A Randomized Trial of Dichoptic Treatment for Amblyopia in Children 8 to 12 Years of Age
Phase: PHASE3
Conditions: Amblyopia
Sponsor: Jaeb Center for Health Research

**CONFIDENTIAL** 
Signature Page 
 
AMBLYOPIA TREATMENT STUDY  
 
A Randomized Trial of Dichoptic Treatment for 
Amblyopia in Children 8 to 12 Years of Age 
 
Protocol Identifying Number: ATS24 
 
Version Number: 1.0 
 
29 April 2024 
 
 
JCHR Principal Investigator 
 
Name, degree 
Robert Henderson, MS 
Signature/Date 
 
 
Protocol Chair(s) (as applicable) 
 
Name, degree 
Marjean T. Kulp, OD 
Signature/Date 
 
 
Protocol Chair(s) (as applicable) 
 
Name, degree 
Benjamin G. Jastrzembski, MD 
Signature/Date 
 

JAEB CENTER FOR HEALTH RESEARCH 
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AMBLYOPIA TREATMENT STUDY  
 
A Randomized Trial of Dichoptic Treatment for 
Amblyopia in Children 8 to 12 Years of Age 
 
Protocol Identifying Number: ATS24 
 
 
Version Number: 1.0 
 
29 April 2024 

JAEB CENTER FOR HEALTH RESEARCH 
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PAGE 3 OF 57 
KEY ROLES 
 
 
JCHR Principal Investigator 
 
Name, degree 
Robert Henderson, MS 
Title 
Principal Investigator 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: rhenderson@jaeb.org 
http://www.pedig.net 
 
Protocol Co-Chair 
 
Name, degree 
Marjean T. Kulp, OD 
Title 
Protocol Co-Chair 
Institution Name 
The Ohio State University 
338 West 10th Ave. 
Columbus, Ohio 43210 
Phone: 1-614-688-3336 
Fax:  
Email: kulp.6@osu.edu 
 
Protocol Co-Chair 
 
Name, degree 
Benjamin G. Jastrzembski, MD 
Title 
Protocol Co-Chair 
Institution Name 
University of California, Davis 
4860 Y Street, Sacramento, CA 95817 
1-916-734-6602 
1-916-703-5076 
benjast@ucdavis.edu 
 

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VERSION HISTORY 
 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0  
R. Kraker 
R. Henderson 
29Apr2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   *Version in effect at study initiation 

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 15 
1.1 Epidemiology and Clinical Characteristics ....................................................................................... 15 
1.2 Current Practice ................................................................................................................................. 15 
1.2.1 Monocular Penalization ............................................................................................................... 15 
1.2.2 Dichoptic Treatments .................................................................................................................. 15 
1.2.2.1 Dichoptic Games ................................................................................................................. 16 
1.2.2.2 Dichoptic Movies/Shows .................................................................................................... 17 
1.3 Choice of Study Design and Control Group ...................................................................................... 17 
1.4 Rationale for Present Study ............................................................................................................... 18 
1.5 Potential Risks and Benefits of Study Treatment .............................................................................. 18 
1.5.1 Known Potential Risks ................................................................................................................ 18 
1.5.1.1 Luminopia ........................................................................................................................... 18 
1.5.1.2 Vivid Vision ........................................................................................................................ 19 
1.5.2 Known Potential Benefits ............................................................................................................ 19 
1.5.3 Risk Assessment .......................................................................................................................... 19 
1.6 General Considerations...................................................................................................................... 20 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 21 
2.1 Participant Recruitment and Enrollment ........................................................................................... 21 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 21 
2.2 New or Change in Spectacle Correction If Needed ........................................................................... 21 
2.3 Participant Inclusion Criteria ............................................................................................................. 22 
2.4 Participant Exclusion Criteria ............................................................................................................ 24 
2.5 Procedures at Enrollment Visit .......................................................................................................... 24 
2.5.1 Historical Information ................................................................................................................. 24 
2.5.2 Ability to Use Luminopia or Vivid Vision .................................................................................. 24 
2.5.3 Clinical Testing ........................................................................................................................... 25 
2.6 Randomization ................................................................................................................................... 26 
CHAPTER 3: RANDOMIZED TRIAL PROCEDURES .................................................................................... 27 
3.1 Treatment ........................................................................................................................................... 27 
3.1.1 Luminopia Dichoptic Group ........................................................................................................ 27 
3.1.2 Vivid Vision Dichoptic Group .................................................................................................... 27 
3.1.3 Continued Optical Correction Group .......................................................................................... 27 
3.2 Phone Call ......................................................................................................................................... 27 
3.3 Follow-up Schedule Through 18-Week Primary Outcome ............................................................... 27 

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3.4 Continued Follow-up Post 18-Week Primary Outcome .................................................................... 28 
3.4.1 Treatment Post 18-Week Primary Outcome ................................................................................ 28 
3.5 Follow-up Visit Testing Procedures .................................................................................................. 28 
3.6 Masked Examiner .............................................................................................................................. 30 
3.7 Non-Study Visits and Treatment ....................................................................................................... 30 
3.8 Management of Refractive Error ....................................................................................................... 30 
3.9 Management of Strabismus ............................................................................................................... 31 
CHAPTER 4: STUDY DEVICES .................................................................................................................... 32 
4.1 Description of the Luminopia Device................................................................................................ 32 
4.1.1 Headset ........................................................................................................................................ 32 
4.2 Description of Vivid Vision .............................................................................................................. 32 
4.2.1 Headset ........................................................................................................................................ 33 
4.2.2 Vivid Vision Handheld Controller .............................................................................................. 33 
4.2.3 Vivid Vision Patient Portal .......................................................................................................... 33 
4.3 Internet Requirements........................................................................................................................ 33 
4.3.1 Luminopia ................................................................................................................................... 33 
4.3.2 Vivid Vision ................................................................................................................................ 33 
4.4 Device Delivery and Return .............................................................................................................. 34 
4.5 Device Accountability Procedures .................................................................................................... 34 
4.5.1 Device Failure ............................................................................................................................. 34 
4.5.2 Participant Access to Study Device After 18-Week Primary Outcome ...................................... 34 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 35 
5.1 Questionnaires ................................................................................................................................... 35 
5.2 Clinical Assessments ......................................................................................................................... 36 
CHAPTER 6: MISCELLANEOUS CONSIDERATIONS ................................................................................... 37 
6.1 Contacts by the Jaeb Center for Health Research and Sites .............................................................. 37 
6.2 Participant Compensation .................................................................................................................. 37 
6.3 Cost of Treatment .............................................................................................................................. 37 
6.4 Participant Withdrawal ...................................................................................................................... 37 
6.5 Confidentiality ................................................................................................................................... 37 
CHAPTER 7: UNANTICIPATED PROBLEM / ADVERSE EVENT REPORTING ............................................. 38 
7.1 Unanticipated Problems ..................................................................................................................... 38 
7.2 Adverse Events .................................................................................................................................. 38 
7.2.1 Reportable Adverse Events ......................................................................................................... 38 
7.2.2 Safety Oversight .......................................................................................................................... 38 

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7.2.3 Stopping Criteria ......................................................................................................................... 39 
7.2.4 Participant Discontinuation of Study Treatment ......................................................................... 39 
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 40 
8.1 Statistical and Analytical Plans ......................................................................................................... 40 
8.2 Study Objective and Statistical Hypothesis ....................................................................................... 40 
8.2.1 Primary Efficacy Outcomes ........................................................................................................ 40 
8.2.2 Study Objectives .......................................................................................................................... 40 
8.2.3 Hypotheses .................................................................................................................................. 40 
8.3 Sample Size ....................................................................................................................................... 41 
8.3.1 Effect of GLASSES ..................................................................................................................... 41 
8.3.2 Effect of LUMINOPIA................................................................................................................ 41 
8.3.3 Effect of VIVID VISION ............................................................................................................ 42 
8.3.4 Summary of Previous Studies ..................................................................................................... 42 
8.3.5 Sample Size for Superiority of Each Dichoptic Treatment Versus 
GLASSES ............................................................................................................................................. 42 
8.3.6 Power and Precision for Superiority of LUMINOPIA vs. VIVID VISION ................................ 43 
8.4 Outcome Measures ............................................................................................................................ 44 
8.4.1 Primary Efficacy Endpoint .......................................................................................................... 44 
8.4.2 Secondary Efficacy Endpoints .................................................................................................... 44 
8.4.3 Exploratory Efficacy Endpoints .................................................................................................. 44 
8.5 Analysis Datasets and Sensitivity Analyses ...................................................................................... 44 
8.6 Analysis of the Primary Efficacy Outcome ....................................................................................... 45 
8.7 Analysis of the Secondary Efficacy Outcomes ................................................................................. 45 
8.7.1 Pediatric Eye Disease Questionnaire (PedEyeQ) ........................................................................ 46 
8.8 Intervention Adherence ..................................................................................................................... 46 
8.9 Protocol Adherence and Retention .................................................................................................... 46 
8.9.1 Intercurrent Events ...................................................................................................................... 46 
8.10 Safety Analyses ............................................................................................................................... 47 
8.11 Baseline Descriptive Statistics ......................................................................................................... 47 
8.12 Planned Interim Analyses ................................................................................................................ 47 
8.13 Subgroup Analyses .......................................................................................................................... 48 
8.14 Multiple Comparisons / Multiplicity ............................................................................................... 48 
8.15 Exploratory Analyses ...................................................................................................................... 49 
8.15.1 Mean Change in Distance VA at 9 weeks ................................................................................. 49 
8.15.2 Mean Change in Distance VA over 18 weeks (area under the curve) ....................................... 49 
8.15.3 Improvement of Amblyopic-eye Distance VA by 2 or More Lines .......................................... 49 

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8.15.4 Resolution of Amblyopia at 9 weeks and 18 weeks .................................................................. 49 
8.15.5 Binocular Function .................................................................................................................... 49 
8.15.6 Treatment Impact Questionnaire ............................................................................................... 50 
8.16 Dichoptic Therapy after GLASSES................................................................................................. 50 
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 50 
9.1 Case Report Forms and Other Data Collection ................................................................................. 50 
9.2 Study Records Retention ................................................................................................................... 51 
9.3 Quality Assurance and Monitoring .................................................................................................... 51 
9.4 Protocol Deviations ........................................................................................................................... 52 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 53 
10.1 Ethical Standard ............................................................................................................................... 53 
10.2 Institutional Review Boards ............................................................................................................ 53 
10.3 Informed Consent Process ............................................................................................................... 53 
10.3.1 Consent Procedures and Documentation ................................................................................... 53 
10.3.2 Participant and Data Confidentiality ......................................................................................... 54 
10.3.3 Future Use of Data..................................................................................................................... 54 
CHAPTER 11: REFERENCES ....................................................................................................................... 55 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
ANCOVA 
Analysis of covariance 
ATS 
Amblyopia Treatment Study  
BCVA 
Best corrected visual acuity 
CI 
Confidence interval 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
D 
Diopter 
DHHS 
Department of Health and Human Services 
DSMC 
Data safety and monitoring committee 
eCRF 
Electronic case report form  
E-ETDRS 
Electronic-Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP  
Good clinical practice 
ICH 
International Council for Harmonisation 
IOD 
Interocular difference 
IRB 
Institutional Review Board 
JCHR 
Jaeb Center for Health Research 
logMAR 
Logarithm of the minimal angle of resolution 
NIH 
National Institutes of Health 
ODM 
Occlusion dose monitor 
PACT 
Prism and alternate cover test 
PedEyeQ 
Pediatric Eye Questionnaire 
PEDIG 
Pediatric Eye Disease Investigator Group  
QA 
Quality assurance 
QC 
Quality control 
RBM 
Risk based monitoring 
RCT 
Randomized clinical trial 
SAP 
Statistical Analysis Plan 
SPCT 
Simultaneous prism and cover test 
VA 
Visual Acuity 

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PROTOCOL SUMMARY 
1 
 
2 
PARTICIPANT AREA 
DESCRIPTION 
Title 
A Randomized Trial of Dichoptic Treatment for Amblyopia in Children 8 to 12 Years of Age. 
 
Précis 
In older children, standard amblyopia treatments appear to be less effective, and many children 
have residual amblyopia after treatment. Dichoptic technology provides a more immersive and 
engaging treatment environment which may result in improved adherence and greater treatment 
benefit. However, dichoptic treatments have not been studied in older children with amblyopia. 
This study will evaluate two dichoptic treatments to determine effectiveness over continued 
optical correction alone in older children with amblyopia. 
 
Investigational Devices 
Luminopia digital and Vivid Vision digital therapeutic systems. 
 
Primary Objectives 
To formally compare the effectiveness of Luminopia 1 hour / day, 6 days per week while 
wearing optical correction if needed versus continued optical correction alone if needed, in 
children 8 to 12 years of age, as a superiority test. 
 
To formally compare the effectiveness of Vivid Vision 25 minutes / day, 6 days per week while 
wearing optical correction if needed versus continued optical correction alone if needed, in 
children 8 to 12 years of age, as a superiority test. 
 
If both Luminopia and Vivid Vision are superior to continued optical correction alone if needed, 
then the effectiveness of Luminopia versus Vivid Vision will be formally compared in children 8 
to 12 years of age, as a superiority test.   
 
If either Luminopia or Vivid Vision is NOT superior to continued optical correction alone if 
needed, then the treatment group difference and 95% CI for the difference between treatment 
groups will be calculated with no p-value and the results will be considered exploratory only.  
 
It is noted for the comparison of Luminopia versus Vivid Vision, the absence of a statistically 
significant difference cannot rule out the presence of a clinically meaningful difference between 
active treatment groups. The test is powered assuming a difference between treatments as small 
as 3.75 letters with a standard deviation of 7.0 letters 
 
Study Design 
Multicenter, randomized clinical trial.  
 
Number of Sites 
The study is open to all clinical sites approved to participate in the PEDIG network. 
 
Endpoints 
Primary Efficacy Outcome:  
• 
Change in amblyopic eye logMAR distance VA between randomization and 18 weeks.  
 
Key Secondary Efficacy Outcomes: 
• 
Functional Vision, Social, and Frustration/Worry quality of life domains as measured 
by the Pediatric Eye Questionnaire (PedEyeQ).  
 
Key Safety Outcomes:  
• 
Change in fellow eye logMAR distance VA between randomization and 18 weeks.  
• 
Proportion of participants with no strabismus who develop a new strabismus.   
• 
Proportion of participants with strabismus who develop a worsening strabismus ≥10∆.   
• 
Proportion of participants with parental report of diplopia more than once per week.  
• 
Proportion of participants reporting headache, eyestrain, nausea, seizures, dizziness, 
increase in frequency of night terrors, or skin irritation.   
 
Population 
Key Inclusion Criteria: 
• 
Age 8 to 12 years. 
• 
Amblyopia associated with anisometropia, strabismus (<=5∆ at distance and near 
measured by SPCT), or both. 

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PARTICIPANT AREA 
DESCRIPTION 
• 
VA, measured in each eye without cycloplegia in current refractive correction (if 
applicable) using the E-ETDRS VA protocol on a study-approved device displaying 
single surrounded optotypes, as follows: 
o 
VA in the amblyopic eye 20/40 to 20/200 inclusive (33 to 72 letters with E-
ETDRS). 
o 
VA in the fellow eye 20/25 or better (≥ 78 letters with E-ETDRS). 
o 
Interocular difference ≥ 3 logMAR lines (≥ 15 letters), i.e., amblyopic eye 
VA at least 3 logMAR lines worse than fellow eye VA.   
• 
Spectacles/contact lens correction (if needed) worn for at least 18 weeks, or until 
stability of VA is demonstrated (<1-line [5-letter] change by the same testing method 
measured on 2 exams at least 9 weeks apart). 
• 
Interpupillary distance of 52mm to 72mm inclusive.  
• 
No treatment with cycloplegic eyedrops (e.g., atropine) in the last 2 weeks. 
• 
No more than 2 weeks (cumulative) prior dichoptic treatment. 
• 
No diplopia by parental report (defined as no more than once per week). 
• 
No myopia greater than -6.00D SE in either eye.  
 
