A Randomized Trial of Dichoptic Treatment for Amblyopia in Children 4 to 7 Years of Age
Phase: PHASE3
Conditions: Amblyopia
Sponsor: Jaeb Center for Health Research

JAEB CENTER FOR HEALTH RESEARCH 
 
 
Signature Page 
 
AMBLYOPIA TREATMENT STUDY  
 
A Randomized Trial of Dichoptic Treatment for 
Amblyopia in Children 4 to 7 Years of Age 
 
Protocol Identifying Number: ATS23 
 
Version Number: 1.0 
 
01 April 2024 
 
 
JCHR Principal Investigator 
 
Name, degree 
Robert Henderson, MS 
Signature/Date 
 
 
Protocol Chair(s) (as applicable) 
 
Name, degree 
Aparna Raghuram, OD, PhD 
Signature/Date 
 
 
Protocol Chair(s) (as applicable) 
 
Name, degree 
Kammi B. Gunton, MD 
Signature/Date 
 
 

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AMBLYOPIA TREATMENT STUDY  
 
A Randomized Trial of Dichoptic Treatment for 
Amblyopia in Children 4 to 7 Years of Age 
 
Protocol Identifying Number: ATS23 
 
Version Number: 1.0 
 
01 April 2024 

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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: rkraker@jaeb.org 
http://www.pedig.net 
 
Protocol Co-Chair 
 
Name, degree 
Aparna Raghuram, OD, PhD 
Title 
Protocol Co-Chair 
Institution Name 
Boston Children’s Hospital/ Harvard Medical School 
Department of Ophthalmology, Fegan 4, 4th Floor 
300 Longwood Avenue  
Boston, MA 02115 
Phone: 1-617-355-6401 
Fax: 1-617-730-0392 
Email: aparna.raghuram@childrens.harvard.edu 
 
Protocol Co-Chair 
 
Name, degree 
Kammi B. Gunton, MD 
Title 
Protocol Co-Chair 
Institution Name 
Wills Eye Hospital 
840 Walnut Street Suite 1530 
Philadelphia, PA 19107 
Phone: 1-215-928-3914 
Fax: 1-215-928-3983 
Email: kbgunton@comcast.net 
 

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VERSION HISTORY 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0  
R. Kraker 
R. Henderson 
01Apr2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   *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 ................................................................................................................. 15 
1.2.2.2 Dichoptic Movies/Shows .................................................................................................... 16 
1.3 Rationale for the Present Study ......................................................................................................... 16 
1.4 Potential Risks and Benefits of Study Treatment .............................................................................. 17 
1.4.1 Known Potential Risks ................................................................................................................ 17 
1.4.1.1 Patching............................................................................................................................... 17 
1.4.1.2 Luminopia ........................................................................................................................... 18 
1.4.2 Known Potential Benefits ............................................................................................................ 18 
1.4.3 Risk Assessment .......................................................................................................................... 18 
1.5 General Considerations...................................................................................................................... 19 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 20 
2.1 Participant Recruitment and Enrollment ........................................................................................... 20 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 20 
2.2 New or Change in Spectacle Correction If Needed ........................................................................... 20 
2.3 Participant Inclusion Criteria ............................................................................................................. 21 
2.4 Participant Exclusion Criteria ............................................................................................................ 22 
2.5 Procedures at Enrollment Visit .......................................................................................................... 23 
2.5.1 Historical Information ................................................................................................................. 23 
2.5.2 Ability to Use Luminopia ............................................................................................................ 23 
2.5.3 Clinical Testing ........................................................................................................................... 23 
2.6 Randomization of Eligible Participants ............................................................................................. 25 
CHAPTER 3: RANDOMIZED TRIAL PROCEDURES .................................................................................... 26 
3.1 Treatment ........................................................................................................................................... 26 
3.1.1 Luminopia Group ........................................................................................................................ 26 
3.1.2 Patching Group ............................................................................................................................ 26 
3.2 Phone Call ......................................................................................................................................... 26 
3.3 Follow-up Schedule Through 26-Week Primary Outcome ............................................................... 26 
3.3.1 Resolution of Amblyopia at 13-Week Office Visit ..................................................................... 27 

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3.4 Continued Follow-up Post 26-Week Primary Outcome .................................................................... 27 
3.4.1 Resolution of Amblyopia at 39-Week Office Visit ..................................................................... 27 
3.5 Follow-up Visit Testing Procedures .................................................................................................. 27 
3.5.1 Masked Examiner ........................................................................................................................ 29 
3.6 Non-Study Visits and Treatment ....................................................................................................... 29 
3.7 Management of Refractive Error ....................................................................................................... 29 
3.8 Management of Strabismus ............................................................................................................... 30 
CHAPTER 4: STUDY DEVICE ...................................................................................................................... 31 
4.1 Description of the Luminopia Device................................................................................................ 31 
4.1.1 Headset ........................................................................................................................................ 31 
4.1.2 Internet Requirements ................................................................................................................. 31 
4.2 Device Delivery and Return .............................................................................................................. 31 
4.3 Device Accountability Procedures .................................................................................................... 31 
4.3.1 Device Failure ............................................................................................................................. 31 
4.3.2 Participant Access to Study Device After Primary Outcome Visit ............................................. 32 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 33 
5.1 Questionnaires ................................................................................................................................... 33 
5.2 Clinical Assessments ......................................................................................................................... 33 
CHAPTER 6: MISCELLANEOUS CONSIDERATIONS ................................................................................... 35 
6.1 Contacts by the Jaeb Center for Health Research and Sites .............................................................. 35 
6.2 Participant Compensation .................................................................................................................. 35 
6.3 Cost of Treatment .............................................................................................................................. 35 
6.4 Participant Withdrawal ...................................................................................................................... 35 
6.5 Confidentiality ................................................................................................................................... 35 
CHAPTER 7: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING ....................................... 36 
7.1 Unanticipated Problems ..................................................................................................................... 36 
7.2 Adverse Events .................................................................................................................................. 36 
7.2.1 Reportable Adverse Events ......................................................................................................... 36 
7.2.2 Safety Oversight .......................................................................................................................... 36 
7.2.3 Stopping Criteria ......................................................................................................................... 37 
7.2.4 Participant Discontinuation of Study Treatment ......................................................................... 37 
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 38 
8.1 Statistical and Analytical Plans ......................................................................................................... 38 
8.2 Study Objective and Statistical Hypothesis ....................................................................................... 38 
8.2.1 Primary Efficacy Outcome .......................................................................................................... 38 

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8.3 Sample Size ....................................................................................................................................... 39 
8.3.1 Effect of PATCHING .................................................................................................................. 39 
8.3.2 Effect of LUMINOPIA................................................................................................................ 39 
8.3.3 Selection of Noninferiority Margin ............................................................................................. 40 
8.3.4 Sample Size Calculations and Assumptions ................................................................................ 40 
8.3.5 Power for Superiority .................................................................................................................. 41 
8.4 Outcome Measures ............................................................................................................................ 41 
8.5 Analysis Datasets and Sensitivity Analyses ...................................................................................... 42 
8.6 Analysis of the Primary Efficacy Outcome ....................................................................................... 42 
8.7 Analysis of the Secondary Efficacy Outcomes ................................................................................. 43 
8.7.1 Pediatric Eye Disease Questionnaire (PedEyeQ) ........................................................................ 43 
8.8 Intervention Adherence ..................................................................................................................... 43 
8.9 Protocol Adherence and Retention .................................................................................................... 44 
8.10 Intercurrent Events .......................................................................................................................... 44 
8.11 Safety Analyses ............................................................................................................................... 44 
8.12 Baseline Descriptive Statistics ......................................................................................................... 45 
8.13 Planned Interim Analyses ................................................................................................................ 45 
8.14 Subgroup Analyses .......................................................................................................................... 45 
8.15 Multiple Comparison/Multiplicity ................................................................................................... 45 
8.16 Exploratory Analyses ...................................................................................................................... 46 
8.16.1 Mean Change in Distance VA at 13 Weeks .............................................................................. 46 
8.16.2 Mean Change in Distance VA over 26 weeks (area under the curve) ....................................... 46 
8.16.3 Improvement of Amblyopic-eye Distance VA by 2 or More Lines .......................................... 46 
8.16.4 Binocular Function .................................................................................................................... 46 
8.16.5 Resolution of Amblyopia at 13 weeks and 26 weeks ................................................................ 46 
8.16.6 Treatment Impact Questionnaire ............................................................................................... 47 
8.16.7 Improvement with Dichoptic Therapy after PATCHING ......................................................... 47 
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 48 
9.1 Case Report Forms and Other Data Collection ................................................................................. 48 
9.2 Study Records Retention ................................................................................................................... 48 
9.3 Quality Assurance and Monitoring .................................................................................................... 48 
9.4 Protocol Deviations ........................................................................................................................... 49 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 50 
10.1 Ethical Standard ............................................................................................................................... 50 
10.2 Institutional Review Boards ............................................................................................................ 50 
10.3 Informed Consent Process ............................................................................................................... 50 

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10.3.1 Consent Procedures and Documentation ................................................................................... 50 
10.4 Participant and Data Confidentiality ............................................................................................... 51 
10.5 Future Use of Data ........................................................................................................................... 51 
CHAPTER 11: REFERENCES ....................................................................................................................... 52 
 
 
 
 

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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  
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 
 
 
 
Title 
A Randomized Trial of Dichoptic Treatment for Amblyopia in Children 4 to 7 Years of Age. 
 
