “Parent study” or 
not enough participants from “Parent study” meeting enrollment criteria).  
Up to thirty subjects from the Parent study will be recruited to complete the EndeavorRx intervention.  
The intervention will be played at home for ~25 min/day), 5x per week, for 4 weeks. Designed as an 
exciting, youth-friendly computer game, EndeavorRx engages and trains cognitive control across 
component processes of attention, response inhibition, shifting and working memory. Of note, EndeavorRx 
game difficulty is titrated to individual performance, and thus age; the increasing difficulty helps to reduce 
participant boredom and progressively train cognitive control. Adherence to prescribed training will be 
monitored using an Akili-provided dashboard, available to the research study team, that interfaces real-time 
as participants access EndeavorRx via their iPads. If there is no game play for ≥48 hours, a parent will be 
contacted in order to ensure compliance with the intervention. 
If the Parent study does not yield sufficient participation, then we will recruit through the community 
using the social media campaign strategies that have proven effective in our past work, including 
UMHealthResearch. The proposed study will add up to three additional timepoints of assessment (pre-
intervention, post-intervention, and (if applicable) 3-months post-intervention. All study activities will be 
completely remotely via an encrypted HIPAA-compliant video conferencing platform (e.g., Zoom), phone 

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call, and/or Qualtrics links. Depressive symptoms, anxiety symptoms, general psychopathology, and 
cognitive control behavior as  indexed by a Millisecond Inquisit Web Cognitive Battery will be assessed 
pre-intervention. After the intervention, the same symptoms and cognitive control behavioral will be 
assessed. These variables will optionally be assessed again 3-months post intervention.  
Data analyses will compare pre- and post-CCT data. Additionally, multilevel models will assess change 
in depressive symptoms and cognitive control over time and comparing between those who received CBT 
as compared to those who received RMT in the Parent study. These data will include Millisecond measures 
of behavioral capacity for cognitive control and detailed assessment of depressive and anxiety symptoms 
using both clinician-interview and self-report. Pre- to post-CCT change in depressive symptom severity 
(clinician-measured) will serve as the primary outcome variable.  
 
At protocol version 2.1 (02 April 2024), Assessment #3 (3-month follow-up) was removed to increase 
feasibility so that resources could focused on increased recruitment. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We hypothesize that CCT will improve cognitive control capacity and thereby reduce depressive 
symptoms post-intervention and (if applicable) after a 3-month period post intervention. Therefore, we 
will enroll youth with subclinical depressive symptoms to complete the CCT intervention and measuring 
their cognitive control capacity and clinical symptomology after the intervention.  
 
The aims of this project are to: 
1. Examine whether CCT will reduce depressive and anxiety symptoms and improve cognitive 
control after the 4-week intervention.  
2. If applicable, examine whether the effects of CCT change in a 3-month period after the CCT 
intervention. 
3. Examine the feasibility and accessibility of the CCT intervention. 
4. If applicable, examine whether the effects of cognitive behavioral therapy (CBT) in a previous 
intervention and protocol have been maintained at a 2-year follow-up.  
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
The CCT intervention will consist 4-weeks of video game play (for 25 minutes/day, 5 
days/week).The EndeavorRx video game is designed to target focused attention, response inhibition, 
working memory and multiple simultaneous attention to constitute a general executive function training, 
and activate neural systems associated with executive function/cognitive control. All video game play will 
be done remotely, at-home, via iPad. iPads will have EndeavorRx preloaded or downloaded onto a personal 
iPad, which participants will access through a unique username and password. Difficulty of the games will 
be titrated individually and by session to avoid boredom and progressively activate the functional systems 
underlying cognitive control, which we hypothesize will subsequently reduce depressive symptoms. Prior 
clinical trials have administered EndeavorRx for this duration and frequency (4 weeks, 25 minutes/day, 5 
days/week) in youth (Kollins et al., 2020).  
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the baseline 
assessment, at least 4 weeks of CCT intervention, Millisecond battery, post-intervention assessment, and 

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the final assessment. If a participant completes all these activities but not the final, optional (3-month post-
intervention) assessment, then they will, at PI discretion, still be considered to have completed the study. 
In other words, if a participant does not to participate in Assessment #3, they will still be considered to have 
completed the study. At protocol version 2.1 (02 April 2024), Assessment #3 (3-month follow-up) was 
removed altogether. 
 
 
5 
STUDY POPULATION 
  
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet the following criteria: 
1. Parent or guardian willing to give informed consent, and children willing to give informed assent 
to participate in the study. 
2. Males and females (age 9 – 17.99) 
3. Participant is willing to engage in a technology-based intervention (technology will be provided 
to participants who live in the state of Michigan, if not already accessible to participant). 
4. Self-reported depressive symptoms (CDI score between 3-19 at Assessment 1) 
5. Participants will be required to maintain a stable dose of medications for 4 weeks prior to the first 
assessment and stable medication throughout the intervention period. Participants may change 
medication after completion of the post-intervention assessment (i.e. in between the post-
intervention assessment and follow-up assessment).  
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
An individual who meets the following criteria will be excluded from participation in this study: 
1. Color blindness 
2. Unable to play the video game for any reason 
3. K-SADS diagnosis of clinical depression, psychosis, or Autism Spectrum Disorder 
4. Has enrolled in new psychotherapy (for the treatment of a mood or anxiety disorder) or had changes 
to their psychotherapy in the 4-weeks prior to study enrollment  
5. Endorses items #1, #2, #3, #4, #5. #6 on the C-SSRS Screener (Past-Month); i.e., has present 
suicidal intention/behavior. 
6. Has had any changes to their medication in the 4-weeks prior to study enrollment 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Participants must maintain stable doses of any medication throughout participation in this study. Initiation 
of new medications, or substantial changes in dosage of current medications, prior to the end of the study, 
may be requested by the patient. In this event, the patient will be withdrawn from the study and referred to 
clinical care.   
 