Sample Size 
252 accounting for lost to follow-up (84 in each treatment group) 
 
Phase 
Phase III Randomized Clinical Trial 
 
Treatment Groups 
Random assignment (1:1:1) to: 
 
• 
Luminopia Group: dichoptic movies/shows wearing the Luminopia headset prescribed 
1 hour per day (treatment time can be split into shorter sessions totaling 1 hour each 
day) 6 days a week with current optical correction if needed 
• 
Vivid Vision Group: dichoptic games using the Vivid Vision headset, prescribed 
approximately 25 minutes per day (treatment time to complete the day’s sessions can 
be split into shorter sessions totaling about 25 minutes each day) 6 days per week with 
current optical correction if needed  
• 
Continued Optical Correction Group: continued full-time optical correction alone if 
needed 
 
Participant Duration 
If randomized, participation in the study will last 36 weeks or less.   
 
Study Duration 
Thirty-five (35) months from first enrollment to last participant visit (26 months to recruit, 
followed by 9 months of follow up).  
 
Protocol Overview/Synopsis 
Participants eligible for the study will be randomly allocated (1:1:1) to receive either Luminopia 
dichoptic treatment while wearing optical correction if needed, Vivid Vision dichoptic treatment 
while wearing optical correction if needed, or continued optical correction alone if needed, with 
clinical assessments at 9- and 18-weeks post-randomization.   
 
At the 18-week primary outcome visit, participants who were randomly assigned to receive 
optical correction alone if needed with an IOD of 1 logMAR line (5 letters) or more, will be 
offered randomization to Luminopia or Vivid Vision dichoptic therapy and if they accept, 
followed forward with visits at 27- and 36-weeks post-randomization. 
 
The study will end for all other participants at 18 weeks.   
 
 
3 

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STUDY SUMMARY FLOW CHART  
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
 
 
15 
 
 
16 
Primary Outcome Exam (18 Weeks ± 2 weeks from Randomization) 
•
Assessment of Diplopia and Adverse events 
•
Treatment Impact Questionnaire  
•
PedEyeQ Visual Function Domain  
•
Monocular distance VA testing (E-ETDRS) (Masked) 
•
Binocular function testing (Randot Preschool; if nil, test Butterfly; if nil, test Worth 4-shape) (Masked) 
•
Ocular alignment testing (cover/uncover, SPCT, PACT) at distance and near 
1-Week Phone Call 7 to 13 days from Randomization 
Inquire if any problems with randomized treatment (completed by site personnel) 
Follow-Up Exam (9 Weeks ± 2 weeks from Randomization) 
•
Assessment of Diplopia and Adverse Events 
•
Treatment Impact Questionnaire   
•
PedEyeQ Social and Frustration Worry Domains 
•
Monocular distance VA testing (E-ETDRS) (Masked) 
•
Binocular function testing (Randot Preschool; if nil, test Butterfly; if nil, test Worth 4-shape) (Masked) 
•
Ocular alignment testing (cover/uncover, SPCT, PACT) at distance and near 
 
Baseline Measurements (with best correction) 
•
Binocular Diplopia Questionnaire 
•
Monocular distance VA testing (E-ETDRS) 
•
Binocular function testing (Randot Preschool; if nil, test Butterfly; if nil, test Worth 4-shape) 
•
Ocular alignment testing (cover/uncover, SPCT, PACT) at distance and near 
•
PedEyeQ Functional Vision, Social, and Frustration/Worry domains 
Major Eligibility Criteria 
•
Age 8 to 12 years 
•
Amblyopia associated with anisometropia, strabismus (<=5∆ at distance and near, by SPCT), or both 
•
No more than 2 weeks (cumulative) prior dichoptic treatment 
•
No treatment with cycloplegic eyedrops (e.g., atropine) in the last 2 weeks 
•
Spectacles/contact lens correction (if needed) worn for at least 18 weeks, or demonstrated stability of 
amblyopic eye VA (<1-line change or by the same testing method measured on 2 exams at least 9 weeks 
apart) 
•
Visual acuity in the amblyopic eye of 20/40 to 20/200 (33 to 72 letters inclusive) by E-ETDRS 
•
Interocular difference in VA of 3 or more logMAR lines (15 or more letters) by E-ETDRS 
•
Age-normal VA in the fellow eye (20/25 or better, 78 or more letters by E-ETDRS) 
•
No diplopia by parental report (defined as no more than once per week) 
•
No myopia greater than -6.00D SE in either eye 
•
Interpupillary distance of 52mm to 72mm inclusive 
•
No history of light-induced seizures or simulator sickness
 Luminopia Group 
Dichoptic movies/shows 1 hour per 
day, 6 days per week 
 Vivid Vision Group 
Dichoptic games 25 minutes per 
day, 6 days per week 
Randomize 
Optical Correction Group 
Continue full-time correction if 
needed 
New or Change in Spectacle Correction if Needed  
• 
Participants meeting all eligibility criteria except for refractive error may be prescribed spectacles paid for by the study 
if investigator verifies visual acuity with the intended spectacle prescription is expected to meet eligibility criteria.  
• 
Participants will return for standard of care visits until they meet eligibility criteria below and complete enrollment 
testing in new spectacles.   

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17 
 
18 
 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
 
25 
 
26 
 
27 
 
28 
 
29 
 
30 
 
31 
 
32 
 
33 
 
34 
 
35 
 
36 
 
 
37 
RESIDUAL AMBLYOPIA 
AT 18-WEEKS? 
  
1 logMAR line (5 letters) or more IOD 
(amblyopic eye worse) AND willing to 
accept trial of Luminopia or Vivid Vision? 
 
  
Luminopia Group or 
Vivid Vision Group 
Secondary Outcome Exam: 27 Weeks ± 2 weeks from Randomization 
 
• 
Monocular distance VA testing (E-ETDRS) 
• 
Binocular function testing (Randot Preschool; if nil, test Butterfly; if nil, test Worth 4-shape) 
• 
Ocular alignment testing (cover/uncover, SPCT, PACT) at distance and near 
• 
Assessment of Diplopia and Adverse events 
 
Secondary Outcome Exam: 36 Weeks ± 2 weeks from Randomization 
 
• 
Monocular distance VA testing (E-ETDRS) 
• 
Binocular function testing (Randot Preschool; if nil, test Butterfly; if nil, test Worth 4-shape) 
• 
Ocular alignment testing (cover/uncover, SPCT, PACT) at distance and near 
• 
Assessment of Diplopia and Adverse events 
  
Optical Correction Group 
  
Study Ends at 18 Weeks 
Yes 
No 
19-Week Phone Call  
(7 to 13 days from 18-week visit)  
Inquire if any problems  
(completed by site personnel) 
RANDOMIZED TO 
LUMINOPIA OR VIVID 
VISION 

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
38 
*19-week phone call timed 7 to 13 days after the 18-week primary outcome only for participants 
39 
assigned to optical correction alone (if needed) who have residual amblyopia and accept 
40 
randomization to treatment with Luminopia or Vivid Vision at the 18-week primary outcome.   
41 
 
42 
†The 27-week and 36-week post-randomization visits are completed by any participant assigned 
43 
to optical correction alone (if needed) who has residual amblyopia and accepts randomized 
44 
allocation of treatment with either Luminopia or Vivid Vision at the 18-week primary outcome.     
45 
 
46 
 
 
47 
Visit 
Informed Consent 
(and Assent if required) 
Demographics / Medical History 
Distance VA 
Binocular Function Testing 
Ocular Alignment 
PedEyeQ  
Functional Vision 
PedEyeQ  
Social/Frustration/Worry 
Binocular Diplopia Questionnaire 
Adverse Events Questionnaire 
Treatment Impact Questionnaire 
Enrollment 
Visit 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1-week Call 
 
 
 
 
 
 
 
 
 
 
9-week Visit 
 
 
X 
masked  
X 
masked  
X 
 
X 
X 
X 
X 
18-week Visit  
 
 
X 
masked  
X 
masked 
X 
X 
 
X 
X 
X 
19-week Call* 
 
 
 
 
 
 
 
 
 
 
27-week Visit† 
 
 
X 
X 
X 
 
 
X 
X 
 
36-week Visit† 
 
 
X 
X 
X 
 
 
X 
X 
 

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Chapter 1: Background Information 
48 
 
49 
1.1 Epidemiology and Clinical Characteristics 
50 
Amblyopia is the most common cause of reduced monocular visual acuity (VA) in children and 
51 
young adults, with estimates of prevalence ranging from 1% to 5%.1,2  The most commonly 
52 
associated risk factors are uncorrected anisometropia, strabismus, or a combination of both. In 
53 
addition to reduced VA, amblyopia may also be associated with dysfunctions of accommodation, 
54 
fixation, binocularity, vergence, reading speed and fluency, and contrast sensitivity.3-12  
55 
 56 
1.2 Current Practice 
57 
 58 
1.2.1 Monocular Penalization   
59 
The current foundation of amblyopia treatment is optical correction (when there is uncorrected 
60 
refractive error) followed (if needed) by part-time patching or atropine penalization of the fellow 
61 
eye.13-18 While this has long been the standard treatment approach, it is known to be less 
62 
effective when treating older children,19 the majority stabilizing with residual amblyopia.20-22   
63 
 
64 
In older children, there are limited data showing added benefit from monocular penalization with 
65 
patching and/or atropine versus continued optical correction alone. A PEDIG randomized trial of 
66 
patching 2-6 hours/day plus daily atropine versus continued glasses alone in 8-12 year olds 
67 
(n=404) found 53% of the participants treated with patching and atropine improved 10 or more 
68 
letters by 24 weeks compared with 25% of those continuing with optical correction alone (a 
69 
difference of 28%, 95% confidence interval (CI) for difference = 19% to 37%).22    
70 
 
71 
One possible reason for failure of part-time patching treatment in older children is poor 
72 
adherence with the prescribed treatment regimens.23,24 Nevertheless, data from studies using 
73 
occlusion dose monitors show that adherence with patching in older children is no different than 
74 
adherence in younger children,25 yet treatment effect appears to decline with age, especially after 
75 
7 years.19,22,25 Such data suggest that part-time patching and atropine may simply be inadequate 
76 
treatment approaches in some older children with amblyopia. In addition, some children and 
77 
their parents report adverse effects from patching, including negative psychosocial effects, 
78 
bullying and social stigma.26-30  
79 
 
80 
The limited effectiveness of standard treatment approaches results in many 8- to 12-year-olds 
81 
having residual amblyopia. This, in addition to the challenges of acceptability with patching, 
82 
calls for consideration of alternative amblyopia treatments that are better suited to older children.  
83 
 
84 
1.2.2 Dichoptic Treatments 
85 
Although the predominant approach for amblyopia treatment is monocular penalization, some 
86 
have advocated an alternative dichoptic (binocular) treatment approach. Dichoptic treatments for 
87 
amblyopia provide simultaneous but separate stimulation to each eye, incorporating elements of 
88 
binocular engagement, but modifying the input to the sound eye by blur and/or reduced contrast 
89 
sensitivity and/or reduced luminance. Dichoptic treatment strategies may also differentially 
90 
modify central versus peripheral vision and may utilize other motor skills such as those requiring 
91 
hand-eye coordination. The neuro-physiological basis for dichoptic treatment is supported by 
92 

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evidence that binocular cortical mechanisms remain intact even in adults with strabismic 
93 
amblyopia.31 
94 
 
95 
Over the past 20 years, dichoptic treatments have evolved from office-based technologies32-34 to 
96 
those that can be conducted in the home. Home-based technologies have many advantages, 
97 
including convenience and the reduced cost associated with less in-office care-provider time. 
98 
Current home-based dichoptic treatments typically utilize either games, movies, or web-based 
99 
content.  
100 
 
101 
Both dichoptic games and dichoptic movies have been previously studied to some extent in older 
102 
children and adults with amblyopia, but there are very few data on outcomes specifically in 8- to 
103 
12-year-olds. To provide optimal relevance for the present study proposal, the following 
104 
summary of prior data is limited to previous studies conducted by PEDIG and other studies on 
105 
technologies that are currently available for future study and that do not require patching as part 
106 
of the treatment approach. 
107 
 
108 
1.2.2.1 Dichoptic Games 
109 
PEDIG has previously evaluated two dichoptic iPad games as treatment for amblyopia in 
110 
randomized clinical trials: the Tetris falling blocks game in ATS1835,36 and the Dig Rush game in 
111 
ATS20.37 In ATS18, the Tetris falling blocks game was found not to be non-inferior to patching, 
112 
with an adjusted treatment group difference at 16 weeks in 5- to <13-year-olds of 0.31 lines, 
113 
favoring patching (upper limit of the 1-sided 95% CI, 0.53 lines).27 Nevertheless, only 22% 
114 
completed >75% of prescribed gameplay. In the ATS20 older cohort (7- to 12-year-olds),37 there 
115 
was no difference in letter scores at 8 weeks between those randomized to the dichoptic Dig 
116 
Rush game and those randomized to continued spectacles alone (adjusted mean difference: -0.1, 
117 
98.3% CI: -2.4 to 2.1 letters); 56% completed >75% of prescribed gameplay.37  
118 
 
119 
These previous data strongly suggest that poor adherence with these types of games, 
120 
accompanied by inattention and short, sporadic treatment sessions likely contributed to failure to 
121 
show a benefit of this modality of dichoptic treatment. 
122 
 
123 
Vivid Vision is a dichoptic game technology currently certified in the Europe Union (CE 
124 
approved 2017). Vivid Vision utilizes a virtual reality (VR) mobile headset to display child-
125 
appropriate, interactive games and activities. Treatment of amblyopia is achieved by balancing 
126 
interocular blur and/or luminance to restore perceptual contributions from the amblyopic eye. 
127 
Binocular viewing is required for game play. The games require recognition of binocular cues 
128 
targeting suppression, stereoscopic vision, and vergence, each treated in turn at the threshold of 
129 
the patient's ability. There are no prior Vivid Vision outcome data specifically in 8- to 12-year-
130 
olds, but all prior studies are summarized below.  
131 
 
132 
Ziak et al38 used the beta version of Vivid Vision in 17 adults (age 17 to 69 years) with 
133 
anisometropic amblyopia. After eight 40-minute in-office sessions (2 per week), mean 
134 
amblyopic-eye VA improved from 0.58 ± 0.35 to 0.43 ± 0.38 logMAR (mean change: 0.15, 95% 
135 
CI: 0.07 to 0.22 logMAR); 47% achieved 20/40 or better after treatment versus 30% before 
136 
treatment.  
137 
 
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Ho et al39 (poster presentation only) used Vivid Vision over 8, 30-minute treatment sessions (one 
139 
per week), to treat residual amblyopia in 34 patients aged 3 to 69 years. Data displayed in a bar 
140 
chart suggest estimated mean change was 0.17 logMAR (95% CI: 0.16 to 0.18) in participants 
141 
aged <=11 years (N=18) and 0.15 logMAR (95% CI: 0.11 to 0.19) in participants aged >11 years 
142 
(N=16). 
143 
 
144 
Halička et al40 studied Vivid Vision in a single arm prospective study including 84 adults (aged 
145 
18-54 years) and found an average improvement of 0.1 logMAR (no standard deviation or 95% 
146 
CI reported) after 4 weeks (8 hours) of in-office treatment.  
147 
 
148 
Meqdad et al41 studied Vivid Vision and patching in a randomized trial including 86 subjects 
149 
aged 12 (range 6 to 37) years, and found an average improvement of 0.89 lines (95% CI: 0.73 to 
150 
1.35 lines; P< 0.001) after 10 weeks (20 hours) of in-office therapy.    
151 
 
152 
1.2.2.2 Dichoptic Movies/Shows 
153 
Luminopia is a dichoptic movie technology (often termed a digital therapeutic with software as 
154 
the medical device) available for use in the USA since 2022 and has been approved by the FDA 
155 
for the treatment of amblyopia in children 4 to 7 years of age. 
156 
 