Précis 
Current treatments for amblyopia have limited effectiveness in a notable proportion of young 
children. In addition, the standard treatment of patching may be associated with adverse 
psychosocial effects. Home-based dichoptic movies/shows present an appealing alternative to 
patching, but there are few data on comparative effectiveness.  
 
Dichoptic movies/shows with Luminopia technology show promise of better adherence, and an 
easier treatment experience.  
 
If dichoptic therapy using Luminopia is confirmed to be non-inferior to standard part-time 
patching for best-corrected visual acuity, this study will have provided evidence to support 
Luminopia as a reasonable alternative to patching in young children. In addition, we plan to 
assess treatment impact and quality of life to provide data on whether there are advantages to 
Luminopia.  
 
Investigational Device 
Luminopia digital therapeutic system. 
 
Primary Objective 
In children 4 to 7 years of age, to determine if treatment with 1 hour per day 6 days per week of 
watching dichoptic movies/shows wearing the Luminopia headset is non-inferior to treatment 
with 2 hours of patching per day 7 days per week with respect to change in amblyopic eye 
distance VA from randomization to 26 weeks. 
 
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 26 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 26 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.   
 

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Population 
Key Inclusion Criteria: 
 
• 
Age 4 to 7 years. 
• 
Amblyopia associated with anisometropia, strabismus (<=5∆ at distance and near 
measured by SPCT), or both. 
• 
Amblyopic-eye VA of 20/40 to 20/200 inclusive by ATS-HOTV. 
• 
Age normal VA in the fellow eye by ATS-HOTV (20/40 or better if age 4 years, 20/32 
or better if age 5-6 years, 20/25 or better if age 7 years). 
• 
Interocular difference in VA of 3 logMAR lines or more by ATS-HOTV. 
• 
Spectacles/contact lens correction (if required) worn for at least 18 weeks, or until 
stability of VA is demonstrated (<1-line 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 
238 total participants (119 in each treatment group)   
 
Phase 
Phase III Randomized Clinical Trial 
 
Treatment Groups 
Random assignment (1:1) to: 
 
• 
Luminopia Group:  watching 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 optical correction, if needed. 
• 
Patching Group:  patching of the fellow eye 2 hours per day (treatment time can be 
split into shorter sessions totaling 2 hours each day) 7 days per week with optical 
correction, if needed.  
 
Participant Duration 
If randomized, participation in the study will last 1 year or less.   
 
Study Duration 
Thirty-seven (37) months from first enrollment to last participant visit (25 months to recruit, 
followed by 12 months of follow up).  
 
Protocol 
Overview/Synopsis 
Participants eligible for the study will be randomly allocated (1:1) to receive either dichoptic 
treatment while wearing the Luminopia headset or patching treatment of the fellow eye for 
amblyopia with clinical assessments at 13, and 26-weeks post-randomization.   
 
At the 26-week primary outcome visit, participants who were randomly assigned to receive 
patching treatment with an IOD of 1 logMAR line or more, will be offered Luminopia dichoptic 
therapy and if they accept, followed forward with visits at 39- and 52-weeks post-randomization. 
 
The study will end for all other participants.   
 

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STUDY SUMMARY FLOW CHART  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Measurements (with best correction) 
• 
Monocular distance VA testing (ATS-HOTV) 
• 
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 4 to 7 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 required) worn for at least 18 weeks, or demonstrated stability of amblyopic eye VA 
(<1-line change 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 inclusive by ATS-HOTV 
• 
Interocular difference in VA of 3 logMAR lines or more by ATS-HOTV. 
• 
Age normal VA in the fellow eye (20/40 or better if age 4, 20/32 or better if 5-6, 20/25 or better if age 7) by ATS-HOTV 
• 
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 
• 
History of light-induced seizures. 
Patching Group 
Patch fellow eye 2 hours per day, 
7 days per week 
Randomize 
 Luminopia Group 
Dichoptic movies/shows 1 hour per day,  
6 days per week 
1-Week Phone Call 7 to 13 days from Randomization 
Inquire if any problems with randomized treatment (completed by site personnel) 
Follow-Up Exam (13 Weeks ± 2 weeks from Randomization) 
• 
Assessment of Diplopia and Adverse Events 
• 
Treatment Impact Questionnaire   
• 
PedEyeQ Social and Frustration Worry Domains 
• 
Monocular distance VA testing (ATS-HOTV) (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 
• 
Stop randomized treatment if amblyopia resolves (defined as <0 logMAR lines IOD with fellow eye VA no 
worse than 1-line below baseline).  
Primary Outcome Exam (26 Weeks ± 2 weeks from Randomization) 
• 
Assessment of Diplopia and Adverse events 
• 
Treatment Impact Questionnaire  
• 
PedEyeQ Visual Function Domain  
• 
Monocular distance VA testing (ATS-HOTV) (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 
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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RESIDUAL AMBLYOPIA 
AT 26-WEEKS? 
  
1 logMAR line or more IOD (amblyopic eye 
worse) AND accept trial of Luminopia? 
 
Secondary Outcome Exam: 39 Weeks ± 2 weeks from Randomization 
 
• 
Monocular distance VA testing (ATS-HOTV) 
• 
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 
• 
Stop LUMINOPIA treatment if amblyopia resolves (defined as <0 logMAR lines IOD with fellow eye VA no 
worse than 1 logMAR line below baseline)  
Secondary Outcome Exam: 52 Weeks ± 2 weeks from Randomization 
 
• 
Monocular distance VA testing (ATS-HOTV) 
• 
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 
 
  
Patching Group 
Yes 
No 
27-Week Phone Call  
(7 to 13 days from 26-week visit)  
Inquire if any problems  
(completed by site personnel) 
  
Luminopia Group 
  
Study Ends at 26-Weeks 

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
*27-week phone call timed 7 to 13 days after the 26-week primary outcome only for participants 
assigned to patching who have residual amblyopia and accept treatment with Luminopia at the 
26-week primary outcome.   
 
†The 39-week and 52-week post-randomization visits are completed by any participant assigned 
to patching who has residual amblyopia and accepts treatment with Luminopia at the 26-week 
primary outcome.     
Visit 
Informed Consent 
 
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 
 
 
 
 
 
 
 
 
 
 
13-week Visit 
 
 
X 
masked  
X 
masked  
X 
 
X 
X 
X 
X 
26-week Visit  
 
 
X 
masked  
X 
masked 
X 
X 
 
X 
X 
X 
27-week Call* 
 
 
 
 
 
 
 
 
 
 
39-week Visit† 
 
 
X 
X 
X 
 
 
X 
X 
 
52-week Visit† 
 
 
X 
X 
X 
 
 
X 
X 
 

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Chapter 1: Background Information 
1 
 
2 
1.1 Epidemiology and Clinical Characteristics 
3 
Amblyopia is the most common cause of reduced monocular visual acuity (VA) in children and 
4 
young adults, with estimates of prevalence ranging from 1% to 5%.1,2 Common risk factors are 
5 
uncorrected anisometropia, strabismus, or a combination of these. In addition to reduced VA, 
6 
amblyopia may also be associated with dysfunctions of accommodation, fixation, binocularity, 
7 
vergence, reading speed and fluency, and contrast sensitivity.3-12  
8 
 
9 
1.2 Current Practice 
10 
 
11 
1.2.1 Monocular Penalization 
12 
The current foundation of amblyopia treatment is optical correction (when there is uncorrected 
13 
refractive error) followed, if needed, by part-time patching or atropine penalization of the fellow 
14 
eye.13-18 This treatment approach has been shown to be effective in many younger children (3 to 
15 
<7 years),13-18 but residual amblyopia (20/32 or worse) is present in approximately 54% at age 10 
16 
years19 and 40% at age 15 years.20  
17 
 
18 
A possible explanation for failure of part-time patching treatment in some younger children is 
19 
poor adherence with prescribed treatment regimens.21,22 Nevertheless, data from studies using 
20 
occlusion dose monitors23,24 indicate that many children who successfully adhere to prescribed 
21 
part-time patching still fail to respond fully. Such data suggest that part-time patching may 
22 
simply be inadequate in some young children with amblyopia.  
23 
 
24 
1.2.2 Dichoptic Treatments 
25 
An alternative treatment approach that has gained momentum in recent years is dichoptic 
26 
therapy.25 Although monocular penalization has been the predominant amblyopia treatment 
27 
approach for many years, some have advocated that a dichoptic (binocular) approach has 
28 
additional value.26 Dichoptic treatments for amblyopia provide simultaneous but separate and 
29 
independent stimulation to each eye, incorporating binocular elements, but modifying the input 
30 
to the sound eye by introducing blur, reduced contrast, and/or reduced luminance. Dichoptic 
31 
treatment strategies may also differentially modify central versus peripheral vision. The neuro-
32 
physiological basis for dichoptic treatment is supported by evidence that binocular cortical 
33 
mechanisms remain intact even in adults with strabismic amblyopia.27 
34 
 
35 
Over the past 20 years, dichoptic treatments have evolved from office-based technologies28-30 to 
36 
those that can be conducted in the home. Home-based technologies have many advantages, 
37 
including convenience and reduced cost associated with less in-office care-provider time. 
38 
Current home-based dichoptic treatments typically utilize games, movies, or web-based content. 
39 
Both dichoptic games and dichoptic movies have been previously studied to a limited extent in 
40 
younger children with amblyopia.25,31-34 
41 
 
42 
1.2.2.1 Dichoptic Games 
43 
PEDIG has previously evaluated two dichoptic iPad games as treatment for amblyopia in RCTs 
44 
in younger children. In ATS18,31 the Tetris falling blocks game was found not to be non-inferior 
45 
to patching; however, only 22% completed >75% of prescribed gameplay (objectively 
46 

