A Lead-in Study Evaluating Mobile Game Based Therapy Among Children With Autism
Phase: NA
Conditions: Autism, Autism Spectrum Disorder
Sponsor: Stanford University

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A Lead-in Study Evaluating Efficacy of GuessWhat Mobile App Therapy for Children With 
Autism 
PROTOCOL NUMBER: 
60181 
IND#: 
N/A 
INVESTIGATIONAL 
GUESSWHAT 
PRODUCT: 
PROTOCOL VERSION / DATE: 
Version 1: 21Sept2023 
 Original Version 1: 21Sept2023 
SPONSORED BY: Dr. Dennis Wall PhD 
CONTACT INFORMATION:  
Dennis Wall, dpwall@stanford.edu
Multi-Site Coordinator: 
Kaiti Dunlap, kdunlap2@stanford.edu

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Protocol Version and Amendment Tracking 
 
Version Number/Amendment 
Approval Date 
V.01 
9/14/2023 
 
 
 
 
 
 
 
 
 
Summary of Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
Evaluating Efficacy of GuessWhat Mobile System Protocol Number:        
Protocol Version/Date:  Version 1 / 08Aug2023 
Sponsor Name: Dennis Wall 
 
Declaration of Investigator 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the described trial 
in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for Good Clinical Practice 
(GCP). 
  
 
Principal Investigator Name:  Dennis Wall 
                                                         
 
 
 
Principal Investigator Signature:  ___
__________ 
                                                            
 
Date:  09/14/2023 
Date (MM/DD/YYYY)             
                                   
Statement of Compliance 
The signature below provides the necessary assurance that this study will be conducted according to all 
stipulations of the protocol including statements regarding confidentiality, and according to local legal and 
regulatory requirements, US federal regulations, and ICH E6(R2) GCP guidelines. 
 
Site Coordinator:  
 
                                                            
 
 
Site Coordinator Signature:  
                                                
 
Date:  09/14/2023 
          Date (MM/DD/YYYY)                                               
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
• AE 
• Adverse event 
• eCRF 
• Electronic case report form 
• EDC 
• Electronic data capture 
• FDA 
• Food and Drug Administration 
• GCP 
• Good Clinical Practice 

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1. SYNOPSIS 
Title 
A Lead-in Study Evaluating Efficacy of GuessWhat Mobile App Therapy for 
Children With Autism 
 
 
Design 
Randomized, Investigator-Blinded,  
Objectives 
Determine whether GuessWhat Dtx can improve socialization in children 
with ASD after 4 weeks of use.  
Endpoints 
Primary: Change from week 0 to week 4 in the Vineland Adaptive 
Behavior Scales-3 Socialization Subscale, Comprehensive Parent Report  
Secondary: Change from week 0 to week 4 in Parent Stress Scale, and 
Child Emotion Recognition Score 
Exploratory/Descriptive: 
Descriptive analysis of child/parent surveys, treatment regimen 
compliance, demographics, missing data, and any resulting treatment 
related AEs 
 
Study Sites 
Participants will recruited by Stanford via remote online recruitment.  
Planned 
Enrollment  
A minimum of 500 to a maximum of 2,000 participants will be enrolled to 
achieve a minimum of 360 to a maximum 900 completed participants 
(n=180 - 450 in each of 2 arms) evaluable 
Study Population 
Autistic children 3-12 years old.   
Subject Entry 
Criteria 
Inclusion Criteria 
(1) Parent who is at least 18 years old of child with autism. 
(2) Child with autism is between 3 and 12 years old at time of baseline 
data collection. 
Exclusion Criteria 
(1) Parent does not have an Android or iOS smartphone compatible with 
GuessWhat App. 
(2) The parent is unable to speak/read in available translations of the 
study app: English, Spanish, Brazilian Portuguese. 
 
Randomization 
Block randomization stratified by child sex. 
Treatment 
Regimen 
(Standard dose) 
App is used 3 times a week for 15 minutes for 4 weeks 

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Duration of Study 
Participation 
8 weeks  
Statistical 
Methods  
Independent Samples T-Tests 
Study 
Measurements: 
Efficacy, Safety 
Efficacy: Change in Vineland Adaptive Behavior Scales-3 Socialization 
Subscale week 0 to week 4 
Safety: Adverse event reporting  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. TABLE OF CONTENTS 
1. 
Synopsis ............................................................................................................................................... 5 
3. 
Introduction ......................................................................................................................................... 8 
3.1 
Background Information ............................................................................................................................8 

