An Exploratory Study to Assess the Sustained Effects of Digital Therapy in Pediatric Subjects 8 to 12 Years Old With Attention Deficit Hyperactivity Disorder (ADHD)
Phase: NA
Conditions: Attention Deficit Disorder With Hyperactivity
Sponsor: Akili Interactive Labs, Inc.

Akili Interactive Labs, Inc. 
“EVO” Revision 4.3C, ADHD Therapeutic Game 
1.02 
Akili-001R 
  
    1 
Confidential 
1.02/25-Jul-16 
 
 
Aug 09, 2016 
 
 
 
 
Akili-001R 
Version 1.02 
A randomized, controlled parallel-group, intervention study 
to assess at-home, game-based digital therapy for treating 
pediatric participants ages 8 to 12 years old with Attention 
Deficit Hyperactivity Disorder (ADHD) 
 
Date: July 25, 2016 
 
Version: 1.02 
 
 
Principal Investigator: 
Medical Monitor: 
 
Scott H. Kollins, Ph.D. 
Andrew Krystal, M.D. 
 
 
 
 
 
 
 
Akili Interactive Labs, Inc. 

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PROTOCOL APPROVAL PAGE 
 
Study Title: A randomized, controlled parallel-group, intervention study to assess at- 
home game-based digital therapy for treating pediatric participants ages 8 to 12 years old 
with Attention Deficit Hyperactivity Disorder (ADHD). 
Version: 
1.02 
 
Date of Issue: 
July 25, 2016 
 
Study Sponsor: 
Akili Interactive Labs, Inc. 
125 Broad St., 4th Floor 
Boston, MA 02110 
 
 
We, the undersigned, have read and approve this protocol and agree on its content. 
 
 
 
 
Sponsor Representative 
 
 
 
Date 
 
 
 
 
 
Principal investigator 
 
 
 
Date 

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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version 
Number/Amendment 
Approval Date 
1.00 
11/17/15 
1.01/ Amendment 1 
04/06/16 
1.02/Amendment 2 
07/25/16 
 
Summary of Changes 
Amendment 2: 
1) Updated information regarding participant’s ability to access 3rd party applications, 
download additional applications, and store personal information. 
2) Added requirement for sites to hold and document a discussion with each 
participant to describe intended and unintended use of the device, as well as 
study restrictions and requirements. 
3) Added requirement for sites to return the device to Akili for complete erasing of all the 
data entered prior to re-circulating the device. 
4) Updated description of the secondary and descriptive endpoints to be consistent with 
the current SAP 
. 
 
Amendment 1: 
1) Updated Akili business address to reflect current location 
2) Attention Performance Index (API) is an output of TOVA version 8. Specified 
“TOVA 8” where TOVA is mentioned in conjunction with API. Also added clarity 
that API is a “composite measure” 
3) Added analysis of TOVA non-composite measures to the secondary endpoints 
4) Added exclusion criteria that potential subjects could not have previously 
participated in any assessment of Akili’s videogame-like digital therapy 
5) Clarified the study design that the Investigators and Outcome Assessors are 
blinded to the treatment assignment. 
6) Added analysis of responders and descriptive analysis as exploratory endpoints 
7) Timing of interim analysis update to reflect N = 75/75 
8) Clarified that maximum enrolment, following interim analysis, is 1000 subjects 
9) Added a baseline visit expectation survey for the parents to complete 
10) To better preserve the blinding, removed the “A” / “B” labeling of the iPads 
(previously corresponding to treatment assignment) and included an anonymous 
serial number. A separate blinded treatment assignment list will be generated 
11) Clarified instructions for connecting via remote WiFi locations 
12) Updated the statistical analysis section to reference details that are described in a 
separate statistical analysis plan (SAP) and added a non-inferiority test to the 
primary objective 
13) Clarified subject replacement criteria to include subjects that don’t complete the in- 
clinic exit assessments 

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14) Require participants to be able to spell at least 2 words during EVO Words 
assessment 
15) Added requirement where same study staff administers the ADHD-RS, CGI, and 
IRS pre/post visits 
16) Capture any unblinding event in the CRF 

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PROTOCOL SYNOPSIS 
Name of Company 
Akili Interactive Labs, Inc., 125 Broad Street, 4th 
Floor, Boston, MA 02110 
 
Study Product 
“EVO”, 
Multi-tasking 
Game-Based 
Digital 
Therapy or “EVO” Words Game-Based Digital 
Therapy 
Protocol Number 
Akili-001R 
Protocol Title 
A 
randomized, 
controlled 
parallel-group, 
intervention study to assess at-home, game- 
based digital therapy for treating pediatric 
participants ages 8 to 12 years old with Attention 
Deficit Hyperactivity Disorder (ADHD) 
Main Criteria for Inclusion 
Inclusion 
• 
Age 8 years to 12 years, inclusive, at 
the time of parental informed consent 
• 
Male or female 
• 
Confirmed ADHD diagnosis, any 
presentation, at Screening based on 
DSM-V criteria and established via the 
MINI-KID administered by a trained 
clinician 
• 
Screening/Baseline (Visit 1 or 1a) 
score on the clinician-rated ADHD-RS- 
IV score > 28 
• 
Screening/Baseline (Visit 1 or 1a) 
score on the TOVA 8 API < -1.8 
• 
Not undergoing pharmacological 
treatment with methylphenidate or 
amphetamine-based products at time 
of Screening; or, if undergoing 
pharmacological treatment, must be 
willing and appropriate (i.e. not 
optimally treated in the investigator’s 

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judgment) to wash out of current 
regimen. 
• 
Ability to follow written and verbal 
instructions (English), as assessed by 
the PI and/or study coordinator 
• 
Estimated IQ score > 80 as assessed 
by the Kaufmann Brief Intelligence 
Test, Second Edition (KBIT-II) 
• 
Ability to comply with all the testing and 
requirements. 
Exclusion 
• 
Current, controlled (requiring a 
restricted medication) or uncontrolled, 
comorbid psychiatric diagnosis , based 
on MINI-KID and subsequent clinical 
interviewing, with significant symptoms 
including but not limited to post- 
traumatic stress disorder, psychosis, 
bipolar illness, pervasive 
developmental disorder, severe 
obsessive compulsive disorder, severe 
depressive or severe anxiety disorder, 
conduct disorder, or other symptomatic 
manifestations that in the opinion of the 
Investigator that may confound study 
data/assessments. Participants with 
clinical history of learning disorders will 
be allowed to participate, provided the 
disorder does not impact their ability to 
participate in the trial based on PI 
judgment 
• 
Participants who are currently treated 
with a non-stimulant medication for 
ADHD (i.e., atomoxetine, clonidine, 
guanfacine) 
• 
Initiation within the last 4 weeks of 
behavioral therapy. Participants who 
have been in behavior therapy 
consistently for more than 4 weeks 
may participate provided their routine is 
unchanged during the course of the 
study. Participants planning on 
changing or initiating behavior therapy 
during the course of the study will be 
excluded. 

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• 
Participant is currently considered a 
suicide risk in the opinion of the 
Investigator, has previously made a 
suicide attempt, or has a prior history 
of, or is currently demonstrating active 
suicidal ideation or self-injurious 
behavior as measured by C-SSRS at 
screening. 
• 
Motor condition (e.g., physical 
deformity of the hands/arms; 
prostheses) that prevents game playing 
as reported by the parent or observed 
by the investigator. 
• 
Recent history (within the past 6 
months) of suspected substance abuse 
or dependence. 
• 
History of seizures (exclusive of febrile 
seizures), or significant motor or vocal 
tics, including but not limited to 
Tourette's Disorder. 
• 
Has participated in a clinical trial within 
90 days prior to screening. 
• 
Diagnosis of or parent-reported color 
blindness (Confirmed in-clinic via ICBT) 
• 
Uncorrected visual acuity (Confirmed 
in-clinic via ability of subject to play the 
game) 
• 
Regular use of psychoactive drugs 
(other than stimulant) that in the 
opinion of the Investigator may 
confound study data/assessments. 
• 
Any other medical condition that in the 
opinion of the investigator may 
confound study data/assessments. 
• 
Has a sibling also enrolled/currently 
participating in the same study 
• 
Has previously participated in a study 
of Akili’s videogame-like digital therapy 
Concomitant Medication and Treatment 
• 
With the exception of common over the 
counter (OTC) (e.g. ibuprofen, 
acetaminophen) and prescription 
medications (e.g. antibiotics) for minor 

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transient ailments, regular use of 
concomitant medications (i.e., sleep 
aids, etc.) are not permitted during the 
study. Transient use of some 
medications (i.e., non-sedating 
antihistamines to treat seasonal 
allergies) may be permitted on a case- 
by-case basis with PI and medical 
monitor review/approval. Families should 
advise the study staff if it becomes 
necessary to use other types of 
medication. Study investigators can 
approve short-term use of other 
medications that are not anticipated to 
confound study assessments. 
• 
Initiation of or significant changes in non- 
pharmacological treatment for ADHD is 
not permitted during the course of the 
study. Participants actively engaged in 
non-pharmacological treatment at 
Screening, may be eligible if they meet 
all inclusion criteria and do not undergo 
changes to their treatment during the 
course of the study. 
Study Objective 
To evaluate the effects of EVO Multitasking 
digital therapy versus EVO Words digital therapy 
on attentional functioning (measured by the 
TOVA) and symptoms in children diagnosed 
with ADHD 
Study Design 
Blinded (Investigator / Outcome Assessor), 
Randomized, Parallel-group 
Treatment Regimen 
25 minutes/day for 5 days/week of either EVO 
multitasking digital therapy or EVO Words digital 
therapy across the 4-week (28 Day) treatment 
period. 
Duration of Study Participation 36 days 
Number of Participants 
A minimum of 300 to a maximum of 1,000 
participants will be enrolled to achieve a 
minimum of 300 to a maximum 900 completed 

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participants (n=150 - 450 in each of 2 arms) 
evaluable 
Number of Sites 
6-9 
Primary Endpoint 
Change (from Study Day 0 to Study Day 28) on 
the Attention Performance Index (API), an 
overall composite score, from the Test of 
Variables of Attention (TOVA 8) 
Secondary Endpoints 
Change (from Study Day 0 to Study Day 28) in: 
• 
ADHD Symptoms as reported on the 
ADHD-RS 
total 
score, 
ADHD-RS 
Inattentive 
Sub-scale, 
ADHD-RS 
hyperactivity sub-scale, BRIEF working 
memory 
percentile, 
BRIEF 
inhibit 
percentile, Impairment Rating Scale, and 
Clinical Global Impression Scale. 
• 
Objective Working Memory as measured 
by the CANTAB spatial working memory 
test 
• 
 Objective Inhibition as measured by the 
TOVA commission error standard score 
in half-2. 
Exploratory/Descriptive 
Endpoints 
Analysis includes: 
• 
Responder 
analysis, 
percentage 
of 
responders to primary and secondary 
endpoints 
• 
Descriptive 
analysis 
of 
child/parent 
surveys, treatment regimen compliance, 
demographics, 
missing 
data, 
site 
poolability, and any resulting treatment 
related AEs 
• 
Analysis of secondary symptom and 
executive function endpoints adjusted for 
baseline parent expectations 
Interim Analyses 
An interim analysis will be conducted at N =75 / 
75 (EVO Multitask / EVO Words) to confirm 
powering and to finalize sample size 

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INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and I agree that it contains all 
necessary details for me and my staff to conduct this study as described. I will 
personally oversee the conduct of this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. 
 
I will provide all study personnel under my supervision with copies of the protocol 
and access to all information provided by Akili Interactive Labs, Inc. [Sponsor]. I 
will discuss this material with them to ensure that they are fully informed about the 
efficacy and safety parameters and the conduct of the study in general. I am aware 
that, before beginning this study, the institutional review board responsible for such 
matters must approve this protocol in the clinical facility where it will be conducted. 
I agree to make all reasonable efforts to adhere to the attached protocol. 
 