157 
Luminopia displays a large library of web-based video content through a virtual reality (VR) 
158 
headset, utilizing computational algorithms to split the source video into 2 streams (one to each 
159 
eye) and modify the input in real time. Contrast in the sound eye is reduced to 15% and a series 
160 
of 6 different dichoptic masks overlay the video content, rotating every 30 seconds.   
161 
Complementary dichoptic masks are superimposed on the images such that binocular viewing is 
162 
required to fully appreciate the video content. There are some limited prior data in older children.  
163 
 
164 
In a single-arm pilot study (n=90)42 evaluating a younger cohort with amblyopia (4- to 12-year-
165 
olds; mean 6.7±2.0 years), Luminopia was prescribed 1 hour/day for 12 weeks. Overall (n=74 
166 
outcomes) mean amblyopic-eye BCVA improved from 0.50±0.15 to 0.35±0.21 logMAR (1.5 
167 
logMAR lines, 95% CI, 1.2-1.8 lines, P<0.0001) over 12 weeks.42 For the 17 participants aged 8 
168 
to 12 years, amblyopic-eye VA improved an average of 0.14± 0.11 logMAR after 12 weeks of 
169 
treatment (95% CI, 0.09 to 0.19 logMAR).42  
170 
 
171 
1.3 Choice of Study Design and Control Group  
172 
In designing this study, the planning committee carefully considered the most important 
173 
questions to answer in this older age group. Over several months of discussion, it became clear 
174 
that the planning committee, executive committee and investigator group had strong interest in 
175 
answering treatment effectiveness questions for both a dichoptic game technology (Vivid Vision) 
176 
and a dichoptic movie technology (Luminopia). As a result, the planning committee moved 
177 
forward with the current proposal to include two active treatment groups.  
178 
 
179 
Both glasses alone and part-time patching were considered as candidates for a control group but 
180 
given the paucity of any evidence for effectiveness of dichoptic treatments in older children, it 
181 
was considered necessary to first answer the basic question of whether there is any treatment 
182 
benefit for dichoptic treatments when compared with continued optical correction alone if 
183 
needed.  
184 
 
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Therefore, this study is a 3-arm randomized trial designed to answer two primary questions:  
186 
 
187 
1) Is Luminopia superior to continued optical correction alone (if needed)? and  
188 
2) Is Vivid Vision superior to continued optical correction alone (if needed)?   
189 
 
190 
If both Vivid Vision and Luminopia are superior to continued optical correction alone (if 
191 
needed), a formal comparison between the two dichoptic treatments (Luminopia versus Vivid 
192 
Vision) will be made. If either Vivid Vision or Luminopia are not superior to continued optical 
193 
correction alone (if needed), the difference between active treatment groups will be considered 
194 
exploratory only.  
195 
 
196 
It is noted for the comparison of Luminopia versus Vivid Vision, the absence of a statistically 
197 
significant difference cannot rule out the presence of a clinically meaningful difference between 
198 
active treatment groups. The test is powered assuming a difference between treatments as small 
199 
as 3.75 letters with a standard deviation of 7.0 letters. 
200 
  
201 
1.4 Rationale for Present Study  
202 
Successful treatment continues to be an elusive goal in older children with amblyopia and the 
203 
protracted clinical course presents an ongoing healthcare burden. Standard patching treatment 
204 
appears to be less effective in older children, with an outcome of residual amblyopia for many. In 
205 
addition, patching may be difficult for social reasons, making adherence more challenging to 
206 
achieve. Given these concerns, alternative treatments for older children with amblyopia need to 
207 
be seriously considered.  
208 
 
209 
Although previous PEDIG studies in older children failed to show effectiveness of dichoptic 
210 
treatment for amblyopia, there were notable challenges in maintaining engagement and achieving 
211 
adherence. Technologies that utilize a more immersive and engaging environment are more 
212 
likely to maintain interest and result in improved adherence and greater treatment benefit. 
213 
Further study is needed to evaluate the effectiveness of engaging and immersive home-based 
214 
dichoptic treatments for amblyopia, to determine whether they provide a viable treatment option 
215 
for those who refuse or are noncompliant with patching and atropine and to treat residual 
216 
amblyopia in those previously treated. 
217 
 
218 
In addition to evaluating VA outcomes, we plan to assess treatment impact to provide valuable 
219 
data on patient experience with each dichoptic technology. We also plan to assess functional 
220 
vision and social and frustration / worry quality of life to evaluate everyday life treatment 
221 
benefits. 
222 
 
223 
1.5 Potential Risks and Benefits of Study Treatment  
224 
 
225 
1.5.1 Known Potential Risks 
226 
 
227 
1.5.1.1 Luminopia 
228 
In a previous randomized clinical trial evaluating Luminopia vs continued glasses alone in 
229 
children aged 4 to 7 years43, 10 (20%) of 51 patients experienced non-serious adverse events in 
230 
the treatment group vs. 7 (13%) of 54 patients in the continued glasses group. In the Luminopia 
231 
treatment group adverse events were new heterotropia in 3 (6%), worsening VA in the 
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amblyopic eye in 2 (4%), worsening VA in the fellow eye in 2 (4%), headache in 4 (8%), 
233 
eyestrain in 1 (4%), with single cases each of dizziness, increase in frequency of night terrors, 
234 
eye twitching, and facial redness.  
235 
 
236 
In the continued glasses group adverse events were diplopia in 1 (2%), new heterotropia in 2 
237 
(4%), worsening heterotropia in 1 (2%), worsening VA in the amblyopic eye in 4 (7%), headache 
238 
in 1 (2%) and pain from glasses in 1 (2%). No serious adverse events were reported. The most 
239 
frequent non-serious adverse event potentially related to Luminopia was headache (8%). 
240 
In a preceding non-randomized study evaluating 90 participants aged 4 to 12 years, 40 the most 
241 
common adverse events were headaches (n=6), eye strain (n=3), blurry vision (n=2), and 
242 
worsening VA (n=2). One participant developed a new strabismus.  All adverse events were 
243 
graded as mild in severity.  
244 
 
245 
The Luminopia headset may become warm during normal usage. If the surface touching the face 
246 
feels hot, the participant should stop using immediately and wait for it to cool down before re-
247 
using. 
248 
 
249 
1.5.1.2 Vivid Vision 
250 
Meqdad et al41 assessed participants aged 6 to 37 years after each week of treatment with Vivid 
251 
Vision for any sense of dizziness, vertigo, diplopia, new / increasing tropia or worsening of VA 
252 
in the fellow eye. A single patient reported tolerable diplopia in the first couple of treatment 
253 
sessions which resolved spontaneously in subsequent sessions.41 According to the Vivid Vision 
254 
user manual, participants may experience temporary symptoms of eye strain, which may include 
255 
blurred vision, a tired sensation, dry, irritated, or watery eyes, and fatigue. In addition, 
256 
participants who have suffered a head injury, vertigo, a vestibular / balance / headache disorder, 
257 
or who are at risk for photosensitive seizures may have exacerbated symptoms. Parents will be 
258 
advised that the headset should be removed immediately if the participant feels nausea, 
259 
dizziness, or headaches.  
260 
 
261 
1.5.2 Known Potential Benefits 
262 
The potential benefits of treatment are improved amblyopic eye VA and improved stereoacuity. 
263 
 
264 
1.5.3 Risk Assessment 
265 
The expected adverse events from Luminopia are summarized in 1.5.1.2 and do not pose a 
266 
greater risk than what a typical child would experience in their normal day-to-day activities (e.g., 
267 
wearing glasses, wearing small adhesives like band aids, watching television, playing 
268 
videogames, etc.).   
269 
 
270 
 
271 
The expected adverse events from Vivid Vision are summarized in 1.5.1.2 and do not pose a 
272 
greater risk than what a typical child would experience in their normal day-to-day activities (e.g., 
273 
wearing glasses, wearing small adhesives like band aids, watching television, playing 
274 
videogames, etc.). 
275 
Since Luminopia and Vivid Vision do not pose a significant risk to participants, the Sponsor has 
276 
determined that both Luminopia and Vivid Vision are nonsignificant risk devices.    
277 
 
278 

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The Sponsor has determined that the protocol’s level of risk is consistent with 45 CFR 46.404 
279 
and 21 CFR 50.51, which indicates research not involving greater than minimal risk.  
280 
 
281 
1.6 General Considerations 
282 
The study is being conducted in compliance with the policies described in the network policies 
283 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
284 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
285 
 
286 
Luminopia has been approved by the FDA for treatment of amblyopia in children aged 4 to 7 
287 
years for up to 12 weeks. In this younger population, serious side effects were rare. Risks are not 
288 
expected to be different in children aged 8 to 12 years, or for the extended use. The delivery of 
289 
virtual media using Vivid Vision is by means of a similar headset and therefore no significant 
290 
risks are expected using Vivid Vision either. As such, both investigational devices are considered 
291 
by the sponsor to be non-significant risk devices and are considered to have an approved 
292 
application for investigational device exemption (conditioned upon IRB agreement of device risk 
293 
determination), whereby compliance with the abbreviated requirements of 21 CFR 812.2(b) will 
294 
be maintained.  
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Chapter 2: Study Enrollment and Screening 
296 
 
297 
2.1 Participant Recruitment and Enrollment 
298 
The study plans to enroll a minimum of 252 participants. As the enrollment goal approaches, 
299 
sites will be notified of the end date for recruitment. Study participants whose parents have 
300 
signed an informed consent form (and child has signed assent form, if required) can be enrolled 
301 
up until the end date, which means the recruitment goals might be exceeded; however, total 
302 
recruitment will not exceed 265 participants.    
303 
 
304 
Study participants will be recruited from approximately 70 clinical centers in North America. All 
305 
eligible participants will be included without regard to sex, race, or ethnicity. There is no 
306 
restriction on the number of participants to be enrolled or randomized by each site toward the 
307 
overall recruitment goal. 
308 
 
309 
2.1.1 Informed Consent and Authorization Procedures 
310 
A child is considered for the study after undergoing a routine eye examination as part of standard 
311 
of care that identifies amblyopia appearing to meet the eligibility criteria. Children may also be 
312 
referred to a study investigator from another eye-care or health-care provider. The study will be 
313 
discussed with the child’s parent(s) or legal guardian(s) (referred to subsequently as parent(s)). 
314 
Parent(s) who express an interest in the study will be given a copy of the informed consent form 
315 
to read. Written informed consent and assent must be obtained from a parent and child prior to 
316 
performing any study-specific procedures that are not part of the child’s routine care and/or 
317 
collecting any data for the study. 
318 
 
319 
If the participant and/or parent(s) are not fluent in written or spoken English, then the consent 
320 
and/or assent forms must be translated into a language understandable by the 
321 
participant/parent(s). Further, a qualified interpreter must be available for the consent process 
322 
and for all subsequent study-related interactions. 
323 
 
324 
A participant is considered enrolled when the informed consent and assent forms have been 
325 
signed, as applicable.  
326 
 
327 
2.2 New or Change in Spectacle Correction If Needed 
328 
New spectacles or a change in spectacles may be prescribed for participants who have not had 
329 
a cycloplegic refraction within 7 months OR if their current spectacles do not meet spectacle 
330 
tolerance criteria (2.3 #6) OR in cases where the investigator determines that updating the 
331 
spectacles is necessary for best clinical care, IF they ALSO meet ALL the other inclusion criteria 
332 
(2.3) while wearing their current refractive correction. 
333 
The prescribed spectacles must be based upon a cycloplegic refraction performed on the day of 
334 
enrollment or within 7 months and must meet eligibility criteria in 2.3 #6. If new spectacles are 
335 
prescribed and paid for by the study, the investigator should ensure that visual acuity is still 
336 
expected to meet eligibility criteria in 2.3 #2. As needed, VA should be measured (using the 
337 
investigator’s preferred VA testing method) in the intended spectacle prescription if the child is 
338 
not cyclopleged or in the full cycloplegic refractive error if the child is cyclopleged. 
339 
 
340 

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The participant will return for standard of care visits until they meet eligibility criteria (including 
341 
stability criteria) below in 2.3 #6.  
342 
 
343 
Any new contact lenses or change to contact lenses will NOT be paid for by the study. 
344 
 
345 
2.3 Participant Inclusion Criteria 
346 
Individuals must meet all the following inclusion criteria to be eligible to participate in the study. 
347 
 
348 
1. Age 8 to <13 years. 
349 
2. VA, measured in each eye without cycloplegia in current refractive correction (if 
350 
applicable) using the E-ETDRS VA protocol on a study-approved device displaying 
351 
single surrounded optotypes, as follows: 
352 
a. VA in the amblyopic eye 20/40 to 20/200 inclusive (33 to 72 letters with E-
353 
ETDRS). 
354 
b. VA in the fellow eye 20/25 or better (≥ 78 letters with E-ETDRS). 
355 
c. Interocular difference ≥ 3 logMAR lines (≥ 15 letters) i.e., amblyopic eye VA at 
356 
least 3 logMAR lines worse than fellow eye VA).   
357 
3. Amblyopia associated with strabismus, anisometropia, or both (previously treated or 
358 
untreated). 
359 
a. Criteria for strabismic amblyopia: At least one of the following must be met: 
360 
• Presence of a heterotropia on examination at distance or near fixation (with 
361 
optical correction), must be <=5 prism diopters (∆) by SPCT at distance and 
362 
near fixation. 
363 
• Documented history of strabismus which is no longer present (which in the 
364 
judgment of the investigator could have caused amblyopia). 
365 
b. Criteria for anisometropia: At least one of the following criteria must be met: 
366 
• ≥1.00 D difference between eyes in spherical equivalent (SE). 
367 
• ≥1.50 D difference in astigmatism between corresponding meridians in the 
368 
two eyes. 
369 
c. Criteria for combined-mechanism: Both of the following criteria must be met: 
370 
• A criterion for strabismus is met (see above). 
371 
• ≥1.00 D difference between eyes in SE OR ≥1.50 D difference in astigmatism 
372 
between corresponding meridians in the two eyes. 
373 
4. No more than 2 weeks (cumulative) of prior dichoptic treatment 
374 
5. No treatment with cycloplegic eyedrops (e.g., atropine) in the past 2 weeks; other 
375 
treatments allowed up to enrollment but then must be discontinued. 
376 
6. Refractive correction is required (single vision lenses or contact lenses) for any of the 
377 
following refractive errors based on a cycloplegic refraction completed within the last 7 
378 
months:  
379 
• Hypermetropia of 2.50 D or more by SE 
380 
• Myopia of amblyopic eye of 0.50D or more SE 
381 
• Astigmatism of 1.00D or more  
382 
• Anisometropia of more than 0.50D SE 
383 
 
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NOTE: Children with cycloplegic refractive errors that do not fall within the requirements above for 
385 
refractive correction may be given refractive correction at investigator discretion but must follow the 
386 
study-specified prescribing guidelines, as detailed below. 
387 
 
388 
NOTE: Monocular or binocular contact lens wear is allowed provided the contact lenses meet the 
389 
refractive error correction requirements below. For each child, all testing must be performed using the 
390 
same form of optical correction (i.e., no changing between contacts and spectacles).  
391 
a. Spectacles/contact lens correction prescribing instructions referenced to the 
392 
cycloplegic refraction completed within the last 7 months: 
393 
• SE must be within 0.50D of fully correcting the anisometropia (if new glasses are 
394 
prescribed, reduction in plus sphere must be symmetric in the two eyes). 
395 
• SE must not be under corrected by more than 1.50D SE.  
396 
• Cylinder power in both eyes must be within 0.50D of fully correcting the 
397 
astigmatism. 
398 
• Axis must be within +/- 10 degrees if cylinder power is ≤1.00D, and within +/- 5 
399 
degrees if cylinder power is >1.00D. 
400 
• Myopia must not be under corrected by more than 0.25D or over corrected by 
401 
more than 0.50D SE, and any change must be symmetrical in the two eyes.  
402 
 