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3.2 
Previous studies .........................................................................................................................................9 
3.3 
Rationale for the Current Study ..................................................................................................................9 
4. 
Design .................................................................................................................................................. 9 
4.1 
Study Design ..............................................................................................................................................9 
4.2 
Study Sites .................................................................................................................................................9 
5. 
Objectives .......................................................................................................................................... 10 
5.1 
Primary Objective .................................................................................................................................... 10 
5.2 
Secondary Objectives ............................................................................................................................... 10 
6. 
Subject Population ............................................................................................................................. 10 
6.1 
Inclusion Criteria ...................................................................................................................................... 10 
6.2 
Exclusion Criteria ..................................................................................................................................... 10 
6.3 
Removal of Subjects from Treatment........................................................................................................ 11 
6.4 
Compensation ......................................................................................................................................... 11 
7. 
Study Treatment - GuessWhat ............................................................................................................ 11 
7.1 
Study Intervention ................................................................................................................................... 11 
Standard Dose .................................................................................................................................................................................. 12 
7.2 
Administration of GuessWhat .................................................................................................................. 12 
Treatment Compliance .................................................................................................................................................................... 13 
Treatment Precautions .................................................................................................................................................................... 13 
Concomitant Therapy ...................................................................................................................................................................... 13 
8. 
Study Procedures ................................................................................................................................ 13 
8.1 
Screening and Enrollment Steps ............................................................................................................... 13 
Week 0/Screening and Baseline Assessment .................................................................................................................................. 13 
Week 1: Enrollment and Allocation ................................................................................................................................................. 13 
Weeks 1-8: Intervention .................................................................................................................................................................. 14 
Week 4 Post-Test 1 .......................................................................................................................................................................... 14 
Week 8 Post-test 2 & Cross Over ..................................................................................................................................................... 14 
Week 12 Post-test 3 Follow-Up ....................................................................................................................................................... 14 
Week 16 Post-Test 3 ........................................................................................................................................................................ 13 
9. 
Efficacy and Safety Assessments ......................................................................................................... 14 
9.1 
Efficacy Assessments ................................................................................................................................ 14 
Primary Measurement (Efficacy): .................................................................................................................................................... 14 
Secondary Measurements (Efficacy): .............................................................................................................................................. 14 
9.2 
Descriptive/Exploratory Measurements ................................................................................................... 15 
9.3 
Safety Assessments .................................................................................................................................. 15 
Adverse Events ................................................................................................................................................................................. 15 
10. 
Statistical methods and analysis plan .............................................................................................. 17 

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10.1 
General Considerations ............................................................................................................................ 17 
10.2 
Sample Size Justification and Power Calculation ....................................................................................... 17 
10.3 
Demographic and Baseline Characteristics ................................................................................................ 17 
10.4 
Analysis Populations ................................................................................................................................ 17 
10.5 
Stratification, Subgroup Analysis and Pooled Analysis ............................................................................... 17 
Interim Analysis................................................................................................................................................................................ 16 
Efficacy Endpoint Analysis ............................................................................................................................................................... 17 
Eight-Week Follow-up Analysis ........................................................................................................................................................ 17 
Descriptive analyses ......................................................................................................................................................................... 18 
Safety Analysis ................................................................................................................................................................................. 18 
11. 
Recording and collection of data ..................................................................................................... 19 
11.1 
Case Report Form .................................................................................................................................... 19 
11.2 
Study Files and Subject Source Documents ............................................................................................... 19 
11.3 
Monitoring .............................................................................................................................................. 19 
11.4 
Audit ....................................................................................................................................................... 19 
11.5 
Retention of Data .................................................................................................................................... 20 
12. 
Ethics ............................................................................................................................................. 20 
12.1 
Ethics Committee ..................................................................................................................................... 20 
12.2 
Subject Information and Consent ............................................................................................................. 20 
13. 
SCHEDULE OF ASSESSMENTS ........................................................................................................... 20 
 
 
 
 
 
 
 
3. INTRODUCTION 
3.1  Background Information 
We have built a prototype mobile app (guesswhat.stanford.edu) that engages children in a fluid social 
interaction with a social partner (e.g. mom or dad), turning the focus of the camera on the child and reinforcing 
prosocial learning while simultaneously measuring the child's progress in socialization. Our pilot statistics 
demonstrate that our development efforts are making the application more popular and engaging, with the 28-
day active user base currently at over 500 users (~80% of whom are on iOS as the leading version of the app 
and average 4-week retention up to 25% and climbing too, respectively. To date, the app has generated more 
than 16,000 game sessions yielding 3,000+ videos (75+ hours) and more than 2 million highly emotive frames 