I agree to provide all participants with informed consent forms, as required by 
government and International Conference on Harmonization regulations. I further 
agree to report to the sponsor any adverse experiences in accordance with the 
terms of this protocol and U.S. Food and Drug Administration regulation 21 Code 
of Federal Regulations 812.2(b). 
 
 
 
 
Principal investigator Name (print) 
 
 
 
 
Signature 
 
 
 
Date 

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Contents 
 
 
.................................................................................................................1 
Akili-001R ............................................................................................................... 1 
Version 1.01 ........................................................................................................... 1 
Protocol Approval Page ....................................................................................................... 2 
Protocol Version and Amendment Tracking ....................................................................... 3 
Protocol Synopsis ................................................................................................................ 5 
investigator statement ........................................................................................................ 11 
1. Introduction ...................................................................................................... 17 
1.1 Background ......................................................................................... 17 
1.2 
Clinical Experience with Study Agent(s) ......................................... 17 
1.2.2  Rationale ........................................................................................ 19 
2. Objectives ....................................................................................................... 22 
2.1 
Primary Objective ........................................................................... 22 
2.2 
Secondary Objectives ..................................................................... 22 
2.3 
Exploratory & Descriptive Objectives .............................................. 22 
3. Subject Selection ............................................................................................. 23 
3.1 
Inclusion Criteria ............................................................................. 23 
3.2 
Exclusion Criteria ............................................................................ 23 
4. STUDY DESIGN  4.1.  overview of Study ........................................................ 26 
4.2 
Treatment Arms .............................................................................. 27 
4.3 
Screening/Baseline Procedures ..................................................... 30 
4.4 
Washout Procedures & Screening/Baseline (Post Washout) 
Procedures ..................................................................................... 33 
4.5 
Treatment Procedures – In-Home Game Play and Post- 
Treatment Visit ............................................................................... 35 
4.6 
Procedures to minimize bias and blinding to treatment 
assignment ..................................................................................... 37 
4.6.1 
Procedures to minimize bias in parents and 
participants. ....................................................................... 38 

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4.6.2 
Procedures to blind/minimize bias in site staff and 
investigators. ..................................................................... 38 
4.6.3 
Procedures in the event of possible or probable 
unblinding .......................................................................... 38 
5 Study Device ..................................................................................................... 40 
5.1 Study Device Usage ............................................................................ 40 
5.2 Potential Benefits/Risks of Study Device ............................................. 41 
5.3 Procedures for Monitoring Compliance and Replacing Participants .... 42 
5.3 Discontinuation of Study Device .......................................................... 43 
6 Concomitant Medications .................................................................................. 44 
6.1 Allowed Medications ................................................................. 44 
6.2 Prohibited Medications ............................................................. 44 
7.0 Adverse Device Effect Reporting and Follow-up ............................................ 45 
7.1 
Definitions ......................................................................................... 45 
Unanticipated Adverse Device Effects (UADEs) ....................................... 45 
7.2 
Assessment ..................................................................................... 46 
7.2.1 Time Frame ....................................................................................... 46 
An ADE observed from the time of randomization through the final 
study visit (day 28) will be collected in clinical database eCOS ...... 46 
7.2.2 
Causality Rating ............................................................................. 46 
7.2.3 Severity of Adverse Device Effects .................................................. 46 
7.3 Previously Noted Adverse Device Effects ........................................... 47 
7.4 
Reporting .......................................................................................... 47 
7.4.2 Regulatory Reporting of Unanticipated Adverse Device Effects ....... 48 
8.0 STATISTICAL Analysis Plan and Determination of Sample Size ................... 49 
8.1 Primary Analysis .................................................................................. 49 
8.2 Secondary Analyses ............................................................................ 50 
8.2.1 Additional TOVA Outcome Measures (non-composite 
measures) ......................................................................... 50 
8.2.2 Attention Deficit and Hyperactive Disorder Rating Scale 
(ADHD-RS) ....................................................................... 50 
8.2.3 Cambridge Neuropsychological Test Automated Battery 
(CANTAB): Spatial Working Memory (SWM) .................... 51 
8.2.4 Behavior Rating Inventory of Executive Function 
(BRIEF) .................................. Error! Bookmark not defined. 
8.2.5 Clinical Global Impression Scale (CGI-S) Error! Bookmark not 
defined. 
8.3 Exploratory Analyses ........................................................................... 51 
8.3.1 Responder Analysis ............................................................... 51 
8.3.2 Gameplay Surveys ................................................................ 51 
8.3.3 Additional Endpoints & Expectation Adjustment ............. Error! 
Bookmark not defined. 
8.4 Safety Analysis .................................................................................... 52 

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8.5 Descriptive Analyses ........................................................................... 52 
8.5.1 Compliance ................................. Error! Bookmark not defined. 
8.5.2 Group Demographics and Site Differences ... Error! Bookmark 
not defined. 
8.6 General Statistical Methods ................................................................ 52 
8.6.1 Hypothesis Tests and Multiplicity Adjustments ...................... 52 
8.6.2 
Analysis Populations and Missing Data ............................ 53 
8.6.4 Power and Sample Size ........................................................ 54 
9. Data and Safety Monitoring .............................................................................. 55 
9.1 
Endpoint Determination .................................................................. 55 
9.2 
Safety Monitoring ............................................................................ 55 
9.3 
Data Management to Maintain Blinding .......................................... 55 
10 
Data Monitoring and Quality Control ......................................................... 56 
10.1 Required Data ................................................................................... 56 
10.2 Subject and Clinical Data .................................................................. 56 
11 
STUDY RESPONSIBILITIES .................................................................... 57 
11.1 Study Data Reporting and Processing .............................................. 57 
11.2 Training ............................................................................................. 57 
11.3 Monitoring the Investigational Sites ................................................... 57 
11.4 Study Documentation ........................................................................ 58 
11.5 Protocol Deviations ........................................................................... 58 
11.6 Study Supply Accountability .............................................................. 59 
11.7 Data Transmittal and Record Retention ............................................ 59 
11.8 Study Closeout .................................................................................. 59 
11.9 Audit/Inspections ............................................................................... 60 

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Abbreviations 
ADHD 
Attention Deficit Hyperactivity Disorder 
DSM-V 
Diagnostic and Statistical Manual of Mental Health-Fifth Edition 
MINI-KID 
MINI International Neuropsychiatric Interview for Children and Adolescents 
ADHD-RS- 
IV 
Attention Deficit Hyperactivity Disorder Rating Scale 
TOVA 
Test of Variables of Attention 
API 
Attention Performance Index 
KBIT 
Kaufman Brief Intelligence Test 
PI 
Principal Investigator 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ICBT 
Ishihara Color Blindness Test 
OTC 
Over the counter 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
BRIEF 
Behavior Rating Inventory of Executive Function 
CGI-I 
Clinical Global Impression-Improvement 
IRS 
Impairment Rating Scale 
ASD 
Autism Spectrum Disorder 
LD 
Learning Disability 
CANTAB 
SWM 
Cambridge Neuropsychological Test Automated Battery Spatial Working 
Memory 
ICF 
Informed Consent Form 
DCRI 
Duke Clinical Research Institute 
SSRI 
Selective Serotonin Reuptake Inhibitor 
MAOI 
Monoamine Oxidase Inhibitor 
ADE 
Adverse Device Effect 
UADE 
Unanticipated Adverse Device Effect 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
IRB 
Institutional Review Board 
CPT 
Continuous Performance Test 
ComSS 
Commission Error Standard Score 
ROC 
Receiver Operator Curve 
SAP 
Statistical Analysis Plan 
APP 
Application 

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GCP 
Good Clinical Practice 
CMP 
Clinical Monitoring Plan 
HIPPA 
Health Insurance Portability and Accountability Act 

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1. INTRODUCTION 
 
1.1 Background 
Front-line treatment for ADHD includes the use of stimulant medications, which is 
effective in reducing the core symptoms of the disorder but are associated with 
well-documented side effects. In addition, there is recent evidence that 
pharmacological treatment may not show optimal benefits in some cognitive 
domains. (Biederman, J, et al 2015). Computerized cognitive training programs 
have shown some promise to improve working memory and attention in ADHD 
populations. (Klinberg, T.)[Further research is needed to validate the 
effectiveness of currently available computerized cognitive interventions as well 
as for consumer-grade gamified therapies that are still being developed. 
 
This protocol will evaluate the effects of a novel, highly-immersive, videogame- 
based interventions for ADHD Project: EVO that was derived from a comparable 
cognitive training program shown to have robust effects on working memory, 
attention, and related constructs in older adults.(Angora, J.A., et al) EVO Multitask 
incorporates adaptive, simultaneous cognitive tasks into a consumer-grade action 
video gaming-like platform with high-quality graphics and reward loops, and is 
deployed on mobile devices (i.e., tablets). We hypothesized that EVO Multitask 
digital therapy would be well-tolerated and feasible to administer to pediatric 
participants with ADHD, and would improve functioning in relevant cognitive 
domains. As a control, this protocol will also evaluate the effects of a highly- 
immersive educational videogame, “EVO Words” in a matched, time-on-task 
manner. 
 
Novel, cost-effective, and easy to implement/disseminate non-pharmacological 
interventions for ADHD could be helpful for many participants given limitations of 
other approved interventions. 
 
1.2   Clinical Experience with Study Agent(s) 
Akili has evaluated the EVO Multitask digital therapy in various clinical populations 
as described below. 
 
Most relevant to the current protocol, a multi-site, open-label, proof-of- 
concept study was recently completed in children with ADHD. In this study, 
ADHD (N = 40, Mean Age = 10.3 years) and age-matched neuro-typical control (N 
=40, Mean Age = 10.5 years) participants were recruited from 3 sites and screened 
for enrollment. A one month, at-home intervention followed, which 

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consisted of 5 weekly 30-minute sessions of digital therapy play. Participants then 
returned to the clinic for post-intervention assessment. Measures of cognitive 
function (TOVA, CANTAB) and behaviors (Parent-BRIEF) were collected at 
Screening and Post-Intervention. Tolerability, compliance, and acceptability were 
also assessed. No treatment related adverse events were reported. The ADHD 
group completed an average of 81% of the required at-home sessions, and 
reported a high level of enjoyment on average. The Attention Performance Index 
composite score from the TOVA improved significantly from pre-post intervention 
(p = 0.033, Cohen’s d = 0.35) in the ADHD group. There was no change in the 
neuro-typical group (p = 0.30, Cohen’s d = 0.16). A post-hoc sub-population 
analysis of a large group of ADHD participants with greater cognitive and symptom 
severity at Baseline (TOVA API <= -1.8 & ADHD-RS >=30) showed a larger effect 
of the intervention (p = 0.003, Cohen’s d = 0.71). The CANTAB Spatial Working 
Memory test showed statistically significant improvements on 9 of its 19 reported 
measures for the ADHD group while the neuro-typical group improved on 3 of the 
19 measures. For the Parent-BRIEF, the ADHD group showed improvements for 
working memory, however this measure did not meet the alpha criterion for 
multiple comparisons. No change was found for the Parent-BRIEF in the neuro- 
typical population. Results from this proof-of-concept study provide initial support 
for this novel, consumer-grade video game intervention as a potential treatment 
for attention and working memory symptoms in pediatric ADHD populations. 
 
Additional studies using EVO Multitask in related populations include: 
 
A feasibility study was conducted at a small college for individuals with 
ADHD and other related learning difficulties. Forty-four students with a 
diagnosis of ADHD, ASD, LD (or a combination thereof), were asked to play 
EVO Multitask in their dorm rooms for 30 minutes/day for 1 week. The study 
showed that EVO Multitask was generally engaging and the one week protocol 
was feasible. 
General Results: 
• 
Over the week, participants were able to complete, on average, 25% 
progress through the game (matching the expected pace of 100% 
progress through 4 weeks). 
• 
The participants demonstrated an expected deficit in baseline game 
performance when playing in the multi-task environment as compared to 
single-task, confirming an interference processing deficit. 

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• 
Over the week protocol, there was significant improvement in subject 
reaction time, as measured in the EVO Multitask program. 
• 
No treatment related adverse events were reported. 
 