403 
b.  Spectacles/contact lens correction (with or without other treatment such as patching) 
404 
meeting the above criteria must be worn: 
405 
• For at least 18 weeks OR until VA stability is documented (defined as <1-line change 
406 
by the same testing method measured on 2 consecutive exams at least 9 weeks apart).   
407 
• For determining VA stability (non-improvement): 
408 
o The first of two measurements may be made 1) in current correction, 
409 
or 2) in trial frames with or without cycloplegia or 3) without 
410 
correction (if new correction is prescribed),   
411 
o The second measurement must be made without cycloplegia in the 
412 
correct spectacles/contact lens correction that has been worn for at 
413 
least 9 weeks.   
414 
o NOTE: Because this determination is a pre-randomization, the method 
415 
of measuring VA is not mandated. 
416 
7. Participant is willing to wear a headset.  
417 
8. Participant is willing to continue full-time spectacles/contact lens wear (if needed). 
418 
9. Interpupillary distance of 52mm to 72mm inclusive. 
419 
10. Investigator is willing to prescribe continued spectacles/contact lens correction (if 
420 
needed) or either dichoptic device per protocol.  
421 
11. Participant is willing to accept assignment to either continued spectacles/ contact lens 
422 
wear alone, dichoptic movies/shows (view 1 hour per day 6 days per week) OR dichoptic 
423 
games (play approximately 25 minutes per day, 6 days per week) for 19 weeks. 
424 
12. Parent understands the protocol and is willing to accept randomization. 
425 
13. Parent has phone (or access to phone) and is willing to be contacted by JAEB Center 
426 
staff. 
427 
14. Relocation outside of area of an active PEDIG site for this study within the next 36 weeks 
428 
is not anticipated. 
429 

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430 
2.4 Participant Exclusion Criteria 
431 
Individuals meeting any of the following criteria will be excluded from study participation. 
432 
 
433 
1. Heterotropia more than 5∆ at distance or near (measured by SPCT in current correction) 
434 
2. Prism lenses or need of a prism prescription at enrollment. 
435 
3. Current bifocal spectacles (eligible only if bifocal discontinued 2 weeks prior to 
436 
enrollment). 
437 
4. Myopia greater than -6.00D spherical equivalent in either eye. 
438 
5. Ocular co-morbidity that may reduce VA determined by an ocular examination 
439 
performed within the past 7 months (Note: nystagmus per se does not exclude the 
440 
participant if the above visual acuity criteria are met using patch occlusion. Fogging is 
441 
not permitted). 
442 
6. Diplopia more than once per week over the last week prior to enrollment by parental 
443 
report. 
444 
7. History of light-induced seizures. 
445 
8. Known simulator sickness. 
446 
9. Severe developmental delay that would interfere with treatment or evaluation (in the 
447 
opinion of the investigator). Participants with mild speech delay or reading and/or 
448 
learning disabilities are not excluded. 
449 
10. Immediate family member (biological or legal guardian, child, sibling, parent) of 
450 
investigative site personnel directly affiliated with this study or an employee of the JAEB 
451 
center for Health Research. 
452 
 
453 
2.5 Procedures at Enrollment Visit 
454 
 
455 
2.5.1 Historical Information 
456 
After informed consent has been signed, historical information elicited will include the 
457 
following: date of birth, sex, race, ethnicity, current medication use, history of and current 
458 
medical conditions, and prior amblyopia therapy including refractive correction.      
459 
 
460 
2.5.2 Ability to Use Luminopia or Vivid Vision 
461 
Interpupillary distance will be measured using investigator’s standard method or a PEDIG-
462 
provided IPD ruler. Participants with interpupillary distance <52mm or >72mm will not be 
463 
eligible to participate in the study.  
464 
 
465 
Site personnel will confirm that the participant is able and willing to wear the Luminopia or 
466 
Vivid Vision headsets by:  
467 
 
468 
1. Showing the child the devices in the clinic and allowing them to try them on, if desired.   
469 
2. Asking the child if they are willing to wear the headset for up to an hour a day, 6 days a 
470 
week.  
471 
 
472 

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2.5.3 Clinical Testing 
473 
Participants who meet all eligibility criteria in section 2.3 and 2.4 including visual acuity stability 
474 
criteria in current spectacles/contract lens correction will complete the following tests and 
475 
assessments.   
476 
 
477 
All examination procedures must be tested on the date of enrollment, except the cycloplegic 
478 
refraction and ocular examination, which must be performed within 7 months prior to the day of 
479 
enrollment. The following procedures should be performed at the enrollment visit in the 
480 
following order: 
481 
 
482 
Lensometry: 
483 
Verify current refractive correction by lensometry. If a participant is wearing contact lenses, 
484 
verify contact lens prescription.  
485 
 
486 
Questionnaires: 
487 
 
488 
1. Assessment of Binocular Diplopia:  
489 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
490 
“has your child complained of double vision over the last week.” If yes, the parent is 
491 
asked how frequently during the last week the child has complained of double vision: 
492 
“once per week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study 
493 
personnel may assess diplopia. Children who have reported diplopia more than once over 
494 
the past week are ineligible (see section 2.3).  
495 
2. PedEyeQ Functional Vision Domain44:  
496 
A child questionnaire for children, a proxy questionnaire completed by the parent 
497 
regarding their child’s functional vision.  The child questionnaire is either completed by 
498 
the child themselves or administered to the child by study personnel and the Proxy 
499 
questionnaire is completed by the parent.  
500 
3. PedEyeQ Social Domain and Frustration/Worry Domain44:  
501 
Child questionnaire for children, proxy questionnaire completed by the parent regarding 
502 
their child. The child questionnaire is either completed by the child themselves or 
503 
administered to the child by study personnel and the Proxy questionnaire is completed by 
504 
the parent.  
505 
 
506 
Clinical Testing (in the following order) is performed in the participant’s current refractive 
507 
correction, if required, without cycloplegia: 
508 
 
509 
4. Distance Visual Acuity Testing: 
510 
Monocular distance VA testing will be performed in current refractive correction (if 
511 
required) in each eye by a certified examiner using the electronic E-ETDRS VA on a 
512 
study-certified VA tester displaying single surrounded optotypes.  
513 
5. Binocular Function Testing (by a certified examiner):  
514 
• Stereoacuity will be tested at 40cms in current refractive correction using the Randot 
515 
Preschool Test.  
516 
• If nil stereoacuity on the Randot Preschool Test, the Random Dot Butterfly test will 
517 
be performed at 40cms.   
518 

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• If nil stereoacuity on the Random Dot Butterfly, the Worth 4-shape will be 
519 
administered.  
520 
6. Ocular Alignment Testing:  
521 
Ocular alignment will be assessed in current spectacle/contact lens correction by the 
522 
cover test, simultaneous prism and cover test (SPCT) (in cases of strabismus detected by 
523 
cover test), and prism and alternate cover test (PACT) in primary gaze at distance (3 
524 
meters) and at near (1/3 meter). 
525 
7. Additional Clinical Testing:  
526 
Ocular examination as per investigator’s clinical routine.   
527 
     
528 
2.6 Randomization 
529 
The JAEB Center will construct a Master Randomization List using a permutated block design 
530 
stratified by VA in the amblyopic eye as moderate (20/40 to 20/80 [72 to 53 letters]) versus 
531 
severe (20/100 to 20/200 [52 to 33 letters]) which will specify the order of treatment group 
532 
assignments.   
533 
 
534 
All eligible participants enrolled in the study will be followed for up to 36 weeks. Participants 
535 
will be randomly assigned in a 1:1:1 allocation to one of the following three treatment groups for 
536 
18 weeks:  
537 
• Luminopia Group: dichoptic movies/shows wearing the Luminopia headset prescribed 1 
538 
hour per day (treatment time can be split into shorter sessions totaling 1 hour each day) 6 
539 
days a week with current optical correction, if needed. 
540 
• Vivid Vision Group: dichoptic games using the Vivid Vision headset, prescribed 
541 
approximately 25 minutes per day (treatment time to complete the day’s sessions can be 
542 
split into shorter sessions totaling about 25 minutes each day) 6 days per week with 
543 
current optical correction, if needed.  
544 
• Continued Optical Correction Group: continued full-time optical correction alone, if 
545 
needed.   
546 
 
547 
Once a child is assigned to treatment, they will be included in the analysis regardless of whether 
548 
the assigned treatment is performed. Thus, the investigator must not randomize a participant 
549 
unless convinced that the parent will accept any of the treatments. 
 
550 

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Chapter 3: Randomized Trial Procedures 
551 
 
552 
3.1 Treatment 
553 
Investigators must not start any additional treatment (other than assigned treatment as outlined 
554 
below) prior to the 18-week primary outcome visit.   
555 
 
556 
3.1.1 Luminopia Dichoptic Group 
557 
Participants randomized to the Luminopia group will be asked to watch dichoptic movies/shows 
558 
using the Luminopia device at home, for 1 hour per day, 6 days per week, for 18 weeks, while 
559 
continuing to wear any optical correction (including while wearing the Luminopia device).     
560 
 
561 
Parents will be instructed that the 1 hour of daily treatment should be completed in a single 60-
562 
minute session, but if this is not possible for whatever reason, the treatment may be divided into 
563 
shorter sessions totaling 1 hour per day. Adherence with Luminopia treatment will be recorded 
564 
electronically throughout the study and will be accessible by the study coordinator and 
565 
investigator through the Luminopia online portal. 
566 
 
567 
3.1.2 Vivid Vision Dichoptic Group 
568 
Participants randomized to the Vivid Vision group will be instructed to play dichoptic games 
569 
using the Vivid Vision device with the Smart Assist 2 treatment program at home for 
570 
approximately 25 minutes per day, 6 days per week, for 18 weeks while continuing to wear any 
571 
optical correction (including while wearing the Vivid Vision device).    
572 
 
573 
The therapy session can be paused by taking a rest with the headset on, or by taking the headset 
574 
off. In either case, game play resumes when the headset is put back on. An unfinished session 
575 
can be resumed at any time later on the same day, but sessions that are not completed within 10 
576 
hours of the start time will end. Any data will be saved. The next day, the next session will start, 
577 
even if the previous session was not completed. Thus, participants will be instructed to complete 
578 
one treatment session each day. Adherence with Vivid Vision treatment will be recorded 
579 
electronically throughout the study and will be accessible by the study coordinator, investigator 
580 
and by the parent through the Vivid Vision online portal.   
581 
 
582 
3.1.3 Continued Optical Correction Group 
583 
Participants assigned to the continued optical correction group will continue to wear any needed 
584 
refractive correction full-time for 18 weeks. 
585 
 
586 
3.2 Phone Call   
587 
Site personnel will call all participants 1 week (7 to 13 days) after randomization to encourage 
588 
adherence and confirm that there are no problems with randomized treatment. Site personnel will 
589 
also call participants in the optical correction alone group who switch to Luminopia or Vivid 
590 
Vision treatment at the 18-week primary outcome visit (7 to 13 days after the 18-week visit), 
591 
again to encourage adherence with treatment and to confirm that there are no problems with the 
592 
Luminopia or Vivid Vision device.   
593 
 
594 
3.3 Follow-up Schedule Through 18-Week Primary Outcome 
595 
The follow-up schedule through 18-week primary outcome is timed from randomization: 
596 

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Visit 
Target Day  
Post-Randomization 
Target Window  
Post-Randomization*  
Allowable Window 
Post-Randomization 
1-Week Phone Call  
7 days 
7 to 13 days 
7 to 27 days 
9-Week Office Visit 
63 days 
49 days to 77 days 
42 days to 104 days 
18-Week Primary Outcome 
126 days 
112 days to 140 days 
105 days to 168 days  
* Target window for phone calls is 7 to 13 days from previous office visit.  Target window for office visits is target 
597 
day +/- 2 weeks.  
598 
 
599 
3.4 Continued Follow-up Post 18-Week Primary Outcome 
600 
Children originally randomized to Luminopia or Vivid Vision will end the study at 18 weeks.  
601 
 
602 
Children originally randomized to continued optical correction alone whose amblyopia HAS 
603 
NOT resolved (1 or more logMAR lines IOD is present with the originally amblyopic eye worse 
604 
than fellow eye) at the 18-week primary outcome visit, will be offered randomization to an 18-
605 
week trial of dichoptic treatment (Luminopia or Vivid Vision); and if they accept treatment, will 
606 
continue in follow-up as defined below. Otherwise, the study will end.  
607 
 
608 
Visit 
Target Day  
Post-18-week 
Target Window  
Post-18-week*  
Allowable Window 
Post-18-week 
19-Week Phone Call 
7 days 
7 to 13 days 
7 to 27 days 
27-Week Office Visit 
63 days 
49 days to 77 days 
42 days to 104 days 
36-Week Office Visit 
126 days 
112 days to 140 days 
105 days to 168 days  
* Target window for phone call is 7 to 13 days from previous office visit. Target window for office visits is target 
609 
day +/- 2 weeks.  
610 
 
611 
3.4.1 Treatment Post 18-Week Primary Outcome 
612 
Participants will continue dichoptic treatment until the 36-week visit.   No other treatment should 
613 
be prescribed before the 36-week outcome visit.   
614 
 
615 
3.5 Follow-up Visit Testing Procedures 
616 
Participants will be seen at follow-up visits as outlined in sections 3.3 and 3.4.   
617 
 
618 
All procedures will be performed with the participant’s current refractive correction without 
619 
cycloplegia.  
620 
• If a participant currently wears spectacles or contact lenses but they are not available or 
621 
are not within tolerance at the 9-week follow-up examination, testing may be performed 
622 
with current correction in trial frames. 
623 
• Habitual refractive correction (meeting study requirements) must be worn for the primary 
624 
outcome visit at 18 weeks.  
625 
 
626 
A Masked Examiner must complete distance VA and binocular function testing at the 9, and 18-
627 
week visits. The masked examiner must be PEDIG certified for the required testing. All other 
628 
assessments are unmasked. Prior to the Masked Examiner entering the room, participants and 
629 
parents should be instructed not to discuss their treatment with the Masked Examiner.   
630 
 
631 
The following procedures should be performed at each visit in the following order: 
632 
 
633 

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Lensometry (unmasked): 
634 
Verify current refractive correction by lensometry. If participant wearing contact lenses, verify 
635 
contact lens prescription.  
636 
 
637 
Questionnaires (all unmasked): 
638 
 
639 
1. Assessment of Binocular Diplopia (at 9, and 18 weeks; and at 27, and 36 weeks if treated 
640 
with Luminopia or Vivid Vision):  
641 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
642 
“has your child complained of double vision over the last week.” If yes, the parent is 
643 
asked how frequently during the last week the child has complained of double vision: 
644 
“once per week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study 
645 
personnel may assess diplopia.  
646 
2. Adverse Events (at 9, and 18 weeks [all participants]; and at 27, and 36 weeks if treated 
647 
with Luminopia or Vivid Vision):  
648 
A standardized questionnaire will be administered to the parent to collect data on possible 
649 
adverse events. 
650 
3. Treatment Impact Questionnaire (at 9, and 18 weeks):  
651 
An item bank of participant-derived questionnaire items will be completed by the child 
652 
themselves and by the child’s parent (proxy rating regarding impact on their child and 
653 
also questions regarding impact on the parent themselves).  Questions pertain to the 
654 
impact of the child’s specific treatment on the child themselves and on the parent / 
655 
family.    
656 
4. PedEyeQ Social Domain and Frustration/Worry Domain (at 9 weeks only): 
657 
Child questionnaire for children and proxy questionnaire for the parent regarding their 
658 
child. The Child questionnaire is either completed by the child themselves or 
659 
administered to the child by study personnel and the Proxy questionnaire is completed by 
660 
the parent.  
661 
5. PedEyeQ Functional Vision Domain (at 18 weeks only):  
662 
A child questionnaire for children and proxy questionnaire for the parent regarding their 
663 
child’s functional vision.  The child questionnaire is either completed by the child 
664 
themselves or administered to the child by study personnel. The Proxy questionnaire is 
665 
completed by the parent.  
666 
 
667 
Clinical Testing performed in the participant’s current refractive correction (if 
668 
required) without cycloplegia in the following order at ALL VISITS. Masked testing 
669 
must be performed by a PEDIG certified examiner. 
670 
• Habitual refractive correction (meeting study criteria) is required for the 18-week 
671 
primary outcome exam. 
672 
• Testing in trial frames with current Rx is allowed at 9, 27 and 36 weeks if current 
673 
refractive correction is not available or does not meet study criteria.  
674 
 
675 
6. Distance VA Testing (at 9, and 18 weeks Masked; at 27, and 36 weeks if applicable 
676 
unmasked): Monocular distance VA testing will be performed in current refractive 
677 
correction (if required) in each eye by a certified examiner using the electronic ATS-
678 
ETDRS on a study-certified VA tester displaying single surrounded optotypes.  
679 

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7. Binocular Function Testing by a certified examiner in current refractive correction if 
680 
required (at 9, and 18 weeks masked; at 27, and 36 weeks if applicable unmasked):   
681 
a. Stereoacuity will be tested at 40cms in current refractive correction using the 
682 
Randot Preschool Test.  
683 
b. If nil stereoacuity on the Randot Preschool Test, the Random Dot Butterfly test 
684 
will be administered at 40cms.  
685 
c. If nil stereoacuity on the Random Dot Butterfly, then the Worth 4-shape will be 
686 
administered at 40cms.  
 