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that demonstrate the app's potency for data acquisition. This early success supports the prediction that GW will 
generate enough data to build computer vision algorithms that can automatically classify key features including, 
but not limited to, emotion, eye gaze, and gestures. In addition to the potential for AI model development is 
GW's potential for therapeutic intervention.  
3.2  Previous studies 
We examined the therapeutic feasibility of GuessWhat in 72 children (75% male, average age 8 years 2 months) 
with autism who were asked to play the game for three 90- second sessions per day, 3 days per week, for a total 
of 4 weeks. The group showed significant improvements in Social Responsiveness Score-2 (SRS-2) total (3.97, 
p <.001) and Vineland Adaptive Behavior Scales-II (VABS-II) socialization standard (5.27, p=0.002) scores.  
These results demonstrated clinically significant improvements consistent with or better than previously 
reported behavioral therapy intervention outcomes in similarly aged participants. Overall, families played an 
average of 18 90-second game sessions over the four weeks, with an average of three 90-second gameplay 
sessions per day of use and average of six days of use over the four weeks. These sessions generated almost 
1,000 videos (24 hours in total) used to generate 300,000+ frames labeled with a host of app and sensor data 
such as choice of game deck, number of correct guesses, etc., providing strong evidence for the feasibility of 
using GW to generate a rich behavioral database for training pediatric neurodevelopmental AI models. 
3.3  Rationale for the Current Study 
While multiple studies have demonstrated that the delivery of behavioral therapy as early as possible can 
effectively treat and even eliminate an ASD diagnosis,9–13 wait times to receive a diagnostic evaluation can,14 
exceed 14 months,15 and out-of-pocket expenses can reach $80,000 per year16 leaving one in three autistic 
children in the United States unable to receive the standard care. Geographic isolation and coronavirus disease 
2019 (COVID-19) related lockdowns present further limitations in access to consistent and adequate treatment. 
We previously demonstrated that wearable augmented reality glasses such as Superpower Glass, can deliver 
significant therapeutic benefits to children with autism using a fun exchange between the autistic child and a 
caregiver through games such as “Capture The Smile” where the child must get the caregiver to express a series 
of emotions. Other mobile interventions, such as AKL-T01 (EndeavorRx, Akili Interactive Labs, San Francisco, 
California, United States), the first game-based therapeutic to receive market clearance by the FDA in June 
2020, have shown therapeutic effectiveness in attention deficit/hyperactivity disorder (ADHD), anxiety, 
depression, and other mental health conditions. This growing body of evidence highlights the potential for 
scalable digital therapies to provide access to care to patient populations in the United States and globally. 
4.  DESIGN 
4.1  Study Design 
This is a Phase 2 randomized design. The intervention period is 4 weeks. Total study length is 8 weeks. Outcomes 
assessors will not be blinded, but the investigator will be blinded. 
4.2  Study Sites 
We will recruit remotely via email marketing. 

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Requirements for site selection and site registration: Sites will be evaluated by Stanford team and the main PI 
prior to selection or activation. 
Recruitment and enrollment will be decentralized and handled by a single study coordinator located at Stanford.  
We will enter into formal collaboration/DUA agreements with sites who wish to be involved in the study/have 
access to the study data. 
We will evaluate potential study sites by 
1/Patient population and demographics: are there patients who meet study criteria who will be willing/able to 
participate?  
2/ Is the study site willing to post promotional materials on site and support communication via initial recruitment 
email/contact?  
5. OBJECTIVES 
5.1  Primary Objective 
To evaluate the effects of a social game-based digital therapeutic, GuessWhat, on adaptive socialization when used 
consistently over 4 weeks in children with autism 3-12 years compared to a waitlist control group. 
5.2  Secondary Objectives  
To see if use of a social game-based digital therapeutic can lead to changes in emotion recognition and parent 
stress when used consistently over 4 weeks.  
To understand whether there is a difference in clinically meaningful changes if the device is used 4 weeks 
continuously.  
To understand what demographic variables (if any) make patients more likely to respond to the treatment. 
To understand the safety of device when used at home with a parent/caregiver. 
6. SUBJECT POPULATION 
6.1  Inclusion Criteria 
(1) Parent who is at least 18 years old of child with autism. 
(2) Child with autism is between 3 and 12 years old at time of baseline data collection. 
6.2 Exclusion Criteria 
(1) Parent does not have an Android or iOS smartphone compatible with GuessWhat App. 