In a pilot study of pediatric sensory processing disorder at the University of 
California, San Francisco (UCSF), 45 children ages 6 to 14 (23 with sensory 
processing disorders / 22 age-matched neuro-typical children), were asked to play 
EVO Multitask at home for 30 minutes/day, 5 days a week, for 4 weeks. Both 
groups demonstrated that EVO was generally engaging and a 4-week at-home 
protocol in these populations was feasible. 
General Results: 
• 
Participants completed, on average, greater than 70% of the game 
sessions. 
• 
Over the first ~1.5 weeks of at-home play, there was improvement (~70 – 
150%) in reaction time, as measured in the EVO program. 
• 
No treatment related adverse events were reported. 
 
In a feasibility study at the Center for Autism Research Disorders (CARD- 
ABA Clinic), 10 children with low-functioning autism ages 4 to 14, were 
evaluated for their ability to engage with the EVO Multitask digital therapy during 
an in-clinic visit. Optionally they could take the game home for 1 week of at-home 
intervention play. 
General Results: 
• 
Younger participants with more severe ASD were unable to engage with 
EVO Multitask (the digital therapy mechanics and instruction were too 
difficult). 
• 
Two of the older participants with somewhat less impairment took EVO 
Multitask home. These participants completed less than 25% of the game 
over the week, implying that at-home gameplay may not be feasible for 
this population. 
• 
No treatment related adverse events were reported in any of the 
participants. 
 
Additionally, Akili is currently conducting ongoing research in several additional 
clinical populations including geriatric depression, traumatic brain injury, 
Parkinson’s disease, cerebrovascular disease, and prodromal Alzheimer’s 
disease. To date no treatment related adverse events have been reported. 
 
 
1.2.2 Rationale 
ADHD is one of the most common pediatric psychiatric conditions and best 
practice for its treatment includes both pharmacological (usually psychostimulants 

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– methylphenidate or amphetamine) and non-pharmacological (behavioral or 
cognitive-behavioral therapy). These treatment modalities have demonstrated 
incontrovertible short-term benefits across core symptoms of ADHD and 
associated impairments. However, there are limitations to current best practices 
for the treatment of ADHD. 
With respect to pharmacological interventions, they are accompanied by adverse 
events in many children, do not normalize functioning, and adherence rates over 
time are generally low. The latter aspect is likely related to the fact that longer-term 
benefits of medication for ADHD are modest. Longitudinal studies have shown that 
acute improvements in ADHD symptoms and functioning are not maintained 
beyond 24-36 months. 
With respect to non-pharmacological interventions, access to such services can 
be a challenge for a number of reasons, including the number of qualified providers 
and coverage by third-party payers. 
Given these limitations to current standards of care, there is a strong need for the 
development of additional interventions for ADHD that can be easily and widely 
disseminated. Given the central role of attention and other aspects of cognition in 
the pathophysiology of ADHD, interventions that specifically target these 
constructs in safe and effective ways are particularly needed. 
In recent years, there has been considerable interest in the use of computer-based 
software and to improve various aspects of cognition across a range of clinical 
populations, including those with ADHD. The CogMed Working Memory Training 
platform was one of the first interventions in this genre to be explored specifically 
with ADHD and showed promising results in several randomized studies. 
Although there are multiple products in the marketplace that make various claims 
about effects on cognition in general, and in some cases, ADHD specifically, there 
have been no large scale, randomized trials of a digital therapeutic intervention 
versus an educational control intervention. Additionally, no approved treatments 
have been designed to provide an engaging, consumer-level experience that will 
promote high compliance when administered remotely (i.e., outside of a clinic). 
This study will fill this gap with a large (minimum of 300 participants) randomized 
parallel group, controlled trial. Participants will be randomized (1:1) to receive 
either the EVO Multitask experimental intervention or the EVO Words educational 
control and instructed to play the digital therapies for typically 25 minutes/day for 
5 days/week over a 4 week treatment period. Change in Baseline on the Attention 
Performance Index from the TOVA 8 will serve as the primary outcome variable 
and will allow for a determination of whether EVO Multitask significantly improves 
attentional functioning in pediatric participants with ADHD. Secondary measures 
will include measures of ADHD symptoms, other measures of cognition and 
executive functioning, and measures of patient and parent/caregiver experience 
and satisfaction. 

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The therapeutic play regimen for the current study (typically 25 minutes/day; 5 
days/week; 4 weeks) was established based on previous work with the EVO 
Multitask digital therapy. Specifically, a proof-of-concept study demonstrated that 
this regimen resulted in significant improvements in API scores in a sample of 
children with similar characteristics as proposed for this study. Results from the 
current study may also inform the development of additional dose-finding studies 
to determine whether additional (or less) game play might yield different results. It 
will also form the basis of additional studies to examine the durability of the 
intervention over time. 

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2. OBJECTIVES 
To evaluate the effects of EVO Multitask game-based digital therapy versus EVO 
Words game-based digital therapy on attentional functioning (measured by the 
TOVA), ADHD symptoms, cognitive/executive functioning, and clinical impairment, 
in children diagnosed with ADHD. 
 
2.1  Primary Objective 
To evaluate the effects of EVO Multitask play versus EVO Words play on 
attentional functioning (measured by the API change score from the TOVA 8). 
 
2.2  Secondary Objectives 
To evaluate the effects of EVO Multitask play versus EVO Words play on ADHD 
symptoms (measured via a clinician and parent rating scales of ADHD symptoms) 
 
To evaluate the effects of EVO Multitask play versus EVO Words play on objective 
working memory as measured by the CANTAB Spatial Working Memory (SWM) 
computerized test. 
 
To evaluate the effects of EVO Multitask play versus EVO Words play on objective 
inhibition as measures by the TOVA commission error standard score in TOVA 
half-2. 
 
2.3 Exploratory & Descriptive Objectives 
To explore the percentage of responders (defined in the Statistical Analysis Plan) 
to primary and secondary objectives along with descriptive analysis of child/parent 
surveys, treatment regimen compliance, demographics, secondary symptom / 
executive function measures adjusted for baseline parent expectation, and any 
resulting treatment related AEs. In addition multiple sensitivity analyses will be 
conducted to assess the effects of site poolability, age, gender, missing data (if 
appropriate), and baseline TOVA API. 

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3. SUBJECT SELECTION 
 
3.1 Inclusion Criteria 
To be eligible for this trial, participants must meet all of the following criteria: 
 
1. Age 8 years to 12 years, inclusive, at the time of parental informed 
consent 
2. Male or female 
3. Confirmed ADHD diagnosis, any presentation, at Screening based on 
DSM-V criteria and established via the MINI-KID administered by a 
trained clinician 
4. Screening/Baseline (Visit 1 or 1a) score on the clinician-rated ADHD- 
RS-IV score > 28 
5. Screening/Baseline (Visit 1 or 1a) score on the TOVA API < -1.8 
6. Not undergoing pharmacological treatment with methylphenidate or 
amphetamine-based products at time of Screening; or, if undergoing 
pharmacological treatment, must be willing and appropriate (i.e. not 
optimally treated in the investigator’s judgment) to wash out of current 
regimen. 
7. Ability to follow written and verbal instructions (English), as assessed 
by the PI and/or study coordinator 
8. Estimated IQ score > 80 as assessed by the Kaufmann Brief 
Intelligence Test, Second Edition (KBIT-II) 
9. Ability to comply with all the testing and requirements. 
 
3.2  Exclusion Criteria 
If a subject meets any of the following criteria, he or she may not be enrolled in the 
study: 
 
1. Current, controlled (requiring a restricted medication) or uncontrolled, 
comorbid psychiatric diagnosis , based on MINI-KID and subsequent 
clinical interviewing, with significant symptoms including but not 
limited to post-traumatic stress disorder, psychosis, bipolar illness, 
pervasive developmental disorder, severe obsessive compulsive 
disorder, severe depressive or severe anxiety disorder, conduct 
disorder, or other symptomatic manifestations that in the opinion of 
the Investigator may confound study data/assessments. Participants 
with clinical history of learning disorders will be allowed to participate, 
provided the disorder does not impact their ability to participate in the 
trial based on PI judgment 
2. Participants who are currently treated with a non-stimulant medication 
for ADHD (i.e., atomoxetine, clonidine, guanfacine) 
3. Initiation within the last 4 weeks of behavioral therapy. Participants 
who have been in behavior therapy consistently for more than 4 
weeks may participate provided their routine is unchanged during the 

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course of the study. Participants planning on changing or initiating 
behavior therapy during the course of the study will be excluded. 
4. Participant is currently considered a suicide risk in the opinion of the 
Investigator, has previously made a suicide attempt, or has a prior 
history of, or is currently demonstrating active suicidal ideation or self- 
injurious behavior as measured by C-SSRS at screening. 
5. Motor condition (e.g., physical deformity of the hands/arms; 
prostheses) that prevents playing the digital therapy as reported by 
the parent or observed by the investigator. 
6. Recent history (within the past 6 months) of suspected substance 
abuse or dependence. 
7. History of seizures (exclusive of febrile seizures), or significant motor 
or vocal tics, including but not limited to Tourette's Disorder. 
8. Has participated in a clinical trial within 90 days prior to screening. 
9. Diagnosis of or parent-reported color blindness (Confirmed in-clinic 
via ICBT) 
10. Uncorrected visual acuity (Confirmed in-clinic via ability of subject to 
play the game) 
11. Regular use of psychoactive drugs (non-stimulant) that in the opinion 
of the Investigator may confound study data/assessments. 
12. Any other medical condition that in the opinion of the investigator may 
confound study data/assessments. 
13. Has a sibling also enrolled/currently participating in the same study 
14. Has previously participated in a study of Akili’s videogame-like digital 
therapy 
 
3.3 Concomitant Medications and Treatment 
 
1. With the exception of common over the counter (OTC) (e.g. ibuprofen, 
acetaminophen) and prescription medications (e.g. antibiotics) for 
minor transient ailments, regular use of concomitant medications (i.e., 
sleep aids, etc.) are not permitted during the study. Section 6 lists 
allowed and prohibited medications. Transient use of some 
medications (i.e., non-sedating antihistamines to treat seasonal 
allergies) may be permitted on a case-by-case basis with PI and 
medical monitor review/approval. Families should advise the study 
staff if it becomes necessary to use other types of medication. Study 
investigators can approve short-term use of other medications that are 
not anticipated to confound study assessments. 
 
2. Initiation of or significant changes in non-pharmacological treatment for 
ADHD is not permitted during the course of the study. Participants 
actively engaged in non-pharmacological treatment at Screening, may 

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be eligible if they meet all inclusion criteria and do not undergo 
changes to their treatment during the course of the study. 

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4. STUDY DESIGN 
 
4.1. OVERVIEW OF STUDY 
The study will be a blinded (investigators and outcome assessors) randomized, 
parallel group, controlled trial of EVO Multitasking game-based digital therapy 
versus EVO Words game-based digital therapy. 
The trial will consist of 3 primary phases: Screening, Washout/Baseline, and 
Treatment. During the Screening Phase (Day -28 to Day -7), participants will 
undergo screening to evaluate eligibility for the study. Screening may take place 
up to 28 days before the Baseline Visit (Day 0). For those children currently on 
medication for ADHD the Washout period will begin 7 days prior to Baseline where 
treatment will be discontinued. On Day 0, the Baseline visit will occur wherein 
additional eligibility criteria will be established (ADHD-RS scores and API scores). 
The Treatment Phase (Day 1 to Day 27) will involve playing the digital therapy at 
home for each participant followed by an In-Clinic assessment on Day 28 to assess 
key outcomes. Compliance with play requirements will be monitored remotely 
during this phase. 
Participants for this study will be male and female children between the ages of 8 
years, 0 months and 12 years 11 months at the time of consent who meet full 
criteria for ADHD, any subtype, as assessed by the MINI-KID. Children must also 
be medically healthy, willing to discontinue any ongoing treatment, and free from 
other significant psychiatric comorbidities. 
Two different electronically administered digital therapies will comprise the 
treatments under study: 
Treatment #1 will consist of Project: EVO Mobile Game-Based Digital Therapy 
Intervention (EVO Multitasking therapy), a proprietary system based on a 
prototype cognitive training videogame called Neuroracer. EVO Multitasking digital 
therapy was designed to incorporate the fundamental features of Neuroracer into 
a state-of-the-art mobile video game-like platform, which deploys modern 
videogame graphics, engaging reward loops, and real-time adaptive mechanics to 
dynamically personalize difficulty based on the user’s ability. EVO Multitasking 
therapy employs a perceptual discrimination attention/memory task as well as a 
continuous motor 'driving' task. Performance on these tasks are assessed in 
isolation and when performed together to calculate a performance index for each 
individual user. A personalized multi-task training regimen is automatically 
configured and delivered to the user, and is optimized adaptively to increase multi- 
task performance. As players proceed through the therapy periodic re-calibration 
occurs to maintain an optimal difficulty level. 
 