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monitored).34 In the ATS20 younger cohort of 4- to 6-year-olds,32 binocular Dig Rush treatment 
47 
resulted in greater improvement in amblyopic-eye VA at 4 weeks but not at 8 weeks compared 
48 
with continued spectacles alone. Only half of 46 participants (57%) completed >75% of 
49 
prescribed gameplay (objectively monitored) over the entire 8 weeks.32  
50 
 
51 
Another RCT of dichoptic game play reported similar problems with adherence in younger 
52 
children.33 Likewise, a study evaluating barriers to successful dichoptic video game play35 
53 
reported that inability to understand game requirements was a significant barrier to successful 
54 
treatment in children <5.5 years of age.   
55 
 
56 
These previous data strongly suggest that poor comprehension and poor adherence with game 
57 
play are factors that have likely contributed to failure to show a benefit of this modality of 
58 
dichoptic treatment. 
59 
 
60 
1.2.2.2 Dichoptic Movies/Shows 
61 
Home-based dichoptic movies have been evaluated in younger children in a small number of 
62 
previous randomized trials.36,37 Luminopia is a dichoptic movie technology (often termed a 
63 
digital therapeutic with software as the medical device) available for use in the USA since 2022 
64 
and has been approved by the FDA for the treatment of amblyopia in children 4 to 7 years of age. 
65 
 
66 
Luminopia displays a large library of web-based video content through a virtual reality (VR) 
67 
headset, utilizing computational algorithms to split the source video into 2 streams (one to each 
68 
eye) and modify the input in real time. Contrast in the sound eye is reduced to 15% and a series 
69 
of 6 different dichoptic masks overlay the video content, rotating every 30 seconds.   
70 
 
71 
Xiao et al36 conducted a randomized trial comparing dichoptic movies using the Luminopia 
72 
device versus continued glasses alone. Of 103 enrolled children (aged 4 to 7 years) 52 were 
73 
randomly assigned to continued glasses and 51 to dichoptic movies using Luminopia 1 hour/day, 
74 
6 days a week. At the 12-week outcome, mean amblyopic eye VA had improved 1.8 lines (95% 
75 
CI: 1.4 to 2.3 lines; n=45) in the Luminopia group and 0.8 lines (95% CI: 0.4 to 1.3 lines; n=45) 
76 
in the continued glasses group. At the planned interim analysis, the difference between groups 
77 
was significant favoring Luminopia by 1.0 line (P=0.001; 96.14% CI: 0.3 to 1.6 lines) and the 
78 
study was stopped early for success. Median adherence with Luminopia (objectively monitored 
79 
by the device) was 88% over 12 weeks (IQR, 61 to 99%). 
80 
 
81 
In a preceding non-randomized study,38 Xiao et al prescribed Luminopia 1 hour/day for 12 
82 
weeks to 90 children 4- to 12-years of age (mean 6.7 ± 2.0 years) with amblyopia. Overall 
83 
(n=74) the mean amblyopic-eye VA improved from 0.50±0.15 to 0.35±0.21 logMAR (1.5 
84 
logMAR lines, 95% CI: 1.2-1.8 lines, P<0.001) over 12 weeks.38 Median adherence (objectively 
85 
monitored by the device) was 86% (IQR, 70% to 97%). 
86 
 
87 
1.3 Rationale for the Present Study  
88 
Current treatments for amblyopia have limited effectiveness in some young children. In a 
89 
previous large, multicenter RCT, home-based dichoptic movies were shown to be superior to 
90 
continued glasses alone, but treatment effectiveness compared with patching has not yet been 
91 

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established. It is possible that dichoptic movies/shows are as effective as patching, in which case 
92 
they would provide an appealing alternative treatment.  
93 
 
94 
Standard patching treatment may also be associated with adverse effects including negative 
95 
psychosocial experiences, bullying, and social stigma.39-43 There are few direct measures of 
96 
treatment impact and there is a need for instruments that assess the impact a treatment has on the 
97 
child and their family. Such an assessment is of value especially for treatments that may be 
98 
similar regarding effectiveness but differ regarding treatment experience. Dichoptic 
99 
movies/shows with Luminopia technology show promise of better adherence and an easier 
100 
treatment experience.  
101 
 
102 
Treatment outcomes are typically measured only in terms of monocular VA despite evidence that 
103 
amblyopia impacts many other visual functions.3-12 An expanded assessment of amblyopia 
104 
treatment outcomes, including evaluation of functional vision and quality of life, is important for 
105 
future practice and research. Such testing will lead to an improved understanding of the wider-
106 
reaching benefits of amblyopia treatment and enable further exploration of possible differential 
107 
treatment benefits with different modalities.  
108 
 
109 
In summary, while current treatment approaches are moderately effective in many younger 
110 
children with amblyopia, the high prevalence of residual amblyopia and the challenges 
111 
associated with patching treatment call for consideration of alternative, age-appropriate 
112 
treatments. Treatments less onerous than patching need to be considered even if treatment 
113 
outcomes are only equally effective.  
114 
 
115 
If dichoptic therapy using the Luminopia digital therapeutic system is confirmed to be non-
116 
inferior to standard part-time patching for improving amblyopic eye best-corrected VA, this 
117 
study would provide evidence to support Luminopia as a reasonable alternative to patching in 
118 
young children. In addition, we plan to assess: 1) treatment impact to provide data on whether 
119 
there are advantages to Luminopia regarding treatment burden and treatment difficulty, 2) impact 
120 
on functional vision and 3) impact on social and frustration / worry quality of life concerns. 
121 
 
122 
1.4 Potential Risks and Benefits of Study Treatment  
123 
 
124 
1.4.1 Known Potential Risks 
125 
 
126 
1.4.1.1 Patching 
127 
Patching treatment may potentially cause a decrease of VA in the non-amblyopic eye (reverse 
128 
amblyopia), but this is extremely unlikely when the fellow eye has several hours without 
129 
occlusion each day, and should it occur, is almost always reversible. If reverse amblyopia occurs, 
130 
investigators should contact one of the protocol chairs to discuss future management.  
131 
 
132 
Skin irritation may develop due to the adhesive patch, but this is expected to be rare with only 2 
133 
hours per day of patching. If irritation develops the participant will be provided with a fabric 
134 
patch to wear on their glasses (plano glasses will be provided for children who are not already 
135 
wearing glasses).  
136 
 
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Diplopia with patching is expected to be rare based on our experience in ATS18 in which only 
138 
2% reported diplopia at a frequency of once per week (the maximum frequency reported).31  
139 
 
140 
Likewise, the development of a new strabismus or worsening of a preexisting strabismus is 
141 
expected to be rare with a rate of 5.9% found in the patching group in ATS18.31 
142 
 
143 
1.4.1.2 Luminopia 
144 
In a previous randomized clinical trial evaluating Luminopia vs continued glasses alone in 
145 
children aged 4 to 7 years36, 10 (20%) of 51 patients experienced non-serious adverse events in 
146 
the treatment group vs. 7 (13%) of 54 patients in the continued glasses group. In the Luminopia 
147 
treatment group adverse events were new heterotropia in 3 (6%), worsening VA in the 
148 
amblyopic eye in 2 (4%), worsening VA in the fellow eye in 2 (4%), headache in 4 (8%), 
149 
eyestrain in 1 (4%), with single cases each of dizziness, increase in frequency of night terrors, 
150 
eye twitching, and facial redness.  
151 
 
152 
In the continued glasses group adverse events were diplopia in 1 (2%), new heterotropia in 2 
153 
(4%), worsening heterotropia in 1 (2%), worsening VA in the amblyopic eye in 4 (7%), headache 
154 
in 1 (2%) and pain from glasses in 1 (2%). No serious adverse events were reported. The most 
155 
frequent non-serious adverse event potentially related to Luminopia was headache (8%). 
156 
In a preceding non-randomized study evaluating 90 participants aged 4 to 12 years,40 the most 
157 
common adverse events were headaches (n=6), eye strain (n=3), blurry vision (n=2), and 
158 
worsening VA (n=2). One participant developed a new strabismus.  All adverse events were 
159 
graded as mild in severity.  
160 
 
161 
The Luminopia headset may become warm during normal usage. If the surface touching the face 
162 
feels hot, the participant should stop using the headset immediately and wait for it to cool down 
163 
before re-using. 
164 
 
165 
Luminopia treatment is considered “digital media” use for children. An American Academy of 
166 
Pediatrics (AAP) policy statement recommends that children 2 to 5 years should be limited to no 
167 
more than 1 hour per day of digital media use, noting that heavy media use during preschool 
168 
years is associated with small but significant increases in BMI and sets the stage for weight gain 
169 
later in childhood. During the informed consent process, parents of children aged 4 or 5 years 
170 
will be advised of these potential risks associated with digital media if they are prescribed 
171 
Luminopia therapy.    
172 
 
173 
1.4.2 Known Potential Benefits 
174 
The potential benefit of treatment with patching or treatment with Luminopia is improvement in 
175 
amblyopic eye VA.  
176 
 
177 
1.4.3 Risk Assessment 
178 
Luminopia is a software-only digital therapeutic designed to be used with commercially 
179 
available Head-Mounted Displays (HMDs) which are compatible with a software application. 
180 
Luminopia is approved by the FDA and indicated for improvement in visual acuity in amblyopia 
181 
patients, aged 4-7, associated with anisometropia and/or with mild strabismus, having received 
182 
treatment instructions (frequency and duration) as prescribed by a trained eye-care professional. 
183 