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(2) The parent is unable to speak/read in available translations of the study app: English, Spanish, Brazilian 
Portuguese. 
(3) We will exclude participants who have a self-reported concurrent psychiatric or neurologic diagnosis 
including genetic syndromes and epilepsy.  
6.3  Removal of Subjects from Treatment 
We will remove subjects from treatment if they experience any negative effects. We will also remove subjects 
from treatment if there is suspicion of fraudulent activity (i.e. impersonating a parent of child, etc.)  
6.4  Compensation  
Following completion of measures after completion of the 4-week intervention period, participants will receive 
$50 e-gift card for their participation in the study. Participants who go on to complete T measures will receive a 
$20 e-gift card. There will be opportunities for continued follow-up from T3. Participants will be able to volunteer 
for these additional follow-ups. 
7. STUDY TREATMENT - GUESSWHAT 
7.1  Study Intervention 
We invented a digital treatment, GuessWhat, that operates on smartphones to create a fluid social engagement 
with an autistic child and his/her social partner to reinforce prosocial learning while simultaneously collecting 
game metric and video data that can be used to measure the child’s progress and symptoms. The GuessWhat 
app challenges the child to interpret and imitate social and emotion-centric prompts shown on the screen of a 
smartphone held just above the eyes of a parent/guardian. The parent flips the phone upward/downward if 
able/unable to correctly guess what the child is acting, switching to the next image in the deck with each flip. 
The phone’s front camera (facing the child) records the entire gameplay session and after each gameplay 
session, caregivers can choose to share the video with our research team.  
Preliminary work to-date resulted in positive user feedback, evidence of engagement for both the parents and 
children, and meaningful gains in socialization in the child.  
Parents and children choose from a variety of different game decks, with decks showing faces emoting the 
standard Ekman emotion expressions, cartoon characters playing sports activities, occupations, etc. Key 
mechanisms include facial expression labeling, imitation of varied social emotional prompts, and joint attention 
with a social partner during play to act out prompts and earn points. 

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Figure 1. Mobile Intervention User Experience.  GuessWhat is a mobile game available for any smartphone 
device that uses varied a) reward systems, and b) social emotional games to help children practice facial 
expression and emotion recognition, joint attention, and play. In a typical game session, c) the parent and child 
play a round of “MojiMatch” where the child matches an emoji to an animated GIF of a facial expression. 
Afterwards, the parent reviews and makes their own choices about the expression. d) Then they play “Act it 
Out,” where the parent holds the smartphone to their forehead and tries to guess the emotion mimicked by the 
child in response to the prompt shown on the phone’s screen. Upon guessing, the parent tilts the phone to 
proceed to the next prompt through the end of the session. After each game, parent and child can review a video 
of the session together. In-app game modes, unlocking deck and character choices based on coins earned, and 
activity-based achievement badges reinforce positive progression and ensure optimal child engagement through 
time.  
Standard Dose 
GuessWhat is a digital therapeutic application intended to improve socialization skills including joint attention 
and facial expression/emotion recognition in children with Autism Spectrum Disorder (ASD) between the ages 
of 3 and 12 years old. It is designed to be used regularly with a caregiver 3-4 times a week for 15-20 minutes. 
GuessWhat is intended for use as a part of a therapeutic program that may include clinician directed therapy, 
medication, and/or education programs, which further address symptoms of ASD.  
7.2  Administration of GuessWhat  
We will include several screening steps prior to enrollment. These will include: (1) completion of a short 
screening questionnaire, (2) Completion of baseline measures online, Demographics age matches baseline 
DOB, Time to complete baseline >20 minutes (not required, but will be flagged if not met), Missing data <40% 
(not required, but will be flagged if not met), Commitment task where a parent is asked to upload a picture of 
their child participating and confirm they understand participant responsibilities.  
A coordinator will complete the above screening steps, and if the participant meets all requirements, will 
randomize the participant. Treamtent participants will receive a link to download the app.  
GuessWhat is administered by the parent initiating play with the child. The parent interacts with the child 
throughout gameplay to administer the treatment for the recommended dose.  