Treatment #2 will consist of the EVO Words Mobile Game-Based Digital-Therapy 
Intervention (EVO Words Therapy), which is based off a popular Brain Training 

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PERIOD 
Screening/Baselinea 
Washouta 
Baselinea 
Stimulant washout 
group only 
1a 
0 
Xc 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
At-Home 
Intervention 
Post- 
Treatment 
Visit 
Visit 
1 
- 
2 
Day 
0 or up to 7 days prior to Baseline for those 
children requiring washout 
1 - 27 
28 
Informed consent and child assent 
Demographic & contact information 
X 
X 
Developmental & Medical History 
X 
MINI-KID 
X 
Kaufmann Brief Intelligence Test, Second 
Edition 
C-SSRS assessment 
X 
X 
X 
Ishihara Color Blindness Test 
X 
Discontinue Medication 
TOVA assessment 
Xd 
X 
CANTAB Spatial Working Memory 
Xd 
X 
ADHD-RS 
Xd 
X 
Parent BRIEF 
Xd 
X 
Impairment Rating Scale 
Xd 
X 
Clinical Global Impressions Scaleb 
Xd 
X 
Randomization 
Xd 
EVO Multitasking intervention or EVO 
Words intervention in-clinic assessment 
(+Parent Expectation Survey) 
At-home EVO Multitasking intervention or 
EVO Words intervention play 
Xd 
X 

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Optional weekly performance report to 
parents 
X 
Compliance monitoring and feedbackf 
X 
Patient Experience/Satisfaction Measure- 
Parent Version 
Patient Experience/Satisfaction Measure- 
Child Version 
X 
X 
Safety assessments /AEs and 
concomitant medication / therapy 
X 
X 
X 
X 
Collect iPads & Return to Akili for erasing 
Xg 
 
 
aParticipants who are not currently on ADHD medications at Screening will have a combined Screening/Baseline visit where all measures are completed. For participants currently 
treated with stimulant medications and who are eligible to initiate a washout period, a separate Baseline visit will be scheduled 3-7 days after Screening where the additional 
measures will be completed. 
bFor CGI measure, CGI Severity Scale will be assessed at Screening and CGI-Improvement Scale will be assessed at the Follow-Up Visit. 
cTo be initiated for participants who are currently treated with psychostimulants for ADHD at Screening; and for whom study participation is still indicated based on procedures 
described in Section 4.5. Washout should be scheduled at Screening visit and overseen by a qualified provider at each study site. 
dFor children currently not treated with stimulant medication, these procedures will occur at Visit 1. 
eFor children currently treated with stimulant medication who are eligible to continue following a washout of medication, these procedures will occur at Visit 1a. 
fCompliance with intervention play requirements will be monitored via automatic uploading of play information to DCRI and a daily email report to DCRI and the clinical sites from the 
sponsor or their designated representative. The sites will provide feedback to the parents (via a pre-established contact method and will indicate when play drops below the 
minimum requirements. 
gSites are required to return the device to Akili for complete erasing of all data entered prior to re-circulation of the device. This process must be documented on the iPad 
Accountability Log. 

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4.3 Screening/Baseline Procedures 
At the Screening/Baseline Visit (Visit 1) participants’ parents or legal caregivers 
will be asked to provide informed consent; children will provide assent that will be 
documented appropriately. Participants and their parents/caregivers will then 
undergo a comprehensive evaluation to determine eligibility and whether 
inclusion/exclusion criteria are met. All of the following assessments will be 
recorded in the CRF if the subject is recruited into the study. Medical and 
psychiatric history, and demographic information will be obtained. Current 
medications and those taken during the past 30 days. Lifetime history of ADHD 
treatments taken will be obtained. The Kaufman Brief Intelligence Test, Second 
Edition will be administered to children and they must score > 80 to continue in the 
study. The MINI-KID, a semi-structured interview, will be administered by qualified 
and trained clinicians to confirm ADHD diagnosis and determine whether 
psychiatric comorbidities are present. The C-SSRS, CGI-Severity, Ishihara Color 
Blindness Test, Impairment Rating Scale will then be completed. Ongoing medical 
issues will be assessed. Participants 
 
Specific Procedures to be completed at the Screening/Baseline Visit (Visit 1) for 
all participants include: 
 
• 
Informed consent with parent/caregiver; assent with child 
• 
Demographic and Family information: Age and gender should be recorded 
in the screening log and the full demographics should be recorded in the 
CRF. 
 
• 
Developmental and Medical History: Should be recorded in the screening 
log and in the CRF. 
 
• 
MINI-KID completed by a trained clinician: Should be recorded in the 
screening log and in the CRF. 
 
• 
C-SSRS (Lifetime): Should be recorded in the screening log and in the 
CRF. 
 
• 
Ishihara Color Blindness Test: Should be recorded in the screening log and 
in the CRF. 
 
• 
 Kaufman Brief Intelligence Scale, Second Edition: Age-adjusted raw 
scores and percentiles for Matrices, Vocabulary, and Composite should be 
recorded in the screening log and in the CRF. 

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• 
Assessment of Ongoing Medical Issues/Concomitant Treatments: Should 
be recorded in the CRF. 
 
Note that the following procedures will take place at the Screening/Baseline Visit 
(Visit 1) ONLY FOR THOSE PARTICIPANTS WHO ARE NOT CURRENTLY 
TREATED WITH PSYCHOSTIMULANTS: 
 
The child will complete the following procedures: 
 
• 
TOVA; Child must score <-1.8 on the API to remain eligible: The TOVA test 
will take approximately 25 minutes to complete. Separate instructions will 
be provided to the blinded raters to administer this test and to download and 
save the test results. The TOVA API score should be recorded in the CRF. 
 
• 
CANTAB Spatial Working Memory task: The CANTAB SWM task will take 
approximately 9 minutes to complete. Separate instructions will be provided 
to the blinded raters to administer this test and to download and save the 
test results 
 
While the child completes the TOVA and CANTAB, parents will complete the 
following procedures: 
 
• 
Clinician completed ADHD-RS; must score >28 to remain eligible: The 
results of the ADHD-RS should be recorded in the CRF. 
 
• 
Parent-Completed BRIEF: The parents should be instructed by a blinded 
rater to focus their evaluation over their child’s past week behavior. The 
BRIEF Raw, T, %ile, negativity, and inconsistency scores should be 
recorded in the CRF. 
 
• 
Impairment Rating Scale: A blinded rater will review the Impairment Rating 
Scale with the parent. The results of the Impairment Rating Scale should be 
recorded in the CRF. 
 
• 
CGI-Severity Scale. A blinded rater will complete the CGI-Severity scale 
based on all available information. The results of the CGI-Severity scale 
should be recorded in the CRF. 
 
• 
Randomization: The participants will be provided with an iPad which is 
engraved in the back with a serial number (“AL-###”). The iPads will be 
preloaded with either EVO Multitasking therapy or EVO Words therapy. A 
separate document will list the blinded treatment assignment. 

  
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• 
Break: Participants should be allowed a 10 minute break following the 
TOVA / CANTAB tests. During the break they may have a snack but no 
caffeinated beverages are allowed 
 
• 
In-Clinic Assessment/Training for EVO Multitasking therapy OR EVO 
Words therapy (depending upon randomization). The subject will only 
practice on the therapy to which they were randomized. The subject should 
play either EVO Multitask or Words for approximately 10 minutes. (Note: 
The parents should observe their child interact with the therapy as they will 
be asked to rate their expectations of possible benefit). Separate 
instructions will be provided to an unblinded clinical coordinator to log the 
subject into either the EVO or Words therapy. During the 10 minutes of in- 
clinic play, the unblinded coordinator should observe the participants play 
to ensure he or she can follow the rules (which are in English) of their 
assigned therapy. The unblinded coordinator should also make note of any 
motor conditions or uncorrected visual acuity that prevents proper game 
play. Participants that are unable to properly play their therapy will be 
withdrawn from the study. Note: For EVO Words the participant should be 
able to spell at least two words during the assessment. At the end of 
approximately 10 minutes the unblinded coordinator should have the 
subject stop his/her play (at an obvious break point in the game) and turn 
the iPad off. At this point, the parent should complete the Baseline 
Expectation Survey 
 
• 
Materials to go home: An unblinded coordinator should provide the parents 
with of a copy of their ICF and child assent along with the instructions for 
their child’s therapy. The parents should be told that their child is expected 
to play their therapy for typically 25 minutes/day, 5 days/week. NOTE: The 
parent and child should be told that no one except the child may play 
the therapy for any reason. The child should be provided with same iPad 
they previously played in the clinic along with a battery charger. In addition, 
both parent and participant should be instruction on intended and 
unintended use of the device. These are defined as: 
 
§ Intended use- Set up of the participant’s local WiFi network for 
internet access to push play and compliance data to the Akili 
secure severs, and completion of at-home interventional play 
for the assigned 25 minutes per day, during 5 days of each 
calendar week. 
 
§ Unintended use – Any and all other features or applications of 
the device, including accessing the internet, downloading of 
additional applications, use of features such as music, 
calendar, or notes, and inputting any personal information 
other than participant’s home WiFi network as described 
above. 

  
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4.4 Washout Procedures & Screening/Baseline (Post Washout) Procedures 
For participants who are currently treated with psychostimulants for ADHD 
and are still eligible to continue in the trial following Screening, procedures for 
washout and Baseline will be discussed with the parents/caregivers. 
 
Qualifications for treated participants to enroll in trial: Participants who meet full 
criteria for ADHD at Screening based on the MINI-KID, and who the PI believes 
are not optimally treated with current medication will be eligible to washout of their 
current medication regimen and enroll in the trial. Suboptimal response to current 
treatment may be assessed by the PI on the basis of MINI-KID symptom 
presentation and CGI-Severity scores that are 3 (minimally impaired) or higher. 
 
For those participants eligible to enroll and initiate washout of their current 
medication, treatment will be discontinued between 7 and 3 days prior to their 
scheduled Screening/Baseline Visit (Visit 1a). Study staff will be available via 
phone or unscheduled visit during this period should clinical issues rise that 
warrant attention. 
 
Note that the following procedures will take place at the Screening/Baseline (Visit 
1a) ONLY FOR THOSE PARTICIPANTS WHO WASHED OUT/ DISCONTINUED 
PSYCHOSTIMULANTS. Following their washout period, during Visit 1a, the child 
will complete the following procedures: 
 
• 
TOVA; Child must score <-1.8 on the API to remain eligible. The TOVA test 
will take approximately 25 minutes to complete. Separate instructions will 
be provided to the blinded raters to administer this test and to download and 
save the test results. The TOVA API score should be recorded in the CRF. 
 
• 
CANTAB Spatial Working Memory task: The CANTAB SWM task will take 
approximately 9 minutes to complete. Separate instructions will be provided 
to the blinded raters to administer this test and to download and save the 
test results 
 
While the child completes the TOVA and CANTAB, parents will complete the 
following procedures: 
 
• 
Clinician completed ADHD-RS; must score >28 to remain eligible: The 
results of the ADHD-RS should be recorded in the CRF. 
 