5.4 
SCREEN FAILURES 
 

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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. Individuals who do not meet the criteria for 
participation in this trial (screen failure) because of meeting one or more exclusion criteria that are likely 
to change over time may be rescreened. Rescreened participants will be assigned the same participant 
number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment will be mostly from participants who had already enrolled in the Parent study and who, at 
the time of enrollment in the parent study, had consented to be re-contacted for research purposes. All 
participants will be contacted via phone call or email and asked if they are interested in hearing about 
another research study involving a preventative intervention. If they are, we will conduct our phone screen 
to determine initial eligibility and whether they should be scheduled for a consent visit. After the original 
contact, we may also reach out to parents via text message (using a prepared and approved message 
template) to direct their attention to their voicemail or email, and request to schedule a phone screen. Parents 
of potential participants will be contacted from the sample of eligible participants of the Parent study until 
target enrollment of the current protocol is reached. If it is decided to recruit from outside of the Parent 
study, those new participants will be not be contacted via text message to complete the phone screen, as we 
will not have access to their contact information at that time. Only participants from the Parent study (who 
had consented to be re-contacted originally) will be contacted via text message).  
 Participants from the Parent study were initially recruited to the Parent study from outpatient 
psychiatry programs at the University of Michigan Health System, from multi-media advertisements 
(UMClinicalStudies.org, passive advertisements on social media sites and Craigslist Ann Arbor, Google 
Adword campaigns, print and electronic media, radio ads and flyers) and by referral from community 
clinicians. Participants from the Parent study can be enrolled in the current protocol if they previously 
endorsed elevated depressive symptoms during the Parent study and do not possess any of the exclusionary 
criteria.  Initial screening will occur in a telephone interview. Participants can enroll in the study from 
anywhere in the United States, as all aspects of the study protocol will be completed remotely. Based on 
the demographic characteristics of the sample with elevated depressive symptoms (CDI T-scores > 50) 
from in the Parent study, we anticipate that the sample of the current protocol will be primarily composed 
of youth that identify as female (90%) and are Caucasian (75%). 
If needed to reach recruitment goals, new participants may be recruited through multi-media 
advertisements (UMHealthResearch.org, passive advertisements on social media sites, print and 
electronic media, and flyers). If additional recruitment is conducted, recruitment of male youth and youth 
from unrepresented racial and ethnic groups will be prioritized. Additionally, recruitment outside of the 
Parent study will be restricted to potential participants who live in the state of Michigan, in order to 
ensure that an iPad can be provided to participants (via drop-off, pickup, or mail delivery) if they do not 
already have access to one. Interested participants (i.e., as indicated on UMHealthResearch) will fill out 
several pre-screen eligibility questions on UMHealthResearch. If eligible based on these pre-screening 
questions, participants will be contacted via phone or email to complete the phone screen.  
Minimizing the potential for coercion of patients to participate: Because members of the research team are 
involved in clinical care and research, there is the potential that some patients of the study team may be 
recruited.  It will be made clear to all potential subjects that participation is entirely optional and not a part 
of regular treatment.  The bulk of the recruitment process will occur with the study coordinator, who does 
not treat patients in any of the clinical venues where recruitment will occur. Overall, the research team is 
experienced in clinical research and very mindful of the conflict between the dual roles of clinician and 
researcher.  They firmly believe that the safety and desires of the patient take precedence over any research 
protocol, and work hard to assure their patients that research participation is not required for treatment.  In 

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the case where a patient of a study team member is recruited, the consent process and signature on the 
informed consent document and will be obtained by the study coordinator. 
 
Payment of participants 
 
In the current protocol, participants will receive the following payments: 
1. After completing Assessment #1 (including semi-structured interview, Millisecond battery, and 
self-report clinical measures), participants will earn $50. If participants screen out during 
Assessment 1, participants will receive up to $50 for their participation (according to the time spent 
completing the assessment; up to 2 hrs ($25), up to 4 hours (the full $50). 
2. After completing one half of the CCT training (2 weeks), participants will earn an additional $25.  
3. Once the full training has been completed (4 weeks of at least 80% compliance), participants will 
earn another $25. 
4. *After completing Assessment #2, participants will earn another $25.  
5. **For those who have completed Assessment #3 3-months post-intervention, participants earn an 
additional $25.  
 