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The current trial’s control is a treatment as usual group. Control participants will be asked to continue their 
treatment, and to inform the study team of any changes in treatment regimen during follow up assessments.  
Treatment Compliance 
After randomization and enrollment, research coordinators will monitor activity and contact participants by 
phone or email if there is no activity within the first 7 days. Participants will receive 3 reminders before being 
marked as lost to follow-up. The app will also send automatic notifications and automated email reminders will 
be sent weekly to remind parents to engage with the app. 
Treatment Precautions 
We identified no critical tasks during our use related risk analysis. We used simulated use to identify user tasks 
and determine associated hazards. To date No Adverse Events have been reported through testing. Following 
completion of Clinical Trial, we will include all adverse event information. We determined that use of the app 
presents no greater risk than a child and parent encounters in daily life. 
Concomitant Therapy 
We will not prohibit any concomitant therapy, pharmaceutical or behavioral. We will collect information on 
concomitant therapy and treatment at week 4, 8, 12. 
8. STUDY PROCEDURES 
• Refer also to Schedule of Assessments 
8.1  Screening and Enrollment Steps  
Week 0/Screening and Baseline Assessment 
Participants will be screened, consented, and enrolled entirely online using electronic data capture. 
Parents/Guardians and coordinators will complete the following steps prior to enrollment via online forms:  
• Screening questionnaire completed online 
• Informed Consent administered and obtained online (waiver of documentation approved) 
• Baseline questionnaires completed (Demographics, Mobile Autism Risk Assessment (MARA), Parent Stress 
Scale, VABS-3 Socialization subscale parent report, Emotion Recognition Child online Task  
• review of baseline data completed by coordinator 
Week 1: Enrollment and Allocation 
• Upon receiving notification with download link and download access code, participant downloads the 
app and is automatically randomized to treatment or control using a pre-defined block randomization 
scheme developed by the statistician.  

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Weeks 1-4: Intervention 
If randomized to Control, participants will continue treatment as usual. When they log-in to the app, they will 
receive a message that they will wait a few more weeks before beginning treatment. 
If randomized to Treatment, participants will be asked to play the app 3 times a week for 10-15 minutes for the 
next 4 weeks and they will receive weekly push notifications and email reminders.  
Week 4 Post-Test 1   
Treatment and Control will be asked to complete all outcome measures and will be asked about any changes in 
treatment or safety events at week 4. Participants will also be asked to complete a question assessing time spent 
playing with their child over the last month in emotion-centric theatrical play.  
Week 8 Post-test 2  
At week 4 from initial app download date, participants will be asked via email to complete all outcome 
measures as well as check-in on any changes in treatment and any safety events. These will be collected via 
RedCap online surveys.  
Week 12 Post-test 3 Follow-Up 
Treatment and Control will be asked to complete all outcome measures and will be asked about any changes in 
treatment or safety events at week 4. Participants will also be asked to complete a question assessing time spent 
playing with their child over the last month in emotion-centric theatrical play.  
9. EFFICACY AND SAFETY ASSESSMENTS 
9.1  Efficacy Assessments 
Primary Measurement (Efficacy): 
1. Change in Vineland Adaptive Behavior Socialization Parent Report from baseline (week 0) to week 4  
Vineland Adaptive Behavior Scales, 3rd edition (VABS-3) Socialization subscale of the Parent/Caregiver 
Comprehensive form will be administered online to the parents. Scores from the socialization domain of the 
VABS-3 reflects one's functioning in social situations. The socialization subscale is up to 112 items depending on 
age and development, where raw scores are converted to IQ-type standard scores--v-scale scores (M=15, SD=3) 
where scores range from 1 to 24, and factor in age equivalents, growth scale values, and higher scores indicate 
better adaptive functioning 
Secondary Measurements (Efficacy): 
1. Change in Parent Stress Scale from baseline (week 0) to week 4  
The Parental Stress Scale is an 18-item parent report scale that evaluates the extent of parent stress. Scores range 
from 18-90, where higher scores indicate a higher level of Parental stress. 
2. Change in Child Emotion Recognition score from baseline (week 0) to week 4 
Study team will use an image-based emotion recognition task where participants will select the emotion that 
corresponds to an emotional facial image in the form of a GIF (Graphics Interchange Format) image. Participants 
will select 1 of 8 available Ekman emotion labels for 16 facial emotional image stimuli presented in random order. 