• 
Parent-Completed BRIEF: The parents should be instructed by a blinded 
rater to focus their evaluation over their child’s past week behavior The 
BRIEF Raw, T, %ile, negativity, and inconsistency scores should be 
recorded in the CRF. 

  
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• 
Impairment Rating Scale: A blinded rater will review the Impairment Rating 
Scale with the parent. The results of the Impairment rating Scale should be 
recorded in the CRF. 
 
• 
CGI-Severity Scale. A blinded rater will complete the CGI-Severity scale 
based on all available information. The results of the CGI-Severity scale 
should be recorded in the CRF 
 
• 
Randomization: The participants will be provided with an iPad which is 
engraved in the back with a serial number (“AL-###”). The iPads will be 
preloaded with either EVO Multitasking therapy or EVO Words therapy. A 
separate document will list the blinded treatment assignment. 
 
• 
Break: Participants should be allowed a 10 minute break following the 
TOVA / CANTAB tests. During the break they may have a snack but no 
caffeinated beverages are allowed 
 
• 
In-Clinic Assessment/Training for EVO Multitasking therapy OR EVO 
Words therapy (depending upon randomization): The subject should play: 
either EVO Multitask or EVO Words for approximately 10 minutes. (Note: 
The parents should observe their child interact with the therapy as they will 
be asked to rate their expectations of possible benefit). Separate 
instructions will be provided to an unblinded clinical coordinator to log the 
subject into either the EVO Multitask or EVO Words therapy. During the 10 
minutes of in-clinic play, the un-blinded coordinator should observe the 
participants play to ensure he or she can follow the rules (which are in 
English) of their assigned game. The un-blinded coordinator should also 
make note of any motor conditions or uncorrected visual acuity that 
prevents proper game play. Participants that are unable to properly play 
their therapy will be withdrawn from the study. Note: For EVO Words the 
participant should be able to spell at least two words during the assessment. 
At the end of approximately 10 minutes the unblinded coordinator should 
have the subject stop his/her play (at an obvious break point in the game) 
and turn the iPad off. At this point, the parent should complete the Baseline 
Expectation Survey 
 
• 
Materials to go home: An un-blinded coordinator should provide the parents 
with of a copy of their ICF and child assent along with the instructions for 
their child’s therapy. The parents should be told that their child is expected 
to play their therapy for typically 25 minutes/day, 5 days/week. NOTE: The 
parent and child should be told that no one except the child may play 
the game for any reason. The child should be provided with same iPad 
they previously played in the clinic along with a battery charger. In addition, 
both parent and participant should be instructed on intended and 
unintended use of the device. These are defined as: 

  
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§ Intended use- Set up of the participant’s local WiFi network for 
internet access to push play and compliance data to the Akili 
secure severs, and completion of at-home interventional play 
for the assigned 25 minutes per day, during 5 days of each 
calendar week. 
 
§ Unintended use – Any and all other features or applications of 
the device, including accessing the internet, downloading of 
additional applications, use of features such as music, 
calendar, or notes, and inputting any personal information 
other than participant’s home wifi network as described 
above. 
 
4.5 Treatment Procedures – In-Home Game Play and Post-Treatment Visit 
Beginning on the first day after the Screening/Baseline Visit (Visit 1 for untreated 
children at Screening; Visit 1a for those children requiring medication washout), 
participants will initiate at-home play with their randomized therapy (EVO 
Multitasking or EVO Words). The therapy will pick up from where it left off during 
the in-clinic session. Participants and their parents will be instructed during 
Screening and Baseline that the expectations for play will be typically 25 
minutes/day, 5 days/week. 
 
For each play episode, participants will logon to their assigned iPad with a unique 
ID and initiate therapeutic play. Log on passwords and game instructions will be 
provided separately. Details about performance and duration of play will be 
recorded and uploaded to central servers (when the iPad is connected to WiFi) for 
data capture. Compliance with therapy play requirements will be monitored 
automatically and sites will receive daily email notifications. For participants not 
meeting the requirements, email reminders and instructions will be provided. 
Additionally, EVO Multitasking and EVO Words both contain built-in features that 
remind the participant to play. Participants who fail to meet play requirements will 
be contacted by an un-blinded site clinical coordinator to troubleshoot problems 
and problem-solve to increase compliance (Scripts for these communications will 
be described in a separate document). During the demographic data collection, 
the parent should specify the preferred method by which they would like to be 
contacted (e.g. phone, text, or email). Additionally parents will receive a weekly 
and automatically generated progress email report directly from the Sponsor (Akili) 
by sharing their email at informed consent. However, parents may elect to opt-out 
at the time of informed consent. 

  
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On day 21 the study site should remind the parents by phone, preferably (email 
and/or text are also acceptable), that their child is entering the last week of the 
study (A script for this communication will be described in a separate document). 
 
The post-treatment visit (Visit 2 will be scheduled to occur 4 weeks after the 
Baseline Visit. If the parent and child are unable to return to the clinic on Day 28, 
Day 28 + 3 days is acceptable (the subject should be encouraged to continue to 
play their therapy during this exception period). Children who have been ill or taken 
medication within 48 hours of their scheduled Visit 2 should contact DCRI CRA 
and the medical monitor to advise regarding scheduling, In general, participants 
should not be scheduled for their Visit 2 if they have been sick enough to skip 
school, or if they have taken any medications that may have impacted functioning 
within 48 hours. At this visit, participants will be re-assessed for attentional 
functioning, ADHD symptoms, and impairment. Additional information regarding 
satisfaction and experience with the therapy will be collected from both participants 
and their parents/caregivers. 
 
NOTE: The parent and subject should return to the clinic at approximately the 
same time of day (i.e. morning or afternoon) as was done for the 
Screening/Baseline Visit (Visit 1 or 1a for untreated or treated children, 
respectively). Assessments should also be administered in the same order per the 
Table of Procedures in Section 4.3. Also, all attempts should be made to ensure 
that the same parent/caregiver accompany the subject and complete the outcome 
measures. Also, all attempts should be made to ensure that the same study staff 
administers the subjective clinical outcome measures (ADHD-RS, CGI, and IRS). 
 
Specific procedures to be completed during the Post-Treatment Visit include: 
 
• 
C-SSRS (Since last visit): The results of the C-SSRS should be recorded 
in the CRF 
 
• 
Clinician completed ADHD-RS: Results of the ADHD-RS should be 
recorded in the CRF 
 
 
• 
Clinician  Completed  CGI Improvement Scale. 
The results of the CGI 
Improvement Scale should be recorded in the CRF 
 
• 
Impairment Rating Scale. The results of the Impairment Rating Scale 
should be recorded in the CRF 

  
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• 
TOVA: The TOVA test will take approximately 25 minutes to complete. 
Separate instructions will be provided to the blinded raters to administer this 
test and to download and save the test results The TOVA API score should 
be recorded in the CRF. 
 
• 
CANTAB Spatial Working Memory task: The CANTAB SWM task will take 
approximately 9 minutes to complete. Separate instructions will be provided 
to the blinded raters to administer this test and to download and save the 
test results 
 
• 
Parent-Completed BRIEF: While the subject is performing the CANTAB 
SWM and TOVA, the parents will be asked to complete the BRIEF. The 
parents should be instructed by a blinded rater to focus their evaluation over 
their child’s past week behavior. The BRIEF Raw, T, %ile, negativity, and 
inconsistency scores should be recorded in the CRF 
 
• 
Patient Experience/Satisfaction Measure – Parent Version: The un-blinded 
rater will complete a parent survey. The results will be captured in the CRF 
 
• 
Patient Experience/Satisfaction Measure – Child Version: The un-blinded 
rater will compete a child survey. The results will be captured in the CRF. 
 
• 
Assessment of Adverse Events/Concomitant Treatment: AEs and Con- 
Meds will be captured in the CRF 
 
• 
The iPad and battery charger will be returned to site 
• 
Prior to re-circulation of the device to future participants, the device will be 
returned to Akili for complete erasing of all data entered by the participant. 
 
4.6   Procedures to minimize bias and blinding to treatment assignment 
Participants and their parents will not be aware of which of the interventions to be 
used in the study is the test device and which is the comparator. The clinicians and 
staff completing assessments will be blinded to which device each participant is 
assigned. An un-blinded staff member at each site will be designated in order to 
provide initial instructions for use at the Screening/Baseline Visit, monitor 
compliance, and follow up with parents as required. Parents and participants will 
be instructed not to share instructions about the details of the intervention to which 
they were assigned to the study staff during their subsequent End of Treatment 
visit (Visit 2).). Additional details around the procedures to be used to minimize 
bias and blind participants/parents and site staff are as follows. 
 
Since the EVO Multitasking therapy and the EVO Words therapy are fundamentally 
different, true blinding is not possible for this study. The following study procedures 
will be implemented to maximize the chances that 1) participants and their parents 
are not aware of which treatment condition is the test intervention and which is the 

  
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comparator; and 2) that site staff involved in completing outcome measures are 
blinded to treatment assignment. 
 
4.6.1 Procedures to minimize bias in parents and participants. 
 
All communication between site staff and participants/parents should 
emphasize that this is a study to evaluate the effects of 2 different therapies 
on ADHD symptoms. This communication should be reviewed in the 
consent procedures. If parents raise questions about whether 1 of the 
treatments is expected to have a different effect, they should be informed 
that the study is designed to evaluate how they compare to one another on 
ADHD functioning. During Screening/Baseline, participants/parents will be 
reminded not to discuss the details or content of their assigned treatment 
with anyone at the site other than the un-blinded coordinator who will review 
the instructions for the randomized therapy with each participant. 
Participants/parent will also be discouraged from discussing the 
details/content of their assigned therapy with other children/families outside 
of the study. 
 
4.6.2 Procedures to blind/minimize bias in site staff and investigators. 
 
Following Screening and prior to randomization, investigators and site staff 
will remind participants/parents not to discuss the content/details of their 
assigned treatment with anyone at the site except the un-blinded 
coordinator. Upon returning to the clinical site for their Baseline 1a visit (for 
participants who require washout) and for their follow-up (Visit 2) visit, 
participants and their families will be reminded not to discuss the 
content/details of their assigned treatment with other site staff. Following 
randomization at the end of Visit 1 (or Visit 1a for participants requiring 
washout), participants/parents will only have direct contact with the 
unblinded coordinator who will review instructions for their assigned 
treatment condition. Participants/parents will be reminded not to discuss the 
content/details of their assigned treatment in the event of any phone calls 
or unscheduled visits that might occur prior to the Visit 2. Investigators and 
other blinded site staff will not have access to any source documents or 
CRFs that may compromise the blind. 
 
 
4.6.3 Procedures in the event of possible or probable unblinding. 
 
If at any point after randomization an Investigator or other site staff 
responsible for completing any of the outcome measures becomes possibly 
or probably un-blinded, the following procedures should be implemented: 

  
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• 
A description of the un-blinding event should be generated and sent 
to the DCRI Coordinating PI (Kollins), Medical Monitor (Krystal) and 
Project Leader. 
 
• 
If there are still study assessments that need to be completed, an 
alternative and blinded rater should be used, if available at the site 
(e.g., a Sub-I) 
 
• 
If a blinded Sub-I or other trained and qualified blinded rater is not 
available, the measures should be completed by the unblinded 
rater. 
 
Note: In the event of unblinding as described above or if study staff 
explicitly unblinds the parent or participant to the study hypothesis, the 
unblinding event will be noted in the CRF. 
 
4.8 Randomization Procedures 
 
Participants who meet all inclusion/exclusion criteria and sign the informed 
consent/assent will be enrolled. Randomization will occur during the baseline visit 
only after ADHD diagnosis is confirmed via the MINI-Kid. The treatment given to 
individual participants will be determined by a randomization schedule will be 
generated by the scheme prepared by Duke Clinical Research Institute (DCRI) 
statistics group using a validated computer software (SAS) that incorporates a 
standard procedure for generating random numbers. A copy of the randomization 
schedule scheme will be held by the DCRI Statistics Department. The 
randomization scheme will be monitored monthly through the enrollment period 
for accuracy. This schedule will be loaded into the clinical database 
randomization module. Participants randomized into the study will be assigned 
the treatment corresponding to the next available number in the randomization 
schedule. Any participants that show non-compliance as described in Section 
8.5.1 will be replaced. 
 
