Improving Cognitive Health in COVID-19 Survivors Through Digital Therapeutics
Phase: PHASE2
Conditions: Cognitive Dysfunction, Covid19
Sponsor: Weill Medical College of Cornell University

 
 
  
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IMPROVING COGNITIVE HEALTH IN COVID-19 SURVIVORS 
THROUGH DIGITAL THERAPEUTICS 
 
IRB Protocol #: 20-11022977 
NCT #: NCT04843930 
Version Date: 11/18/2022 
Funding Source(s): Funding and Devices provided by Akili Interactive 
 
 
Principal Investigator: 
 
Name: Faith Gunning, PhD 
Address: 525 E 68th Street, Baker Building F-1341 
Telephone: 212.746.5832 
E-mail address: fgd2002@med.cornell.edu 
 
 
Statistician: 
 
Medical Monitor: 
N/A 
N/A 
 
 
 
Participating Sites:  List all participating sites (include site name, PI, and contact information).  
 
Site Name: Weill Cornell Medicine 
PI: Faith Gunning, PhD  
Address: 525 E 68th Street, Baker Building F-1341 
Telephone: 212.746.5832 
 
E-mail address: fgd2002@med.cornell.edu 
 
 
 

Protocol # 20-11022977 
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Table of Contents 
CONFIDENTIALITY STATEMENT ................................................................................... VII 
LIST OF ABBREVIATIONS ............................................................................................. VIII 
1. PROTOCOL SUMMARY ................................................................................................. 1 
1.1 
Schema ..................................................................................................................... 4 
1.2 
Study Objectives and End Points ......................................................................... 6 
1.2.1  Primary Objectives ........................................................................................... 6 
1.2.2  Secondary Objectives ..................................................................................... 6 
1.2.3  Exploratory Objectives .................................................................................... 6 
1.2.4 
Primary Endpoints ........................................................................................... 7 
1.2.5 
Secondary Endpoints ...................................................................................... 7 
2. BACKGROUND ................................................................................................................ 8 
2.1 
Disease ..................................................................................................................... 8 
2.2 
Investigational Agent/Device, or Surgical Treatment/Method ......................... 8 
2.3 
Rationale ................................................................................................................... 9 
2.4 
 Risk/Benefit Assessment ...................................................................................... 9 
2.4.1 
Known Potential Risks .................................................................................... 9 
2.4.2 
Known Potential Benefits ............................................................................. 10 
2.4.3 
Assessment of Potential Risks and Benefits ............................................. 10 
2.5 
Correlative Studies Background ........................................................................ 11 
3. STUDY DESIGN ............................................................................................................. 11 
3.1 
Overall Design ....................................................................................................... 11 
3.2 
Scientific Rationale for Study Design ................................................................ 13 
3.3 
Justification for Dose ........................................................................................... 13 
3.4 
End of Study Definition ........................................................................................ 13 
4. SUBJECT SELECTION ................................................................................................. 13 
4.1 
Study Population ................................................................................................... 13 
4.2 
Inclusion Criteria ................................................................................................... 13 
4.3 
Exclusion Criteria .................................................................................................. 14 
4.4 
Lifestyle Considerations ...................................................................................... 14 
4.5 
Screen Failures ...................................................................................................... 14 
4.6 
Strategies for Recruitment and Retention ........................................................ 15 
5. REGISTRATION PROCEDURES ................................................................................. 16 
5.1 
Subject Registration (WCM only) ....................................................................... 16 
5.2 Subject Registration (Sub-sites) ............................................................................ 16 
6. STUDY PROCEDURES ................................................................................................. 16 

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6.1 
Schedule of Assessments ................................................................................... 16 
6.1.1 
Screening Visit (-X days before start of treatment) .................................. 17 
6.1.2 
Treatment Phase ............................................................................................ 17 
6.1.2.1 
Visit 1 (baseline; Cycle 1 Day 1) ............................................................... 17 
6.1.2.2 
Visit 2 (± X day(s)) ....................................................................................... 18 
6.1.3 
Follow-up Phase ............................................................................................. 18 
7. STUDY INTERVENTION ............................................................................................... 19 
7.1 
Study Intervention/Device Description .............................................................. 19 
7.2 
Availability .............................................................................................................. 19 
7.3 
Acquisition and Accountability ........................................................................... 19 
7.4 
Formulation, Appearance, Packaging, and Labeling ...................................... 19 
7.5 
Product Storage and Stability ............................................................................. 19 
7.6 
Preparation ............................................................................................................. 19 
7.7 
Dosing and Administration .................................................................................. 19 
7.7.1 
Dosing Delays/Dose Modifications ............................................................. 20 
7.8 
General Concomitant Medication and Supportive Care Guidelines ............. 20 
7.9 
Duration of Therapy and Criteria for Removal from Study ............................. 20 
7.10  Duration of Follow Up ........................................................................................... 20 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................... 20 
7.12 Study Intervention/Follow-up Compliance ......................................................... 21 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................... 21 
8.1 
Discontinuation of Study Intervention ............................................................... 21 
8.2 
Participant Discontinuation/Withdrawal from the Study ................................ 21 
8.3 
Lost to Follow Up .................................................................................................. 22 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................ 22 
9.1 
Laboratory Correlative Studies ........................................................................... 22 
9.1.1 
Title – Laboratory Correlative Study #1 ...................................................... 22 
9.1.1.1 
Collection of Specimen(s) ......................................................................... 22 
9.1.1.2 
Handling of Specimen(s) ........................................................................... 22 
9.1.1.3 
Shipping of Specimen(s) (if multicenter) ................................................ 22 
9.1.1.4 
Site(s) Performing Correlative Study (if multicenter) ............................ 22 
9.2 
Special Studies ...................................................................................................... 22 
9.2.1 
Title – Special Correlative Study #1 ............................................................ 22 
9.2.1.1 
Assessment ................................................................................................. 22 
9.2.1.2 
Method of Assessment .............................................................................. 22 
9.2.1.3 
Timing of Assessment ............................................................................... 22 
10.  MEASUREMENT OF EFFECT ................................................................................... 22 
10.1 Response Criteria ................................................................................................... 23 
10.2 Duration of Response ............................................................................................ 23 

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10.3 Progression-Free Survival .................................................................................... 23 
10.4 Other Response Parameters ................................................................................. 23 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 23 
11.1 Data Collection ........................................................................................................ 23 
11.1.1 REDCap ............................................................................................................. 24 
11.2 Regulatory Considerations ................................................................................... 24 
11.2.1 Institutional Review Board/Ethics Committee Approval ........................... 24 
11.2.2 Ethical Conduct of the Study ......................................................................... 25 
11.2.3 Informed Consent ............................................................................................ 25 
11.2.4 Compliance with Trial Registration and Results Posting Requirements 25 
11.2.5 Record Retention ............................................................................................. 26 
12. STATISTICAL CONSIDERATIONS ............................................................................ 26 
12.1 Study Design/Endpoints ........................................................................................ 26 
12.2 Sample Size/Accrual Rate ..................................................................................... 26 
12.3 Stratification Factors .............................................................................................. 27 
12.4 Analysis of Endpoints ............................................................................................ 27 
12.4.1 
Analysis of Primary Endpoints ................................................................. 27 
12.4.2 
Analysis of Secondary Endpoints ............................................................ 27 
12.5 Interim Analysis ...................................................................................................... 27 
12.6 Reporting and Exclusions ..................................................................................... 27 
12.6.1 
Evaluation of Toxicity ................................................................................ 28 
12.6.2 
Evaluation of Response ............................................................................. 28 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................. 28 
13.1 Adverse Event Definition ....................................................................................... 28 
13.1.1 
Investigational Agent or Device Risks (Expected Adverse Events) ... 28 
13.1.2 
Adverse Event Characteristics and Related Attributions ..................... 28 
13.1.3 
Recording of Adverse Events ................................................................... 29 
13.1.4 
Reporting of AE to WCM IRB .................................................................... 29 
13.1.5 
Reporting Events to Participants ............................................................. 29 
13.1.6 
Events of Special Interest .......................................................................... 29 
13.1.7 
Reporting of Pregnancy ............................................................................. 29 
13.2 Definition of SAE ..................................................................................................... 29 
13.2.1 
Reporting of SAE to IRB ............................................................................ 30 
13.2.2 
Reporting of SAE to FDA [For Protocols Where WCMC is the 
Sponsor-Investigator] ................................................................................................. 30 
13.2.3 
Reporting of SAE to Akili Interactive ....................................................... 30 
13.3 AE/SAE Follow Up .................................................................................................. 30 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............... 30 
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS31 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 

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(UPIRTSO) ........................................................................................................................ 31 
14.1.2 
Unanticipated Problem Reporting ............................................................ 31 
15. DATA AND SAFETY MONITORING PLAN (DSMP) ................................................. 32 
16. REFERENCES ............................................................................................................. 33 
APPENDIX A ...................................................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Statement of Compliance 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), 
and the Akili Interactive Terms and Conditions of Award. The Principal Investigator will assure 
that no deviation from, or changes to the protocol will take place without prior agreement from the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding 
agency and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  All changes to 
the consent form 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. 
 