687 
8. Ocular Alignment Testing (Unmasked): Ocular alignment will be assessed by a certified 
688 
examiner in current refractive correction (if required) by the cover test, SPCT (in cases of 
689 
strabismus detected by cover test), and PACT in primary gaze at distance (3 meters) and 
690 
at near (1/3 meter). 
691 
9. Adherence Monitoring (Unmasked): Adherence data for Luminopia and Vivid Vision 
692 
will be downloaded and reviewed.   
693 
 
694 
3.6 Masked Examiner 
695 
The Masked Examiner must be certified to test VA and binocular function testing. Because the 
696 
Masked Examiner must be masked to the participant’s treatment group they must be someone 
697 
other than the managing clinician (in many cases the managing clinician will be the investigator, 
698 
but this is not required).     
699 
 
700 
3.7 Non-Study Visits and Treatment 
701 
Investigators may schedule additional visits at their own discretion. Participants will continue to 
702 
follow the study-specified follow-up schedule regardless of any non-study visits. No data will be 
703 
collected at non-study visits for the purpose of the study.  
704 
 
705 
Investigators must not start any additional non-randomized treatment or stop randomized 
706 
treatment prior to the 18-week primary outcome visit without first contacting a protocol chair.  
707 
 
708 
For participants who continue in the study after 18 weeks, Luminopia or Vivid Vision treatment 
709 
should continue until the 36-week visit with no other treatment prescribed prior to the 36-week 
710 
outcome visit.  
711 
 
712 
3.8 Management of Refractive Error 
713 
No cycloplegic refraction is mandated during the study. Nevertheless, if the investigator suspects 
714 
that refractive error may not be corrected according to study guidelines, a cycloplegic refraction 
715 
should be performed. If the new cycloplegic refraction compared to the old cycloplegic 
716 
refraction differs by >0.75 D sphere or >0.75 D cylinder or >0.75 D in SE anisometropia or axis 
717 
change of 6 degrees or more when cylinder is 1.00 D or more; then a change in spectacles is 
718 
required.  Whether to update the spectacles for smaller changes in refraction is at investigator 
719 
discretion. 
720 
   
721 
When new spectacles are prescribed, the refractive correction prescribed must meet the 
722 
requirements as described in section 2.2 #6.  The updated spectacles will be paid for by the 
723 
study.  
724 

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725 
3.9 Management of Strabismus  
726 
Because of the short duration of the primary outcome for the study and the age group being 
727 
studied, strabismus surgery is not allowed prior to the 18-week primary outcome visit.     
728 
 
729 
If surgery must be performed, a protocol chair should be contacted and a masked exam prior to 
730 
surgery scheduled. The participant should remain in the study and complete all necessary visits. 
731 
If surgery is performed, it must be recorded in the comment section of the Follow-up 
732 
Examination Form. 
 
733 

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Chapter 4: Study Devices 
734 
 
735 
4.1 Description of the Luminopia Device 
736 
Luminopia is a software-only digital therapeutic designed to be used with commercially 
737 
available Head-Mounted Displays (HMDs) which are compatible with the software application.  
738 
The software application requires an internet connection for treatment. The Luminopia medical 
739 
software application presents slightly different video content to each eye to encourage amblyopic 
740 
eye usage. Treatment using Luminopia will be prescribed for 1 hour per day, 6 days per week.   
741 
 
742 
4.1.1 Headset 
743 
The study will provide each participant with a VR headset pre-loaded with Luminopia software. 
744 
The VR headset has a screen resolution of 564 pixels per inch, which constitutes the minimum 
745 
display resolution requirement. The Luminopia system has been approved by the FDA for the 
746 
treatment of moderate or severe amblyopia in children 4 to 7 years of age. 
747 
 
748 
The Luminopia device should only be used in accordance with the manufacturer’s instructions.   
749 
The Luminopia device should only be used in a safe and stationary environment with the HMD 
750 
connected to Wi-Fi. Luminopia should only be used with the participant seated or lying down. If 
751 
the participant experiences discomfort because the Luminopia device feels too heavy, the 
752 
participant should try to use the Luminopia device while lying down on their back. 
753 
 
754 
The HMD should be kept away from heat sources, water, moisture, open flames, or direct 
755 
sunlight. If the participant intends to use the Luminopia device away from home for an extended 
756 
period of time, the parent should bring the charger provided with the HMD to charge the device 
757 
as needed. The participant should not use the Luminopia device while the HMD is charging. 
758 
 
759 
 
760 
4.2 Description of Vivid Vision 
761 
Vivid Vision utilizes gamification to provide dichoptic anti-suppression therapy to treat 
762 
amblyopia in an engaging VR game-based format.  Each session is approx. 23 to 27 minutes and 
763 
includes 3 to 4 games which vary each day to increase engagement with the therapy. The therapy 
764 
is programmed such that the “visual” difficulty is separate from the “game” difficulty; the 
765 
program continually adjusts to keep both visual and game difficulty at an appropriate level for 
766 
the child. As vision improves, the size of the amblyopic eye target decreases, fellow eye blur 
767 
decreases, and fellow eye contrast increases, binocular disparity decreases, and vergence demand 
768 
increases.  
769 
 
770 
Vivid Vision includes four games that focus on anti-suppression (Hoopie, Ring Runner, Breaker, 
771 
Pepper Picker). Each game has multiple levels to keep the participant engaged.  Vivid Vision 
772 
therapy also includes disparity tuning guided therapy (popping bubbles game and bullseye target 
773 
shooting game) to enhance binocularity.  For children who have approx. 600 arc sec of contour-
774 
based lateral stereoacuity or better, games also include orthoptic vergence therapy to improve 
775 
binocularity. Anti-suppression therapy continues throughout the therapy program. 
776 
 
777 

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4.2.1 Headset 
778 
The prescribed software will run on a stand-alone/all-in-one headset (DPVR P1 Pro). The 
779 
headset has an on/off button, volume control, and USB port for charging. It is secured to the head 
780 
by an adjustable head strap. The DPVR P1 Pro headset is a three-degrees-of-freedom (3DoF) 
781 
headset, designed to be used by the participant-user in a comfortable seated position. It should 
782 
not be used while standing or walking. 
783 
 
784 
The Vivid Vision device should only be used in a safe and stationary environment. Vivid Vision 
785 
should only be used while the participant is seated. If the participant experiences discomfort 
786 
because the device feels too heavy, the participant should try to use the Vivid Vision device 
787 
while leaning their head back on a high-backed chair. 
788 
 
789 
The HMD should be kept away from heat sources, water, moisture, open flames, or direct 
790 
sunlight. If the participant intends to use the device away from home for an extended period of 
791 
time, the parent should bring the charger provided with the HMD to charge the device as needed.  
792 
 
793 
4.2.2 Vivid Vision Handheld Controller 
794 
A handheld remote-control device called the hand controller is used to interact with the games 
795 
during game play. The hand controller communicates with the headset via wireless bluetooth and 
796 
is “paired” with a particular headset. It detects changes of orientation in space (3DoF), but not 
797 
changes in position. It communicates with the Headset wirelessly to transmit information about 
798 
the orientation and button presses of the remote controller.  
799 
 
800 
4.2.3 Vivid Vision Patient Portal 
801 
Two levels of access to the participant's data are provided during treatment: the Site Portal and 
802 
the Patient Portal. The Site Portal allows a study site to monitor adherence, session times, missed 
803 
sessions, and treatment progress for each patient at that site. Notifications are sent to the Site 
804 
Portal in case of red flag events such as missed treatment sessions or unexpected loss of 
805 
performance. The Patient Portal allows the parent to monitor their child's adherence and session 
806 
times, using a secure login. 
807 
 
808 
4.3 Internet Requirements 
809 
Potential study participants who do not have the required internet capabilities in their home will 
810 
be provided Wi-Fi access using a Hotspot at no cost for the duration of the study. 
811 
 
812 
4.3.1 Luminopia 
813 
Wireless internet with Wi-Fi speed near the router that exceeds 5 Mbs is required to operate 
814 
Luminopia. Faster network speeds will result in a better product experience.  
815 
 
816 
4.3.2 Vivid Vision 
817 
Prior to the first session at home, a Wi-Fi connection should be made in order to connect the 
818 
headset to the internet. The Wi-Fi connection can be made using either a home Wi-Fi network or 
819 
a mobile hotspot device. If the headset loses connectivity afterward, then the session will still 
820 
proceed, with visual difficulty being updated according to the previous session. When the 
821 
headset reconnects, a local copy of the data will be uploaded to the server. The best practice is to 
822 
remain connected to the internet so that data will be transferred immediately. A daily connection 
823 

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would be acceptable. After one week of not connecting, the session may not be able to continue 
824 
until connecting again. 
825 
 
826 
4.4 Device Delivery and Return 
827 
Device Delivery and Return procedures will be detailed in the site instruction manual.  
828 
 
829 
4.5 Device Accountability Procedures 
830 
Device accountability procedures will be detailed in the site instruction manual. 
831 
 
832 
4.5.1 Device Failure 
833 
Parents will be provided with written instructions regarding the process to follow should the 
834 
Luminopia or Vivid Vision device fail. If the device needs to be replaced PEDIG will provision a 
835 
replacement. 
836 
 
837 
4.5.2 Participant Access to Study Device After 18-Week Primary Outcome  
838 
Participants randomly assigned to receive continued optical correction alone who have not 
839 
resolved at the 18-week primary outcome visit, will be offered random allocation to a trial of 
840 
Luminopia or Vivid Vision therapy and if accepted, followed forward with a 19-week phone call 
841 
and follow-up visits at 27-weeks and 36-weeks post-randomization. Luminopia or Vivid Vision 
842 
therapy will NOT continue beyond the 36-week visit.  
843 
 
844 
Participants randomly assigned to receive Luminopia or Vivid Vision will end treatment after the 
845 
18-week primary outcome visit.   
846 
 
 
847 

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Chapter 5: Testing Procedures and Questionnaires 
848 
 
849 
5.1 Questionnaires 
850 
 
851 
1. Assessment of Binocular Diplopia:  
852 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
853 
“has your child complained of double vision over the last week.” If yes, the parent is 
854 
asked how frequently during the last week the child has complained of double vision: 
855 
“once per week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study 
856 
personnel may ask the parent to rate diplopia. Testing time is approximately 1 minute. 
857 
 
858 
2. PedEyeQ Functional Vision Domain:  
859 
A child questionnaire for children and a proxy questionnaire completed by the parent 
860 
regarding their child’s functional vision.  The child questionnaire is either completed by 
861 
the child themselves or administered by study personnel and the Proxy questionnaire is 
862 
completed by the parent. The questionnaires take about 3-4 minutes to complete. 
863 
 
864 
3. PedEyeQ Social Domain: 
865 
A child questionnaire for children and a proxy questionnaire completed by the parent 
866 
regarding their child’s Social concerns. The child questionnaire is either completed by the 
867 
child themselves or administered by study personnel and the Proxy questionnaire is 
868 
completed by the parent. The questionnaires take about 3-4 minutes to complete. 
869 
 
870 
4. PedEyeQ Frustration / Worry Domain: 
871 
A child questionnaire for children, a proxy questionnaire completed by the parent 
872 
regarding their child’s Frustration / Worry. The child questionnaire is either completed by 
873 
the child themselves or administered by study personnel and the Proxy questionnaire is 
874 
completed by the parent. The questionnaires take about 3-4 minutes to complete. 
875 
 
876 
5. Treatment Impact Questionnaire:  
877 
An item bank of participant-derived questionnaire items will be completed by the child 
878 
themselves and by the child’s parent (proxy rating regarding impact on their child and 
879 
also questions regarding impact on the parent themselves). Questions pertain to the 
880 
impact of the child’s specific treatment on the child themselves and on the parent / 
881 
family. Testing is anticipated to take 5-7 minutes. 
882 
 
883 
6. Adverse Event Questionnaire: 
884 
A standardized questionnaire will be administered to the parent to collect data on possible 
885 
adverse events. The questionnaire is anticipated to take 1 minute to complete.  
886 
 
887 
 
888 
 
889 
 
890 
 
891 

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5.2 Clinical Assessments 
892 
The following procedures will be performed at each visit as defined in the ATS Procedures 
893 
Manual:  
894 
 
895 
7. Distance VA Testing:   
896 
Monocular distance VA testing will be performed in refractive correction if required in 
897 
each eye by a certified examiner using the electronic ETDRS VA protocol on a study-
898 
certified VA tester displaying single surrounded optotypes.  
899 
The VA protocol used at enrollment will be used throughout the study regardless of age 
900 
at follow-up. Testing time for both eyes typically is in the range of 5 to 15 minutes. 
901 
 
902 
8. Binocular Function Testing (by a certified examiner):  
903 
Stereoacuity will be tested at 40cms in current refractive correction using the Randot 
904 
Preschool Test.  
905 
• If nil stereoacuity on the Randot Preschool Test, then the Random Dot Butterfly 
906 
test will be administered at 40cms.  
907 
• If nil stereoacuity on the Random Dot Butterfly, the hand-held Worth 4-Shape test 
908 
will be performed at 40 cm. 
909 
• Testing typically takes 3-5 minutes.  
910 
 
911 
9. Ocular Alignment Testing: Ocular alignment will be assessed by a certified examiner in 
912 
current refractive correction if required by the cover test, simultaneous prism and cover 
913 
test (SPCT) (in cases of strabismus detected by cover test), and prism and alternate cover 
914 
test (PACT) in primary gaze at distance (3 meters) and at near (1/3 meter). Testing time 
915 
is typically 1 to 3 minutes. 
916 
 
 
917 

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Chapter 6: Miscellaneous Considerations 
918 
 
919 
6.1 Contacts by the Jaeb Center for Health Research and Sites 
920 
The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided the 
921 
parents’ contact information. The Jaeb Center may contact the parents of the participants. 
922 
Permission for such contacts will be included in the Informed Consent Form. The principal 
923 
purpose of the contacts will be to develop and maintain rapport with the participant’s family and 
924 
to help coordinate the scheduling of study visits, when needed.  
925 
 
926 
6.2 Participant Compensation 
927 
Participant compensation will be specified in the informed consent form. 
928 
 
929 
6.3 Cost of Treatment 
930 
Any new or changes to optical correction will be paid for during the study.  
931 
 
932 
For those randomized to Luminopia or Vivid Vision, the cost of prescribed dichoptic treatment 
933 
for 18-weeks will be paid for by the study.  
934 
 