Therefore, if all three assessments are completed in addition to the full EndeavorRx intervention, each 
participant will receive a total of $150. All participants will have the opportunity to earn the same amount 
of compensation (if completed Assessment #3). Incentives are structured to promote retention of 
participants throughout the full intervention period, as well as for Assessment #3 (if applicable). Payment 
for all enrolled participants will be made in up to two payments: at payment step #4* and again at 
payment step #5**, if all activities completed. If participants screen out during Assessment 1, they will be 
provided payment after screening out. The participant will receive the incentive directly. If a participant 
withdraws from the study or does not complete certain parts of the study, payment will be distributed for 
the amount earned at the point of study discontinuation. If a participant does not complete at least 2 weeks 
of the CCT intervention, they will not complete the post-intervention assessments.   
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY 
INTERVENTION(S) 
OR 
EXPERIMENTAL 
MANIPULATION(S) 
ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
The EndeavorRx video game is a digital therapeutic designed to improve attention and related cognitive 
control processes by training interference management. The video game design displays two tasks that are 
to be completed in parallel, which requires multitasking and thus cognitive control. Task performance is 
assessed during single and interference (multitask) conditions. Difficulty of the game is titrated, in real 
time, to adapt to the individual’s performance. The game-player makes progress by earning rewards and 
thus unlocking new environments. Periodic recalibration occurs throughout gameplay to maintain an 
optimal difficulty level. This feature of the game helps to avoid participant boredom and progressively 
activate the functional systems underlying cognitive control. EndeavorRx is similar to other cognitive 
training intervention games used in prior research and are well-tolerated by participants of varying ages 
(Keefe et al., 2022).   
6.1.2 ADMINISTRATION AND/OR DOSING 

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Computerized cognitive training: The CCT intervention will consist of ~25 minutes of EndeavorRx video 
gameplay per day (at any time of the day), for 5 days/week, for 4 weeks. This is the duration of gameplay 
used in prior studies of the EndeavorRx game (Kollins et al., 2020) and the dose suggested by Akili 
Interactive. Participants will be instructed to try not to play the game for more than 30 minutes a day, though 
time of gameplay will be monitored directly by the research team using Akili software. If participants are 
playing the video game too much, or for not enough time, parents will be contacted via email. The video 
game is designed to improve attention and engage cognitive control. Gameplay sessions will be completed 
at home. Participants will complete CCT on an iPad provided by the research team, or they may complete 
CCT by downloading the Akili Interactive application onto their own Akili-compatible personal device. 
 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
An evaluator will assess the patients with the scales described below. The assessments will be completed 
via Zoom.  
 
To ensure that there is consistency across participants in understanding of gameplay instructions, 
participants will be instructed to play the CCT intervention for about 5 minutes while the coordinator 
monitors the session over Zoom. The research coordinator will then be able to answer any questions that 
the participant might have about game instructions. All participants will also be provided with the same 
instruction manual.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
There is no randomization in this pilot study.  
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Tolerability and compliance with the intervention will also be assessed. The CCT application will 
measure the amount of time each day that the child spends playing the video game. Additionally, 
completion of self-report questionnaires and Millisecond assessments will be tracked to ensure that these 
assessments are completed within the specified time period. If the cognitive task battery and start of the 
cognitive training intervention are not completed within sufficient time of the baseline clinical and self-
report assessment (i.e., within 14 days of completing the CDI; due to scheduling and/or equipment 
constraints), then the CDI and CDRS-R will be re-administered prior to initiating the cognitive task 
battery and cognitive training.  
 
Assessments will include (refer to 1.3 Schedule of Activities for a list of which measures are completed at 
each assessment): 
 
Assessments by Clinician 
a) C-SRSS 
b) CDRS-R 
c) K-SADS 

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Assessments Completed by Subjects  
a) MASC  
b) CDI 
c) SCARED (parent)  
d) CBCL (parent) 
e) ERQ-CA 
 
Other Assessments  
a)  ESS (parent and child) 
 
 
6.5 
CONCOMITANT THERAPY 
 
Participants can remain on medication throughout the duration of the study, so long as a stable 
dose was maintained at least 4 weeks prior to study enrollment, and that this dose in maintained 
throughout the study’s duration. Participants will be excused from the study if they decide to seek 
new therapy or medication during the course of the study.   
6.5.1 RESCUE THERAPY 
  
If a participant’s depression symptoms worsen over the duration of the study (as measured at Assessment 
#2 or spontaneously reported), the participant will be referred to receive therapy. Please refer to section 
2.1.3 for additional details on the safety procedure if depressive symptoms worsen.  
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION 
OF 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
 
When a subject discontinues from CCT but not from the study, remaining study procedures will be 
completed as indicated by the study protocol.  If a clinically significant finding is identified (including, but 
not limited to changes from baseline) after enrollment, the investigator or qualified designee will determine 
if any change in participant management is needed.  
 
Discontinuation of study for a given participant will occur in the event of any of the following: 
• 
Suicidal thoughts with specific plans and intentions (Endorse item 9 the CDI) 
• 
The participant is hospitalized for any psychiatric symptoms 
• 
A participant reports symptom worsening:  > 25% increased CDI score (referenced to baseline)  
 
Reasons for discontinuation will be documented, and all outcome assessments will proceed as scheduled, 
if possible. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 

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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: 
 
• 
Significant study intervention non-compliance, such as not engaging in the video game intervention 
at all (compliance will be monitored in real-time using Akili software).  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
• 
The study is suspended or canceled 
 
The reason for participant discontinuation or withdrawal from the study will be recorded. Subjects who sign 
the informed consent form but do not receive the study intervention, may be replaced.  Subjects who sign 
the informed consent form and receive the study intervention, and subsequently withdraw, or are 
discontinued from the study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled visit and study 
staff are unable to contact the participant after at least 3 attempts for each visit.  
 