 

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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required. 
 
 
 
 
 
 
 
 
 
 
Department of Psychiatry, Weill Cornell Medicine 
_________________________________________________________________ 
Institution Name 
 
 
 
 
 
Faith Gunning, PhD
  
 
 
 
 
12/31/2020 
______________________________       _____________________________     ____________ 
Principal Investigator’s Name                 Principal Investigator’s Signature     Date 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
Weill Cornell Medicine 

Protocol # 20-11022977 
Version Date 12/10/20 
 
  
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1. Protocol Summary 
 
Full Title:  
 
 
 
Improving Cognitive Health in COVID-19 Survivors through Digital 
Therapeutics 
Short Title: 
 
 
 
Cognitive Health in COVID-19  
Clinical Phase: 
 
 
II 
Principal Investigator:  
Faith Gunning, PhD 
 
Study Description:   
Emerging evidence suggests a subgroup of survivors of COVID-
19 have residual difficulties with cognition and daily functioning. 
These deficits are pronounced in cognitive domains including 
attention, learning and executive skills, and may continue to 
impact quality of life after recovery from other COVID-19 
symptoms. This study aims to investigate the efficacy of AKL-T01 
(Akili Interactive), a remotely-delivered digital cognitive 
intervention, in targeting and improving cognition and functional 
outcomes in individuals recovering from COVID-19. The efficacy 
of the AKL-T01 intervention will be measured relative to a waitlist 
control group. 
 
Sample Size: 
 
Our target sample size will be 100 COVID-19 survivors, of which 
50 participants will be randomized to the AKL-T01 intervention 
arm and 50 participants will be randomized to a waitlist control 
arm. 
 
Enrollment: 
 
Our total enrollment will be 125, requiring that we screen up to 
500 individuals. We anticipate approximately 75% of individuals 
will not be eligible based on screening criteria. Further we 
anticipate approximately 20% of participants who are eligible will 
elect not to continue participation prior to initiation of intervention.   
 
Study Population: 
 
The study population will be individuals who were diagnosed with 
COVID-19 and have a deficit in cognition (i.e., attention and/or 
executive skills > 1 SD below the normal range). The target age 
range will be adults 18-89 years of age.  
 
Enrollment Period:  
We expect the enrollment period to last 12 months.  
 
Study Design: 
 
This study is a randomized clinical trial designed to compare 
efficacy of the AKL-T01 intervention relative to a waitlist control in 
patients who were infected with COVID-19. Participants will be 
selected for the presence of cognitive dysfunction prior to 
enrollment in the trial and will be randomized to the intervention 
arm or the waitlist control arm. They will complete an assessment 
battery designed to assess cognition, functional outcomes, and 

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mood symptoms at pre-intervention (at study entry) and post-
intervention (following 6 weeks of AKL-T01 or waitlist). The 
assessment battery will also be administered bi-weekly during the 
intervention period (i.e., at weeks 2 and 4), and 4 weeks after the 
end of the intervention period for longitudinal follow-up. We will 
use a waitlist design; at the end of the intervention period, 
participants in the control group will have the option to receive the 
6-week AKL-T01 intervention. Note that study visits will take place 
remotely and devices for intervention administration will be mailed 
to participants. 
Description of Sites/  
Facilities Enrolling 
Participants: 
 
Participants will be enrolled through facilities of the Manhattan 
Campuses of NewYork-Presbyterian Hospital (NYP)/Weill Cornell 
Medicine (WCM), as well as the NewYork-Presbyterian 
Westchester Behavioral Health Center.  
 
Study Duration: 
 
The study duration will be two years, including 12 months to 
recruit, collect data, and conduct data analysis and one additional 
year to publish results of the study. 
 
Participant Duration: 
Participants in the AKL-T01 intervention group will be enrolled in 
this study for approximately 10 weeks, comprised of the 6-week 
intervention period and week 10 longitudinal follow-up (4 weeks 
after completing the intervention). Participants in the waitlist 
control group who choose to begin the intervention after the initial 
6-week period will be enrolled for 16 weeks, comprised of the 6-
week waitlist period, the 6-week intervention, and week 16 
longitudinal follow-up (4 weeks after completing the intervention). 
 
Study Agent/Device Name  
Intervention Description: 
AKL-T01 will be administered as a 6-week intervention. It is an 
algorithmically delivered iPad-based video game designed to 
improve cognitive health by targeting attention and attentional 
control processes. Participants enrolled in the intervention arm will 
play the game via an iPad application for 20-25 minutes daily for 
at least  5 days a week (but up to 7 days a week). Participants will 
also have weekly check-in visits via phone or a secure HIPAA-
compliant videoconferencing platform (Zoom) with a care 
manager, who will monitor mood symptoms and gameplay 
adherence. 
 
Primary Objective: 
The primary objective of this study is to investigate the efficacy of 
the AKL-T01 intervention relative to a waitlist control in improving 

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cognitive functioning in COVID-19 survivors. Our primary measure 
of cognition is performance on a Digit Symbol Matching Task. 
 
Secondary Objectives: 
1) Our main secondary objective is to investigate the efficacy of 
the AKL-T01 intervention relative to a waitlist control in improving 
functional outcomes. The main measure of daily functioning is the 
NeuroQOL Cognitive Function scale. 
 
Additional Secondary Objectives: 
 
2) To examine the effect of cognition across a range of domains, 
including sustained attention, cognitive control, working memory, 
and processing speed. We will assess these cognitive functions 
with a remotely-delivered task battery that includes the following 
tasks: 
• 
Multiple Object Tracking 
• 
Digit Span Backwards 
• 
Simple Reaction Time 
• 
Choice Reaction Time 
• 
Letter-Number Switching 
• 
Gradual Onset Continuous Performance Test 
 
3) To investigate the efficacy of the AKL-T01 intervention relative 
to a waitlist control in improving daily functioning and quality of life, 
as measured by the World Health Organization Disability 
Assessment Schedule Version 2 (WHODAS 2.0). The WHODAS 
2.0 assesses the following domains of functioning that are 
relevant to our post-COVID sample: 
• 
Cognition – understanding & communicating 
• 
Mobility – moving & getting around 
• 
Self-care – hygiene, dressing, eating & staying alone 
• 
Getting along – interacting with other people 
• 
Life activities – domestic responsibilities, leisure, work & 
school 
• 
Participation – joining in community activities 
 
 
Exploratory Objectives: 
1) We will explore long-term change in cognition and daily 
functioning 4 weeks following the end of the intervention. 
 
 
 
2) To investigate improvement in learning and episodic memory, 
as measured by a Visual Paired Associates Task, in the AKL-T01 
intervention relative to a waitlist control. This measure is a 
cognitive domain that is not captured in the primary and 
secondary tasks listed above and will allow for the measurement 
of far transfer to less-related cognitive domains. 
 

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3) To investigate improvement in fatigue, as measured by the 
Modified Fatigue Impact Scale, in the AKL-T01 intervention 
relative to a waitlist control. 
 
 
 
 
 
4) Explore improvement in mood symptoms from pre- to post-
intervention in the AKL-T01 intervention relative to a waitlist 
control. Symptoms of depression will be measured with the 
Patient Health Questionnaire (PHQ-9) and symptoms of anxiety 
will be measured with the Generalized Anxiety Disorder Scale 
(GADS-7). 
 
Primary Endpoints: 
The primary endpoints for our measure of cognitive function is 
mean change from pre-intervention (baseline) to post-intervention 
(week 6) on Digit Symbol Matching Task performance. 
 
 
To assess efficacy of the intervention relative to the wait list 
control, change scores from baseline to week 6 will be calculated 
separately and compared for the AKL-T01 intervention arm and 
the waitlist control arm for the Digit Symbol Matching Task. 
 
Secondary Endpoints: 
1) The main secondary endpoint for our measure of functional 
outcomes is mean change from pre-intervention (baseline) to 
post-intervention (week 6) on the NeuroQOL Cognitive Function 
Scale.  
 
To assess efficacy of the intervention relative to the control, 
change scores from baseline to week 6 will be calculated 
separately and compared for the AKL-T01 intervention arm and 
the waitlist control for the NeuroQOL scale score. 
 