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184 
The expected adverse events from Luminopia are summarized in 1.4.1.2 and do not pose a 
185 
greater risk than what the typical child would experience in their normal day-to-day activities 
186 
(e.g., wearing glasses, wearing small adhesives like band aids, watching television, playing 
187 
videogames, etc.).   
188 
 
189 
The safety of Luminopia beyond 12 weeks is unknown; however, the expected adverse events 
190 
between 12 weeks and 26 weeks in the current study are expected to be similar in type and 
191 
severity to the type and severity summarized in 1.4.1.2.     
192 
 
193 
Since Luminopia does not pose a significant risk to participants, the Sponsor has determined that 
194 
Luminopia is not a significant risk device.    
195 
 
196 
The expected adverse events from patching are summarized in 1.4.1.1 and are non-significant.  
197 
 
198 
The Sponsor has determined that the protocol’s level of risk is consistent with 45 CFR 46.404 
199 
and 21 CFR 50.51, which indicates research not involving greater than minimal risk.  
200 
 
201 
1.5 General Considerations 
202 
The study is being conducted in compliance with the policies described in the study policies 
203 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
204 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
205 
 
206 
The protocol is not considered a significant risk device study, since Luminopia is a non-invasive 
207 
product that has been approved by the U.S. Food and Drug Administration (FDA) as treatment 
208 
for amblyopia in children aged 4 to 7 years for up to 12 weeks. Therefore, an investigational 
209 
device exemption (IDE) from the FDA is not required to conduct the study. However, the study 
210 
must still comply with the abbreviated requirements of 21 CFR 812.2(b) as a non-significant risk 
211 
device under an investigation to evaluate safety and efficacy as used specified in accordance with 
212 
this protocol. 
213 

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Chapter 2: Study Enrollment and Screening 
214 
 
215 
2.1 Participant Recruitment and Enrollment 
216 
The study plans to enroll a minimum of 238 participants. As the enrollment goal approaches, 
217 
sites will be notified of the end date for recruitment. Study participants whose parents have 
218 
signed an informed consent form (and child has signed assent form, if required) can be enrolled 
219 
up until the end date, which means the recruitment goals might be exceeded; however, total 
220 
recruitment will not exceed 250 participants.    
221 
 
222 
Study participants will be recruited from approximately 70 clinical centers in North America. All 
223 
eligible participants will be included without regard to sex, race, or ethnicity. There is no 
224 
restriction on the number of participants to be enrolled or randomized by each site toward the 
225 
overall recruitment goal. 
226 
 
227 
2.1.1 Informed Consent and Authorization Procedures 
228 
A child is considered for the study after undergoing a routine eye examination as part of standard 
229 
of care that identifies amblyopia appearing to meet the eligibility criteria. Children may also be 
230 
referred to a study investigator from another eye-care or health-care provider. The study will be 
231 
discussed with the child’s parent(s) or legal guardian(s) (referred to subsequently as parent(s)). 
232 
Parent(s) who express an interest in the study will be given a copy of the informed consent form 
233 
to read. Written informed consent and assent must be obtained from a parent prior to performing 
234 
any study-specific procedures that are not part of the child’s routine care and/or collecting any 
235 
data for the study. 
236 
 
237 
 
238 
If the participant and/or parents are not fluent in written and spoken English, then the consent 
239 
and/or assent forms must be translated into a language of fluence for the participant/parent. 
240 
Further, a qualified interpreter must be available for the consent process and for all subsequent 
241 
study-related interactions. 
242 
 
243 
A participant is considered enrolled when the informed consent and assent forms have been 
244 
signed, as applicable.  
245 
 
246 
2.2 New or Change in Spectacle Correction If Needed 
247 
New spectacles or a change in spectacles may be prescribed for participants who have not had 
248 
a cycloplegic refraction within 7 months OR if their current spectacles do not meet spectacle 
249 
tolerance criteria (2.3 #6) OR in cases where the investigator determines that updating the 
250 
spectacles is necessary for best clinical care, IF they ALSO meet ALL the other inclusion criteria 
251 
(2.3) while wearing their current refractive correction. 
252 
The prescribed spectacles must be based upon a cycloplegic refraction performed on the day of 
253 
enrollment or within 7 months and must meet eligibility criteria in 2.3 #6. If new spectacles are 
254 
prescribed and paid for by the study, the investigator should ensure that visual acuity is still 
255 
expected to meet eligibility criteria in 2.3 #2. As needed, VA should be measured (using the 
256 
investigator’s preferred VA testing method) in the intended spectacle prescription if the child is 
257 
not cyclopleged or in the full cycloplegic refractive error if the child is cyclopleged. 
258 

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259 
The participant will return for standard of care visits until they meet eligibility criteria (including 
260 
stability criteria) below in 2.3 #6.  
261 
 
262 
Any new contact lenses or change to contact lenses will NOT be paid for by the study. 
263 
 
264 
2.3 Participant Inclusion Criteria 
265 
At the time of enrollment, individuals must meet all the following inclusion criteria to be eligible 
266 
to participate in the study. 
267 
 
268 
1. Age 4 to 7 years.  
269 
2. Visual acuity, measured in each eye without cycloplegia in current refractive correction 
270 
(if applicable) using the ATS-HOTV VA protocol on a study-approved device displaying 
271 
single surrounded optotypes, as follows: 
272 
a. VA in the amblyopic eye 20/40 to 20/200 inclusive.  
273 
b. Age-normal VA in the fellow eye:44,45 
274 
• 4 years: 20/40 or better; 5-6 years: 20/32 or better; 7 years: 20/25 or better 
275 
c. Interocular difference ≥ 3 logMAR lines (i.e., amblyopic eye VA at least 3 logMAR 
276 
lines worse than fellow eye VA).  
277 
3. Amblyopia associated with strabismus, anisometropia, or both (previously treated or 
278 
untreated). 
279 
a. Criteria for strabismic amblyopia: At least one of the following must be met: 
280 
• Presence of a heterotropia on examination at distance or near fixation (with 
281 
optical correction), must be <=5 prism diopters (∆) by SPCT at distance and near 
282 
fixation. 
283 
• Documented history of strabismus which is no longer present (which in the 
284 
judgment of the investigator could have caused amblyopia). 
285 
b. Criteria for anisometropia: At least one of the following criteria must be met: 
286 
• ≥1.00 D difference between eyes in spherical equivalent (SE). 
287 
• ≥1.50 D difference in astigmatism between corresponding meridians in the two 
288 
eyes. 
289 
c. Criteria for combined-mechanism: Both of the following criteria must be met: 
290 
• A criterion for strabismus is met (see above). 
291 
• ≥1.00 D difference between eyes in spherical equivalent OR ≥1.50 D difference in 
292 
astigmatism between corresponding meridians in the two eyes. 
293 
4. No more than 2 weeks (cumulative) of prior dichoptic treatment. 
294 
5. No treatment with cycloplegic eyedrops (e.g., atropine) in the past 2 weeks; other 
295 
treatments allowed up to enrollment but then must be discontinued. 
296 
6. Refractive correction is required (single vision lenses or contact lenses) for any of the 
297 
following refractive errors based on a cycloplegic refraction completed within the last 7 
298 
months:  
299 
• Hypermetropia of 2.50 D or more by SE 
300 
• Myopia of amblyopic eye of 0.50D or more SE 
301 
• Astigmatism of 1.00D or more  
302 
• Anisometropia of more than 0.50D SE 
303 
 
304 

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NOTE: Monocular or binocular contact lens wear is allowed provided the contact lenses meet the 
305 
refractive error correction requirements below. For each child, all testing must be performed using the 
306 
same form of optical correction (i.e., no changing between contacts and spectacles).  
307 
 
308 
a. Spectacles/contact lens correction prescribing instructions referenced to the 
309 
cycloplegic refraction completed within the last 7 months: 
310 
• SE must be within 0.50D of fully correcting the anisometropia (if new glasses are 
311 
prescribed, reduction in plus sphere must be symmetric in the two eyes). 
312 
• SE must not be under corrected by more than 1.50D SE.  
313 
• Cylinder power in both eyes must be within 0.50D of fully correcting the 
314 
astigmatism. 
315 
• Axis must be within +/- 10 degrees if cylinder power is ≤1.00D, and within +/- 5 
316 
degrees if cylinder power is >1.00D. 
317 
• Myopia must not be under corrected by more than 0.25D or over corrected by 
318 
more than 0.50D SE, and any change must be symmetrical in the two eyes.  
319 
 
320 
b. Spectacles/contact lens correction (with or without other treatment such as patching) 
321 
meeting the above criteria must be worn: 
322 
• For at least 18 weeks (immediately prior to enrollment) OR until VA stability is 
323 
documented (defined as <0.1 logMAR change by the same testing method 
324 
measured on 2 consecutive exams at least 9 weeks apart).   
325 
• For determining VA stability (non-improvement): 
326 
o The first of two measurements may be made 1) in current correction, 
327 
or 2) in trial frames with or without cycloplegia or 3) without 
328 
correction (if new correction is prescribed),   
329 
o The second measurement must be made without cycloplegia in the 
330 
correct spectacles/contact lens correction that has been worn for at 
331 
least 9 weeks.   
332 
o NOTE: Because this determination is a pre-randomization, the method 
333 
of measuring VA is not mandated. 
334 
7. Participant is willing to wear the Luminopia headset.  
335 
8. Participant is willing to continue full-time spectacles/contact lens wear (if needed). 
336 
9. Participant is willing to accept assignment to either dichoptic shows (view 1 hour per day 
337 
6 days per week) OR part-time patching (2 hours per day 7 days per week) for 26 weeks. 
338 
10. Interpupillary distance of 52mm to 72mm inclusive. 
339 
11. Investigator is willing to prescribe Luminopia or patching per protocol.  
340 
12. Parent understands the protocol and is willing to accept randomization. 
341 
13. Parent has phone (or access to phone) and is willing to be contacted by JAEB Center. 
342 
14. Relocation outside area of active PEDIG site within the next 52 weeks is not anticipated. 
343 
 