The following actions must be taken if a participant fails to for a required study visit: 
• 
The site will attempt to contact the participant via email to the parent and/or phone call to parent, 
reschedule the missed visit within two weeks, counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort 
to regain contact with the participant (where possible, 3 telephone calls or emails). These contact 
attempts will be documented in the participant’s study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Participants will complete questionnaires in order to collect basic health and demographics information.  
The initial assessment is completed as part of the parent study and will occur during Visit 1 (or the day 
prior for the Qualtrics questionnaires). Data collected from this assessment will be used for analysis for this 
protocol. The following evaluations and assessment tools (or subsets of questions from these measures) 
may be used to determine eligibility for the study and gather baseline information:    
 
1) 
Demographics and medical history form.  An in-house form for basic demographic 
information, medical and family history completed by study team or as self-report. 

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2) 
Child Behavior Checklist (CBCL; Achenbach and Rescorla 2001). A 126-item parent-
completed checklist which provides DSM-IV oriented subscales for Depressive Problems, 
Anxiety Problems and Attention Deficit/Hyperactivity Problems (Inattention and 
Hyperactivity/Impulsivity subscales).  Approximately 10 minutes. 
3) 
Screen for Child Anxiety Related Disorders (SCARED Parent Version): Developed by Boris 
Birmaher, M.D., Suneeta Khetarpal, M.D., Marlane Cully, M.Ed., David Brent, M.D., and 
Sandra McKenzie, Ph.D., Western Psychiatric Institute and Clinic, University of Pittsburgh 
(October, 1995). The SCARED consists of 41 items and 5 factors that parallel the DSM-IV 
classification of anxiety disorders. 
4) 
Multidimensional Anxiety Scale for Children (MASC); (March, Parker et al. 1997). Self-report 
assessing anxiety. Approximately 10-15 minutes. 
5) 
Children’s Depression Inventory (CDI); (Kovacs, 1992). Self-report, 27 item scale on 
depressive symptoms. Approximately 5 minutes. 
6) 
Columbia Suicide Severity Rating Scale, Screen Version - Recent (Posner, Oquendo et al. 
2007).  A clinician-rated scale assessing suicidal ideation and behavior. Approximately 5 min.  
7) 
Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS); (Kaufman, Birmaher 
et al., 1997). Standard assessment tool to obtain a diagnosis, may include parent interview.  
Approximately 3-4 hours. 
8) 
Children’s Depression Rating Scale, Revised (CDRS-R); (Poznanski & Mokros, 1996). A 
clinician-administered semistructured interview to assess depression symptoms in children and 
adolescents. Can be used to monitor intervention response as it captures slight changes in 
symptoms. Approximately 15-20 minutes.  
9) 
Endeavor Satisfaction Survey (ESS; Subject, may be completed before and after CCT 
intervention) – A 5-item scale rating the participant’s and participant guardian’s feelings of 
satisfaction with the video game and its effect on participant’s symptoms – approximately 1 
minute.  
10) 
Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CA) – (Gullone & 
Taffe, 2012). A 10-item self-report questionnaire to assess emotion regulation (subcomponents 
of reappraisal and suppression) in children and adolescents. Approximately 5 minutes.  
 
 
Electronic data capture:   
Subjects will complete the self-report forms described above using Qualtrics.  Qualtrics is an Application 
Service Provider (ASP) with a Software-as-a-Service (SaaS) platform for creating and distributing online 
surveys and related research services. The platform records response data, performs analysis, and reports 
on the data. All services are online and require no download software; only modern JavaScript-enabled 
browsers are required (no Java/JVM or Flash). Surveys are usually taken online within a web browser, with 
optional SMS surveys and offline methods available for smartphones/tablets. Qualtrics has been approved 
for the University of Michigan research community, and individual investigators access the web interface 
through a University of Michigan Qualtrics portal. Subjects will receive a coded link via email which will 
take them to the required surveys. The emailed link contains no identifiable information about the subjects, 
and once activated, establishes an https encrypted link with the Qualtrics server. Once completed, each 
survey is locked so that re-access is not permitted. We can also adapt the process for each subject, e.g. 
provide access on computers or tablets in the Department of Psychiatry for subjects who do wish or cannot 
use email. Some subjects may request paper, and, if so, paper forms will be provided. 
Subjects will be asked to complete the consent form online (provided through a secure web-link sent via 
email) via SignNow prior to their initial evaluation. A copy of the consent will be emailed to the subject. 
Data will be downloaded from Qualtrics and stored on protected computers to be used for analysis.  

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Responses entered by subjects will be available to the clinicians working with the subjects in the study. 
Please note that the suicide assessment rating (C-SSRS) is administered at the screening evaluation in 
Assessment 1. Thus, any potentially dangerous clinical condition will be identified prior to further 
enrollment in the study and the participant will not continue with the current protocol or start the 
intervention. If suicidal ideation is endorsed at any point on self-report measure of CDI, this will be flagged 
in Qualtrics and a member of the study team will act accordingly on this information and in a timely fashion. 
Additionally, language is provided at the top of every Qualtrics page assessing clinical symptomology (from 
parent- or child-report) in which the child or parent is notified that survey responses may not be read 
immediately by study staff and that the child or parent should contact emergency services (with numbers 
provided) if the parent or child is worried about the current safety of the child.  
EXPERIMENTAL NEUROCOGNITIVE TASKS  
 
During the first, second, and third visit, participants may be asked to complete a Millisecond Inquisit Web 
Cognitive Battery. 
 