Additional Secondary Endpoints: 
 
2) Secondary endpoints for our measures of cognition is mean 
change in performance from pre-intervention (baseline) to post-
intervention (week 6) on the following tasks: Multiple Object 
Tracking, Digit Span Backwards, Simple Reaction Time, Choice 
Reaction Time, Letter-Number Switching, and Gradual Onset 
Continuous Performance Test, and Visual Paired Associated 
Task. 
 
 
3) Additional secondary endpoints for our measure of daily 
functioning is mean change in WHODAS 2.0 score from pre-
intervention (baseline) to post-intervention (week 6).  

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1.1 Schema 
 
 
Assess Potential Participants According to Inclusion / Exclusion Criteria, 
Screen for Cognitive Deficit, Obtain Informed Consent
Arm 1: AKL-T01 Intervention
N = 50
Arm 2: Waitlist Control
N = 50
Perform Baseline Assessments
See Schedule of Assessments (Section 6.1) for list of visit procedures.
Weekly check-in visits with study therapist, monitoring of mood symptoms.
(Check gameplay adherence – AKL-T01 intervention only.)
Perform Week 6 Assessments
See Schedule of Assessments (Section 6.1) for list of visit procedures.
Pre-
Intervention 
Screening 
Visit
RANDOMIZATION
Pre-
Intervention 
Baseline 
Assessment 
Visit
Weeks 1,3,5:
Weekly 
Intervention 
Visits
Post-
Intervention 
Assessment 
Visit
Weeks 2 & 4: 
Intervention 
Assessment 
Visit
Perform Intermediate Assessments
See Schedule of Assessments (Section 6.1) for list of visit procedures.
Perform Week 10 
Follow-Up Assessments 
(see Section 6.1)
Week 10: 
Longitudinal 
Assessment 
Visit
Cross Over:
Control Arm Offered AKL-T01: 
6 Weeks of Intervention & 
Bi-Weekly Assessments
END OF WAITLIST
Perform Week 10 
Follow-Up (Control 
Participants Who 
Decline Intervention)
Perform Week 16 
Follow-Up (Control 
Participants Who 
Receive Intervention)

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1.2 
Study Objectives and Endpoints 
 
 
 
1.2.1  Primary Objectives  
 
The primary objective of this study is to investigate the efficacy of the AKL-T01 
intervention relative to a waitlist control in improving cognitive functioning in COVID-19 
survivors. Our primary measure of cognition is performance on a Digit Symbol Matching 
Task. 
 
1.2.2  Secondary Objectives  
 
 
1) Our main secondary objective is to investigate the efficacy of the AKL-T01 
intervention relative to a waitlist control in improving functional outcomes. The main 
measure of daily functioning is the NeuroQOL Cognitive Function scale. 
 
 
Additional Secondary Objectives: 
 
2) A secondary objective of the study is to investigate the efficacy of the AKL-T01 
intervention relative to a waitlist control in improving cognition across a range of 
domains, including sustained attention, cognitive control, working memory, and 
processing speed. We will assess these cognitive functions with a remotely-delivered 
task battery that, in addition to our primary Digit Symbol Matching Task, also includes 
the following tasks: 
• 
Multiple Object Tracking 
• 
Digit Span Backwards 
• 
Simple Reaction Time 
• 
Choice Reaction Time 
• 
Letter-Number Switching 
• 
Gradual Onset Continuous Performance Test 
 
3) Another secondary objective of the study is to investigate the efficacy of the AKL-T01 
intervention relative to a waitlist control in improving daily functioning and quality of life, 
as measured by the World Health Organization Disability Assessment Schedule 
(WHODAS). The WHODAS assesses the following domains of functioning that are 
relevant to our post-COVID sample: 
• 
Cognition – understanding & communicating 
• 
Mobility – moving & getting around 
• 
Self-care – hygiene, dressing, eating & staying alone 
• 
Getting along – interacting with other people 
• 
Life activities – domestic responsibilities, leisure, work & school 
• 
Participation – joining in community activities 
 
1.2.3  Exploratory Objectives 
 
 
 
1) We will explore long-term change in cognition and daily functioning 4 weeks following 
the end of the intervention. 
 

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2) An exploratory objective related to cognition is to investigate improvement in learning 
and episodic memory, as measured by a Visual Paired Associates Task, in the AKL-T01 
intervention relative to a waitlist control, in order to evaluate far transfer to untrained 
tasks. 
 
3) An exploratory objective related to functional outcomes is to investigate improvement 
in fatigue, as measured by the Modified Fatigue Impact Scale, in the AKL-T01 
intervention relative to a waitlist control. 
 
 
 
4) We will also explore improvement in mood symptoms from pre- to post-intervention in 
the AKL-T01 intervention relative to a waitlist control. Symptoms of depression will be 
measured with the Patient Health Questionnaire (PHQ-9) and symptoms of anxiety will 
be measured with the Generalized Anxiety Disorder Scale (GADS-7). 
 
 
1.2.4 Primary Endpoints 
 
The primary endpoints for our measure of cognitive function and is mean change from 
pre-intervention (baseline) to post-intervention (week 6) on Digit Symbol Matching Task 
performance. 
 
To assess efficacy of the intervention relative to the control, change scores from 
baseline to week 6 will be calculated separately and compared for the AKL-T01 
intervention arm and the waitlist control arm for the Digit Symbol Matching Task. 
 
1.2.5 Secondary Endpoints 
 
1) The main secondary endpoint for our measure of functional outcomes is mean 
change from pre-intervention (baseline) to post-intervention (week 6) on the NeuroQOL 
Cognitive Function Scale.  
 
To assess efficacy of the intervention relative to the control, change scores from 
baseline to week 6 will be calculated separately and compared for the AKL-T01 
intervention arm and the waitlist control for the NeuroQOL scale score. 
 
Additional Secondary Endpoints: 
 
2) Secondary endpoints for our measures of cognition is mean change in performance 
from pre-intervention (baseline) to post-intervention (week 6) on the following tasks: 
Multiple Object Tracking, Digit Span Backwards, Simple Reaction Time, Choice 
Reaction Time, Letter-Number Switching, and Gradual Onset Continuous Performance 
Test, and Visual Paired Associated Task. 
 
3) The secondary endpoint for our measure of daily functioning is mean change in 
WHODAS 2.0 score from pre-intervention (baseline) to post-intervention (week 6).  
 
1.2.6 
Exploratory Endpoints 
 

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1) Long-term change in cognition and daily functioning 4 weeks following the end of the 
intervention will be assessed by calculating change scores from baseline to week 10 and 
from week 6 to week 10 in our primary and secondary measures of cognitive and daily 
function. 
 
2) To explore improvement in far transfer to an untrained cognitive domain, we will 
calculate mean change in score on the Visual Paired Associates task from pre-
intervention (baseline) to post-intervention (week 6). 
 
3) The exploratory endpoint for our measure of fatigue is mean change in Modified 
Fatigue Impact Scale score from pre-intervention (baseline) to post-intervention (week 
6).  
 
4) The exploratory endpoints for our measure of moody symptoms is mean change in 
PHQ-9 and GADS-7 scores from pre-intervention (baseline) to post-intervention (week 
6).  
 
2. Background 
 
2.1 Disease 
 
Cognitive deficits are frequent, persistent, and disabling following critical illness. They are 
increasingly recognized as a common complication of COVID-19. Multiple factors associated 
with the illness and its treatment may contribute to cognitive sequelae. These include 
hypoxia, ventilation, sedation, delirium, cerebrovascular events, and inflammation. 81% of 
patients had cognitive impairment, ranging from mild to severe. In our preliminary study of 
cognitive impairment in 57 hospitalized patients recovering from COVID-19, deficits were 
most common in working memory (55% of patients impaired), multitasking (47%), divided 
attention (46%), and processing speed (40%) (Jaywant et al., under review); these deficits 
were more common than deficits in memory. An additional study of 29 community-dwelling 
adults in China recovered from COVID-19 found a deficit in sustained attention relative to a 
control group, Thus, the emerging research suggests that aspects of attention and executive 
functions are commonly affected after COVID-19. The time-sensitive need to understand 
and address cognitive deficits early in the disease course is underscored by the surging 
incidence of COVID-19 coupled with the long-term cognitive complications that were 
associated with the coronaviruses that caused the first Severe Acute Respiratory Syndrome 
(SARS) and Middle East Respiratory Syndrome (MERS). Further, cognitive dysfunction is a 
known predictor of long-term functional disability. 
 