344 
2.4 Participant Exclusion Criteria 
345 
Individuals meeting any of the following criteria will be excluded from study participation. 
346 
 
347 
1. Heterotropia more than 5∆ at distance or near (measured by SPCT in current correction) 
348 
2. Prism lenses or need of a prism prescription at enrollment. 
349 
3. Current bifocal spectacles (eligible only if bifocal discontinued 2 weeks prior to 
350 
enrollment). 
351 

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4. Myopia greater than -6.00D spherical equivalent in either eye. 
352 
5. Previous intraocular or refractive surgery. 
353 
6. Known skin reactions to patch or bandage adhesives. 
354 
7. Ocular co-morbidity that may reduce VA determined by an ocular examination 
355 
performed within the past 7 months (Note: nystagmus per se does not exclude the 
356 
participant if the above visual acuity criteria are met using patch occlusion. Fogging is 
357 
not permitted). 
358 
8. Diplopia more than once per week over the last week prior to enrollment by parental 
359 
report. 
360 
9. History of light-induced seizures. 
361 
10. Severe developmental delay that would interfere with treatment or evaluation (in the 
362 
opinion of the investigator). Participants with mild speech delay or reading and/or 
363 
learning disabilities are not excluded. 
364 
11. Participation in a prior study involving patching for amblyopia 
365 
12. Immediate family member (biological or legal guardian, child, sibling, parent) of 
366 
investigative site personnel directly affiliated with this study or an employee of the JAEB 
367 
center for Health Research. 
368 
 
369 
2.5 Procedures at Enrollment Visit 
370 
 
371 
2.5.1 Historical Information 
372 
After informed consent has been signed, historical information elicited will include the 
373 
following: date of birth, sex, race, ethnicity, history of allergy to patching, and prior amblyopia 
374 
therapy including refractive correction.     
375 
 
376 
2.5.2 Ability to Use Luminopia  
377 
Interpupillary distance will be measured using investigator’s standard method or a PEDIG-
378 
provided IPD ruler. Participants with interpupillary distance <52mm or >72mm will not be 
379 
eligible to participate in the study.  
380 
 
381 
Site personnel will confirm that the participant is able and willing to wear the Luminopia headset 
382 
by: 
383 
1. Showing the child the devices in the clinic and allowing them to try them on, if desired.   
384 
2. Asking the child if they are willing to wear the headset for up to an hour a day, 6 days a 
385 
week.  
386 
 
387 
2.5.3 Clinical Testing 
388 
Participants who meet all eligibility criteria in section 2.3 and 2.4 including visual acuity stability 
389 
criteria in current spectacles/contract lens correction will complete the following tests and 
390 
assessments.   
391 
 
392 
All examination procedures must be tested on the day of enrollment, except the cycloplegic 
393 
refraction and ocular examination, which may be performed within 7 months prior to enrollment.  
394 
 
395 
The following procedures should be performed at the enrollment visit in the following order: 
396 
 
397 

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Lensometry: 
398 
Verify current refractive correction by lensometry. If a participant is wearing contact lenses, 
399 
verify contact lens prescription.  
400 
 
401 
Questionnaires: 
402 
 
403 
1. Assessment of Binocular Diplopia:  
404 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
405 
“has your child complained of double vision over the last week.” If yes, the parent is asked 
406 
how frequently during the last week the child has complained of double vision: “once per 
407 
week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study personnel may 
408 
assess diplopia. Children who have reported diplopia more than once over the past week are 
409 
ineligible (see section 2.3).  
410 
2. PedEyeQ Functional Vision Domain46:  
411 
A child questionnaire for children ages 5-7 years (inclusive), and a proxy questionnaire 
412 
completed by the parent regarding their child’s functional vision. The child questionnaire is 
413 
administered to the child by study personnel. The Proxy questionnaire is completed by the 
414 
parent.  
415 
3. PedEyeQ Social Domain and Frustration/Worry Domain46:  
416 
Child questionnaire for children ages 5-7 years (inclusive), and proxy questionnaire 
417 
completed by the parent regarding their child. The child questionnaire is administered to the 
418 
child by study personnel. The Proxy questionnaire is completed by the parent.  
419 
 
420 
Clinical Testing (in the following order) is performed in the participant’s current refractive 
421 
correction, if required, without cycloplegia: 
422 
 
423 
4. Distance Visual Acuity Testing:   
424 
Monocular distance VA testing will be performed in current refractive correction (if 
425 
required) in each eye by a certified examiner using the electronic ATS-HOTV VA on a 
426 
study-certified VA tester displaying single surrounded optotypes. 
427 
5. Binocular Function Testing (by a certified examiner):  
428 
• Stereoacuity will be tested at 40cms in current refractive correction using the Randot 
429 
Preschool Test.  
430 
• If nil stereoacuity on the Randot Preschool Test, the Random Dot Butterfly test will 
431 
be performed at 40cms.   
432 
• If nil stereoacuity on the Random Dot Butterfly, the Worth 4-shape will be 
433 
administered.  
434 
6. Ocular Alignment Testing:  
435 
Ocular alignment will be assessed in current spectacle/contact lens correction by the cover 
436 
test, simultaneous prism and cover test (SPCT) (in cases of strabismus detected by cover 
437 
test), and prism and alternate cover test (PACT) in primary gaze at distance (3 meters) and at 
438 
near (1/3 meter). 
439 
7. Additional Clinical Testing:  
440 
Ocular examination as per investigator’s clinical routine.   
441 
 
442 

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2.6 Randomization of Eligible Participants 
443 
The JAEB Center will construct a Master Randomization List using a permutated block design 
444 
stratified by VA in the amblyopic eye as 20/40 to 20/80 (moderate impairment) versus 20/100 to 
445 
20/200 (severe impairment) and any previous treatment (glasses only versus other treatment in 
446 
addition to glasses) which will specify the order of treatment group assignments.   
447 
 
448 
All eligible participants enrolled in the study will be followed for up to 52 weeks. Participants 
449 
will be randomly assigned in a 1:1 allocation to one of the following two treatment groups for 26 
450 
weeks:  
451 
 
452 
• Luminopia Group:  dichoptic movies/shows wearing the Luminopia headset prescribed 
453 
1 hour per day (treatment time can be split into shorter sessions totaling 1 hour each day) 
454 
6 days a week with optical correction, if needed. 
455 
 
456 
• Patching Group:  patching of the fellow eye 2 hours per day (treatment time can be split 
457 
into shorter sessions totaling 2 hours each day) 7 days per week with optical correction, if 
458 
needed.   
459 
 
460 
Once a child is assigned to treatment, they will be included in the analysis regardless of whether 
461 
the assigned treatment is received. Thus, the investigator must not randomly assign a participant 
462 
to treatment unless convinced that the parent will accept either of the treatments. 
463 

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Chapter 3: Randomized Trial Procedures 
464 
 
465 
3.1 Treatment 
466 
Investigators must not start any additional amblyopia treatment (other than that outlined below) 
467 
prior to the 26-week primary outcome visit.  
468 
 
469 
3.1.1 Luminopia Group 
470 
Participants randomized to the Luminopia group will be instructed to watch dichoptic 
471 
movies/shows using the Luminopia device at home, for 1 hour/day, 6 days/week, for 26 weeks 
472 
unless resolved at 13 weeks (see below), while continuing to wear any optical correction 
473 
(including while wearing the Luminopia device).     
474 
 
475 
Parents will be instructed that the 1 hour of daily treatment should be completed in a single 60-
476 
minute session, but if this is not possible for whatever reason, the treatment may be divided into 
477 
shorter sessions totaling 1 hour per day. Adherence with Luminopia treatment will be recorded 
478 
electronically throughout the study. 
479 
 
480 
3.1.2 Patching Group 
481 
Participants assigned to the patching group will be instructed to wear an adhesive patch over the 
482 
fellow eye (while continuing to wear any optical correction) for 2 hours per day, 7 days per week 
483 
for 26 weeks. Parents of participants will be instructed that the 2 hours of daily patching should 
484 
be completed in a single 2-hour session, but if this is not possible for whatever reason, the 
485 
treatment may be divided into shorter sessions totaling 2 hours per day. 
486 
 
487 
Adherence with prescribed patching treatment will be monitored throughout the study using a 
488 
parental calendar. Parents will be asked to complete an adherence calendar by manually 
489 
recording the number of minutes that the child wore the patch each day. The investigator will 
490 
review the calendars at each follow-up visit.   
491 
 
492 
3.2 Phone Call  
493 
Site personnel will call all participants 1 week (7 to 13 days) after randomization to encourage 
494 
adherence and confirm that there are no problems with randomized treatment. Site personnel will 
495 
also call participants in the patching group who switch to Luminopia treatment at the 26-week 
496 
primary outcome visit (7 to 13 days after the 26-week visit), again to encourage adherence with 
497 
treatment and to confirm that there are no problems with the Luminopia device.   
498 
 