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Correct responses will be measured against a predetermined majority rules consensus of the emotional content of 
the GIFs. 
3. Change in Vineland Adaptive Behavior Socialization Parent Report from baseline (week 0) to week 4 
4. Change in Parent Stress Scale from baseline (week 0) to week 4 
5. Change in Child Emotion Recognition score from baseline (week 0) to week 4 
9.2  Descriptive/Exploratory Measurements 
1. Game metric Analysis for Treatment participants 
▪ 
Average duration (average time playing per day)  
▪ 
Average frequency (days played per week) of play 
▪ 
% Moji Match GIFs with disagreement between parent and child  
▪ 
 Average emotion confusion for each of the Ekman emotions pre vs. post 
▪ 
Average time to guess in Act in Out 
▪ 
Time spent acting out a prompt, by prompt type (Sports, Emotions, Occupations, etc.)  
▪ 
Frequency of correct vs. incorrect guesses during Act it Out 
2. treatment regimen compliance 
3. demographics 
4. missing data 
9.3  Safety Assessments 
Adverse Events 
Definition of an Adverse Event 
The FDA Safety Guidance, referencing 21CFR312.32(a), defines an Adverse Event as follows: 
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.    
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
and does not imply any judgment about causality.  An adverse event can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose.   
Evaluating and Reporting of Adverse Events  
All AEs will be promptly documented on the Adverse Event in RedCap and assessed by the Principal Investigator.  
Details of the event must include the dates of onset and resolution, severity, relationship to study drug, seriousness, 
and whether the event caused the subject to withdraw from the study, outcome and timing with regard to 
administration of the study drug.  
Severity: Severity should be graded and recorded as follows: 
• Mild: Awareness of event but easily tolerated 
• Moderate: Discomfort enough to cause interference with usual activity 

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• Severe: Inability to carry out usual activity, incapacitating, requires medical intervention 
Relationship: The relationship of the Adverse Event to the study device will be determined initially by the 
Investigator, and assessed using the following definitions: 
• Related: There is a distinct temporal relationship between the event onset and administration of the study drug.  
There is a known reaction to agent or chemical group or predicted by known pharmacology.  The event cannot 
be explained by subject’s clinical state or other factors. 
• Unrelated:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication). 
Final determination of relatedness will be made by the Stanford Institutional Review Board during an unanticipated 
proble or adverse event submission. 
Expectedness: Whether or not the event was excepted or unexpected. Further details on this can be found in 
section 8.5. 
These criteria, in addition to good clinical judgment, should be used as a guide for determining the causal 
assessment.  If it is felt that the event is not related to study therapy, then an alternative explanation should be 
provided. 
Serious Adverse Events (SAEs) 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A SUSAR carries specific and time-based reporting requirements for the Sponsor of a clinical trial. Thus, after a 
Site Investigator reports an SAE, the FDA expects the Sponsor will determine whether it meets the definition of a 
SUSAR. 
A SUSAR is defined according to 3 criteria:  
1. The AE is deemed a “suspected adverse reaction” if there is a reasonable possibility that the study drug caused 
the AE.  A “reasonable possibility” means there is evidence to suggest a causal relationship between the drug 
and adverse event. 
2. The AE is “Serious” if it meets the definition of an SAE.  
3. The AE is deemed “unexpected” if it is not listed in the Investigator’s Brochure (IB) or if in the IB, has not 
been reported at the severity observed. 
In cases where the Investigator deems a SUSAR has occurred, it must file an IND Safety Report with the FDA.  
FPHU will require the assistance and cooperation of the Investigator and staff to provide accurate and complete 
information on the subject and observed SAE so that reporting requirements to the FDA can be met. 
Reporting SUSARs to the FDA: IND Safety Reports 
IND safety reports are used to submit reports of SUSARs to the FDA.  There are 2 types of reports:  
• A “15-day report” is used when the reported SAE is a SUSAR and requires that as much information as is 
available to the investigator and the sponsor, be submitted to the FDA in on the appropriate form. For US trials, 
the appropriate form is the FDA Form 3500A also commonly known as a “MedWatch” form. 
• A “7-day report” is used when the SUSAR is considered to be fatal or life-threatening. 
The 7-day and 15-day timelines begin the day that the Sponsor determines the information qualifies for reporting 
and are counted in calendar days – not business days.  Therefore, it is important that the Site investigator carefully 
follow the reporting requirements. 