Participants will be randomized in a 1:1 ratio to receive either an iPad preloaded 
with EVO Multitasking therapy or an iPad preloaded with EVO Words therapy. 
Randomization will be stratified by drug washout or no drug washout. Group #1 - 
washed out of stimulant (at time of informed consent) and group #2 - wasn’t on 
stimulant (at time of informed consent). Although no official gender stratification is 
indicated, study sites will use their best efforts to gender-match and enroll a 
minimum of 30% girls. 

  
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5 STUDY DEVICE 
The study devices are NOT intended to be used for any purpose other than that 
outlined in this protocol. 
 
Description of Study Device (EVO Multitasking therapy): EVO Multitasking therapy 
will be loaded by the sponsor (Akili) onto iPad Mini II tablets. The iPads are 
configured to minimize the participants’ ability to utilize non-study related 
applications. Features such as browsing the internet, downloading apps, deleting 
apps, and messaging are restricted. However, some functions such as Music 
(which may provide for downloading via iTunes), Notes, Calendar, and Reminders 
may potentially be accessed by participants. Unblinded site staff will instruct 
participants and parents on intended and unintended use, as outlined in this 
protocol. The iPads along with chargers will be provided by the sponsor to the 
clinical sites. In a separate document, a list of logon credential (Subject IDs and 
Passwords) will be provided. All data entered by the participant onto the device 
will be erased before reusing the device. 
 
Description of Study Device (EVO Words therapy): EVO Words therapy will be 
loaded by the sponsor (Akili) onto iPad Mini II tablets. The iPads are configured 
to minimize the participants’ ability to utilize non-study related applications. 
Features such as browsing internet, downloading apps, deleting apps, and 
messaging are restricted. However, some functions such as Music (which may 
provide for downloading via iTunes), Notes, Calendar, and Reminders may 
potentially be accessed by participants. Unblinded site staff will instruct 
participants and parents on intended and unintended use, as outlined in this 
protocol. The iPads along with chargers will be provided by the sponsor to the 
clinical sites. In a separate document, a list of logon credential (Subject IDs and 
Passwords) will be provided. All data entered by the participant onto the device 
will be erased before reusing the device. 
 
5.1 Study Device Usage 
Participants and their parents/caregivers will be instructed to play their assigned 
therapy for a duration of typically 25 minutes/day for 5 days/week during each of 
the 4 weeks of the treatment phase of the study. For EVO Multitask 25 minutes/day 
is accomplished by playing 5 “sessions” of 4 to 5 minutes each. For EVO Words 
25 minutes/day is accomplished via a displayed minute timer. Participants should 
initiate play on the first day after the Baseline Visit. Specifics about which days and 
times during those days can be used for play will be free to vary among the 
participants based on their schedules. Time of play will be captured. Therapeutic 
play should continue up until the day prior to the End of Treatment visit (Visit 2.). 
Prior to initiating play, the subject should block out 25 minutes of uninterrupted 
time in a quite location where he or she can focus on playing their therapy. It’s 
very important that only the study subject plays the therapy. At no other time 
should anyone else be allowed to play the therapy. 

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Also, it’s important to make sure the iPad is connected to the participants home 
WiFi. If home WiFi is not available the study staff and parents need to establish a 
plan where the iPad will be connected to remote WiFi on a periodic basis during 
subject play (Note: The remote WiFi location should not require webpage 
authentication). The iPad will cache all data locally but without WiFi access the 
study sites will not receive accurate compliance reports 
To initiate play, the subject taps on the game therapy icon displayed on the screen 
and follows the in-program instructions. Also, separate hard-copy instructions will 
be sent home with the parent. The instructions are specific to EVO Multitasking or 
EVO Words therapies, so the un-blinded clinical coordinator will need to provide 
these. 
For any calendar day the therapy will automatically lock after approximately 25 
minutes of play and no further play will be allowed until the next calendar day. For 
EVO Multitasking this lockout is accomplished after the subject completes 5 
“sessions” of 4 to 5 minutes each. For EVO Words, the therapy stops after 25 
minutes. 
 
5.2 Potential Benefits/Risks of Study Device 
Based on preliminary data obtained in several studies, including a Proof-of- 
Concept trial in children with ADHD, the potential benefits of the EVO Multitasking 
game-based therapy for this population are to increase attentional functioning. 
Given the central role of attention in the pathophysiology of ADHD, this benefit is 
substantial. 
To date, there have been no adverse events reported across several early studies 
with the device. The risk/benefit ratio for use is favorable. 
Use of the EVO Words therapy has not been evaluated systematically. However, 
no adverse events are expected with the amount of play required in the present 
study. Moreover, given the nature of the EVO Words therapy, expected benefit for 
the primary outcome measure and secondary measures is expected to be minimal. 
The risks to a participant participating in this study are very small. The study 
involves completing some computerized tests, game-based digital therapies, and 
answering some questions. It is possible that the participant could become 
frustrated by some of the tasks. The participant could become fatigued by the 
computer tests or therapeutic play. If the participant becomes frustrated or 
fatigued, they may stop at any time. There is a risk that the participant may access 
unintended features (e.g. Music, Contacts, Reminders, Notes, or Calendar) during 
the course of their participation in the at-home portion of this study. In this instance, 
the participant may enter personal information onto the device. To circumvent 
associated risk, all data entered by the participant onto the device will be erased 
before reusing the device. There are no other risks to taking part in this study of 
which we are aware. 

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The participant will not receive any direct benefit from participating in this study. 
No guarantee can be made concerning the study outcome, because results from 
a clinical research study cannot be predicted. 
 
5.3 Procedures for Monitoring Compliance and Replacing Participants 
Both EVO Multitask and EVO Words automatically capture gameplay compliance 
and upload these data directly to a central server when connected to WiFi. The 
server will automatically push daily compliance emails to the clinical sites (the 
format of which is described in a separate document). Based on these emails, un- 
blinded study staff can then reach out to the parents or participants (via the 
preferred contact method captured in the demographic collection) to trouble shoot 
technical problems and/or encourage more play. The rules for compliance 
outreach follow: 
 
1) Participants that fail to play any EVO Multitask or EVO Words sessions 
over two or more days will be contacted to trouble shoot potential WiFi 
connection problems (These participants will be highlighted in yellow in 
the daily compliance email 
 
2) Participants fail to play at least 5 sessions of EVO Multitask or 25 minutes 
of EVO Words over 3 or more days will be contacted and reminded to play 
more (These participants will be highlighted in yellow in the daily compliance 
email) 
 
3) Participants that fail to play any EVO Multitask or EVO Words sessions over 
7 days will be replaced (These participants will be highlighted in red in the daily 
compliance report). These participants should NOT be told they are being 
replaced and should be encouraged to keep playing (as with other 
participants) and reminded to return to the clinic for their exit visit at the end of 
the study. 
 
4) Participants that fail to play at least 12 sessions of EVO Multitask or 60 
minutes of EVO Words over 14 days will be replaced (These participants will 
be highlighted in red in the daily compliance report). These participants should 
NOT be told they are being replaced and should be encouraged to keep 
playing (as with other participants) and reminded to return to the clinic for their 
exit visit at the end of the study. 
 
Additionally, parents will receive a weekly and automatically generated progress 
email report directly from the Sponsor (Akili), unless they have opted-out at the 
time of informed consent. 
 
Note: In the event a subject does not return to the clinic for their final exit visit or 
does not complete their assessments during the exit visit, this subject will be 
replaced. 

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 5.3 Discontinuation of Study Device 
Participants may withdraw at any time during the study without prejudice or be 
discontinued from study treatment at the discretion of the investigator if medically 
necessary or if any untoward effects occur. In addition, a subject may be withdrawn 
by the investigator or DCRI if the subject is noncompliant with their assigned 
treatment (as described above) or otherwise violates the study plan, or for 
administrative and/or other safety reason. In the case where a subject withdraws 
from the study, the subject will be replaced. 
 
The investigator or designee will notify the sponsor or their designee immediately 
when a subject has been discontinued or withdrawn from study treatment because 
of an adverse experience. When a subject discontinues or is withdrawn from 
treatment before study completion, all applicable activities scheduled for the final 
study visit should be performed at the time of discontinuation. Any adverse 
experiences that are present at the time of discontinuation/withdrawal should be 
reported and followed up in accordance with the safety requirements outlined in 
Section 7.0 (Adverse Events). 

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6 CONCOMITANT MEDICATIONS 
Central nervous system stimulants will be discontinued at the beginning of the 
washout phase and not allowed for the duration of the trial. 
 
6.1 Allowed Medications 
Non-sedating antihistamines 
Analgesics including acetaminophen and ibuprofen 
Antibiotics required for the treatment of minor illnesses 
Vitamins 
 
6.2 Prohibited Medications 
Prohibited medications 30 days prior to screening (for this purpose, defined as 
the day of informed consent) and through the duration of the trial include: 
SSRIs (e.g., fluoxetine, paroxetine) 
MAOIs (monoamine oxidase inhibitors) 
Mood stabilizers (e.g., lithium, valproate, quetiapine) 
Antipsychotics (e.g., risperidone, olanzapine) 
Anticonvulsants (e.g., phenobarbital, phenytoin, primidone) 
Anticoagulants 
Dextromethorphan 
Halogenated anesthetics 
Tricyclic antidepressants 
Atomoxetine 
Guanfacine 
Clonidine 
Phenylbutazone 
Sedating antihistamines 
Decongestants with stimulant properties 

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7.0 ADVERSE DEVICE EFFECT REPORTING AND FOLLOW-UP 
 
7.1 
Definitions 
 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. This includes 
any adverse event resulting from insufficiencies or inadequacies in the instructions 
for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. This also includes any event that 
is a result of a use error or intentional misuse. 
 
Unanticipated Adverse Device Effects (UADEs) 
Per 21 CFR 812.3, an Unanticipated Adverse Device Effect is 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 participants. 
 
Unanticipated Adverse Device Effects will include events meeting either A or B 
as stated below: 
A. Events meeting ALL of the following criteria: 
• 
Not included in the list of Anticipated Events (refer to I protocol 
section 7.3) 
• 
Possibly, probably, or definitely related to the investigational 
device per the site principal investigator 
Serious (meets any of the following criteria): 
Is life-threatening illness or injury 
Results in permanent impairment of a body structure 
or a body structure 
Necessitates medical or surgical intervention to 
prevent permanent impairment of a body function or a 
body structure 
Led to fetal distress, fetal death or a congenital 
abnormality or birth defect 
Led to death 
(Permanent means irreversible impairment or damage to a body 
structure or function, excluding trivial impairment or damage). 

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B. Any other unanticipated serious problem associated with the investigational 
device that relates to the rights, safety, or welfare of participants. 
 
7.2 
Assessment 
 
7.2.1 Time Frame 
 
An ADE observed from the time of randomization through the final 
study visit (day 28) will be collected in clinical database eCOS 
 
7.2.2 Causality Rating 
 
The causal relationship of an adverse event to either study game will 
be rated as follows: 
 
Possible: An event that might be due to the use of the study device. 
An alternative explanation - e.g., concomitant drug(s), concomitant 
disease(s) - is inconclusive. The relationship in time is reasonable; 
therefore the causal relationship cannot be excluded. 
 
Probable: An event that might be due to the use of the study device. 
An alternative explanation is less likely - e.g., concomitant drug(s), 
concomitant disease(s). The relationship in time is suggestive. 
 
Definitely: An event that is due to the use of the study device. The 
event cannot be reasonably explained by an alternative explanation 
- e.g., concomitant drug(s), concomitant disease(s). 
 
7.2.3 Severity of Adverse Device Effects 
The severity of an ADE will be rated as follows: 
 
• 
Mild: Awareness of sign, symptom, or event, but easily tolerated. 
• 
Moderate: Discomfort enough to cause interference with usual activity 
and may warrant intervention. 
 