499 
3.3 Follow-up Schedule Through 26-Week Primary Outcome 
500 
The follow-up schedule through 26-week primary outcome is timed from randomization: 
501 
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 
13-Week Office Visit 
91 days 
77 days to 105 days 
56 days to 125 days 
26-Week Primary Outcome 
182 days 
168 days to 196 days 
126 days to 238 days 
* Target window for phone calls is 7 to 13 days from previous office visit.  Target window for office visits is target 
502 
day +/- 2 weeks.  
503 
 
504 

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3.3.1 Resolution of Amblyopia at 13-Week Office Visit 
505 
If amblyopia resolves at the 13-week visit (defined as <0 logMAR lines IOD with fellow eye VA 
506 
no worse than 1 logMAR line below baseline), participants will discontinue Luminopia or 
507 
patching treatment but return for the 26-week primary outcome visit. No other treatment should 
508 
be prescribed before the 26-week outcome visit.   
509 
 
510 
3.4 Continued Follow-up Post 26-Week Primary Outcome 
511 
Children originally randomized to Luminopia will end the study at 26 weeks.  
512 
 
513 
Children originally randomized to Patching whose amblyopia HAS NOT resolved (1 or more 
514 
logMAR lines IOD is present with the originally amblyopic eye worse than fellow eye) at the 26-
515 
week primary outcome visit, will be offered a trial of Luminopia treatment, and if accept 
516 
treatment, will continue in follow-up as defined below.  Otherwise, the study will end.  
517 
 
518 
The follow-up schedule through 52-week outcome is timed from the 26-week visit: 
519 
 
520 
Visit 
Target Day  
Post 26-week visit 
Target Window  
Post-26-week*  
Allowable Window 
Post-26-week 
27-Week Phone Call 
7 days 
7 to 13 days 
7 to 27 days 
39-Week Office Visit 
91 days 
77 days to 105 days 
56 days to 125 days 
52-Week Office Visit 
182 days 
168 days to 196 days 
126 days to 238 days 
 
521 
* Target window for phone call is 7 to 13 days from previous office visit. Target window for office visits is target 
522 
day +/- 2 weeks.  
523 
 
524 
3.4.1 Resolution of Amblyopia at 39-Week Office Visit 
525 
If amblyopia resolves at the 39-week visit (defined as <0 logMAR lines IOD with fellow eye VA 
526 
no worse than 1 logMAR line below baseline), participants will discontinue treatment with 
527 
Luminopia, but continue follow-up until the 52-week visit. 
528 
 
529 
3.5 Follow-up Visit Testing Procedures 
530 
Participants will be seen at follow-up visits as outlined in sections 3.3 and 3.4.   
531 
 
532 
All procedures will be performed with the participant’s current refractive correction without 
533 
cycloplegia.  
534 
• If a participant currently wears spectacles or contact lenses but they are not available or 
535 
are not within tolerance at the 13-week follow-up examination, testing may be performed 
536 
with current correction in trial frames. 
537 
• Habitual refractive correction (meeting study requirements) must be worn for the primary 
538 
outcome visit at 26 weeks.  
539 
 
540 
A Masked Examiner must complete distance VA and binocular function testing at the 13, and 
541 
26-week visits. The masked examiner must be PEDIG certified for the required testing. All other 
542 
assessments are unmasked. Prior to the Masked Examiner entering the room, participants and 
543 
parents should be instructed not to discuss their treatment with the Masked Examiner.   
544 
 
545 

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The following procedures should be performed at each visit in the following order: 
546 
 
547 
Lensometry (unmasked): 
548 
Verify current refractive correction by lensometry. If a participant is wearing contact lenses, 
549 
verify contact lens prescription.  
550 
 
551 
Questionnaires (all unmasked): 
552 
 
553 
1. Assessment of Binocular Diplopia (at 13, and 26 weeks; and at 39, and 52 weeks if treated 
554 
with Luminopia):  
555 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
556 
“has your child complained of double vision over the last week.” If yes, the parent is asked 
557 
how frequently during the last week the child has complained of double vision: “once per 
558 
week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study personnel may 
559 
assess diplopia.  
560 
2. Adverse Events (at 13, and 26 weeks; and at 39, and 52 weeks if treated with Luminopia):  
561 
A standardized questionnaire will be administered to the parent to collect data on possible 
562 
adverse events. 
563 
3. Treatment Impact Questionnaire (at 13, and 26 weeks):  
564 
An item bank of participant-derived questionnaire items will be completed by the child 
565 
themselves (for children ages 5-7 years inclusive) and by the child’s parent (proxy rating 
566 
regarding impact on their child and also questions regarding impact on the parent 
567 
themselves). Questions pertain to the impact of the child’s specific treatment on the child 
568 
themselves and on the parent / family.    
569 
4. PedEyeQ Social Domain and Frustration/Worry Domain (at 13 weeks only): 
570 
Child questionnaire for children ages 5-7 years (inclusive) and proxy questionnaire for the 
571 
parent regarding their child. The Child questionnaire is administered to the child by study 
572 
personnel and the Proxy questionnaire is completed by the parent.  
573 
5. PedEyeQ Functional Vision Domain (at 26 weeks only):  
574 
A child questionnaire for children ages 5-7 years (inclusive), and proxy questionnaire for the 
575 
parent regarding their child’s functional vision. The child questionnaire is administered to the 
576 
child by study personnel. The Proxy questionnaire is completed by the parent.  
577 
 
578 
Clinical Testing performed in the participant’s current refractive correction (if required) 
579 
without cycloplegia in the following order at ALL VISITS. Masked testing must be 
580 
performed by a PEDIG certified examiner. 
581 
• Habitual refractive correction (meeting study criteria) is required for the 26-week 
582 
primary outcome exam. 
583 
• Testing in trial frames with current Rx is allowed at 13, 39 and 52 weeks if current 
584 
refractive correction is not available or does not meet study criteria.  
585 
 
586 
6. Distance VA Testing (at 13, and 26 weeks masked; at 39, and 52 weeks if applicable 
587 
unmasked): Monocular distance VA testing will be performed in current refractive correction 
588 
(if required) in each eye by a certified examiner using the electronic ATS-HOTV VA on a 
589 
study-certified VA tester displaying single surrounded optotypes.  
590 

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7. Binocular Function Testing by a certified examiner in current refractive correction if required 
591 
(at 13, and 26 weeks Masked; at 39, and 52 weeks if applicable unmasked):   
592 
• Stereoacuity will be tested at 40cms in current refractive correction using the Randot 
593 
Preschool Test.  
594 
• If nil stereoacuity on the Randot Preschool Test, the Random Dot Butterfly test will 
595 
be administered at 40cms.  
596 
• If nil stereoacuity on the Random Dot Butterfly, then the Worth 4-shape will be 
597 
administered at 40cms.  
598 
8. Ocular Alignment Testing (Unmasked): Ocular alignment will be assessed by a certified 
599 
examiner in current spectacle/contact lens correction by the cover test, SPCT (in cases of 
600 
strabismus detected by cover test), and PACT in primary gaze at distance (3 meters) and at 
601 
near (1/3 meter). 
602 
9. Adherence Monitoring (Unmasked): Adherence data Luminopia will be downloaded and 
603 
patching adherence calendars will be reviewed. 
604 
 
605 
3.5.1 Masked Examiner 
606 
The Masked Examiner must be certified to test VA and binocular function testing. Because the 
607 
Masked Examiner must be masked to the participant’s treatment group and be someone other 
608 
than the managing clinician (in many cases the managing clinician will be the investigator, but 
609 
this is not required).     
610 
 
611 
3.6 Non-Study Visits and Treatment 
612 
Investigators may schedule additional visits at their own discretion. Participants will continue to 
613 
follow the study-specified follow-up schedule regardless of any non-study visits. No data will be 
614 
collected at non-study visits for the purpose of the study.  
615 
 
616 
Investigators must not start any additional non-randomized amblyopia treatment or stop 
617 
randomized treatment prior to the 26-week primary outcome visit without first contacting a 
618 
protocol chair. As part of randomized treatment, if amblyopia is resolved at 13 weeks, 
619 
randomized treatment can be discontinued. 
620 
 
621 
For participants who continue in the study after 26 weeks, Luminopia treatment may be stopped 
622 
at 39 weeks if amblyopia meets resolution criteria, but otherwise Luminopia treatment will 
623 
continue up to the 52-week visit. No other treatment should be prescribed prior to the 52-week 
624 
outcome visit.   
625 
 
626 
3.7 Management of Refractive Error 
627 
No cycloplegic refraction is mandated during the study. Nevertheless, if the investigator suspects 
628 
that refractive error may not be corrected according to study guidelines, a cycloplegic refraction 
629 
should be performed. If the new cycloplegic refraction compared to the old cycloplegic 
630 
refraction differs by >0.75 D sphere or >0.75 D cylinder or >0.75 D in SE anisometropia or axis 
631 
change of 6 degrees or more when cylinder is 1.00 D or more; then a change in spectacles is 
632 
required.  Whether to update the spectacles for smaller changes in refraction is at investigator 
633 
discretion. 
634 
   
635 

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When new spectacles are prescribed, the refractive correction prescribed must meet the 
636 
requirements as described in section 2.3 #6. The updated spectacles will be paid for by the study.  
637 
 
638 
3.8 Management of Strabismus  
639 
Because of the short duration of the primary outcome for the study and the age group being 
640 
studied, strabismus surgery is not allowed prior to the 26-week primary outcome visit.     
641 
 
642 
If surgery must be performed, a protocol chair should be contacted and a masked exam prior to 
643 
surgery scheduled. The participant should remain in the study and complete all necessary visits. 
644 
If surgery is performed, it must be recorded in the comment section of the Follow-up 
645 
Examination Form. 
 