2.2 Investigational Agent/Device, or Surgical Treatment/Method 
 
The study intervention, AKL-T01 (Akili Interactive) is a digital intervention. The intervention 
was designed to target and improve cognition through a fun and engaging video game 
played on an iPad. Its efficacy has been demonstrated in individuals across the lifespan with 
mental health disorders that commonly have symptoms of cognitive dysfunction, such as 
depression and ADHD. AKL-T01 recently received FDA clearance for the improvement of 
attention in children with ADHD (Kollins et al., 2020). Further, our group has shown that this 
video game intervention is non-inferior to gold standard psychotherapy in improving 
cognition and symptoms of depression (Anguera et al., 2017) and improves cognitive control 
at the neural, behavioral, and self-report levels (Gunning et al., under review). 

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The AKL-T01 intervention specifically targets attention and attentional control, two key 
executive skills that we expect to demonstrate deficits in our sample of individuals previously 
diagnosed with COVID-19 (Jaywant et al., under review). The video game combines aspects 
of navigation and target identification. It uses an innovative algorithmic design that adjusts to 
individuals’ ability levels, such that the complexity and cognitive load increases as the game 
progresses in an optimized and personalized fashion. 
 
2.3 Rationale 
 
Emerging evidence suggests a subgroup of survivors of COVID-19 have residual difficulties 
with cognition and daily functioning. These deficits are pronounced in cognitive domains 
including attention, learning and executive skills, and may continue to impact quality of life 
after recovery from other COVID-19 symptoms (Jaywant et al., under review). Thus, there is 
an urgent need to investigate the efficacy of potentially beneficial cognitive interventions 
such as AKL-T01 (primary objective of the study) that can be widely disseminated. The 
telehealth, iPad-based nature of AKL-T01 is critical in mitigating the spread of infection 
during the ongoing COVID-19 pandemic and in the potential for eventually scaling and 
disseminating the intervention broadly.  
 
Whether or not the potential benefit of AKL-T01 can persist post-intervention and generalize 
to related cognitive functions (secondary objectives) is also important in determining the 
transfer of gains to broader cognitive skills and to their endurance once the intervention is 
concluded.  
 
Anxiety, depression, and fatigue have been reported after COVID-19 (Garrigues et al., 
2020), are related to attention and executive functions (Zhou et al., 2020),and are known to 
be associated with daily function. Our previous work has demonstrated that the AKL-T01 
intervention can improve mood symptoms in adults with major depression. Thus, an 
exploratory objective is to determine whether the AKL-T01 intervention improves symptoms 
of depression, anxiety, and fatigue, which is important in determining additional impacts of 
the intervention that have ramifications for COVID-19 survivors’ daily function and quality of 
life.  
 
We anticipate that the results of this study will inform refinement and improvement of AKL-
T01 for COVID-19 and provide valuable data for future study of the intervention. 
 
2.4  Risk/Benefit Assessment  
 
2.4.1 Known Potential Risks 
 
This study presents no greater than minimal risk. The potential risks of participation are 
frustration, feeling anxious and/or fatigued during intervention gameplay and 
assessment administration. There is also a risk that participants may develop headaches 
during gameplay, due to the fast-paced nature of the game and the need to focus on the 
screen during the intervention. To mitigate risk, we will emphasize that participants can 
take breaks as frequently as they would like when completing the intervention exercises. 
The computerized exercises are graded in difficulty (i.e., start relatively easy and 
becoming more challenging over time) and adapt to the participant’s cognitive skill level, 
which will mitigate the risk of frustration and feelings of anxiety. 

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2.4.2 Known Potential Benefits  
 
This study has the potential to improve participants’ cognitive and daily function. The 
AKL-T01 intervention has been shown to improve mood symptoms, as well as executive 
skills and cognitive control through measures of neural activation and connectivity, 
performance on tasks measuring working memory and sustained attention, and self-
reported symptoms of cognitive control function in adults diagnosed with depression 
(Anguera et al, 2017; Bove et al., 2019; Gunning et al., under review). The control group 
also has the potential to improve their cognitive and daily function as they will be given 
the opportunity to begin the intervention after the waitlist period. 
 
2.4.3 Assessment of Potential Risks and Benefits 
 
We will use study procedures designed to maximize the benefit and minimize the risk of 
participation in this study. Participants in the intervention arm will receive adequate 
training in gameplay (~45 minute training session with a member of the study team) and 
have weekly check-ins with trained care managers to troubleshoot issues with the game 
and monitor gameplay adherence. Participants in the waitlist control arm will also have 
weekly check-in visits with a care manager. 
 
Assessment sessions will be conducted by PhD-level investigators of this study protocol 
or Research Assistants who have received extensive training in assessment 
administration. The assessment battery for this study was optimized to provide 
measures across a range of cognitive and functional domains that we expect to be 
impacted in COVID-19 survivors, use well-validated tasks that can be administered 
remotely, and be as brief as possible to minimize participant burden. 
 
This study will also use a waitlist design to ensure that all participants have the 
opportunity to receive the benefits provided by the AKL-T01 intervention. At the 
completion of the 6-week intervention period, participants in the waitlist control group will 
be given the option to begin 6 weeks of the intervention, which will include the same 
schedule of weekly check-in and assessment visits. 
 
We expect that the potential benefits of participation outweigh the minimal risks. 
Participants may experience an improvement in multiple aspects of cognition and daily 
functioning in COVID-19 survivors. The knowledge gained would inform future clinical 
trials. 
 
Plan to Address Subjects with Suicidal Ideation and/or Other Mental Health Needs 
Suicidal ideation may be identified by the PHQ-9. Identification of suicidal ideation will 
trigger a suicide risk assessment following an established protocol and algorithm 
developed by investigators in the Department of Psychiatry (see attached form). The 
suicide risk assessment will be completed under the supervision of a licensed clinician or 
by the licensed clinician themselves. Depending on the level of risk, study staff may 
provide referrals for further care, which may include outpatient or inpatient treatment 
according to clinical indication. Involuntary admission may become necessary in patients 
at acute and imminent risk for harming themselves. In the unlikely event that a licensed 
clinician is not available for immediate clinical evaluation of a subject reporting suicidal 
intent or plan, the research staff member will contact emergency medical services.  

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The suicide risk assessment classifies subjects who endorse suicidal ideation as having 
Mild Risk, Intermediate Risk, or High Risk. For subjects classified as having Mild or 
Intermediate Risk, referrals for outpatient mental health services will be provided and 
study staff will discuss a plan of action should the subject’s frequency or intensity of 
ideation increase (call 911, go to ER). If the subject is classified as having High Risk with 
imminent danger of self-harm, then the study staff member will contact emergency 
medical services.  
Risk assessment and safety monitoring will be conducted under the supervision of study 
staff who are licensed clinical psychologists 
 
2.5 Correlative Studies Background 
 
In a preliminary study (Jaywant et al., under review), we evaluated the frequency, severity, 
and profile of cognitive dysfunction in hospitalized patients recovering from COVID-19. We 
obtained and analyzed cross-sectional neuropsychological data from a cohort of N=57 
patients participating in inpatient rehabilitation. 81% of patients had cognitive impairment, 
ranging from mild to severe. Deficits were most common in working memory (55% of 
patients impaired), set-shifting (47%), divided attention (46%), and processing speed (40%). 
Executive dysfunction was not significantly associated with intubation length or the time from 
extubation to assessment, nor was it associated with the presence of a psychiatric 
diagnosis. The results highlight the importance of studying interventions that target attention 
and executive functioning after COVID-19. Given the prevalence of COVID-19, targeting 
these deficits through scalable cognitive interventions that have been demonstrated to 
improve similar deficits and can be widely disseminated in patients’ homes through reliance 
on technology may support optimal cognitive and functional outcomes. 
 
3. Study Design 
 
3.1 Overall Design 
 
The primary objective of this study is to investigate the efficacy of AKL-T01 (Akili 
Interactive), a remotely-delivered digital cognitive intervention, in targeting and improving 
cognition and functional outcomes in individuals recovering from COVID-19. The efficacy of 
the AKL-T01 intervention will be measured relative to a waitlist control group. We 
hypothesize that the AKL-T01 intervention will show greater efficacy relative to the waitlist 
control at improving cognitive and daily function in COVID-19 survivors.  
 
To test this hypothesis, adults who were previously infected with a diagnosis of COVID-19 
and confirmed history of SARS-CoV-2 infection will be recruited for our study sample. This is 
a single site study, and all participants will be recruited through Weill Cornell Medicine and 
the NewYork-Presbyterian Hospital system. We will screen the electronic medical record 
(Epic) for NYP, Weill Cornell Medicine. Potential participants can also be referred by their 
doctor. We will also contact potential participants who were previously enrolled in COVID-19 
research studies at NYP/WCM and agreed to be contacted for future research opportunities. 
We will also post flyers at NYP/Weill Cornell Medical Center and other relevant locations in 
the greater New York City area. 
 