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10. STATISTICAL METHODS AND ANALYSIS PLAN 
10.1 
 General Considerations  
For the primary comparison, the following will be tested: 
• Null hypothesis: There will be no difference between the observed change in VABS-3 Socialization scores 
from baseline to week 4 between treatment and control participants.  
• Alternative hypothesis: We will observe a minimally clinically important increase on the VABS-3 
Socialization score from baseline to week 4 in the treatment group, but not in the control group. 
Hypothesis tests will be two sided and conducted at an overall alpha = 0.05 level of significance. 
10.2 
 Sample Size Justification and Power Calculation 
We will enroll up to 2,000 participants to achieve a 50% enrollment rate and 36% retention rate. 
We aim to successfully retain 36% of enrolled families and have 360 parents and their child with autism aged 3-
12 years old complete all study procedures (180 Treatment, 180 Control).  
We will close out the study after enrolling 360 participants with completed endpoints, estimated for 90% power 
and 2-sided significance of .05 to detect minimal differences in VABS-III Socialization Standard Score of 3.1 
points, consistent with the results of a GuessWhat feasibility study previously reported by our lab. 
10.3 
 Demographic and Baseline Characteristics 
Summary statistics will be provided per treatment group for demographic (race, gender, age) and other initial 
subject characteristics (e.g., concomitant disorders, concomitant treatments) will be provided per treatment 
group and for the total group.  
10.4 
 Analysis Populations 
The following analysis populations will be defined for the study: 
(1) The intent-to-treat (ITT) population will include all randomized patients. Patients will be analyzed 
according to their assigned treatment arm. All efficacy analyses will be completed in the ITT population. 
 
(2) Per-Protocol (Treatment Compliant): This population is defined as any participant that began the initial 4-
week treatment or control phase, completed both the pre and post assessments, and met a minimum 
compliance level of 50%. Participants that received incorrect intervention after randomization will be 
excluded from this population.  
 
(3) The safety population will include all patients who receive study treatment. Patients will be analyzed 
according to actual treatment received. All safety analyses will be completed in the safety population. 
10.5 
 Stratification, Subgroup Analysis and Pooled Analysis 
Following consent, those subjects meeting all entry criteria will be randomized in a 1:1 ratio. Random blocks of 
size 2 or 4 will be utilized.  
Efficacy Endpoint Analysis 
1. Objective 

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To compare the change in outcome measure scores between treatment and treatment as usual groups in a 
clinical trial. 
2. Study Design 
Participants: Treatment and Treatment as Usual groups 
Outcome Measure: Continuous outcome measure scores measured at baseline and follow-up on VABS-3 
Socialization Subscale and Parent Stress Scale. 
3. Statistical Hypotheses 
Null Hypothesis (H₀): There is no difference in the change in outcome measure scores between treatment and 
control groups. 
Alternative Hypothesis (H₁): There is a significant difference in the change in outcome measure scores between 
treatment and control groups, whereby treatment participants scores demonstrate improvement. 
4. Variables 
Independent Variable: Group (Treatment vs. Control) 
Dependent Variable: Change in outcome measure scores (Post-test score - Pre-test score) 
5. Statistical Method 
Primary Analysis: Independent samples t-tests will be used to compare the mean change in outcome measure 
scores between treatment and control groups. 
6. Assumptions 
Normality: The change in outcome measure scores in each group should be approximately normally distributed. 
If not, consider transformations or non-parametric tests. 
Equal Variances: The variances of change scores in the treatment and control groups should be approximately 
equal. If violated (checked using Levene's test), use Welch's t-test or report results with caution. 
7. Statistical Software 
Analysis Tool: SPSS, R, or any other statistical software capable of performing independent samples t-tests. 
 
Descriptive analyses 
Descriptive statistics (proportions for categorical variables, means, medians, standard deviations, and interquartile 
ranges for continuous variables) will be reported for all key patient variables, including baseline and demographic 
characteristics, use of medications, compliance, and study completion status.  Data that are missing on key patient 
characteristics and the outcome will be fully described, including any patterns of missingness (i.e., any 
relationships between missingness of a variable and patient characteristics). 
 
A CONSORT diagram displaying the number of patients screened, eligible, and consented along with reasons for 
ineligibility will be provided. Graphical tools such as histograms, boxplots, and scatterplots will be created to 
assess quality of data and to display patterns over time. 
 
Safety Analysis 
Treatment related adverse events for GuessWhat intervention will be presented. Any adverse events occurring 
during any phase of the study judged by clinical sites' Primary Investigator (Pl) to be related to the intervention 
will be recorded and presented in a table listing. The Safety population (see analysis population details) will be 
used for this analysis that will include randomized participants. The severity of each event will be evaluated by 
the Pl and presented with the recorded events. If there are frequently occurring treatment related adverse events, 