• 
Millisecond Inquisit Web cognitive battery of assessments will be administered electronically 
using an iPad, and will be completed before and after the CCT intervention, and (if applicable) 
again 3-months after the intervention. Tasks may include Flanker inhibitory control and attention 
task, Game of Dice task, Little Man Test (mental rotation), Emotional Stroop task, BIRD task 
(distress tolerance), and Delay Discounting task; these tasks are not specifically trained in CCT to 
ensure that we measure transfer of training to general cognitive control capacity, rather than 
practice effect on specific tasks. Composite scores may be used to index cognitive control 
capacity. All cognitive tasks were developed by the Adolescent Brain Cognitive Development 
(ABCD) Research Consortium will be completed using the Inquisit Web platform 
(https://www.millisecond.com/). 
 
8.2 
SAFETY ASSESSMENTS 
 
Safety assessments include the following: 
• 
Columbia Suicide Severity Rating Scale (C-SSRS), Screen Version - Recent (Posner, Oquendo 
et al. 2007).  A clinician-rated scale assessing suicidal ideation and behavior.  
• 
Child Depression Inventory (CDI). A self-report assessment to rate the severity of depression 
symptoms in children. Total scores on this measure range from 0 to 54. Symptom worsening:  > 
25% increased CDI score (referenced to baseline).  
 
Any safety-related assessments (C-SSRS administered at Assessment #1) or primary outcome measure 
(CDI at Assessments #1 or #2) that are missed will be reported to the IRB as a protocol deviation. We 
will accept a window of ± 1 week. However, for the other assessments, missing or late assessments will 
not be reported as protocol deviations unless they constitute > 50% of the total assessments. These 
allowances should affect neither the scientific integrity nor the safety monitoring provisions of the 
protocol. 
All SAEs will be: 
• 
recorded on the appropriate SAE Report Form  
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician. 

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The study will comply with IRB reporting requirements and guidelines for SAEs. 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered intervention-
related. 
Any unfavorable or unintended symptom, sign, or disease associated with a medical treatment or procedure 
that may or may not be related to the treatment or procedure. Adverse events can be related to the 
intervention or to the symptoms that the intervention is intended to act on (e.g. subclinical depressive 
symptoms), or to another disorder (e.g. Anxiety), or they could be entirely unrelated to any of these (e.g., 
motor vehicle accident). 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
An SAE is defined as an AE that meets one of the following conditions: 
• 
Death during the period of protocol-defined surveillance 
• 
Life-threatening event (defined as a subject at immediate risk of death at the time of the event) 
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization during the 
period of protocol defined surveillance  
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse/overdose or cancer. 
 
All SAEs will be: 
• 
recorded on the appropriate SAE Report Form  
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician 
 
The study will comply with IRB reporting requirements and guidelines for SAEs. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 

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For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, 
the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 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 clinician based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below.  
• 
Definitely/Probably Related – There is evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal laboratory 
test result, occurs in a plausible time relationship to study procedures administration and is unlikely 
to be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of 
the study procedures should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other factors 
may have contributed to the event (e.g., the participant’s clinical condition, other concomitant 
events). Although an AE may rate only as “possibly related” soon after discovery, it can be flagged 
as requiring more information and later be upgraded to “probably related” or “definitely related”, 
as appropriate. 
• 
Unlikely to be related/Not related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study procedures administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the study 
procedures) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). Or, the AE is 
completely independent of study procedures administration. 
 
8.3.3.3 EXPECTEDNESS  
 
A clinician with appropriate expertise in treating youth anxiety and depression will be responsible for 
determining whether an adverse event (AE) is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study procedures, as outlined in this document, the consent materials and 
documents related to the video game and its use.  
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW -
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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make a 
decision), and time of resolution/stabilization of the event. All AEs occurring while on study will be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution, such 
that the participant has been offered or received necessary care. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
A study team member will record events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. 
Participants and/or their parent can spontaneously notify the investigator of an AE or health status change 
via phone call or email, if necessary, in between scheduled visits. Events will be followed for outcome 
information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
The occurrence of an AE may come to the attention of study personnel during study visits. At each visit, 
subjects will be questioned about putative AEs. Information to be collected includes event description, time 
of onset, clinician’s assessment of severity (mild, moderate, or severe), relationship to study (assessed by 
the study PI and clinical team), expected versus unexpected, local versus systemic, and time of 
resolution/stabilization of the event. All AEs occurring while in the study will be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. Adverse event reporting will 
occur on the standard IRBMED timetable. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
N/A 
 

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8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
N/A 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
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)-
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 participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
The investigator will report an other reportable incident or occurrence (ORIO) to the reviewing Institutional 
Review Board (IRB). The ORIO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an ORIO 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the ORIO 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   

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• 
ORIOs that are serious adverse events (SAEs) will be reported to the IRB and to the study 
sponsor/funding agency within 7 calendar days of the investigator becoming aware of the event  
• 
Any other ORIO will be reported to the IRB within 7 calendar days of the investigator becoming 
aware of the problem  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Endpoint:  
We hypothesize that CCT will increase cognitive control capacity (Millisecond battery composite score 
and individual cognitive test scores) and reduce depressive symptoms (CDI and CDRS-R scores) over 
the 4 week period of the intervention. Specifically, we hypothesize that CCT will improve cognitive 
control which will in turn improve depressive symptoms as a consequence of enhanced emotional 
regulation. Alternatively, our null hypothesis is that there will be no difference in cognitive control 
capacity or depressive symptoms immediately post-intervention as compared to pre-intervention.  
 