646 

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Chapter 4: Study Device 
647 
 
648 
4.1 Description of the Luminopia Device 
649 
Luminopia is a software-only digital therapeutic designed to be used with commercially 
650 
available Head-Mounted Displays (HMDs) which are compatible with the software application.  
651 
The software application requires an internet connection for treatment. The Luminopia medical 
652 
software application presents slightly different video content to each eye to encourage amblyopic 
653 
eye usage. Treatment using Luminopia will be prescribed for 1 hour per day, 6 days per week, 
654 
consistent with its FDA approval. 
655 
 
656 
4.1.1 Headset 
657 
The study will provide each participant with a VR headset pre-loaded with Luminopia software. 
658 
The VR headset has a screen resolution of 564 pixels per inch, which constitutes the minimum 
659 
display resolution requirement. The Luminopia system has been approved by the FDA for the 
660 
treatment of moderate or severe amblyopia in children 4 to 7 years of age. 
661 
 
662 
The Luminopia device should only be used in accordance with the manufacturer’s instructions. 
663 
Use in a safe and stationary environment with the HMD connected to Wi-Fi. Luminopia should 
664 
only be used with the participant seated or lying down. If the participant experiences discomfort 
665 
because the Luminopia device feels too heavy, the participant should try to use the Luminopia 
666 
device while lying down on their back. 
667 
 
668 
The HMD should be kept away from heat sources, water, moisture, open flames, or direct 
669 
sunlight. If the participant intends to use the Luminopia device away from home for an extended 
670 
period of time, the parent should bring the charger provided with the HMD to charge the device 
671 
as needed. The participant should not use the Luminopia device while the HMD is charging. 
672 
 
673 
4.1.2 Internet Requirements 
674 
Wireless internet with Wi-Fi speed near the router that exceeds 5 Mbs is required to operate 
675 
Luminopia. Faster network speeds will result in a better product experience. Potential study 
676 
participants who do not have the required internet capabilities in their home will be provided Wi-
677 
Fi access using a Hotspot at no cost for the duration of the study. 
678 
 
679 
 
680 
4.2 Device Delivery and Return 
681 
Device Delivery and Return procedures will be detailed in the site instruction manual.  
682 
 
683 
4.3 Device Accountability Procedures 
684 
Device accountability procedures will be detailed in the site instruction manual. 
685 
 
686 
4.3.1 Device Failure 
687 
Parents will be provided with written instructions regarding the process to follow should the 
688 
Luminopia device fail. If the device needs to be replaced PEDIG will provision a replacement. 
689 
 
690 

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4.3.2 Participant Access to Study Device After Primary Outcome Visit 
691 
Participants randomly assigned to receive patching treatment who have not resolved at the 26-
692 
week primary outcome visit, will be offered Luminopia therapy and if accepted, followed 
693 
forward with a 27-week phone call and follow-up visits at 39-weeks and 52-weeks post-
694 
randomization. Luminopia therapy will NOT continue beyond the 52-week visit.  
695 
 
696 
Participants randomly assigned to receive Luminopia will end treatment after the 26-week 
697 
primary outcome visit.   
698 
 
 
699 

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Chapter 5: Testing Procedures and Questionnaires 
700 
 
701 
5.1 Questionnaires 
702 
 
703 
1. Assessment of Binocular Diplopia:  
704 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
705 
“has your child has complained of double vision over the last week.” If yes, the parent is 
706 
asked how frequently during the last week the child has complained of double vision: “once 
707 
per week,” or “2 to 3 times per week,” or “4 or more times per week.” Any study personnel 
708 
may ask the parent to rate diplopia. Testing time is approximately 1 minute. 
709 
 
710 
2. PedEyeQ Functional Vision Domain:  
711 
A child questionnaire for children ages 5-7 years (inclusive) and a proxy questionnaire 
712 
completed by the parent regarding their child’s functional vision.  The child questionnaire is 
713 
administered by study personnel. The proxy questionnaire is completed by the parent. The 
714 
questionnaires take about 3-4 minutes to complete. 
715 
 
716 
3. PedEyeQ Social Domain: 
717 
A child questionnaire for children ages 5-7 years (inclusive) and a proxy questionnaire 
718 
completed by the parent regarding their child’s social concerns. The child questionnaire is 
719 
administered by study personnel. The Proxy questionnaire is completed by the parent. The 
720 
questionnaires take about 3-4 minutes to complete. 
721 
 
722 
4. PedEyeQ Frustration / Worry Domain: 
723 
A child questionnaire for children ages 5-7 years (inclusive), a proxy questionnaire 
724 
completed by the parent regarding their child’s Frustration / Worry. The child questionnaire 
725 
is administered by study personnel. The Proxy questionnaire is completed by the parent. The 
726 
questionnaires take about 3-4 minutes to complete. 
727 
 
728 
5. Treatment Impact Questionnaire:  
729 
An item bank of participant-derived questionnaire items will be completed by the child 
730 
themselves (for children ages 5-7 years inclusive) and by the child’s parent (proxy rating 
731 
regarding impact on their child and also questions regarding impact on the parent 
732 
themselves). Questions pertain to the impact of the child’s specific treatment on the child 
733 
themselves and on the parent / family. Testing is anticipated to take 5-7 minutes. 
734 
 
735 
6. Adverse Event Questionnaire: 
736 
A standardized questionnaire will be administered to the parent to collect data on possible 
737 
adverse events. The questionnaire is anticipated to take 1 minute to complete.  
738 
 
739 
5.2 Clinical Assessments 
740 
The following procedures will be performed at each visit as defined in the ATS Procedures 
741 
Manual:  
742 
 
743 
7. Distance VA Testing:   
744 

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Monocular distance VA testing will be performed in refractive correction in each eye by a 
745 
certified examiner using the electronic ATS-HOTV VA protocol on a study-certified VA 
746 
tester displaying single surrounded optotypes. The VA protocol used at enrollment will be 
747 
used throughout the study regardless of age at follow-up. Testing time for both eyes typically 
748 
is in the range of 5 to 15 minutes. 
749 
 
750 
8. Binocular Function Testing (by a certified examiner):  
751 
Stereoacuity will be tested at 40cms in current refractive correction using the Randot 
752 
Preschool Test.  
753 
• If nil stereoacuity on the Randot Preschool Test, then the Random Dot Butterfly test 
754 
will be administered at 40 cm.  
755 
• If nil stereoacuity on the Random Dot Butterfly, the hand-held Worth 4-Shape test 
756 
will be performed at 40 cm. 
757 
• Testing typically takes 3-5 minutes.  
758 
 
759 
9. Ocular Alignment Testing: Ocular alignment will be assessed by a certified examiner in 
760 
current spectacle correction by the cover test, simultaneous prism and cover test (SPCT) (in 
761 
cases of strabismus detected by cover test), and prism and alternate cover test (PACT) in 
762 
primary gaze at distance (3 meters) and at near (1/3 meter). Testing time is typically 1 to 3 
763 
minutes. 
764 
 
 
765 

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Chapter 6: Miscellaneous Considerations 
766 
 
767 
6.1 Contacts by the Jaeb Center for Health Research and Sites 
768 
The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided the 
769 
parents’ contact information. The Jaeb Center may contact the parents of the participants. 
770 
Permission for such contacts will be included in the Informed Consent Form. The principal 
771 
purpose of the contacts will be to develop and maintain rapport with the participant’s family and 
772 
to help coordinate the scheduling of study visits, when needed.  
773 
 
774 
6.2 Participant Compensation 
775 
Participant compensation will be specified in the informed consent form. 
776 
 
777 
6.3 Cost of Treatment 
778 
Any new or changes to optical correction will be paid for during the study.  
779 
 
780 
For those randomized to patching, patches will be paid for by the study for 26-weeks. 
781 
 
782 
For those randomized to Luminopia, the cost of prescribed dichoptic treatment for 26-weeks will 
783 
be paid for by the study.  
784 
 
785 
For those randomized to patching who have residual amblyopia at 26 weeks, the cost of 
786 
dichoptic treatment with Luminopia, if accepted, through 52-weeks will be paid for by the study.  
787 
 
788 
For those randomized to Luminopia, the study will not pay for continued Luminopia treatment 
789 
outside the study.  
790 
 
791 
6.4 Participant Withdrawal 
792 
Participation in the study is voluntary and a participant may withdraw at any time. For 
793 
participants who withdraw, their data collected prior to their withdrawal will be used. This 
794 
stipulation is specified in the consent form. 
795 
 
796 
6.5 Confidentiality 
797 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
798 
used instead of their name. Protected health information gathered for this study will be shared 
799 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
800 
participant information may also be provided to research sites involved in the study. 
801 

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Chapter 7: Unanticipated Problem and Adverse Event Reporting 
802 
 
803 
7.1 Unanticipated Problems 
804 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
805 
problems meeting the criteria below. Sites must report Unanticipated Problems to the IRB within 
806 
seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
807 
experience, or outcome that meets all three (3) of the following criteria: 
808 
 
809 
1. Is unexpected (in terms of nature, severity, or frequency) given (a) the research 
810 
procedures that are described in the protocol-related documents, such as the IRB-
811 
approved research protocol and informed consent document and (b) the characteristics of 
812 
the participant population being studied 
813 
2. Is related or possibly related to participation in the research (possibly related means 
814 
there is a reasonable possibility that the incident, experience, or outcome may have been 
815 
caused by the procedures involved in the research) 
816 
3. Suggests that the research places participants or others at a greater risk of harm than was 
817 
previously known or recognized (including physical, psychological, economic, or social 
818 
harm)  
819 
 