935 
For those randomized to continued optical correction (if needed) who have residual amblyopia at 
936 
18 weeks, the cost of dichoptic treatment with Luminopia or Vivid Vision through 36-weeks will 
937 
be paid for by the study.  
938 
 
939 
For those randomized to Luminopia or Vivid Vision, the study will not pay for continued 
940 
Luminopia or Vivid Vision game treatment outside the study.  
941 
 
942 
6.4 Participant Withdrawal 
943 
Participation in the study is voluntary and a participant may withdraw at any time. For 
944 
participants who withdraw, their data collected prior to their withdrawal will be used. This 
945 
stipulation is specified in the consent form. 
946 
 
947 
6.5 Confidentiality 
948 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
949 
used instead of their name. Protected health information gathered for this study will be shared 
950 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
951 
participant information may also be provided to research sites involved in the study. 
952 

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Chapter 7: Unanticipated Problem / Adverse Event Reporting 
953 
 
954 
7.1 Unanticipated Problems 
955 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
956 
problems meeting the criteria below. Sites must report Unanticipated Problems to the IRB within 
957 
seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
958 
experience, or outcome that meets all three (3) of the following criteria: 
959 
 
960 
1. Is unexpected (in terms of nature, severity, or frequency) given (a) the research 
961 
procedures that are described in the protocol-related documents, such as the IRB-
962 
approved research protocol and informed consent document and (b) the characteristics of 
963 
the participant population being studied 
964 
2. Is related or possibly related to participation in the research (possibly related means 
965 
there is a reasonable possibility that the incident, experience, or outcome may have been 
966 
caused by the procedures involved in the research) 
967 
3. Suggests that the research places participants or others at a greater risk of harm than was 
968 
previously known or recognized (including physical, psychological, economic, or social 
969 
harm)  
970 
 
971 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
972 
involving a specific site such as unanticipated problems that occur at the Coordinating Center. 
973 
These instances must be reported to the JCHR IRB within seven (7) calendar days of recognition. 
974 
The Director of the Human Research Protection Program will report to the appropriate regulatory 
975 
authorities if the IRB determines that the event indeed meets the criteria of an Unanticipated 
976 
Problem that requires further reporting.  
977 
 
978 
7.2 Adverse Events 
979 
 
980 
7.2.1 Reportable Adverse Events 
981 
Because study treatments with Luminopia and Vivid Vision are non-invasive and consistent with 
982 
usual clinical care, it is not expected that there would be significant adverse events other than 
983 
those already being captured as part of the clinical outcome assessments or questionnaire (e.g., 
984 
worsening of fellow eye VA, development of new or worsening strabismus, new diplopia, or 
985 
report of headache, eyestrain, nausea, seizures, dizziness, increase in frequency of night terrors, 
986 
or skin irritation).   
987 
 
988 
7.2.2 Safety Oversight 
989 
A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
990 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to 
991 
the study protocol or suspension or outright stoppage of the study if deemed necessary based on 
992 
the totality of safety data available. Details regarding DSMC review will be documented in a 
993 
separate DSMC charter.  
994 
 
995 
The objective of the DSMC review is to decide whether the study (or study treatment for an 
996 
individual or study cohort) should continue per protocol, proceed with caution, be further 
997 
investigated, be discontinued, or be modified and then proceed. Suspension of enrollment (for a 
998 

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particular group, a particular study site, or for the entire study) is a potential outcome of a DSMC 
999 
safety review. 
1000 
 
1001 
7.2.3 Stopping Criteria 
1002 
The study may be discontinued by the Steering Committee (with approval of DSMC) prior to the 
1003 
preplanned completion of follow-up for all study participants. No formal guidelines for stopping 
1004 
the study for futility or efficacy are pre-specified (see section 7). 
1005 
 
1006 
7.2.4 Participant Discontinuation of Study Treatment 
1007 
Rules for discontinuing study treatment use are one of the following:  
1008 
 
1009 
• The investigator believes it is unsafe for the participant to continue to receive the treatment.  
1010 
• The participant or parent requests that the treatment be stopped. 
1011 
 
1012 
Even if the study treatment is discontinued, the participant will be encouraged to remain in the 
1013 
study through the 18-week Primary Outcome Visit with permission from the parent to allow 
1014 
ongoing data collection. 
1015 
 
 
1016 

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Chapter 8: Statistical Considerations 
1017 
 
1018 
8.1 Statistical and Analytical Plans 
1019 
The approach to sample size and statistical analyses are summarized below.  
1020 
 
1021 
8.2 Study Objective and Statistical Hypothesis 
1022 
 
1023 
8.2.1 Primary Efficacy Outcomes  
1024 
The primary efficacy outcome will be the change in amblyopic eye distance VA (measured in 
1025 
letters) from randomization to 18 weeks. Change in letters will be calculated as [outcome VA] – 
1026 
[randomization VA] such that a positive change indicates improvement in VA letter scores, and a 
1027 
negative change indicates worsening.  
1028 
 
1029 
8.2.2 Study Objectives 
1030 
The primary objectives of the study in children 8 to 12 years of age are:  
1031 
 
1032 
1. To formally compare the effectiveness of Luminopia 1 hr / day 6 days per week while 
1033 
wearing optical correction if needed (hereafter LUMINOPIA) versus continued optical 
1034 
correction alone if needed (hereafter GLASSES), in children 8 to 12 years of age, as a 
1035 
superiority study; and  
1036 
2. To formally compare the effectiveness of Vivid Vision 25 minutes / day 6 days per week 
1037 
while wearing optical correction if needed (hereafter VIVID VISION) versus GLASSES, 
1038 
in children 8 to 12 years of age, as a superiority study. 
1039 
 
1040 
If mean 18-week VA with LUMINOPIA and VIVID VISION are both significantly different 
1041 
from GLASSES, then a hypothesis test will: 
1042 
 
1043 
1. Formally compare the effectiveness of LUMINOPIA vs VIVID VISION after 18 
1044 
weeks of treatment as a superiority study.  
1045 
 
1046 
If the mean 18-week change in VA with LUMINOPIA and/or VIVID VISION is not 
1047 
significantly different than GLASSES, then the difference between active treatment groups will 
1048 
be considered exploratory only.  
1049 
 
1050 
8.2.3 Hypotheses 
1051 
The study is designed to test two, two-sided superiority hypotheses, each designed to evaluate 
1052 
whether the mean change in VA from baseline at 18 weeks with GLASSES is significantly 
1053 
different than either dichoptic treatment (with LUMINOPIA or with VIVID VISION):   
1054 
 
1055 
Superiority Test 1: 
 
 
 
 
Superiority Test 2: 
1056 
H0: μLUMINOPIA-μGLASSES = 0 letters  
H0: μVIVID VISION-μGLASSES = 0 letters 
1057 
Ha: μLUMINOPIA-μGLASSES ≠ 0 letters  
Ha: μVIVID VISION-μGLASSES ≠ 0 letters 
1058 
 
1059 

JAEB CENTER FOR HEALTH RESEARCH ** CONFIDENTIAL** 
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For each hypothesis, the difference in mean VA change at 18 weeks between treatment groups 
1060 
(LUMINOPIA minus GLASSES and VIVID VISION minus GLASSES), and a two-sided 95% 
1061 
confidence interval (CI) for the difference will be constructed.  
1062 
 
1063 
Each hypothesis will be tested independently, such that each will be conducted with an alpha 
1064 
level of 0.05. Although two pairwise comparisons are being evaluated, there will be no formal 
1065 
adjustment to the familywise error rate; because the main objective of this trial is to compare two 
1066 
dichoptic treatments with different mechanisms of action with a shared control group, and not 
1067 
one another, an adjustment (e.g., Bonferroni) is not needed.45-47 The risk of a false positive 
1068 
finding with this approach is lower than if each hypothesis were evaluated in two separate 
1069 
studies with different control groups. 
1070 
 
1071 
If mean 18-week change in VA with LUMINOPIA and VIVID VISION are both superior to 
1072 
GLASSES, then a hypothesis test will evaluate whether there is a difference between active 
1073 
treatments with no adjustment to alpha (per the fixed sequence method):  
1074 
 
1075 
Superiority Test 3: 
 
 
 
 
 
1076 
H0: μLUMINOPIA-μVIVID VISION = 0 letters 
1077 
Ha: μLUMINOPIA-μVIVID VISION ≠ 0 letters 
 
 
1078 
 
1079 
The difference between treatment groups (LUMINOPIA minus VIVID VISION), and a two-
1080 
sided 95% CI for the difference will be constructed, with p-value.  
1081 
 
1082 
However, if the mean 18-week change in VA with either LUMINOPIA or VIVID VISION is not 
1083 
significantly different than GLASSES, then the difference between active treatment groups will 
1084 
be considered exploratory and a p-value will not be reported.  
1085 
 
1086 
8.3 Sample Size 
1087 
 
1088 
8.3.1 Effect of GLASSES 
1089 
To estimate the treatment effect for those randomized to GLASSES in the current study, VA data 
1090 
for participants prescribed continued optical correction alone in a previous PEDIG study, 
1091 
ATS20, were used.  
1092 
 
1093 
The data were limited to participants who met the eligibility criteria for the current study.  In 
1094 
ATS20, 114 participants between the ages of 8 and 12 experienced a 2.2 letter (95% CI 1.2 to 
1095 
3.2) mean improvement in VA after 8 weeks of full-time optical correction alone, with a 
1096 
standard deviation of 5.1 letters (95% CI 4.6 to 5.9).  
1097 
 
1098 
8.3.2 Effect of LUMINOPIA 
1099 
Xiao et al conducted a single-arm pilot study (n=90)48 in children with amblyopia aged 4 to 12 
1100 
years (mean 6.7±2.0 years). Luminopia was prescribed 1 hour/day for 12 weeks. Overall (n=74 
1101 
outcomes) mean amblyopic-eye BCVA improved from 0.50±0.15 to 0.35±0.21 logMAR (1.5 
1102 
logMAR lines, 95% CI = 1.2-1.8 lines, P<0.0001) over 12 weeks.48  
1103 
 
1104 

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For the 17 participants aged 8 to 12 years, amblyopic-eye VA improved an average of 1.4±1.1 
1105 
logMAR lines after 12 weeks of treatment, corresponding to a mean of 7 letters (95% CI, 4.2 to 
1106 
9.8) and SD of 5.5 letters (95% CI, 4.1 to 8.4).48  
1107 
 
1108 
8.3.3 Effect of VIVID VISION 
1109 
Ziak et al49 used the beta version of Vivid Vision in 17 adults (age 17 to 69 years) with 
1110 
anisometropic amblyopia. After eight 40-minute in-office sessions (2 per week), mean 
1111 
amblyopic-eye VA improved from 0.58 ± 0.35 to 0.43 ± 0.38 logMAR (mean change = 0.15 
1112 
[95% CI: 0.07 to 0.22] logMAR; SD = 0.15 [95% CI: 0.11 to 0.22] logMAR). In letters, this 
1113 
corresponds to a mean change of 7.5 [95% CI: 3.5 to 11.0] letters; SD = 7.5 [95% CI: 5.5 to 
1114 
11.0] letters by the 4-week outcome. The proportion with VA 20/40 or better increased from 
1115 
30% to 47% after treatment.  
1116 
 
1117 
8.3.4 Summary of Previous Studies 
1118 
Data from previous studies are summarized in Table 1 below.  
1119 
Table 1 – Summary of Previous Studies in Older Children 
1120 
Study 
Time on 
Treatment 
N 
Mean Change  
from Baseline  
(95% CI for Mean)  
SD for Change  
from Baseline  
(95% CI for SD) 
Continued Optical Correction Alone 
ATS20 RCT, 8-12 years, Glasses Alone  
with Heterotropia <=5 pd at near by SPCT 
8 weeks 
N=114 
2.2 letters 
(1.2 to 3.2) 
5.1 letters  
(4.6 to 5.9) 
Luminopia 
  
  
  
  
Xiao et al. 2021  
(non-RCT, age 8-12 years) 
12 weeks 
N=17 
7 letters  
(4.2 to 9.8) 
5.5 letters  
(4.1 to 8.4) 
Vivid Vision 
  
  
  
  
Ziak et al. 2017  
(non-RCT, age 17-69 years) 
4 weeks 
N=17 
7.5 letters  
(3.5 to 11.0) 
7.5 letters  
(5.5 to 11.0) 
 
1121 
8.3.5 Sample Size for Superiority of Each Dichoptic Treatment Versus GLASSES 
1122 
Table 2 displays the estimated sample sizes corresponding to various treatment group differences 
1123 
(3 to 5 letters) and standard deviations (6, 7, or 8 letters). A common standard deviation (SD) of 
1124 
7.0 letters and a true mean difference of 3.75 letters favoring dichoptic treatment (either 
1125 
LUMINOPIA or VIVID VISION) versus GLASSES after 18 weeks were selected to calculate 
1126 
the required sample size.   
1127 
 
1128 
With a two-sided Type 1 error rate of 0.05 for each comparison, the study would require 75 
1129 
participants in each group to achieve 90% power to reject the null hypotheses that the mean 
1130 
changes in VA between each dichoptic treatment and GLASSES are not different in favor of an 
1131 
alternative hypothesis that they differ (Table 2). Therefore, a total of 225 participants would be 
1132 
necessary to conduct the trial with sufficient power for each of 2 comparisons (75 participants 
1133 
each for LUMINOPIA, VIVID VISION, and GLASSES) assuming no loss to follow-up.  
1134 
 
1135 

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Accounting for 10% loss to follow up in each treatment group (75/.90), the total sample size 
1136 
would increase to 252 (84 participants in each group). 
1137 
Table 2. Total Sample Size Estimates* for Testing  
1138 
Superiority of Each Dichoptic Treatment vs. GLASSES 
1139 
  
Standard Deviation (Letters) 
  
6 
7 
8 
TRUE 
Difference 
(Letters) 
N per 
Group 
N Total 
N per 
Group 
N Total 
N per 
Group 
N Total 
3.00 
86 
258 
116 
348 
151 
453 
3.25 
73 
219 
99 
297 
129 
387 
3.50 
63 
189 
86 
258 
111 
333 
3.75 
55 
165 
75 
225 
97 
291 
4.00 
49 
147 
66 
198 
86 
258 
4.25 
43 
129 
58 
174 
76 
228 
4.50 
39 
117 
52 
156 
68 
204 
*Cells reflect total sample size unadjusted for loss to follow up with  
1140 
two-sided alpha 0.05, and 90% power for each comparison.  
1141 
 
1142 
 
1143 
8.3.6 Power and Precision for Superiority of LUMINOPIA vs. VIVID VISION 
1144 
It is noted that the study is not specifically powered for this objective because evaluation of this 
1145 
hypothesis is conditional on both LUMINOPIA and VIVID VISION being shown to be superior 
1146 
to GLASSES. Power is based on the same mean difference and standard deviation assumptions 
1147 
as the primary hypotheses. Failure to reject the null hypothesis of no difference may not rule out 
1148 
the possibility of a clinically meaningful difference between LUMINOPIA and VIVID VISION. 
1149 
 
1150 
Powers for rejecting a two-sided null hypothesis of no difference in favor of an alternative 
1151 
hypothesis that the treatment groups differ is given in Table 3 for various estimates of standard 
1152 
deviation (6, 7, and 8 letters) and various true treatment group differences (1, 2, 3, 4, and 5 
1153 
letters) using a Type 1 error rate of 0.05 and 75 participants in each treatment group.  
1154 
 
1155 
Table 3. Power for Testing Superiority of LUMINOPIA vs. VIVID VISION 
1156 
True Mean Difference 
1 letter 
2 letters 
3 letters 
4 letters 
5 letters 
(0.02 
logMAR) 
(0.04 
logMAR) 
(0.06  
logMAR) 
(0.08  
logMAR) 
(0.10 
logMAR) 
SD 
Power 
Power 
Power 
Power 
Power 
6 letters 
17% 
52% 
86% 
98% 
99% 
7 letters 
14% 
41% 
74% 
93% 
99% 
8 letters 
11% 
33% 
62% 
86% 
96% 
* N=75 per treatment group, 2-sided alpha (Type 1 error rate) = 0.05 
1157 
 