Secondary Endpoint*: 
We hypothesize that CCT will further increase cognitive control capacity (measured by Millisecond 
battery composite score and individual cognitive test scores) and reduce depressive symptoms (as 
measured by CDI and CDRS-R) further 3-months post-intervention than immediately after the 
intervention. The null hypothesis is that there is no difference in cognitive control capacity or depressive 
symptoms from immediately post-intervention to 3-months after the intervention.  
*Secondary endpoint was optional to participants and then discontinued after protocol version 2.1 (02 April 2024).  
 
Feasibility/Acceptability and Experimental Endpoints:  
1. We hypothesize that the majority of participants will complete the intervention with at least 80% 
compliance.  
2. We hypothesize that participants will have favorable emotions associated with game play.  
3. We hypothesize that depressive symptoms will be reduced from the baseline assessment of the 
Parent study but that they will be slightly elevated from the post-intervention assessment in the 
Parent study.   
 
The statistical tests used to test these hypotheses will be outlined later in this protocol and registered with 
clinicaltrials.gov. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Sample size was determined based on results from a power analysis and feasibility of participant 
recruitment. A sample size of 32 participants would yield 80% power for the planned analyses in the current 
study, but 30 participants is a more achievable initial target for recruitment. Though there is minimal data 

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to generate hypothesized effect sizes, the proposed study will allow for generations of effect sizes to be 
used in future, larger studies.  
 
9.3 
POPULATIONS FOR ANALYSES 
 
Complete-Case Analysis Population: This population will consist of enrolled participants without missing 
data on variables of interest from Assessment #2. 
 
Per-Protocol Analysis Dataset: This population will consist of participants who complete all four weeks of 
the intervention (with at least 80% compliance to the guidelines of 25 minutes/day for 5 days a week across 
the 4 weeks. Compliance of 80% can be achieved by completing at least 20 minutes of gameplay on 80% 
of the days that they could play the game in the 4 week period, if assuming a 5-day week. For instance, 
assuming that a participant would complete at least 20 minutes of gameplay for 20 days during the 4 week 
period, a participant with 80% compliance would engage in at least 20 minutes of gameplay for at least 16 
days during this period. Compliance will be assessed using gameplay metrics provided by Akili that are 
automatically measured when the game is played on a participant’s device.  
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
Data will be analyzed using statistics software such as SPSS and R software. For descriptive statistics, 
means with standard deviation and range will be computed for continuous data (all behavioral data and 
some of the clinical data). In general, statistical significance is reported based on p < 0.05 two-tailed. 
Missing data from Assessment 3 (if applicable) will be handled using pairwise deletion. Missing data from 
Assessment 1 or 2 will be handled using listwise deletion.  
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
We hypothesize that CCT will increase cognitive control capacity and reduce depressive symptoms. The 
hypothesis will be tested using paired samples (repeated measures) t-tests (pre vs. post) for each dependent 
variable (CDI score and Millisecond battery composite score). Both of these dependent variables are 
interval variables. 
Standard deviations and effect sizes will be assessed for each of these analyses. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)* 
 
We hypothesize that CCT will further increase cognitive control capacity (measured by Millisecond battery 
composite scores) and further reduce depressive symptoms (as measured by CDI and CDRS-R) 3-months 
post-intervention than immediately after the intervention. This hypothesis will be tested using repeated-
measures ANOVAs, with three timepoints (pre-intervention, immediately post-intervention, and 3-months 
post intervention), on behavioral performance (cognitive control capacity) and depressive symptoms.  
 
Standard deviations and effect sizes will be assessed for each of these analyses. 
*Secondary endpoint was optional to participants and then discontinued after protocol version 2.1 (02 April 2024).  
9.4.4 SAFETY ANALYSES 

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N/A 
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
N/A 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
At Time 2, after the completion of the CCT intervention, CDI scores will be evaluated across all 
participants. If scores are significantly worse at Time 2 than at Time 1 (a significantly higher average CDI 
score across participants), then the study may be halted. Similarly, if greater than one third of the 
participants (~7 subjects) withdraw from the study due to symptoms, then the study may be halted. If there 
is no change, or an improvement in CDI scores (lower CDI scores), then the study will continue as planned. 
This interim analysis will be conducted with the intention of maintaining safety of participants, rather than 
for assessing the efficacy of the intervention. 
 
9.4.7 SUB-GROUP ANALYSES 
 
The sample included in this pilot study will not be large enough to conduct subgroup analyses based on sex 
or race/ethnicity. However, if applicable, in the secondary endpoint models, age and sex may be included 
as covariates. The current analyses will assess the efficacy of the study intervention in youth only (ages 9-
17).  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
All clinical and behavioral measures will be listed by timepoint when applicable.  
 