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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.  
11. RECORDING AND COLLECTION OF DATA 
11.1 
Case Report Form 
The Investigator or designee will record all data collected on the electronic Case Report Form (eCRF) provided 
for that purpose. For this study, REDCAP will be the eCRF. The site will be suitably trained on the use of the 
eCRF and appropriate site personnel will be provided electronic signatures. 
All site entries will be made in a secured web site and the Principal Investigator will review the record for 
completeness.  Upon completion of the review, the PI will sign electronically in the signature page of the eCRF.  
The Investigator or designee will make necessary eCRF corrections.  The investigator must authorize the 
corrections to the entered data on eCRF. 
Specific instructions on use of the EDC system and guidelines for data entry and correction will be provided to 
the sites. 
11.2 
Study Files and Subject Source Documents 
Subject confidentiality is strictly held in trust by the participating investigators, research staff, the Sponsor and 
their designees.  This confidentiality is extended to cover testing of biological samples in addition to the clinical 
information relating to subjects.  Authorized representatives of the Sponsor may inspect all documents and records 
required to be maintained by the Investigator, including but not limited to, medical records (office, clinic or 
hospital) and pharmacy records for the subjects in this study.  Any data, specimens, forms, reports, and other 
records that leave the site will be identified only by a subject identification number to maintain confidentiality. 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified.  These documents include Investigators’ Study Files 
and original subject clinical source documents generated at the study site.  The term “original” means the first 
recording of the data. 
The Investigator will ensure the site master files are maintained, including the study protocol and its amendments, 
IRB and regulatory approvals with associated correspondence, informed consents, study drug records, staff 
curriculum vitae, all correspondence, and other appropriate documents. 
Subject clinical source documents may include, but are not limited to, subject hospital/clinic records.  The 
Investigator must assure that all original source documents are available to support monitoring activities. 
11.3 
Monitoring 
Monitoring will be conducted according to the applicable ICH and GCP guidelines to ensure protocol adherence, 
quality of data, drug accountability, compliance with regulatory requirements and continued adequacy of the 
investigational site and its facilities.  The site study staff will cooperate in the monitoring process by ensuring the 
availability of the eCRFs, source documents and other necessary documents at the time of monitoring and by 
prompt attention to any matters brought to their attention by the monitor. 
11.4 
Audit 
ICH guidelines for GCP require independent inspection of clinical program activities.  Such inspections may be 
performed at any time - before, during and/or after the study.  The site Investigator and site study staff are 

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responsible for maintaining the site master file containing all study-related regulatory documentation as outlined 
by the Sponsor that will be suitable for inspection at any time by the Sponsor, its designees, and/or regulatory 
agencies.  The Investigator understands and agrees to give access to the necessary documentation and files. 
11.5 
Retention of Data 
The site Pl 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 Pl plans to leave the institution so that 
arrangements can be made for the transfer of records. 
12. ETHICS 
12.1 
Ethics Committee 
A properly constituted, valid IRB/IEC must review the treatment plan and procedures, the Investigator’s informed 
consent document, and related subject information. It is the responsibility of the Investigator to ensure that all 
aspects of institutional review are conducted in accordance with current regulations governing the jurisdiction 
where the study is conducted. The Sponsor (or designee) must receive a letter documenting IRB/IEC approval that 
specifically identifies the title of the treatment plan, subject information sheet, and ICF. 
12.2 
Subject Information and Consent 
It is the responsibility of the site Investigator to ensure that written informed consent is obtained from the subject 
or legal representative before any activity or procedure is undertaken that is not part of routine care. The informed 
consent must comply with local regulations. 
The background of the study, the procedures, the potential benefits and risks of the treatment, and the fact that 
treatment is voluntary for the subject must be explained to the subject or legal representative. The subject or 
representative must be given sufficient time to consider whether to receive compassionate treatment. A copy of 
the ICF, signed and dated by the subject/representative and the site Investigator (or designee), must be given to 
the subject/representative. 
Each consent form should contain an authorization allowing the Investigator and the Sponsor (or designee) to use 
and disclose protected health information (PHI) (i.e., subject-identifiable health information) in compliance with 
local law.  
13. SCHEDULE OF ASSESSMENTS 
 
 
Screening  
Week 0 
Enrollment 
Week 1  
Primary 
Assessment 
Week 4 
Check-In 2 
Week 12 
Screening 
 
 
 
 
Pre-Screening Consent 
X 
 
 
 
Screening Questionnaire 
X 
 
 
 
Informed Consent 
X 
 
 
 

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Assessments 
 
 
 
 
Demographics Questionnaire 
X 
 
 
 
Mobile Autism Risk Assessment 
X 
 
 
 
Parent Stress Scale 
X 
 
X 
X 
Vineland Adaptive Behavior Scales-3 Socialization Subscale Parent Report X 
 
X 
X 
Child Emotion Task 
X 
 
X 
X 
App Download 
X 
 
X 
 
Change in treatment/play questionnaire 
 
 
X 
X 
Allocation/Randomization 
 
X