1158 

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Table 4 summarizes the half-width of a 95% confidence interval for a treatment group difference 
1159 
between LUMINOPIA and VIVID VISION for various pooled standard deviations with a sample 
1160 
size of 75 in each treatment group.  
1161 
 
1162 
Table 4. Half-width 95% Confidence Intervals of the Treatment Group Difference for 
1163 
LUMINOPIA vs. VIVID VISION at Various Standard Deviations 
1164 
Sample Size 
SD = 6 letters 
SD = 7 letters 
SD = 8 letters 
N=75 LUMINOPIA 
N=75 VIVID VISION 
± 1.94 
 ± 2.26 
 ± 2.58 
* With a Type 1 error rate of 0.05, and 75 participants per treatment group, the numbers in 
1165 
the cells represent the estimated half-width 95% confidence interval at the given standard 
1166 
deviation (6, 7, or 8 letters). 
1167 
 
1168 
8.4 Outcome Measures 
1169 
 
1170 
8.4.1 Primary Efficacy Endpoint 
1171 
• Change in amblyopic eye distance VA from baseline at 18 weeks. 
1172 
 
1173 
8.4.2 Secondary Efficacy Endpoints 
1174 
• Change in child and proxy PedEyeQ Functional Vision domain scores from baseline at 
1175 
18 weeks. 
1176 
• Change in child and proxy PedEyeQ Social domain scores from baseline at 9 weeks. 
1177 
• Change in child and proxy PedEyeQ Frustration/Worry domain scores from baseline at 9 
1178 
weeks.  
1179 
 
1180 
8.4.3 Exploratory Efficacy Endpoints 
1181 
• Change in amblyopic eye distance VA at 9 weeks. 
1182 
• Change in amblyopic eye distance VA over 18 weeks (area under the curve). 
1183 
• Improvement of amblyopic eye distance VA by 2 or more lines (≥ 10 letters) at 9 weeks 
1184 
and 18 weeks, respectively. 
1185 
• Resolution of amblyopia at 9 and 18 weeks 
1186 
• Change in binocular function score from baseline at 9 and 18 weeks. 
1187 
• Child, proxy, and parent Treatment Impact Questionnaire scores at 9 weeks and 18 
1188 
weeks. 
1189 
 
1190 
8.5 Analysis Datasets and Sensitivity Analyses 
1191 
Analyses will follow the intent-to-treat principle (ITT); all participants will be analyzed 
1192 
according to their randomized treatment group, irrespective of adherence or compliance. 
1193 
However, a per protocol analysis will be performed for the primary outcome to evaluate the 
1194 
sensitivity of the results to substantial deviations from the protocol (details to be outlined in the 
1195 
statistical analysis plan [SAP]). The intent-to-treat analysis is considered primary. If the results 
1196 
of the per-protocol analysis and intent-to-treat give inconsistent results, exploratory analyses will 
1197 
be performed to evaluate possible factors contributing to the differences. 
1198 
 
1199 

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8.6 Analysis of the Primary Efficacy Outcome 
1200 
The primary outcome, change in amblyopic-eye distance VA letter score from baseline at 18 
1201 
weeks, is a continuous outcome that will be analyzed using an analysis of covariance 
1202 
(ANCOVA) model to estimate the adjusted mean difference between GLASSES and 
1203 
LUMINOPIA, as well as between GLASSES and VIVID VISION. The model will adjust for 
1204 
baseline amblyopic-eye distance VA. The adjusted between-group mean differences and two-
1205 
sided 95% CIs and p-values will be reported. If an imbalance of factors between treatment 
1206 
groups is observed, a sensitivity analysis may be performed to control for these potential 
1207 
confounders.  
1208 
 
1209 
Superiority of the dichoptic treatment (either LUMINOPIA or VIVID VISION) compared to 
1210 
GLASSES will be declared if the two-sided 95% CI for the difference between treatment groups 
1211 
in mean change in distance VA letter score from baseline to 18 weeks excludes 0 letters. 
1212 
 
1213 
If both dichoptic treatments are declared superior to GLASSES, then a test of superiority 
1214 
between LUMINOPIA and VIVID VISION will be performed without further adjustment for 
1215 
multiplicity (see Section 8.14). The same analysis approach will be used. If either of the 
1216 
dichoptic treatments are not declared superior to GLASSES, then LUMINOPIA and VIVID 
1217 
VISION will still be compared, however, the comparison will be considered exploratory, and a 
1218 
p-value will not be presented.  
1219 
 
1220 
Participants who do not complete the 18-week visit will have their 18-week amblyopic eye 
1221 
distance VA imputed. Markov chain Monte Carlo multiple imputation with 100 imputations will 
1222 
be used to impute missing data; variables in the imputation model will include amblyopic-eye 
1223 
VA at baseline, 9, and 18 weeks. Imputation will be carried out separately for each treatment 
1224 
group.50 Reasons for which a participant may not complete the 18-week visit are outlined in 
1225 
section 8.8, “Intercurrent Events.” 
1226 
 
1227 
The ANCOVA model assumptions of linearity, normality, and homoscedasticity will be verified 
1228 
with graphical methods. If assumptions are seriously violated, then an alternative approach such 
1229 
as transformation of dependent or independent variables, elimination or categorization of 
1230 
continuous covariates, a robust method, or a nonparametric method may be considered.  
1231 
 
1232 
As a sensitivity analysis, the primary outcome will be analyzed using complete cases rather than 
1233 
the imputed data. If the results from these analyses are discordant, then differences between 
1234 
participants with and without complete visit data will be evaluated.  
1235 
 
1236 
8.7 Analysis of the Secondary Efficacy Outcomes 
1237 
Secondary analyses will test the null hypothesis of no difference between treatment groups. For 
1238 
any given secondary outcome, if both LUMINOPIA and VIVID VISION are superior to 
1239 
GLASSES, then LUMINOPIA and VIVID VISION will be compared without further adjustment 
1240 
to the type 1 error rate.51 If, however, both dichoptic treatments are not superior to GLASSES, 
1241 
then a p-value for the comparison of LUMINOPIA vs VIVID VISION will not be presented. See 
1242 
section 8.14 for more information on how multiplicity will be handled.  
1243 
 
1244 

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8.7.1 Pediatric Eye Disease Questionnaire (PedEyeQ) 
1245 
The effect of amblyopia on quality of life will be evaluated using the PedEyeQ questionnaire. 
1246 
Scores on Functional Vision, Frustration/Worry, and Social domains will be assessed for both 
1247 
child and proxy (parent answering on behalf of the child) at baseline as well as at the visit week 
1248 
indicated below (Table 5). The responses of child and proxy will be Rasch scored according to 
1249 
reference tables and standardized on a ratio scale ranging from 0 to 100.44  
1250 
 
1251 
Table 5. Structure of the PedEyeQ Analysis: Domains and Respondents 
1252 
Domain 
Respondent  
Level 
Social  
(9 weeks) 
Frustration/Worry  
(9 weeks) 
Functional Vision  
(18 weeks) 
Outcomes 
Child 
1 
1 
1 
3 
Proxy 
1 
1 
1 
3 
Total = 6 
Change in PedEyeQ scores are continuous variables that will be analyzed with analysis of 
1253 
covariance (ANCOVA) to assess the differences between treatment groups across all domains 
1254 
and respondents (3 domains × 2 respondents = 6 outcomes) as shown in Table 5.52 Models will 
1255 
be adjusted for enrollment scores. The treatment effect will be summarized as a mean difference 
1256 
and 95% CI. Similar to the primary outcome, missing data will be imputed using multiple 
1257 
imputation with baseline and outcome scores included in the imputation model and stratified by 
1258 
treatment group. 
1259 
  
1260 
8.8 Intervention Adherence 
1261 
At 9, and 18 weeks, the investigator will assess participant adherence to the assigned treatment. 
1262 
For each participant randomized to LUMINOPIA or VIVID VISION, the number of dichoptic 
1263 
treatment hours will be categorized according to percentage of prescribed treatment time as 75-
1264 
100%, 50-75%, or <50%. Calendar data for the GLASSES group will not be analyzed other than 
1265 
a subjective assessment by the investigator of adherence at 9, and 18 weeks as Excellent, Good, 
1266 
Fair, or Poor after review of the calendar and interview with the parent. The tabulation of data 
1267 
related to treatment adherence is intended for exploratory purposes only, and therefore formal 
1268 
comparisons between treatment groups will not be performed. 
1269 
 
1270 
8.9 Protocol Adherence and Retention 
1271 
Protocol deviations and visit completion rates (excluding participants who die before the end of 
1272 
the visit window) will be tabulated for each treatment group. 
1273 
 
1274 
8.9.1 Intercurrent Events 
1275 
If any of the following events take place before the 18-week outcome, missing follow-up data 
1276 
will be imputed for the participant experiencing the event in the primary ITT analysis. 
1277 
• Death 
1278 
• Lost to follow up 
1279 
• Withdrawal 
1280 
 
1281 

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If any of the following events occur before the 18-week outcome, data will not be imputed for 
1282 
participants experiencing these events, since the event itself does not preclude completion of 
1283 
study visits. Thus, the observed data at the 18-week outcome visit will be utilized.   
1284 
• Treatment discontinuation 
1285 
• Treatment crossover 
1286 
• Receipt of non-protocol treatment 
1287 
 
1288 
8.10 Safety Analyses 
1289 
The cumulative proportions of each of the following adverse events by treatment group will be 
1290 
assessed at the initial study phase (enrollment to 18 weeks) and during the post-primary phase 
1291 
for those originally randomized to GLASSES (18 weeks to 36 weeks). During the initial study 
1292 
phase, the proportions will be compared statistically between all three groups using Fisher’s 
1293 
Exact Test; if the p-value is ≤ .05, then pairwise tests will be performed without further 
1294 
adjustment for multiplicity. As type II error (false negative) is more of a concern than type I error 
1295 
(false positive) in safety analyses, we will use p ≤ 0.05, without adjustment for multiplicity, to 
1296 
define statistical significance in all safety analyses. It is noted that the study is not specifically 
1297 
powered to detect differences in safety outcomes and that the absence of a significant difference 
1298 
should not be viewed as evidence for the absence of a true difference. The proportion of adverse 
1299 
events occurring during the post-primary phase for original glasses participants will be tabulated 
1300 
within each dichoptic treatment group (LUMINOPIA or VIVID VISION) without formal 
1301 
statistical comparison.    
1302 
 
1303 
• Worsening of best-corrected fellow-eye distance VA of 2 lines (10 letters) or more 
1304 
• New onset strabismus >5 ∆ by SPCT in participants with no strabismus at baseline 
1305 
• Strabismus >10 ∆ by SPCT in participants with strabismus at baseline 
1306 
• Parental report of diplopia occurring more than once per week 
1307 
• Skin irritation  
1308 
• Headache 
1309 
• Eyestrain 
1310 
• Dizziness 
1311 
• Night terrors 
1312 
• Eye twitching 
1313 
• Facial redness 
1314 
 
1315 
The PEDIG DSMC will review safety data tabulated by treatment group at each of its semi-
1316 
annual meetings and can request formal statistical comparison of any safety outcome at any time 
1317 
if they have cause for concern.  
1318 
 
1319 
8.11 Baseline Descriptive Statistics 
1320 
Baseline demographic and clinical characteristics will be tabulated by randomized treatment 
1321 
group, and summary statistics appropriate to their distributions will be reported. 
1322 
 
1323 
8.12 Interim Analyses 
1324 
The study may be discontinued by the Steering Committee (with approval of DSMC) prior to the 
1325 
preplanned completion of follow-up for all study participants. No formal analyses and/or 
1326 
guidelines for stopping the study for futility or efficacy are pre-specified (see section 7). 
1327 

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1328 
8.13 Subgroup Analyses 
1329 
Subgroup analyses, i.e., assessments of effect modification, will be conducted for the primary 
1330 
outcome. These analyses will be considered exploratory. Missing data will be imputed like the 
1331 
primary analyses except that the subgroup factors of interest, specified below, will be included in 
1332 
the imputation model, which will be stratified by treatment group. Within-subgroup mean 
1333 
differences for the treatment effects with 95% CIs will be estimated for each subgroup by adding 
1334 
an interaction term to the primary analysis models. Results will be presented as forest plots; p-
1335 
values will not be presented.  
1336 
 
1337 
The baseline factors to be evaluated in pre-planned exploratory subgroup analyses include 
1338 
amblyopic-eye distance VA (categorized), type of amblyopia, prior treatment for amblyopia, age 
1339 
(8 to <10 years or 10 to <13 years), and binocularity. The SAP will provide specific details on 
1340 
categorizations. The subgroup analysis by amblyopic-eye distance VA is considered of greatest 
1341 
interest. 
1342 
 
1343 
There are no data to suggest that the treatment effect will vary by sex, race, or ethnicity. 
1344 
However, each of these factors will be evaluated in exploratory subgroup analyses as mandated 
1345 
by National Institutes of Health (NIH) guidelines. 
1346 
 
1347 
8.14 Multiple Comparisons / Multiplicity 
1348 
For the primary outcome, two tests of superiority for 18-week mean change in amblyopic eye 
1349 
distance VA will be conducted: LUMINOPIA vs GLASSES and VIVID VISION vs GLASSES. 
1350 
The tests will be performed independently, such that each will be conducted with an alpha level 
1351 
of 0.05.  
1352 
 
1353 
Although two pairwise comparisons are being evaluated, there will be no formal adjustment to 
1354 
the familywise error rate; because the main objective of this trial is to compare two dichoptic 
1355 
treatments with different mechanisms of action with a shared control group, and not one another, 
1356 
an adjustment (e.g., Bonferroni) is not needed.45-47 The risk of a false positive finding with this 
1357 
approach is lower than if each hypothesis were evaluated in two separate studies with different 
1358 
control groups. The same logic applies to secondary, exploratory, safety, and subgroup analyses. 
1359 
 
1360 
For the comparison of LUMINOPIA vs VIVID VISION, the familywise error rate will be 
1361 
controlled with a hierarchical (i.e., fixed sequence) approach. If the null hypotheses for 
1362 
LUMINOPIA versus GLASSES and VIVID VISION versus GLASSES are rejected, then 
1363 
LUMINOPIA and VIVID VISION will be compared without further adjustment to the type 1 
1364 
error rate.51 If, however, both null hypotheses are not rejected, then the comparison of 
1365 
LUMINOPIA vs VIVID VISION will be considered exploratory and a p-value will not be 
1366 
presented. It is noted for the comparison of LUMINOPIA versus VIVID VISION, the absence of 
1367 
a statistically significant difference cannot rule out the presence of a clinically meaningful 
1368 
difference between active treatment groups. The study is powered assuming a difference in VA 
1369 
between treatments as small as 3.75 letters with a standard deviation of 7.0 letters. This 
1370 
hierarchical approach for the comparison of LUMINOPIA vs VIVID VISION will be employed 
1371 
in all primary, secondary, and exploratory analyses. 
1372 
 
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For the PedEyeQ questionnaire, the adaptive false discovery rate (FDR) method with two-stage 
1374 
testing will control the FDR at 5% to adjust p-values and CIs for multiplicity.52  Each treatment 
1375 
comparison (LUMINOPIA vs GLASSES, VIVID VISION vs GLASSES, and LUMINOPIA vs 
1376 
VIVID VISION) is conducted separately and will be considered a separate family of tests. 
1377 
 
1378 
8.15 Exploratory Analyses 
1379 
Exploratory analyses will test the null hypothesis of no difference between treatment groups. For 
1380 
any of the following exploratory analyses, if both LUMINOPIA and VIVID VISION are 
1381 
superior to GLASSES, then LUMINOPIA and VIVID VISION will be compared without further 
1382 
adjustment to the type 1 error rate. If, however, both dichoptic treatments are not superior to 
1383 
GLASSES, then a p-value for the comparison of LUMINOPIA vs VIVID VISION will not be 
1384 
presented.  
1385 
 