9.4.9 EXPLORATORY ANALYSES 
 
Linear regression models will be built to test whether change in cognitive control indices (behavioral 
performance on Millisecond battery) will associate with change on clinical outcomes (CDI or CDRS-R 
scores). The standardized parameter estimates in each model will be examined.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 

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Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and electronic documentation of informed consent will be completed prior to starting the study 
intervention.  The following consent materials are submitted to IRBMED with this protocol: Assent Form 
and a Parent-only Consent Form to accompany the child Assent Form.  
  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
The protocol will begin by having the subject (or their parent[s]/guardian[s] for adolescent subjects) provide 
assent and informed consent. Informed consent will be obtained at the beginning of a remote visit. This 
remote visit will include a review of an oral assent script, assent from the minor subject, and signed 
electronic consent from their parent/guardian. Electronic informed consent signatures will be collected 
using SignNow. All procedures will adhere to the IRBMED Guidance for use of SignNow for Electronic 
Informed Consent Procedures. Informed consent is a process that is initiated prior to the individual’s 
agreeing to participate in the study and continues throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of this intervention will be provided to the subject/parents. Consent 
forms (written in non-technical language, understandable by the youngest subject to be enrolled in the 
study) describing in detail the study interventions/products, study procedures, and risks will be given to the 
subject/parent.  Participants may also be presented with a visual timeline of the tasks that may be involved 
in participating in this study, during the consenting process or at another time during the study, to aid their 
understanding of the process. Upon reviewing the document, one of the investigators (or their designee) 
will explain the research study to the subject/parent and answer any questions that may arise.  
All youth subjects will be given an assent form and/or will be read an assent script by study staff. The parent 
will sign the parental informed consent document prior to any procedures being done specifically for the 
study, besides the prescreen questions on UMHealthResearch and/or initial phone screen, which is 
conducted with the parent. Youth subjects will be asked to sign in the assent box on the assent form written 
in language that is developmentally appropriate for their understanding of study participation, along with 
parent signature on the parental consent form. Children under age 10 (age 9) will be read an assent script 
by study staff and will not have to sign the document, but to verbally give assent and study staff will indicate 
their assent and sign the document. If the child wishes to sign, they may do so. For all subjects, parents will 
sign a separate parent consent form. All subjects or their parents may withdraw consent at any time 
throughout the course of the trial. A copy of the parental informed consent and child assent documents will 
be given to the subjects for their records. 
The subjects may withdraw consent at any time throughout the course of the trial.  The rights and welfare 
of the subjects will be protected by emphasizing that the quality of their medical care will not be adversely 
affected if they decline to participate in this study.  NOTE: older teens may become legal adults (i.e., reach 
the age of 18 years) during the course of the study.  If the teen is still actively involved in the study (i.e., 
data collection ongoing), then a new consent form, signed by the teen, will be obtained.  However, if the 
teen reaches 18 years of age after their data collection has been completed, we will not re-contact to re-
consent.  This approach is intended to avoid burdening study participants and their parents.   
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Reasons for discontinuation will be document, and all outcome assessments will proceed as scheduled, if 
possible. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 

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inform study participants, the Institutional Review Board (IRB), and sponsor/funding agency and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension of CCT include, but are not limited to: 
• 
Hospitalization required for any psychiatric symptoms 
• 
Suicide behaviors during the study period (assessed by CDI and CDSRS post-intervention) 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Data that are not sufficiently complete and/or evaluable 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency and IRB.  
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by investigator, research staff, and the 
sponsor(s) and funding agency. This confidentiality is extended to the data being collected as part of this 
study. Data that could be used to identify a specific study participant will be held in strict confidence within 
the research team. No personally-identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency.  
 
All research activities will be conducted virtually, but in as private a setting as possible, so that participants 
feel comfortable to share details about their symptoms to the assessing clinician.  
 
Other authorized representatives of the sponsor or funding agency, representatives of the Institutional 
Review Board (IRB), or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The research team will permit access to such records. 
 
The study participant’s contact information will be securely stored for internal use during the study. At the 
end of the study, all records will continue to be kept in a secure location for as long a period as dictated by 
the reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
All paper and computer research records will be identified by subject ID number rather than name or other 
personally identifying information.  Paper records are stored in a double-locked environment to which only 
authorized study team members have access. The link between subject ID and subject name will be kept 
within a secure study folder (only primary research team members have access; requires Level-2 Login) 
that can only be accessed on computers that are password protected. Consent documents and any other 
forms with identifying information will be maintained separately from research data files (identified by 
subject ID only). 
 
The assessments in this protocol will ask participants about sensitive topics, such as mental illness and 
substance use. We will inform the consenting parents of minor participants at the beginning of the process 
that we will respect the confidentiality of all participants.  It is important for us to let participants know that 
they can be honest about sensitive topics without fear of reprisal from their parents.  However, all 
participants will also be informed about limits to confidentiality.  If we learn that a subject has potential to 
harm him or herself, or another individual, we will break confidentiality and take steps to prevent harm.  
Similarly, any evidence of potential child abuse will be reported to Child Protective Services.  If we become 