Due to the ongoing threat of COVID-19 and the remote nature of this trial, informed consent 
will also be obtained remotely. For participants with access to technology that will allow them 
to consent electronically, the participant and the member of the research team (co-

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investigator or trained research assistant) obtaining informed consent will meet over a 
HIPAA-compliant video conference platform (i.e., Zoom). At the start of this video meeting, 
the researcher will share their screen and highlight each section of the consent form while 
discussing it with the participant. After discussing the consent form with the participant, they 
can then re-read it and sign it via REDCap. These participants will be provided with a PDF of 
their signed consent form for their records. 
 
For participants without access to technology that would allow them to consent 
electronically, the participant and researcher will review to consent form over the phone. A 
copy of the consent form will be mailed or emailed to the participant in advance so that it 
can be viewed by the participant during the phone call. They will return the signed consent 
form in a stamped, self-addressed envelope provided by the researcher. These participants 
will then be mailed a copy of their signed consent form for their records. 
 
To screen prospective participants, we will conduct an initial screening via a secure HIPAA-
compliant videoconferencing platform (Zoom). Participants will be queried for inclusion and 
exclusion criteria. Participants will be administered via Zoom the Oral Trail Making Test, 
Stroop Test, and the Frontal Systems Behavior Rating Scale (FrSBe). Participants will be 
eligible for enrollment if they score <1 standard deviation below their age-normed peers on 
at least one of these three screening tests.  
 
Participants will be randomized into the intervention arm or a waitlist control arm, with an 
option for the control participants to receive the AKL-T01 intervention at the conclusion of 
the initial 6-week waitlist period. 
 
All participants (intervention & waitlist control arm): Full assessment visits will take place 
pre-intervention (baseline) and post-intervention (week 6). During the 6-week intervention 
period, shorter intermediate assessment visits will take place at weeks 2 and 4. Participants 
in the waitlist control arm will continue any ongoing self- or provider-based cognitive 
intervention (or no intervention) during the initial 6-week waitlist period. 
 
Participants in the intervention arm & participants in the control arm who decline the 
intervention: A full assessment session at will take place at week 10 (4 weeks post-
intervention) for longitudinal follow-up.  
 
Participants in the control arm who begin the intervention at the conclusion of the waitlist 
period: The week 6 assessment visit will also serve as the baseline for the beginning of the 
intervention. Intermediate assessment visits will take place at weeks 8 and 10, a full post-
intervention assessment visit will take place at week 12, and a follow-up assessment visit 
will take place at week 16 (4 weeks post-intervention).  
 
See Section 6.1 for the complete Schedule of Assessments.  
 
Participants will be aware of their assignment to study arm because it is not possible to blind 
them. The research team members conducting the study assessments will be blind to 
assignments. The care managers will not be blinded because it is not possible to blind them 
and it is necessary for them to know of a participant’s assignment to assist in 
troubleshooting.  
 

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Our primary cognitive outcome will be measured by performance on a Digit Symbol 
Matching Task and our primary functional outcome will be measured by assessment score 
on the NeuroQOL scale. Additional cognitive tasks will be administered during the 
assessment visits to measure additional domains of cognition and daily functioning for our 
secondary and exploratory endpoint analyses. See Schedule of Assessments (Section 6.1) 
for list of assessments included in battery. 
 
3.2 Scientific Rationale for Study Design 
 
In order to evaluate the efficacy of AKL-T01 for COVID-19, we require comparison to a 
control group. Because of the potential negative impact of COVID-19 on cognition and 
functional outcomes, the control arm will be offered the intervention at the end of 6 weeks to 
ensure all participants ultimately have access to the intervention. Because the control group 
will not be engaging in any active control condition, there is potential for dropout; however, 
we will mitigate this dropout via weekly check-ins from the care managers and by providing 
compensation for those check-in visits to encourage retention.   
 
3.3 Justification for Dose  
 
Participants will complete 6 weeks of the AKL-T01 intervention. Previous research supports 
improvement of cognition following 4 weeks of the intervention, however continued 
improvement in a 4 week period after the intervention was observed. However, we are 
proposing a 6 week intervention to maximize the potential for cognitive change in COVID-19 
survivors and because the overall gameplay dose is small (20-25 minutes daily for 5 days a 
week), and the additional time and remote delivery will not present additional burden to the 
participants. 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study for the primary objective of the 
study if he or she has completed the 6 weeks of the intervention and the post-intervention 
assessment. For the secondary and exploratory objectives, the end of the study is defined 
as completion of the week longitudinal follow-up visit. 
 
4. Subject Selection 
 
4.1 Study Population 
 
The study population will be individuals who were diagnosed with COVID-19 (determined by 
a documented previous positive test results for SARS-CoV-2 infection) and have a deficit in 
cognition (i.e., attention and/or executive skills > 1 SD below the normal range).  
 
4.2 Inclusion Criteria 
1. Male or female 18-89 years of age. 
2. Documentation of a deficit in cognitive function (score > 1 standard deviation below 
normal range) compared to age-adjusted normative data) on at least one screening 
measure of attention and executive function (Oral Trail Making Test, Stroop Test, or 
FrSBe). 

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3. Previous diagnosis of COVID-19 confirmed via SARS-CoV-2 polymerase chain reaction 
(PCR) test (or reported experience of COVID-19 symptoms with a documented positive 
antibody test or clinical diagnosis based on symptoms and accompanying physician’s 
note) documented in the electronic medical record or in other existing medical records. 
4. Access to and self-report of ability to connect wireless devices to a functional wireless 
network. 
5. Ability to follow written and verbal instructions (English) as assessed by the PI and/or co-
investigator. 
6. Able to comply with all testing and study requirements and willingness to participate in 
the full study duration. 
4.3 Exclusion Criteria  
1. History of neurologic disorder prior to COVID-19 diagnosis, such as Parkinson’s disease, 
multiple sclerosis, Alzheimer’s disease, stroke, brain tumor, or dementia.  
2. History of severe mental illness (e.g., schizophrenia, psychosis, history of suicide 
attempt in the last year) or substance use disorder, recent history (in the past year) of 
alcohol/substance use disorder or symptoms of psychosis. 
3. Participant is currently considered at risk for attempting suicide by the Investigator, has 
made a suicide attempt within the past year, or is currently demonstrating active suicidal 
ideation or self-injurious behavior. 
4. Motor condition (e.g., physical deformity of the hands/arms) that prevents game playing 
as reported by the participant or observed by the Investigator. 
5. Recent history (within 6 months prior to screening/baseline) of substance use disorder. 
6. History of seizures (excluding febrile seizures), a tic disorder, significant tics, a current 
diagnosis of Tourette's Disorder. 
7. Color blindness as determined by self-report. 
8. Regular use of psychoactive drugs other than antidepressants or benzodiazepines, 
including stimulants that in the opinion of the Investigator may confound study 
data/assessments. 
9. Any other acute medical condition that may interfere with participation or interpretation of 
the results. 
10. Previous exposure to AKL-T01. 
4.4 Lifestyle Considerations 
 
Not applicable. 
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to be screened to participate in the 
clinical trial but are not subsequently randomly assigned to the study because they do not 
meet inclusion/exclusion criteria. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 

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4.6 Strategies for Recruitment and Retention 
 
We will recruit subjects from the Weill Cornell/NYP system.  We anticipate that we will have 
to screen up to 500 subjects to meet our target enrolment. We will recruit by retrospective 
review of the electronic medical record, via social media, study flyers and posters, and via 
referral from providers throughout NYP and WCM. We will attempt to recruit an equal 
number of males and females; however, anticipate that our sample will reflect current 
demographic estimates of prevalence of COVID-19, i.e., increased prevalence of severe 
illness in men. We anticipate that a significant percentage of our sample may be of African 
American race and/or Hispanic ethnicity due to known racial/ethnic disparities in COVID-19. 
We will contact patients via contact information listed in the electronic medical record.  
 
We will be recruiting individuals with cognitive impairment because we hypothesize that our 
intervention has the potential to improve cognitive deficits in this population. We will 
determine whether participants can sign consent by using teach-back methods to verify 
comprehension of risks and benefits. We will also use a capacity to consent form (see 
attachment) to verify comprehension of risks and benefits for subjects deemed to have more 
than mild impairment based on clinician interview. 
 
Compensation for participation will be provided as follows: 
 
Week 
Visit 
Compensation * Arm 
 
 
AKL-T01 
Intervention 
Waitlist Control 
(No Intervention) 
Waitlist Control 
(Intervention) 
0 
Pre-Intervention 
Assessment 
$50 
$50 
$50 
2 
Intermediate 
Assessment 
$25 
$25 
$25 
4 
Intermediate 
Assessment 
$25 
$25 
$25 
6 
Post-Intervention 
Assessment 
$50 
$50 
$50 
10 
Follow-Up 
Assessment * 
$75 
$75 
 
 
 
End of Waitlist 
8 
Intermediate 
Assessment 
 
 
$25 
10 
Intermediate 
Assessment 
 
 
$25 
12 
Post-Intervention 
Assessment 
 
 
$50 
16 
Follow-Up 
Assessment 
 
 
$75 
 
 
 
 
 
Total Per Participant 
$225 
$225 
$325 
 
* Also serves as pre-intervention assessment for waitlist control participants. 
 