• 
Severe: Incapacitating with inability to do usual activities or 
significantly affects clinical status and warrants intervention. 

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7.3 Previously Noted Adverse Device Effects 
The expectedness of an ADE shall be documented in the informed consent (ICF). 
Any ADE that is not identified in nature, severity, or is not listed below is considered 
unanticipated. 
 
Adverse Device Effects EXPECTED FOR THIS DEVICE: 
1. Dizziness 
2. Nausea 
3. Headache 
4. Increased and unusual levels of frustration during game play 
 
7.4 
Reporting 
It is understood that complete information about an event may not be known at the 
time the initial report is submitted. The investigator must assess the relationship 
of the event to the investigational device (including rationale for assessment) and 
should make every attempt to obtain as much information as possible concerning 
the event. Additional information pertaining to an event should be reported in the 
EDC as it becomes available. 
 
7.4.1 Adverse device effect 
The investigator must report, via eCOS, all Adverse device effects, 
anticipated or unanticipated, occurring from the time of randomization 
through the final study visit (day 28) within 24 hours of knowledge of 
the event. If the eCRF system is temporarily unavailable, the event, 
including investigator-determined causality assessment, should be reported 
to DCRI via a paper back-up ADE form. Upon return of the availability of the 
eCOS system, the ADE information must be entered into the eCRF. 
 
The investigator must report, via eCOS, when important follow-up 
information (final diagnosis, outcome, results of specific investigations, etc.) 
becomes available after submission of the initial Suspected Adverse 
Reaction information. Follow-up information should be submitted according 
to the same process used for reporting the initial event as described above 
(i.e., within 24 hours of knowledge, via eCOS). All adverse device effects 
will be followed through resolution. 
 
DCRI Safety Surveillance will report all adverse device effects to specified 
trial personnel (sponsor, principal investigator [PI] and project leader) 
within 1 to 2 business days of receipt. 

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7.4.2 Regulatory Reporting of Unanticipated Adverse Device Effects 
 
If an investigator reports an UADE to the sponsor (via the EDC), the sponsor 
shall immediately conduct an evaluation of the UADE and will make a 
determination as to whether it meets the “unanticipated” criteria (i.e., are not 
listed in section 7.3 of the protocol) and whether it meets the criteria for 
reporting to regulatory authorities (e.g. FDA, IRBs). 
Any UADE(s) that the sponsor determines is/are reportable will be 
submitted to the FDA, all reviewing IRBs, and all participating investigators 
within 10 working days of when the sponsor makes that determination. 
 
If the sponsor determines that an UADE presents an unreasonable risk to 
participants, all investigations or parts of investigations presenting that risk 
shall be terminated as soon as possible. Termination shall occur not later 
than 5 working days after the sponsor makes this determination and not 
later than 15 working days after the sponsor first received notice of the 
effect. 
 
All Regulatory Reporting to the FDA will be done by DCRI Regulatory. 
 
 
7.5. Institutional Review Boards 
 
All sites will submit the study Adverse Device Effects, Unexpected Adverse Device 
Effects, Adverse Events and Serious Adverse Events to their local/central 
Institutional Review Board (IRB) according to their local IRB polices and 
procedure. 

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8.0 STATISTICAL ANALYSES 
This section will provide an overview of the statistical, descriptive, and qualitative 
analyses for this study. Specific details of the analyses will be described in a 
separate statistical analysis plan (SAP) 
 
The main objective of this study is as follows: 
 
• 
To evaluate the effects of EVO Multitask game-based digital therapy 
versus EVO Words game-based digital therapy on attentional functioning 
(measured by the TOVA API score change) and ADHD symptoms 
(measured by gold-standard qualitative rating scales). 
 
This study has 1 primary and 3 secondary objectives. Success on the Primary 
(P1) and the first Secondary Objective (S1) (Change in ADHD symptoms) will 
provide confirmatory support for the full claim above. If the primary is successful, 
but the ADHD symptom secondary objective fails to meet statistical significance, 
the modified claim below will still be supported: 
 
• 
To evaluate the effects of EVO Multitask game-based digital therapy 
versus EVO Words game-based digital therapy on attentional functioning 
(measured by the TOVA API score change). 
 
Below is a list of primary, secondary, exploratory, safety, and descriptive 
objectives. Missing data and site poolability are addressed as descriptive 
objectives. Details on measures collected are provided in the SAP. 
 
8.1 Primary Objective (P1) - Attention 
P1-Objective) To evaluate the effects of EVO Multitask play versus EVO Words 
play on attentional functioning (measured by the API composite score from the 
TOVA 8). 
 
P1-Outcome Measure(s)) Change from baseline to day 28 on TOVA API 
 
The TOVA is a clinically-relevant and validated continuous performance test (CPT) 
that informs attentional performance in ADHD populations. The API score is a 
composite variable that summarizes the overall result of the TOVA and is 

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composed of age/gender adjusted (z-scores) of reaction time variability, mean 
reaction time, and sensitivity to the target stimuli (d’) 
 
8.2 Secondary Objectives 
 
8.2.1 Major Secondary Objective I (S1) – ADHD Symptoms 
 
S1-Objective) To evaluate the effects of EVO Multitask play versus EVO 
Words play on ADHD symptoms using clinically relevant qualitative rating 
scales of ADHD symptoms, executive function, and global function. 
 
S1-Outcome Measures(s)) 
 
• 
ADHD-RS Total (Change from baseline to day 28) 
• 
ADHD-RS Inattentive Sub-scale (Change from baseline to day 28) 
• 
ADHD-RS Hyperactivity Sub-scale (Change from baseline to day 28) 
• 
BRIEF Working Memory Percentile (Change from baseline to day 
28) 
 
• 
BRIEF Inhibit Percentile (Change from baseline to day 28) 
• 
Impairment Rating Scale (IRS) (Change from baseline to day 28) 
• 
Clinician Global Improvement (CGI) (at day 28) 
8.2.2 Minor Secondary Objective II (S2) – Objective Working Memory 
 
S2-Objective) To evaluate the effects of EVO Multitask versus EVO Words 
play on objective working memory function as measured by CANTAB’s 
Spatial Working Memory (SWM) computerized test. 
 
S2-Outcome Measure(s)) 8 CANTAB SWM outcome measures (Change 
from baseline to day 28) 
 
• 
Mean time to first response (4 boxes) 
• 
Mean time to last response (4 boxes) 
• 
Mean token-search preparation time (4 boxes) 
• 
S.D. time to first response (4 boxes) 
• 
S.D. time to last response (4 boxes) 

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• 
S.D. token-search preparation time (4 boxes) 
• 
Strategy (4 to 8 boxes) 
• 
Total Errors 
8.2.3 Minor Secondary Objective III (S3) – Objective Inhibition 
 
S3-Objective) To evaluate the effects of EVO Multitask versus EVO Words 
play on inhibitory function as measured by TOVA Commission Error 
Standard Score (non-composite score) during the frequent response 
portion of the TOVA (COMSSH2). 
 
S3-Outcome Measure(s))- TOVA COMMSSH2 
 
8.3 Exploratory Analyses 
This section will list the planned exploratory analyses. Full details are provided in 
the SAP. 
 
8.3.1 Exploratory Objective I (E1) - Responders 
 
 
E1-Objective) To evaluate the percentage of responders for select outcome 
measures in both the EVO: Multi and EVO: Words groups. 
 
E1-Outcome Measure(s)) The following outcomes will be examined; 
• 
TOVA API 
• 
ADHD-RS Total 
• 
CGI 
• 
IRS 
Responder cut-off values and details of this analysis will be described in the 
SAP. 
8.3.2 Exploratory Objective II (E2) – Additional TOVA Endpoints 
 
 
E2-Objective) To evaluate the effects of EVO Multitask play versus EVO 
Words play on additional TOVA endpoints not analyzed in other objectives. 
 
E2-Measures) Multiple TOVA outcomes (Change from baseline to day 28). 
See SAP for a list of measures. 

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8.4 Safety Analysis 
Treatment related adverse events for both the EVO Multitask and EVO Words 
interventions will be presented. Any adverse events occurring during any phase 
of the study judged by clinical sites’ Primary Investigator (PI) to be related to either 
intervention will be recorded and presented in a table listing. The Safety population 
(see section 8.6.2 for analysis population details) will be used for this analysis that 
will include randomized participants that began the at-home training phase for 
either intervention. The severity of each event will be evaluated by the PI and 
presented with the recorded events. If there are frequently occurring treatment 
related adverse events, a frequency table will be included, to rank events from 
most frequent to most rare. Subjects will be included in the actual treatment group 
received. 
 
8.5 Descriptive Analyses 
The following additional descriptive analyses will be conducted. Details are 
provided in the SAP. 
 
• 
D1: Gameplay Surveys 
• 
D2: Compliance 
• 
D3: Age and Gender Sensitivity Analysis 
• 
D4: Site Poolability Sensitivity Analysis 
• 
D5: Missing Data Sensitivity Analysis 
• 
D6: Baseline TOVA API sensitivity analysis 
• 
D7: Baseline Parent Expectancy Sensitivity Analysis 
8.6 General Statistical Methods 
This section will present the formal hypotheses, analysis populations, multiplicity 
adjustment consideration, and methods for handling missing data. In addition, 
details about the planned interim analysis and statistical power are presented. 
 
8.6.1 Hypothesis Tests and Multiplicity Adjustments 
 
The aim of all primary and secondary objectives in this study are to 
demonstrate a statistical difference on outcome measure mean change scores 
between the EVO Multitask group and the EVO Words group. Change scores 
are defined as the score obtained on the pre-training assessment subtracted 
from the post-training assessment (Post – Pre). Change score group means 
will be compared using a 2-tailed between participants T-Test with a base alpha 
criterion of 0.05 to meet statistical significance. Note: The assumptions for a 
T-Test will be checked and if the assumptions do not hold true, then other 

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appropriate methods will be used as described in the SAP. Below are general 
formulations of the null and alternative statistical hypotheses, 
 
• 
H0: μEVOMULTI  = μEVOWORDS (1) 
• 
H1: μEVOMULTI  ≠ μEVOWORDS (2) 
 
where H0 is the null hypothesis, H1 is the alternative hypothesis, μEVOMULTI is the 
mean change score for the EVO Multitask group, and μEVOWORDS is the mean of 
the change score for the EVO Words group. The Primary Objective (P1) is a 
special case of this hypothesis test that will use weighted scores to control for 
Type-I error increases due to a sample size re-estimation and potential sample 
size increase at the interim analysis. The calculation of weighed scores will 
use the Chu-Hung-Wang method (Chang, 2014; Chu, Hung, & Wang, 1999). 
 
Multiplicity will be controlled across the Major Objectives of this study (P1 and 
S1). See the SAP for details on multiplicity adjustments 
 
8.6.2 Analysis Populations 
 
Three populations are defined for this study: A per-protocol (PP), intention-to- 
treat (ITT), and safety population. The ITT and PP populations will be used for 
all efficacy analyses. The Safety population will be used for the safety analysis. 
The success of the primary and secondary objectives will be based on an 
assessment of the results from the ITT population. Additional analysis of the 
PP population is supportive. The primary efficacy endpoint must achieve 
significance in the ITT to preserved type I error for the secondary endpoints. 
Details about inclusion into each population are presented below: 
 
• 
Per-Protocol (Treatment Complaint): This population is defined as any 
participant that began the at-home phase, completed both the pre and 
post assessment, and met a minimum compliance level of 50%. 
Additionally the following participants are excluded from this 
population: 
Participants where the subjective clinical assessments (ADHD- 
RS, CGI, and IRS) were not made by the same study staff 
member pre and post 
Participants where it was reported that the blinding was broken 
Participants that received incorrect intervention after 
randomization 
 
• 
Intention-to-Treat (ITT): This population is defined as any randomized 
participant that received a device for at home training. In the case 

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participants received the incorrect intervention after randomization, no 
corrections to group assignment will be made. 
 