1386 
8.15.1 Mean Change in Distance VA at 9 weeks 
1387 
Change in amblyopic eye VA from baseline to 9 weeks is a continuous outcome. Analyses, 
1388 
including imputation of missing data, will mirror the primary outcome.  
1389 
 
1390 
8.15.2 Mean Change in Distance VA over 18 weeks (area under the curve) 
1391 
The change in amblyopic eye distance VA from baseline over 18 weeks (area under the curve) 
1392 
will be calculated for each participant using the trapezoidal rule. The analysis, including 
1393 
imputation of missing data, will mirror the primary outcome.  
1394 
 
1395 
8.15.3 Improvement of Amblyopic-eye Distance VA by 2 or More Lines 
1396 
Improvement of amblyopic-eye distance VA of 2 or more lines (reduction of ≥ 10 letters) at 9 
1397 
and 18 weeks are binary outcomes that will be analyzed using logistic regression adjusting for 
1398 
baseline amblyopic-eye VA. For each time point, the proportions with improvement ≥ 2 lines 
1399 
and 95% confidence interval will be calculated. The risk difference will be calculated using 
1400 
logistic regression with conditional standardization, centering on the mean amblyopic-eye VA at 
1401 
baseline. The delta method will be implemented to construct a 95% CI on the risk difference and 
1402 
the model-based two-sided p-value will be reported.53. Missing data will be imputed as described 
1403 
for the primary outcome.  
1404 
 
1405 
8.15.4 Resolution of Amblyopia at 9 weeks and 18 weeks 
1406 
Resolution of amblyopia is defined as <0 lines IOD and fellow-eye VA no worse than 1 line (5 
1407 
letters) below baseline. The cumulative probability of amblyopia resolution at 9 and 18 weeks 
1408 
will be calculated using Cox proportional hazards regression with adjustment for baseline IOD. 
1409 
For each visit, the rate of resolution (estimated using the survivor function) and 95% CI will be 
1410 
presented for each group using direct adjustment along with the difference in rates, 95% CI, and 
1411 
p-value (based on a Z test). Participants who are lost to follow up will be censored on the day of 
1412 
the last completed visit.  
1413 
 
1414 
8.15.5 Binocular Function  
1415 
The change in binocular function score from enrollment to the 9- and 18-week visits is an ordinal 
1416 
outcome. Components of binocularity include results from the following 3 tests: Randot 
1417 
Preschool Stereoacuity (RPS), Random Dot Butterfly, and Preschool Worth 4-Shape (W4S) at 
1418 
near. These tests will create a composite ordinal binocular function score with 9 levels.54  
1419 

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1420 
The difference between treatment groups for the change in binocularity from baseline to 9 and 18 
1421 
weeks will be evaluated with the nonparametric Wilcoxon Rank-Sum test. Differences between 
1422 
groups will be estimated using the Hodges-Lehmann estimator with 95% CI. Analyses for 
1423 
binocular function score will be limited to complete case data at each respective outcome visit (9 
1424 
weeks or 18 weeks). 
1425 
 
1426 
In a sensitivity analysis, binocular function scores will be analyzed using ANCOVA with 
1427 
adjustment for baseline binocular function score and imputation of missing data. The baseline-
1428 
adjusted mean difference and 95% CI in binocularity between the treatment groups will be 
1429 
presented. 
1430 
 
1431 
8.15.6 Treatment Impact Questionnaire 
1432 
The Treatment Impact Questionnaire (TIQ) will be used as a quantitative measure to evaluate 
1433 
opinions regarding the burdens and impact of the randomized treatment at 9 weeks and 18 weeks 
1434 
(as questions for the child – the Child TIQ, for the parent about the child – the Proxy TIQ, and 
1435 
the parent themselves – the Parent TIQ.   
1436 
 
1437 
The Child-TIQ, Proxy-TIQ, and Parent-TIQ will undergo separate factor analysis to determine 
1438 
the number of domains for each TIQ. Each domain will be refined through the evaluation of 
1439 
misfitting items and will then be Rasch scored.  
1440 
 
1441 
Note that because the TIQ is not administered at baseline (because treatment has not been 
1442 
started), there will be no adjustment for baseline score in any analysis.  
1443 
 
1444 
Additional methods to score and analyze the Treatment Impact Questionnaire will be detailed in 
1445 
a separate SAP. 
1446 
 
1447 
8.16 Dichoptic Therapy after GLASSES 
1448 
Participants who were randomized to GLASSES who have 1 line or more (≥ 5 letters) IOD 
1449 
residual amblyopia will be offered dichoptic treatment with either LUMINOPIA or VIVID 
1450 
VISION after 18 weeks. These participants will be randomized to one of the dichoptic treatments 
1451 
and will have visits at 27 weeks and 36 weeks to evaluate safety and efficacy. The same safety, 
1452 
binocular function, and VA outcomes evaluated at 9 and 18 weeks will be evaluated at 27 and 36 
1453 
weeks with 18 weeks considered the baseline visit for the extended follow-up. 
1454 
 
1455 
  
1456 
Chapter 9: Data Collection and Monitoring 
1457 
 
1458 
9.1 Case Report Forms and Other Data Collection 
1459 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1460 
collected in electronic case report forms in real-time, this will be considered the source data. For 
1461 
any data points for which the eCRF is not considered source (e.g., lab results that are transcribed 
1462 
from a printed report into the eCRF, data not directly entered in real-time), the original source 
1463 
documentation must be maintained in the participant’s study chart or medical record. This source 
1464 
must be readily verifiable against the values entered into eCRF. Even where all study data are 
1465 

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directly entered into the eCRFs at office visits, evidence of interaction with a live participant 
1466 
must be recorded (e.g., office note, visit record, etc.)    
1467 
 
1468 
Electronic device data files are obtained from the study software and individual hardware 
1469 
components.  These electronic device files are considered the primary source documentation. 
1470 
Each participating site will maintain appropriate medical and research records for this trial, in 
1471 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1472 
confidentiality of participants. 
1473 
 
1474 
9.2 Study Records Retention 
1475 
Study documents should be retained for a minimum of 3 years after completion of the final grant 
1476 
reporting.  These documents should be retained for a longer period, however, if required by local 
1477 
regulations.  No records will be destroyed without the written consent of the sponsor, if 
1478 
applicable.  It is the responsibility of the sponsor to inform the investigator when these 
1479 
documents no longer need to be retained. 
1480 
 
1481 
9.3 Quality Assurance and Monitoring 
1482 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1483 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1484 
conducted appropriately, and the data are generated, documented, and reported in compliance 
1485 
with the protocol that adheres to Good Clinical Practice (GCP) and the applicable regulatory 
1486 
requirements. In addition, QC systems will be in place to ensure that the rights and well-being of 
1487 
trial participants are protected, and that the reported trial data are accurate, complete, and 
1488 
verifiable. Adverse events will be prioritized for monitoring. 
1489 
 
1490 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1491 
consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1492 
Based Approach to Monitoring” (August 2013). This plan describes in detail who will conduct 
1493 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
1494 
will be performed, and the distribution of monitoring reports. 
1495 
 
1496 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1497 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1498 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1499 
veracity and completeness of the key site data.  
1500 
 
1501 
Elements of the RBM may include: 
1502 
• Qualification assessment, training, and certification for sites and site personnel 
1503 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1504 
procedures 
1505 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1506 
review of entered data and edits, statistical monitoring, study closeout 
1507 
• On-site monitoring (site visits): source data verification, site visit report 
1508 
• Agent/Device accountability 
1509 
• Communications with site staff 
1510 
• Patient retention and visit completion 
1511 

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• Quality control reports 
1512 
• Management of noncompliance 
1513 
• Documenting monitoring activities 
1514 
• Adverse event reporting and monitoring 
1515 
 
1516 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1517 
order to maintain current and personal knowledge of the study through review of the records, 
1518 
comparison with source documents, observation and discussion of the conduct and progress of 
1519 
the study. The investigational site will provide direct access to all trial related sites, source 
1520 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1521 
inspection by local and regulatory authorities. 
1522 
 
1523 
9.4 Protocol Deviations 
1524 
A protocol deviation is any instance of noncompliance with the clinical trial protocol, GCP, or 
1525 
clinical procedure requirements. The noncompliance may be either on the part of the participant, 
1526 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
1527 
developed by the site and implemented promptly. 
1528 
 
1529 
The site PI, protocol PI (if different) and all study staff are responsible for knowing and adhering 
1530 
to their IRB requirements. Further details about the handling of protocol deviations will be 
1531 
included in the monitoring plan. 
1532 
 
1533 

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Chapter 10: Ethics/Protection of Human Participants 
1534 
 
1535 
10.1 Ethical Standard 
1536 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1537 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1538 
21 CFR Part 56, and/or the ICH E6. 
1539 
 
1540 
10.2 Institutional Review Boards 
1541 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1542 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1543 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1544 
require review and approval by the IRB before the changes are implemented to the study.  All 
1545 
changes to the consent form will be IRB approved; a determination will be made regarding 
1546 
whether previously consented participants need to be re-consented. 
1547 
 
1548 
10.3 Informed Consent Process 
1549 
 
1550 
10.3.1 Consent Procedures and Documentation 
1551 
Informed consent is a process that is initiated prior to an individual agreeing to participate in the 
1552 
study and continues throughout that individual’s study participation. Written IRB-approved 
1553 
consent materials and consent discussions must be in a language understandable to the 
1554 
participants and their parent(s). For example, if the parent(s) primary language is Spanish, then 
1555 
the Spanish consent form, as well as other participant/parent facing materials (e.g., 
1556 
questionnaires) must be in Spanish. Also, the use of an interpreter approved by the Coordinating 
1557 
Center is required to support not only the consent process, but also the participants and their 
1558 
parent(s) understanding and communication for the duration of the study.  
1559 
 
1560 
Extensive discussion of risks and possible benefits of participation will be provided to 
1561 
participants and their families. Consent forms will be approved by the IRB and the parent/legal 
1562 
guardian will be asked to read and review the document. The investigator will explain the 
1563 
research study to the parent and participant and answer any questions that may arise. All parents 
1564 
and participants will receive a verbal explanation in terms suited to their comprehension of the 
1565 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
1566 
Parents and participants (old enough to sign per IRB) will have the opportunity to carefully 
1567 
review the written consent and/or assent form(s) and ask questions prior to signing. 
1568 
 
1569 
Parents should have the opportunity to discuss the study with their partner or family physician or 
1570 
think about it prior to agreeing to participate. Written informed consent will be obtained from a 
1571 
parent and written or verbal assent from the child (depending on age and IRB requirements) prior 
1572 
to performing any study-specific procedures that are not part of the child’s routine care. 
1573 
Participants may withdraw consent at any time throughout the course of the trial. A copy of the 
1574 
informed consent document will be given to the family for their records. The rights and welfare 
1575 
of the participants will be protected by emphasizing to them and their parent(s) that the quality of 
1576 
their medical care will not be adversely affected if they decline to participate in this study. 
1577 
 
1578 

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10.3.2 Participant and Data Confidentiality 
1579 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1580 
and the sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
1581 
biological samples and genetic tests in addition to the clinical information relating to 
1582 
participants.  Therefore, the study protocol, documentation, data, and all other information 
1583 
generated will be held in strict confidence.  No information concerning the study or the data will 
1584 
be released to any unauthorized third party without prior written approval of the sponsor. 
1585 
 
1586 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1587 
regulatory agencies or company supplying study product may inspect all documents and records 
1588 
required to be maintained by the investigator, including but not limited to, medical records 
1589 
(office, clinic, or hospital) and pharmacy records for the participants in this study.  The clinical 
1590 
study site will permit access to such records. 
1591 
 
1592 
The study participant’s contact information will be securely stored at each clinical site for 
1593 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1594 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1595 
sponsor requirements. 
1596 
 
1597 
Study participant research data, which is for purposes of statistical analysis and scientific 
1598 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research.  This will not 
1599 
include the participant’s contact or identifying information.  Rather, individual participants and 
1600 
their research data will be identified by a unique study identification number.  The study data 
1601 
entry and study management systems used by clinical sites and by Jaeb Center for Health 
1602 
Research staff will be secured and password protected.   
1603 
 
1604 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1605 
for Health Research. 
1606 
 
1607 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1608 
obtained from the NIH.  This certificate protects identifiable research information from forced 
1609 
disclosure.  It allows the investigator and others who have access to research records to refuse to 
1610 
disclose identifying information on research participation in any civil, criminal, administrative, 
1611 
legislative, or other proceeding, whether at the federal, state, or local level.  By protecting 
1612 
researchers and institutions from being compelled to disclose information that would identify 
1613 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1614 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1615 
 
1616 
10.3.3 Future Use of Data 
1617 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research.  
1618 
After the study is completed, the de-identified, archived data will be made available to the 
1619 
public. 
1620 

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Chapter 11: References 
1621 
1. 
Holmes JM, Clarke MP. Amblyopia. Lancet. 2006;367(9519):1343-1351. 
1622 
2. 
Webber AL, Wood J. Amblyopia: prevalence, natural history, functional effects and 
1623 
treatment. Clin Exp Optom. 2005;88(6):365-375. 
1624 
3. 
Abraham SV. Accommodation in the amblyopic eye. Am J Ophthalmol. 1961;52:197-
1625 
200. 
1626 
4. 
Agrawal R, Conner IP, Odom JV, Schwartz TL, Mendola JD. Relating binocular and 
1627 
monocular vision in strabismic and anisometropic amblyopia. Arch Ophthalmol. 
1628 
2006;124(6):844-850. 
1629 
5. 
Ciuffreda KJ, Hokoda SC, Hung GK, Semmlow JL, Selenow A. Static aspects of 
1630 
accommodation in human amblyopia. Am J Optom Physiol Opt. 1983;60(6):436-449. 
1631 
6. 
Kelly KR, Jost RM, De La Cruz A, Birch EE. Amblyopic children read more slowly than 
1632 
controls under natural, binocular reading conditions. J AAPOS. 2015;19(6):515-520. 
1633 
7. 
McKee SP, Levi DL, Movshon JA. The pattern of visual deficits in amblyopia. J Vis. 
1634 
2003;3(5):380-405. 
1635 
8. 
Repka MX, Kraker RT, Beck RW, et al. Monocular oral reading performance after 
1636 
amblyopia treatment in children. Am J  Ophthalmol. 2008;146(6):942-947. 
1637 
9. 
Rutstein RP, Corliss D. Relationship between anisometropia, amblyopia, and 
1638 
binocularity. Optom Vis Sci. 1999;76(4):229-233. 
1639 
10. 
Weakley DR, Jr. The association between nonstrabismic anisometropia, amblyopia, and 
1640 
subnormal binocularity. Ophthalmology. 2001;108(1):163-71. 
1641 
11. 
Birch EE, Kelly KR. Pediatric ophthalmology and childhood reading difficulties: 
1642 
Amblyopia and slow reading. J AAPOS. 2017;21(6):442-444. doi: 10.1016/j.jaapos.2017.06.013. 
1643 
Epub 2017 Sep 1. 
1644 
12. 
Kelly KR, Jost RM, De La Cruz A, et al. Slow reading in children with anisometropic 
1645 
amblyopia is associated with fixation instability and increased saccades. J AAPOS. 
1646 
2017;21(6):447-451. 
1647 
13. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 
1648 
treatment of moderate amblyopia in children. Arch Ophthalmol. 2002;120(3):268-278. 
1649 
14. 
Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized 
1650 
trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 
1651 
2005;123(2):149-157. 
1652 
15. 
Pediatric Eye Disease Investigator Group. A comparison of atropine and patching 
1653 
treatments for moderate amblyopia by patient age, cause of amblyopia, depth of amblyopia, and 
1654 
other factors. Ophthalmology. 2003;110(8):1632-8. 
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