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5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure 
for Subject Registration.  
 
 
 
5.2 Subject Registration (Sub-sites) 
 
Not applicable. 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Table 1. Schedule of trial events 
 
 
 
WEEK 
Measure 
Sc 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
Consent 
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive 
Screen 
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention / 
Check-In 
 
v 
v 
v 
v 
v 
v 
v 
« 
« 
« 
« 
« 
« 
« 
Digit Symbol 
Match 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Multiple Object 
Tracking 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Digit Span 
Backwards 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Simple RT 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Choice RT 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Letter/Number 
Switch 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Gradual CPT 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
Visual Paired 
Associates 
 
v 
 
 
 
 
 
v 
 
 
 
£ 
 
« 
« 
NeuroQOL 
 
v 
 
v 
 
v 
 
v 
 
« 
 
v 
 
« 
« 
WHODAS 
(36-item) 
 
v 
 
 
 
 
 
v 
 
 
 
£ 
 
« 
« 
WHODAS 
(12-item) 
 
 
 
v 
 
v 
 
 
 
« 
 
« 
 
 
 

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Modified 
Fatigue Impact 
 
v 
 
 
 
 
 
v 
 
 
 
£ 
 
« 
« 
PHQ-9 
 
v 
v 
v 
v 
v 
v 
v 
« 
« 
« 
£ 
« 
« 
« 
GADS-7 
 
v 
 
 
 
 
 
v 
 
 
 
£ 
 
« 
« 
Adverse Event 
Monitoring 
v ------------------------------------------------------------------------------------------------------------------ v 
 
v All Participants (Intervention & Control Arm) 
« Intervention Arm & No Waitlist Controls ONLY 
£ Waitlist Controls ONLY 
 
6.1.1 Screening Visit (< 1 week before enrollment and randomization) 
 
Participants will be screened and assessed for eligibility before enrollment and 
randomization to the intervention and waitlist control arms. During the screening visit, 
participants will meet via HIPAA-compliant video conferencing platform with a PhD-level 
member of the study team. During this visit, potential participants will be screened for the 
cognitive deficit required for participation in the study. Eligible participants will be 
randomized to the intervention arm or the waitlist control arm in a 1:1 using a computer-
generated randomization scheme developed by the data manager at the conclusion of 
the screening visit. A block randomization approach will be used based on a block of 6. 
 
The screening visit will include the following study procedures: 
• 
Informed consent 
• 
Demographics (in EMR or collected at screening visit) 
• 
Medical / medication history (in EMR or collected at screening visit) 
• 
Additional Medical/Psychiatric symptom screening (completed by member 
of the research team) 
• 
Cognitive screening (Oral Trail Making Test, Stroop Test, FrSBe) 
 
 
 
 
6.1.2 Treatment Phase 
 
 
 
 
 
 
6.1.2.1 Week 0 (Baseline/Pre-Intervention), Week 6 (Post-Intervention), 
Week 12 (Post-Intervention; waitlist control participants only) 
 
 The pre- and post-intervention visits will take place at the beginning and the end 
of the intervention period. Participants in both arms will meet remotely with a 
member of the research team via a HIPAA-compliant video conferencing platform 
(Zoom). The full battery of cognitive tasks (~35 minutes), functional assessments 
(~30 minutes), and mood symptom scales (~10 minutes) will be conducted at the 
baseline visit. Participants in the AKL-T01 intervention arm will be trained in 
procedures for gameplay during this visit. (Note that the week 6 assessment 
session will also serve as the baseline assessment for control participants who 
begin the intervention following the waitlist period.) 
 
The pre- and post-intervention assessment visits will include the following study 
procedures: 
• 
Cognitive Tasks: 
• 
Digit Symbol Matching 

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• 
Multiple Object Tracking 
• 
Digit Span Backwards 
• 
Simple RT 
• 
Choice RT 
• 
Letter/Number Switch 
• 
Gradual CPT 
• 
Visual Paired Associates 
• 
Functional Assessments: 
• 
NeuroQOL 
• 
WHODAS (36-item) 
• 
Modified Fatigue Impact Scale 
• 
Mood Symptom Scales: 
• 
PHQ-9 
• 
GADS-7 
 
 
 
 
6.1.2.2 Weeks 2 & 4 (± 2 days; all participants) & Weeks 8 & 10 (± 2 days; 
waitlist control participants only) 
 
The intermediate assessment visits at weeks 2 & 4 (and weeks 8 & 10 for waitlist 
control participants) will include a shorter battery of cognitive tasks (~25 minutes) 
and functional assessments (~10 minutes) measuring the primary and secondary 
endpoints, as well as the PHQ-9 (~5 minutes) for monitoring of mood symptoms.  
 
The intermediate assessment visits will include the following study procedures: 
• 
Cognitive Tasks: 
• 
Digit Symbol Matching 
• 
Multiple Object Tracking 
• 
Digit Span Backwards 
• 
Simple RT 
• 
Choice RT 
• 
Letter/Number Switch 
• 
Gradual CPT 
• 
Functional Assessments: 
• 
NeuroQOL 
• 
WHODAS (12-item) 
• 
Mood Symptom Scales: 
• 
PHQ-9 
 
6.1.3 Follow-up Phase 
 
Longitudinal follow-up assessment visits will take place 4 weeks after the end of the 
intervention period. For participants in the AKL-T01 intervention arm this visit will take 
place at week 10. For participants in the control arm who do begin the intervention at the 
end of the waitlist period, this visit will take place at week 16. This visit will include the full 
battery of cognitive tasks, functional assessments, and mood symptom scales collected 
at the pre- and post-intervention visits. 
 

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7. Study Intervention 
 
 
7.1 Study Intervention/Device Description   
 
The AKL-T01 intervention and the study assessments will be administered on an Apple 
iPad. The intervention video game is an iPad application that will be pre-installed on the 
iPads provided to participants. The iPad will also include shortcuts to the cognitive tasks 
and the RedCap database through which they will complete the self-report scales. All 
other applications and web pages will be locked on the intervention iPads. Participants in 
both the intervention arm and the waitlist control arm will be provided with iPads to 
ensure consistency in the data collection device. 
 
The iPads will be shipped to participants’ homes with a self-addressed return envelope 
for the iPad to be mailed back to the research team at the conclusion of participation in 
the study. 
 
7.2 Availability 
 
An Apple iPad will be provided to the participants for the duration of their participation by 
Akili Interactive.  
 
7.3 Acquisition and Accountability  
 
iPad Device Logs – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all iPads  
received from Akili Interactive in the study’s Device Log.  
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
The devices provided to the participants will be Apple iPads. Participants will only be 
able to access the AKL-T01 video game interface (intervention arm only), the cognitive 
task battery, and the RedCap database for assessment administration. Participants will 
review instructions for using the iPads with a member of the research team during their 
first weekly check-in visit. 
 
7.5 Product Storage and Stability 
 
Not applicable. 
 
7.6 Preparation 
 
Not applicable. 
 
7.7 Dosing and Administration 
 
Participants in the AKL-T01 intervention arm are required to play the game for 25 minutes 
per day for at least five days (but up to 7 days) per week. The game will automatically “lock” 
after 25 minutes to prevent participants for playing longer than specified.  

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7.7.1 Dosing Delays/Dose Modifications 
 
 
 
Not applicable. 
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
Not applicable. 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of intervention delays due to adverse event(s), intervention may continue 
until one of the following criteria applies: 
• 
Intercurrent illness that prevents further administration of the intervention, 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject’s condition render the subject 
unacceptable for further intervention in the judgment of the investigator. 
• 
The investigators of this study may stop the study or remove participants from 
the study at any time should they judge that it is in the participants’ best interest 
to do so or if they do not comply with the study plan. 
 
 
 
For device/interventional studies -  
Study Termination Guidelines: A subject’s follow-up in the study will end after one of the 
follow applies: 
• 
Subject’s voluntary withdrawal 
• 
Subject lost to follow-up 
• 
Completion of all scheduled study follow-up appointments 
7.10  Duration of Follow Up 
 
Subjects removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
 
A WCM data manager not involved in any other aspects of the study will use a computer-
generated randomization table to determine whether the patient will be assigned to the AKL-
T01 intervention arm or the waitlist control arm.  
 