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aware of imminent risk of harm to a parent, steps will be taken to ensure safety (e.g. referral to psychiatric 
emergency services or contacting appropriate authorities).  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
The value of this research is significantly enhanced by making the data available for the widest possible 
use, and because of the rapidly changing world of data analysis, it is impossible to predict what future 
research will do with data collected for any particular project in the present.  By keeping the data 
indefinitely, it will become available for projects, yet to be determined.  These include projects run by the 
investigators, as well as those outside the institution through data sharing plans or central repositories.   
When data are transferred to co-investigators, de-identification will be performed, removing all HIPAA 
identifiers from the files. 
Subjects will be informed in the consent document that the data will be stored and that it may be shared 
with other investigators, both at the University and outside the University.  The risk posed to subjects will 
be very, very small.  Storing the data for an indefinite amount of time will follow strict protocols, outlined 
above, that will ensure the safety of the data and minimize the risk of accidental disclosure.  Data that is 
shared will be de-identified and will be effectively anonymized, since investigators using the shared data 
will not have access to the keys linking individual subjects to the data. It is extremely unlikely that an 
investigator would even be able identify subjects from shared data, without already having access to a 
subject’s identifiers.   
If subjects object to data sharing, they have the option of not participating in the research.  Although our 
project does provide a potential direct benefit in the form of CCT intervention, this intervention is readily 
available outside of the research protocol. 
In some cases, participants may either be ineligible for the current protocol or be eligible for an additional 
study protocol. In these cases, if participant has indicated in the consent that they would like to be contacted 
for future studies, we will share their contact information with other research teams at the University of 
Michigan for screening purposes, and if eligible, can share some of our data with these investigators to 
assist in their screening and assessment process (per consent form). 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Hannah Becker, M.S., Doctoral Candidate 
Department of Psychology, University of Michigan  
530 Church St, Ann Arbor, MI 48109 
hcbecker@umich.edu 
 
10.1.6 SAFETY OVERSIGHT 
 
The investigator and members of active study team will meet biweekly (as close to that as permitted by 
travel and holidays) to monitor the study activities in order to ensure that the human subject protection, 

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study procedures, administration, and data collection processes are of high quality and meet the appropriate, 
regulatory guidelines.  No regular monitoring by an external monitor is planned. 
 
10.1.7 CLINICAL MONITORING 
 
No additional monitoring is required – the nature and size of this study does not require additional safety 
monitoring to that provided by the IRB. However, participant well-being will be monitored at both of the 
assessments (self-report but also clinical assessments with trained clinician). The study team will check for 
worsening depressive symptoms after the assessment for each participant. Video game play will also be 
monitored by the study team so that families can be contacted if any concern for well-being is implicated 
(i.e., not playing enough or playing the video game with extremely high intensity/frequency). The study 
team will also regularly monitor clinical self-report assessments in Qualtrics (at least 1x/week) to identify 
whether any safety items have been flagged in Qualtrics (Qualtrics will be set up to flag certain self-report 
items if endorsed).   
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well as 
a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy site staff will compare a representative sample of source data against the 
database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related sites, 
source data/documents, and reports for the purpose of monitoring and auditing by the sponsor/funding 
agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 

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Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data.    
 
For the assessments, subjects will enter information directly onto a computer or electronic device. This data 
will be stored within Qualtrics, Data recorded in the electronic case report form (eCRF) derived from source 
documents will be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Michigan Medicine servers in Qualtrics and/or 
statistical datasets.  Clinical data will be entered directly from the source documents. Research data will be 
maintained on password protected computers, on a secure linux cluster maintained in the Psychiatry 
Affective Neuroimaging Laboratory (PANLab) or on secure UMHS-administered servers.  
10.1.9.2 STUDY RECORDS RETENTION  
 
Files will be stored in a double-locked environment and access-limited under the purview of the PI. All 
research records will be identified by subject ID; pre-screening records will be scrubbed of identifiers and 
date shifted to preserve confidentiality.  
 
Study database records will be identified by subject ID, and the link between identifiers and subject ID will 
be maintained by the PI and study coordinator within the protected study folder. The file with this link will 
be destroyed after publication of the primary outcomes manuscript. When the PI has completed their 
training locally (by May 2026), all paper files will be destroyed. Electronic database records will be 
maintained by members of the research study team that remain at the University.  
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions will be developed by the site and implemented promptly.  
 
These practices are consistent with: 
• 
Section 10.1.1: Informed consent procedures 
• 
Section 10.1.3: Confidentiality and privacy 
• 
Section 10.1.4: Future data use and data storing 
• 
Section 10.1.6: Safety oversight 
• 
Section 10.1.8: Quality control 
• 
Section 10.1.9: Data handling 
 

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It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations.   All deviations will be addressed in study source documents and will be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator will be responsible for knowing 
and adhering to the reviewing IRB requirements.  
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Considerations for ensuring confidentiality of these shared data are described in Section 10.1.3. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
CBCL 
Child Behavior Checklist 
CBT 
Cognitive Behavior Therapy 
CCT 
Cognitive Control Training 
CDI 
Children’s Depression Inventory 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CFR 
Code of Federal Regulations 
COC 
Certificate of Confidentiality 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
ERQ-CA 
Emotion Regulation Questionnaire for Children and Adolescents 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  

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IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat  
K-SADS 
Kiddie Schedule for Affective Disorders and Schizophrenia 
MASC  
Multidimensional Anxiety Scale for Children 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
ORIO 
Other Reportable Information or Occurrence  
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
ESS 
Endeavor Satisfaction Survey 
SAP 
Statistical Analysis Plan 
SCARED-P Screen for Child Anxiety Related Disorders 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
US 
United States 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.8 
10/16/23 
Consent process changes 
In response to ORIO 
1.9 
12/11/23 
Additional detail added about 
recruitment outside of parent-study 
Need to recruit outside parent-
study; want to make sure 
processes are outlied 
2.0 
 
 
 
2.1 
4/02/24 
Removed Assessment #3 
Feasibility of enrollment and to 
shorten overall timeframe of 
study 
2.2 
10/8/24 
Added language to clarify optional 
nature of Assessment #3 
In tandem with ORIO, to 
provide clarity of safety 
assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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