• 
Safety: This population is defined as any randomized participant that 
received a device for at home training. The primary safety analyses 
will include participants regardless of if they completed the post- 
treatment assessment and will be analyzed in the group whose 
treatment they actually received. 
 
 
 
8.6.3 Interim Analyses 
 
An interim analysis will be conducted on the primary outcome, TOVA 8 API, to 
determine if the minimum sample size of 300 patients is sufficient to detect a 
statistical difference between EVO Multitask and EVO Words. The population 
for this analysis will follow the same guidelines used for inclusion into the ITT 
population (See section 8.6.2). 
 
The specific results of the interim analysis will remain blinded and will not be 
used to declare success of the primary objective at the interim; Un-blinded 
staff at the DCRI will conduct this analysis for the purpose of finalizing the 
sample size only. To maintain blinding for all other study personnel and 
affiliates, the results of this analysis will only indicate the sample size 
necessary to sustain the power of the study to detect an effect size of 0.4. 
Enrollment in the study will continue until the at least a minimum of 300 
patients have been enrolled and the study has achieve the number of enrolled 
patients necessary to sustain the power of the study. The study will not exceed 
1,000 enrolled patients. Additional details on the interim analysis will be 
presented in the SAP. 
 
8.6.4 Power and Sample Size 
 
To determine an appropriate study sample size to detect a statistical difference 
between change scores of the EVO Multitask group vs. the EVO Words group, 
a preliminary power analysis was conducted. The results indicated that 150 
participants per group is sufficient to detect an effect size of 0.40 at a power > 
90% on a between participants T-test with an alpha criterion of 0.05. 

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9. DATA AND SAFETY MONITORING 
 
9.1 Endpoint Determination 
API scores from the TOVA 8 will be derived directly from the computers used 
to administer the task and these scores will be entered into the database for 
analysis of primary outcome 
 
9.2 Safety Monitoring 
Safety/tolerability will be assessed primarily at the Post-Treatment Visit 
(Visit 3), as well as during the 4-week game play component as necessary. 
 
9.3  Data Management to Maintain Blinding 
As noted above (Section 4.7), instructions will be given to participants, their 
parents and study staff to minimize the possibility that information that may 
potentially unblind treatment assignment (e.g., parent or participant description of 
their assigned game content) is limited. 

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10 DATA MONITORING AND QUALITY CONTROL 
 
10.1 Required Data 
The full study dataset will be collected for participants who enter the treatment 
phase of the study. Limited data (i.e., demographics, adverse events, selection 
criteria, and reason for discontinuation) will be collected for participants who 
discontinue before the treatment phase. 
 
All required data for this study will be entered into the electronic case report form 
(eCRF). 
 
10.2 Subject and Clinical Data 
The collection site will provide the following 
 
This study will use Web-based e-CRFs developed through a validated, electronic 
reporting-electronic-signatures–compliant 
platform 
(21 
Code 
of 
Federal 
Regulations Part 11). Before initiation of the trial, each site will be contacted as to 
computer availability, hardware specifications, and Internet connectivity, to 
evaluate the capacity of the site to use this type of data collection system. The 
investigator's site staff who will be entering data will receive training on the system, 
after which each person will be issued a unique user identification (ID) and 
password. 
 
For security reasons, and in compliance with regulatory guidelines, it is imperative 
that only the persons who own the user IDs and passwords access the system 
using their own unique access codes. Access codes are nontransferable. Site 
personnel who have not undergone training may not use the system and will not 
be issued user ID and password until appropriate training is completed. 
 
During monitoring visits, the site will make their computer and/or high-speed 
Internet access available to the clinical research associate. At the conclusion of 
the study, each enrolling site will be provided with a compact disc containing PDF 
files of both the individual subject's data and the audit trail (changes made to the 
database). This will be maintained at the site according to the requirements for 
records retention. 

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11 STUDY RESPONSIBILITIES 
 
11.1 Study Data Reporting and Processing 
Each page of the electronic case report form (eCRF) will be reviewed by site PI at 
the site. The site PI is required to sign the eCRF on the appropriate pages to verify 
that he or she has reviewed the recorded data. This review and sign-off may be 
delegated to a qualified clinician appointed as a sub investigator by the site PI. The 
transfer of duties to a sub investigator will be recorded on the delegation list (kept 
on file at the site). The investigator must ensure that all site staff involved in the 
conduct of the trial are familiar with the protocol and all study-specific procedures, 
and that they have appropriate knowledge of the study agents. 
 
11.2 Training 
The training of appropriate clinical site personnel across study procedures will be 
the responsibility of Akili Interactive Labs, Inc. and/or their representative(s) (EVO 
Multitask and EVO Words, CANTAB, TOVA, compliance monitoring) and DCRI 
(Protocol procedures, MINI-KID, ADHD-RS, eCRF/data entry, AE reporting, 
general test administration). The site PI is responsible for ensuring that his or her 
staff conduct the study according to the protocol. To ensure proper administration 
of study interventions, uniform data collection, and protocol compliance, Akili 
Interactive Labs, Inc. and their representatives and DCRI will present a formal 
training session to study site personnel, to include instructions for study 
procedures, the investigational plan, instructions on data collection, methods 
schedules for follow-up with the study site coordinators, and regulatory 
requirements. Detailed feedback regarding completion of forms will be provided by 
Akili Interactive Labs, Inc. and their representatives and DCRI in the course of 
regular site monitoring. 
 
 
11.3 Monitoring the Investigational Sites 
As part of a concerted effort to follow the study in a detailed and orderly manner in 
accordance with established principles of GCP and applicable regulations, a study 
monitor will visit the study sites regularly and will maintain frequent telephone and 
written communication. Additional information regarding site management and 
monitoring can be found in the Clinical Monitoring Plan (CMP). 
 
During monitoring visits, the monitor will review informed consent, and HIPAA 
authorization, all inclusion/exclusion criteria, all events meeting criteria for 
expedited event reporting, as well as safety and efficacy endpoints. Additional 
review will be performed on a site-by-site basis, as warranted by the findings of 
previous monitoring visits. Key variables (demographics, inclusion/exclusion 
criteria, and safety) on the eCRFs will be compared with each subject’s source 
documents. Any discrepancies will be noted and resolved. 

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11.4 Study Documentation 
Study documentation includes all electronic case report forms, source documents, 
monitoring 
logs 
and 
appointment 
schedules, 
sponsor-investigator 
correspondence, and regulatory documents (e.g., signed protocol and 
amendments, IRB or EC correspondence and approval, approved and signed 
subject consent forms, Statement of Investigator form, clinical supplies receipts 
and distribution records). 
 
The site PI is responsible for ensuring that complete and accurate is prepare and 
maintain in compliance with GCP standards and applicable federal, state, and local 
laws, rules and regulations; and, for each subject participating in the study, 
promptly complete all eCRFs and such other reports as required by this protocol 
following completion or termination of the clinical study or as otherwise required 
pursuant to any agreement with the sponsor or their designated representative. 
 
By signing the protocol, the site PI acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will 
be promptly and fully disclosed to the sponsor or their designated representative 
by the investigator upon request and also shall be made available at the 
investigator’s site upon request for inspection, copying, review, and audit at 
reasonable times by representatives of the Sponsor and the sponsor or their 
designated representative, or responsible government agencies as required by 
law. 
 
The site PI agrees to promptly ensure that any reasonable steps that are requested 
by Sponsor or the sponsor or their designated representative as a result of an audit 
to cure deficiencies in the study documentation and eCRFs are taken. 
 
11.5 Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel 
did not conduct the study according to the investigational plan or the Investigator 
Agreement. 
 
Investigators are required to obtain approval from the sponsor or their designated 
representative medical monitor before initiating deviations from the investigational 
plan or protocol, except where necessary to protect the life or physical well-being 
of a subject in an emergency. Such approval will be documented in writing and 
maintained in study files. Unless the Sponsor has consented to any such 
deviations in writing, Sponsor will not assume any resulting responsibility or 
liability. Preapproval is generally not expected in situations where unforeseen 
circumstances are beyond the investigator’s control, (e.g., subject did not attend 
scheduled follow-up visit,); however, the event is still considered a deviation. 

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The IRB will be informed of all protocol changes by the sponsor or deviations that 
occur at the investigative site in accordance with applicable regulations and the 
IRB/EC’s established procedures. No deviations from the protocol of any type will 
be made without complying with all the IRB/EC’s established procedures. 
 
11.6 Study Supply Accountability 
The investigator will maintain records of the receipt and disposition of all 
investigational devices (i.e., tablets), including any reported instances of 
unintended usage. When the enrollment is complete, the investigator will be 
notified by the sponsor or their designated representative, and in a timely manner, 
will return all study devices as directed by the Sponsor. 
 
11.7 Data Transmittal and Record Retention 
Required data will be entered in the eCRF as soon as possible after the subject 
visit or the availability of test results, but no later than 3 business days after the 
completed visit. 
 
Study sites will transcribe subject source data into eCRFs using a computerized 
electronic data capture (EDC) system. The EDC system is compliant with all 
relevant aspects of GCP. Edit checks, electronic queries, and audit trails are built 
into the system to ensure accurate and complete data collection. Data will be 
transmitted via the Internet from investigational sites to a central site, utilizing state- 
of-the-art encryption mechanisms to ensure security and confidentiality. 
 
The eCRF will be transmitted to a secure central database (host site) as forms are 
completed or updated. Protocol-specified source documents will be retrieved as 
necessary. Originals of all study-related documentation will be retained at the site. 
 
The site PI will maintain the records of device/tablet disposition, final eCRFs, 
worksheets, and all other study-specific documentation (e.g., study file notebooks 
or source documentation) until notified by the sponsor that records may be 
destroyed. To avoid error, the investigator will contact the sponsor or their 
designated representative before the destruction of any records pertaining to the 
study to ensure they no longer need to be retained. In addition, the sponsor will be 
contacted if the site PI plans to leave the institution so that arrangements can be 
made for the transfer of records. 
 
11.8 Study Closeout 
Upon completion of the study (defined as all participants have completed all 
follow-up visits, all eCRFs are complete, and all queries have been resolved), the 
sponsor or their designated representative will notify the site of closeout, and a 
study closeout visit will be performed. All devices will be collected and returned to 
the sponsor or their designated representative. The sponsor or their designated 
representative monitor will ensure that the site PI’s regulatory files are up-to-date 
and complete and that any outstanding issues from previous visits have been 

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resolved. Other issues to be reviewed at the closeout visit include discussing 
retention of study files, possibility of site audits, publication policy, and notifying the 
IRB of study closure. 
 
11.9 Audit/Inspections 
The sponsor or their designated representative quality assurance personnel may 
conduct audits at the study sites. Audits will include, but not be limited to, audit trail 
of data handling and processes, standard operating procedures, device supply, 
presence of required documents, the informed consent process, and comparison 
of eCRFs with source documents. The site PI agrees to accommodate and 
participate in audits conducted at a reasonable time and in a reasonable manner, 
as needed. 
 
The FDA may also inspect the site during or after the study. The site PI should 
contact the sponsor immediately if this occurs and must fully cooperate with 
governmental (e.g., FDA) inspections conducted at a reasonable time and in a 

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12. REFERENCES 
 
Biederman, J, et al. Evidence of a pharmacological dissociation between the 
robust effects of methylphenidate on ADHD symptoms and working memory. 
Journal of Brain Science 2015; 1(2) 43-53 
 
Klinberg T. Training and Plasticity of Working Memory. Trends in Cognitive 
Scienes. 2010; 14(2) 317-314 
 
Cortese, S, et al. Cognitive Training for Attention Deficit/Hyperactivity Disorder; 
Meta-Analysis of Clinical and Psychological Outcomes from Randomized 
Controlled Trials. Journal of American Academy of Child and Adolescent 
Psychiatry 2015; 54(3) 164-174. 
 
Anguera, J.A., et al. Video Game Training Enhances Cognitive Control in Older 
Adults. Nature 2013; 501, 97-101. 
 
Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials. 
1982;3:345–53