Participants will be aware of their assignment to study arm because it is not possible to blind 
them. The researchers conducting the study assessments will be blind to assignments. The 
care managers will not be blinded because it is not possible to blind them and it is 
necessary for them to know of a participant’s assignment to assist in troubleshooting.  
 
Participants and care managers will be instructed not to reveal the group assignment to the 
member of the research team conducting assessments. Following the completion of 
recruitment, data analysts will be provided with the data for the arms simply labelled as 
“Group A” and “Group B” to avoid bias. These generic labels will be unmasked only after 
completion of all the planned statistical analyses described below. Participants in the waitlist 
control arm who begin the intervention at the end of the waitlist period will have different 

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assessors for the initial 6-week control procedures and the subsequent 6-week intervention 
period so as to maintain the blind.  
 
7.12 Study Intervention/Follow-up Compliance 
 
Adherence to video game play for the participants in the AKL-T01 intervention arm will be 
monitored by a member of the research team using the intervention dashboard, which 
provides the researchers with information about duration and frequency of gameplay, 
progression through game levels, etc. Participants who are not playing for the required 
duration of 25 minutes a day for at least 5 days a week will work with their care manager 
during a weekly check-in visit to make a plan for game play (e.g., playing at a specific time 
each day, setting reminders to play).  
 
Participants will be considered lost to follow up and no longer participating in the study when 
they do not respond to attempts at communication with the researcher for two weeks and 
miss an assessment visit during that window. 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
Discontinuation from the AKL-T01 intervention does not mean discontinuation from the 
study, and we will attempt to complete remaining study procedures 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. 
 
The data to be collected at the time of study intervention discontinuation will include the 
collection of the post-intervention assessment data, including all cognitive tasks, functional 
assessments, and mood symptom scales. 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant. 
• 
Participant lost to follow-up after several attempts to contact subject to schedule study 
visit. 
The reason for participant discontinuation or withdrawal from the study will be recorded in 
the case report form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced.  Subjects who sign 
the informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 

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8.3 Lost to Follow Up 
 
A participant will be considered lost to follow-up if they do not complete a scheduled visit 
within two weeks of the assessment window and is unable to be contacted by the study site 
staff.  
The following actions must be taken if a participant does not complete a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit for two 
weeks and 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 and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or 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. 
 
9. Correlative/Special Studies  
 
Not applicable. 
 
9.1 Laboratory Correlative Studies 
Not applicable. 
 
9.1.1 Title – Laboratory Correlative Study #1 
 
9.1.1.1 Collection of Specimen(s) 
 
9.1.1.2 Handling of Specimen(s) 
 
9.1.1.3 Shipping of Specimen(s) (if multicenter) 
 
9.1.1.4 Site(s) Performing Correlative Study (if multicenter) 
 
9.2 Special Studies 
Not applicable. 
 
9.2.1 Title – Special Correlative Study #1 
 
9.2.1.1 Assessment 
 
9.2.1.2 Method of Assessment 
 
9.2.1.3 Timing of Assessment 
 
10.  Measurement of Effect 
 
Calculated for primary and secondary outcome measures, comparing the active intervention 
(AKL-T01; week 0 to week 6 for intervention arm) to the waitlist control (week 0 to week 6) using 
standard inferential statistical techniques and calculation of effect sizes. Formally, for primary 
and secondary outcomes, we will apply linear mixed effects models with fixed effects for 
treatment group as the between-subjects factor, time (week number) as the within-subjects 
factor, and group-by-time interaction. A random intercept will be included. Effect size will be 
reported in terms of group-by-time interaction (i.e., difference in slope of change between 

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groups). Despite the protection afforded by randomization, should potential confounding 
variables be identified from among baseline sociodemographic and clinical features, secondary 
analyses will incorporate fixed terms for those putative confounders in linear models. 
 
 
10.1 Response Criteria 
 
 
 
Primary Outcome:  
1) Improvement in cognitive function on the Digit Symbol Matching Test from pre-
intervention to post-intervention. 
 
Secondary Outcomes:  
1) Improvement in daily function on the NeuroQOL Cognitive Function Scale from pre-
intervention to post-intervention. 
2) Improvement in cognitive function (improved accuracy and/or decreased response 
time) on Multiple Object Tracking, Digit Span Backwards, Simple RT, Choice RT, 
Letter/Number Switch, Gradual CPT from pre-intervention to post-intervention. 
3) Improvement in daily function on the WHODAS 2.0 from pre-intervention to post-
intervention. 
 
Exploratory Outcomes: 
1) Long-term improvement in cognition and daily function 4 weeks following completion 
of the intervention. 
2) Improvement in cognitive function on the Visual Paired Associates Task. 
3) Improvement in fatigue on the Modified Fatigue Impact Scale. 
4) Improvement in mood symptoms on the PHQ-9 and GADS 7. 
 
10.2 Duration of Response  
 
 
Not applicable. 
 
10.3 Progression-Free Survival  
 
Not applicable. 
 
10.4 Other Response Parameters 
 
 
Not applicable. 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
 
The data collection plan for this study is to utilize REDCap to capture all intervention, 
toxicity, efficacy, and adverse event data for all enrolled subjects. The REDCap 
database will be maintained by WCM and only members of the WCM research team will 
have access to the REDCap data. 
 
Akili Interactive will have access to de-identified data related to gameplay during the 
video game intervention (metrics such as number of sessions played, time spent playing 

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the game, scores and performance, etc.). Gameplay data will be accessible via a 
dashboard linked to the iPad study devices; the device data will be connected to a 
unique ID number and will not be linked to participant PHI or identifiable information. 
Akili will not have access to participant medical records or identifiable information. 
 
The computerized cognitive task battery is administered by a company called 
ManyBrains. They will have access to the scores collected during the cognitive tasks. 
Cognitive task data will be connected to a unique ID number and will not be linked to 
participant PHI or identifiable information. ManyBrains will not have access to participant 
medical records or identifiable information. They will store de-identified task scores in a 
research repository to be analyzed in aggregate form with other task scores to develop 
more optimized cognitive tasks in the future. 
 
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center 
CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full 
array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data 
manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 

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amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
We will use verbal teach-back methods to verify comprehension of risks and benefits and 
capacity to consent to participation. For participants who screen as having moderate 
cognitive impairment (e.g., <2 SD below the normative mean on screening measures), we 
will use additional safeguards to verify comprehension of risks and benefits and study 
procedures, and to verify capacity to consent. The research staff member will conduct a 
formal interview (see attached questionnaire) to ensure that the participant comprehends 
study procedures, risks, and benefits. This questionnaire will ascertain whether the patient 
can communicate their choice; can attend to, understand, and recall the information 
discussed; and can weigh the risks and benefits to participating. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 

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Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents will be retained for 2 years after 
the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 
We will test the hypothesis that patients receiving the AKL-T01 intervention will have 
significantly enhanced improvement in cognition and daily functioning, relative to a waitlist 
control group.  
 
1) Our primary cognitive measure will be change in performance on a Digit Symbol Matching 
Task from baseline (pre-intervention) to week 6 (post-intervention) in all participants 
randomized to the AKL-T01 intervention arm or the waitlist control arm.  
 
2) Our primary daily functioning measure will be change in score on the NeuroQOL 
Cognitive Function scale from baseline (pre-intervention) to week 6 (post-intervention) in all 
participants randomized to the AKL-T01 intervention arm or the waitlist control arm.  
 
We will use analysis of variance (ANOVA) to test for differences in 1) Digit Symbol Matching 
and 2) NeuroQOL change scores across the intervention and control arms. 
 
A secondary outcome analyses will use ANOVA to test for group differences in change in 
performance on the remaining cognitive tasks (Multiple Object Tracking, Digit Span 
Backwards, Simple RT, Choice RT, Letter Number Switch) and group differences in the 
WHODAS 2.0, our secondary measure of daily functioning.  
 
We will use the Holm-Bonferroni method to correct for multiple comparisons. An intent-to-
treat approach will be used in for all of the analyses above, including outcomes in 
participants who did not complete the intervention. 
 
 
12.2 Sample Size/Accrual Rate 
 

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Our target sample size will be 100 COVID-19 survivors. 50 participants will be randomized 
to the AKL-T01 intervention arm and 50 participants will be randomized to a waitlist control 
arm. 
 
Our total enrollment to meet our target sample size of 100 participants will be 125. Based on 
previous research conducted at our institution, we anticipate ~20% of individuals will decide 
not to participate after meeting eligibility criteria. 
 
As primary analysis will utilize linear mixed models (as implemented in lme4) to examine 
slope of symptom change, we utilized the simr package in R (4.0) to estimate power for the 
specified model assuming 50 participants per study arm in 100 simulated data sets. For 
standardized beta coefficient corresponding to Cohen's d of ~0.4, power exceeds 88% (95% 
confidence interval 80.0-93.6%) for the base case, and exceeds 80% under a range of 
conservative assumptions, with alpha=0.05 for the primary hypothesis test. 
 
We expect enrollment to last approximately 12 months, yielding an accrual rate of ~10 
participants per month. 
 
12.3 Stratification Factors  
 
Not applicable. 
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
Our primary cognitive measure will be change in performance on a Digit Symbol 
Matching Task from baseline (pre-intervention) to week 6 (post-intervention) in all 
participants randomized to the intervention or control arm. Our primary daily functioning 
measure will be change in score on the NeuroQOL Cognitive Function scale from 
baseline (pre-intervention) to week 6 (post-intervention) in all participants randomized to 
the intervention or control arm. We will use analysis of variance (ANOVA) to test for 
differences in Digit Symbol Matching and NeuroQOL change scores across the two 
arms. 
 
12.4.2 Analysis of Secondary Endpoints 
 
Our secondary outcome analyses will use ANOVA to test for group differences in 
change in performance on the remaining cognitive tasks (Multiple Object Tracking, Digit 
Span Backwards, Simple RT, Choice RT, Letter Number Switch) and group differences 
in the WHODAS 2.0, our secondary measure of daily functioning.  
 
12.5 Interim Analysis 
 
Interim analyses will be provided to Akili Interactive as requested. 
 
 12.6 Reporting and Exclusions 
 

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12.6.1 Evaluation of Toxicity 
 
Not applicable. 
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to the intervention (if 
they have received the intervention).  
 
 
13. Adverse Event Reporting Requirements  
 
The research team is responsible for notifying the WCM IRB of all unexpected adverse events 
and serious adverse events. After faxing or e-mailing the Cornell IRB reporting forms to Cornell, 
the Research Assistant should follow-up with an e-mail or phone call to verify that the forms 
were received. Additionally, copies of these forms should be kept in the patient file as source 
documentation. 
 
In addition to the WCM IRB, AEs, SAEs, death, protocol violations, non-compliance, 
suspensions and terminations will be reported to the Akili Interactive (as the industry funding 
partner). All reports must be made in writing to Akili. These reports should indicate that the 
monitoring entities (i.e., the PI and IRB) have been notified in accordance with the approved 
monitoring plan. 
 
13.1 Adverse Event Definition 
 
Adverse event is defined as any untoward medical occurrence associated with the use 
of an intervention in humans, whether or not considered intervention-related. 
 
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
We do not anticipate significant risks for our behavioral intervention beyond boredom, 
frustration, fatigue, and/or headaches. 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study device must always be suspect.  
 
o Definitely Related – There is clear 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 intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals.  
o Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other 

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drugs or chemicals.   
o Potentially Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the trial 
medication). 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. 
o Unlikely to be Related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
o Not Related – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to 
another etiology. There must be an alternative, definitive etiology documented by 
the clinician. 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be 
maintained by the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.1.5 Reporting Events to Participants 
 
Events leading to substantive changes in the consent form or procedures will be 
communicated to the current participants enrolled in the study.  
 
13.1.6 Events of Special Interest 
 
Not applicable. 
 
13.1.7 Reporting of Pregnancy 
 
Not applicable. 
 
13.2 Definition of SAE 
 
Serious adverse event or serious suspected adverse reaction. An AE or suspected 
adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse 

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event, inpatient hospitalization or prolongation of existing hospitalization, a persistent 
or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such an event would include a seizure 
or suicide attempt requiring inpatient hospitalization.   
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-
Investigator] 
Not applicable. 
 
13.2.3 Reporting of SAE to Akili Interactive 
 
Institution will send Akili Interactive copies of any and all serious adverse event reports 
filed with the IRB, as well as copies of any correspondence with the IRB, regarding any 
and all serious adverse events, irrespective of association with the AKL-T01 intervention 
in the course of the Clinical Trial, within 5 business days of such report or 
correspondence being sent to the IRB.  Copies should be sent via secure file transfer 
directly to Deb Farlow in the Clinical Research and Operations Department at Akili 
Interactive. 
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the subject 
discontinues participation from the study.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
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 including local and systemic reactions not meeting the criteria for SAEs 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 
product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 

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documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical 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. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
 
 
The study research assistant will record all reportable 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.  Events will be followed for outcome 
information until resolution or stabilization. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) 
 
The Office for Human Research Protections (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. 
 
This definition could include an unanticipated adverse device effect, any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated 
with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the Data Coordinating Center (DCC)/lead 
principal investigator (PI). The UPIRTSO report will include the following information: 
 

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• 
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 UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the DCC/study sponsor within <insert timeline in accordance with policy> 
of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor 
within <insert timeline in accordance with policy> of the investigator becoming 
aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), Food and Drug Administration (FDA), and the Office for Human 
Research Protections (OHRP) within <insert timeline in accordance with policy> 
of the IRB’s receipt of the report of the problem from the investigator. 
 
An investigator will submit to the sponsor and to the reviewing Institutional Review Board 
(IRB) a report of any unanticipated adverse device effect occurring during an 
investigation as soon as possible, but in no event later than 10 working days after the 
investigator first learns of the effect (21 CFR 812.150(a)(1)), A sponsor who conducts an 
evaluation of an unanticipated adverse device effect under 812.46(b) shall report the 
results of such evaluation to the Food and Drug Administration (FDA) and to all 
reviewing IRB's and participating investigators within 10 working days after the sponsor 
first receives notice of the effect. Thereafter the sponsor shall submit such additional 
reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).    
 
15. Data and Safety Monitoring Plan (DSMP) 
 
Data and safety monitoring will be performed internally by licensed clinical psychologists on the 
study protocol. This is a minimal risk study. Safety including AE/SAE will be monitored by 
licensed clinical psychologists (Drs. Gunning, Jaywant, Kanellopoulos) on the study staff. The 
monitoring clinicians will review the data that will be captured will be from 1) the pre-intervention 
assessments; 2) mid-intervention assessments; 3) post-intervention assessments; 4) and 
follow-up assessments. They will also monitor for acute medical illness or change in medical 
status that requires admission to a hospital and/or prevents participation in the study. 
 
Since this is a minimal risk study, there are no stopping rules as the risks are fatigue, frustration, 
and boredom. Subjects will continue to have the right to withdraw at any time. 
 
The monitoring entity’s comments will be submitted to the IRB at the time of continuing review.  
 
 
 
 
 

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16. References 
 
Anguera JA, Boccanfuso J, Rintoul JL, Al-Hashimi O, Faraji F, Janowich J, Kong E, Larraburo 
Y, Rolle C, Johnston E, Gazzaley A. Video game training enhances cognitive control in older 
adults. Nature. 2013 Sep;501(7465):97-101. 
 
Anguera JA, Gunning FM, Areán PA. Improving late life depression and cognitive control 
through the use of therapeutic video game technology: A proof-of-concept randomized trial. 
Depression and anxiety. 2017 Jun;34(6):508-17. 
 
Bove RM, Rush G, Zhao C, Rowles W, Garcha P, Morrissey J, Schembri A, Alailima T, Langdon 
D, Possin K, Gazzaley A. A videogame-based digital therapeutic to improve processing speed 
in people with multiple sclerosis: a feasibility study. Neurology and therapy. 2019 Jun 
1;8(1):135-45. 
 
Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, Doucet L, Berkani S, Oliosi E, 
Mallart E, Corre F. Post-discharge persistent symptoms and health-related quality of life after 
hospitalization for COVID-19. Journal of Infection. 2020 Aug 25. 
 
Gunning FM, Anguera JA, Victoria LW, Arean PA. A Digital Intervention Targeting Cognitive 
Control Network Dysfunction in Middle Age and Older Adults with Major Depression. Under 
Review, Translational Psychiatry. 
 
Jaywant A, Vanderlind WM, Alexopoulos GS, Fridman CB, Perlis RH, Gunning FM. Frequency 
and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19. 
medRxiv. 2020 Jan 1. 
 
Kollins SH, DeLoss DJ, Cañadas E, Lutz J, Findling RL, Keefe RS, Epstein JN, Cutler AJ, 
Faraone SV. A novel digital intervention for actively reducing severity of paediatric ADHD 
(STARS-ADHD): a randomised controlled trial. The Lancet Digital Health. 2020 Feb 24. 
 
Zhou H, Lu S, Chen J, Wei N, Wang D, Lyu H, Shi C, Hu S. The landscape of cognitive function 
in recovered COVID-19 patients. Journal of Psychiatric Research. 2020 Oct 1;129:98-102. 

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Appendix A  
 
Not applicable.