820 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
821 
involving a specific site such as unanticipated problems that occur at the Coordinating Center. 
822 
These instances must be reported to the JCHR IRB within seven (7) calendar days of recognition. 
823 
The Director of the Human Research Protection Program will report to the appropriate regulatory 
824 
authorities if the IRB determines that the event indeed meets the criteria of an Unanticipated 
825 
Problem that requires further reporting.  
826 
 
827 
7.2 Adverse Events 
828 
 
829 
7.2.1 Reportable Adverse Events 
830 
Because study treatment with patching and Luminopia are non-invasive and consistent with 
831 
usual clinical care, it is not expected that there would be significant adverse events other than 
832 
those already being captured as part of the clinical outcome assessments or questionnaire (e.g., 
833 
worsening of fellow eye VA, development of new or worsening of strabismus, new diplopia, or 
834 
report of headache, eyestrain, nausea, seizures, dizziness, increase in frequency of night terrors, 
835 
or skin irritation).  
836 
 
837 
7.2.2 Safety Oversight 
838 
A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
839 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to 
840 
the study protocol or suspension or outright stoppage of the study if deemed necessary based on 
841 
the totality of safety data available. Details regarding DSMC review will be documented in a 
842 
separate DSMC charter.  
843 
 
844 
The objective of the DSMC review is to decide whether the study (or study treatment for an 
845 
individual or study cohort) should continue per protocol, proceed with caution, be further 
846 
investigated, be discontinued, or be modified and then proceed. Suspension of enrollment (for a 
847 

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particular group, a particular study site, or for the entire study) is a potential outcome of a DSMC 
848 
safety review. 
849 
 
850 
7.2.3 Stopping Criteria 
851 
The study may be discontinued by the Steering Committee (with approval of DSMC) prior to the 
852 
preplanned completion of follow-up for all study participants. No formal guidelines for stopping 
853 
the study for futility or efficacy are pre-specified (see section 7). 
854 
 
855 
7.2.4 Participant Discontinuation of Study Treatment 
856 
Rules for discontinuing study treatment use are one of the following:  
857 
 
858 
• The investigator believes it is unsafe for the participant to continue to receive the 
859 
treatment.  
860 
• The participant or parent requests that the treatment be stopped. 
861 
 
862 
Even if the study treatment is discontinued, the participant will be encouraged to remain in the 
863 
study through the 26-week Primary Outcome Visit with permission from the parent to allow 
864 
ongoing data collection. 
 
865 

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Chapter 8: Statistical Considerations 
866 
8.1 Statistical and Analytical Plans 
867 
The approach to sample size and statistical analyses are summarized below.  
868 
 
869 
8.2 Study Objective and Statistical Hypothesis 
870 
 
871 
8.2.1 Primary Efficacy Outcome  
872 
The primary objective of the study is to determine if treatment by watching dichoptic 
873 
movies/shows wearing the Luminopia One headset (subsequently referred to as LUMINOPIA) is 
874 
non-inferior to treatment with 2 hours of patching per day 7 days per week (subsequently 
875 
referred to as PATCHING) with respect to change in amblyopic eye distance VA from 
876 
randomization to 26 weeks. 
877 
 
878 
The primary efficacy outcome will be the change in amblyopic eye distance VA (measured as 
879 
logMAR) from randomization to 26 weeks. Change in logMAR will be calculated as [outcome 
880 
VA] – [randomization VA] such that a negative change indicates improvement in visual acuity, 
881 
and a positive change indicates worsening.  
882 
 
883 
The study is designed to test a one-sided null hypothesis that LUMINOPIA is inferior to 
884 
PATCHING by 0.0625 logMAR (i.e., 5/8 of one line) or more in favor of the alternative 
885 
hypothesis that LUMINOPIA is non-inferior to PATCHING.  
886 
 
887 
H0: μPATCHING-μLUMINOPIA ≤ -0.0625 logMAR (LUMINOPIA inferior to PATCHING)  
888 
Ha: μPATCHING-μLUMINOPIA > -0.0625 logMAR (LUMINOPIA not inferior to PATCHING) 
889 
 
890 
To represent the difference between treatment groups (PATCHING minus LUMINOPIA), a two-
891 
sided 95% confidence interval (CI) will be constructed. Since the LOWER limit of a two-sided 
892 
95% CI is equivalent to the LOWER limit of a one-sided 97.5% CI, this will allocate a 
893 
significance level of 0.025 to be used in testing noninferiority. 
894 
 
895 
Non-inferiority of LUMINOPIA to PATCHING will be declared if the LOWER limit of the two-
896 
sided 95% CI for the difference between treatment groups is greater than the non-inferiority limit 
897 
of -0.0625 logMAR favoring PATCHING (Figure 1).   
898 
 
899 
If non-inferiority is declared, a test of no difference (superiority test) for LUMINOPIA compared 
900 
with PATCHING will be conducted. 
901 
 
902 

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Figure 1. Depiction of Null and Alternative Hypotheses for Treatment Group Difference 
903 
Mean difference (PATCHING – LUMINOPIA) and 95% CI of amblyopic eye distance VA 
904 
 
905 
 
906 
 
907 
8.3 Sample Size 
908 
8.3.1 Effect of PATCHING 
909 
To estimate the treatment effect for those randomized to PATCHING, visual acuity data from 
910 
participants prescribed 2 hours daily patching in a previous PEDIG study, ATS18,31 were used. 
911 
The data were limited to participants who met the eligibility criteria for the current study. In 
912 
ATS18, 75 participants between the ages of 5 to 7 years experienced 0.17 logMAR (95% CI: 
913 
0.14 to 0.20) mean improvement in visual acuity after 16 weeks with a standard deviation of 0.13 
914 
logMAR (95% CI: 0.12 to 0.16).  
915 
8.3.2 Effect of LUMINOPIA 
916 
To estimate the treatment effect for those randomized to LUMINOPIA, visual acuity data from 
917 
participants randomized to LUMINOPIA therapy were reviewed. Xiao et al36 conducted a 
918 
randomized trial comparing dichoptic movies using the Luminopia device versus continued 
919 
glasses alone. Of 103 enrolled children (aged 4 to 7 years) 52 were randomly assigned to 
920 
continued glasses and 51 to dichoptic movies using Luminopia 1 hour/day, 6 days a week. At the 
921 
12-week outcome, mean amblyopic eye VA had improved 0.18 logMAR (95% CI: 0.14 to 0.23; 
922 
n=45) in the Luminopia group and 0.08 logMAR (95% CI: 0.04 to 0.13; n=45) in the continued 
923 
glasses group. The study was stopped early for success having a difference between groups of 
924 
1.0 lines; P = 0.0011; 96.14% CI, 0.33-1.63 lines). 
925 
 
926 
In a preceding non-randomized study,38 Xiao et al prescribed Luminopia 1 hour/day for 12 
927 
weeks to 90 children 4- to 12-years of age (mean 6.7 ± 2.0 years) with amblyopia. Overall 
928 
(n=74) the mean amblyopic-eye VA improved 0.15 logMAR (95% CI: 0.12 to 0.18) after 12 
929 
weeks.38  
930 
 
931 

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8.3.3 Selection of Noninferiority Margin  
932 
The non-inferiority (NI) margin for the primary outcome was determined by the Planning 
933 
Committee using clinical judgment; based on simulated distributions of VA improvement 
934 
corresponding to a mean difference between 2 populations of 0.025, 0.050, 0.0625, 0.075 and 
935 
0.10 logMAR. Side-by-side histograms illustrating the shift in the distribution for each mean 
936 
were reviewed along with corresponding differences in proportions for clinically meaningful cut 
937 
points, e.g., difference in percent improving by 0.2 logMAR or more (2 or more logMAR lines), 
938 
or percent with final VA of 20/32 (0.2 logMAR) or better.  
939 
 
940 
The consensus of the Planning Committee was that if LUMINOPIA was no worse than 
941 
PATCHING by 0.0625 logMAR then LUMINOPIA would be considered non-inferior to 
942 
PATCHING.  This mean difference corresponded to a difference of 16% improving 2 or more 
943 
logMAR lines (59% in the PATCHING group and 43% in the LUMINOPIA group).  
944 
 
945 
As an alternative approach, the NI margin was calculated using statistical criteria, using half the 
946 
lower limit of the 95% CI for change in VA after patching treatment in ATS18 as a guideline. In 
947 
ATS18, half the lower limit of the 95% CI for change after 16 weeks was 0.07 logMAR; 
948 
therefore, 0.0625 logMAR is a conservative choice as a noninferiority (NI) margin.  
949 
 
950 
8.3.4 Sample Size Calculations and Assumptions 
951 
A common standard deviation (SD) of 0.14 logMAR and a true mean difference of 0.00 logMAR 
952 
between LUMINOPIA and PATCHING groups were selected to calculate the required sample 
953 
size for the current study. With the between-group difference of the change in logMAR VA 
954 
calculated as PATCHING minus LUMINOPIA, the noninferiority margin would be -0.0625 
955 
logMAR to show directionality of the primary outcome hypotheses (Figure 1, section 8.2.1). 
956 
 
957 
Using a noninferiority margin of -0.0625 logMAR and a one-sided Type 1 error rate of 0.025, 
958 
the study would require 214 participants total (107 participants in each treatment arm) to 
959 
complete the primary outcome to achieve 90% power to reject the null hypothesis that 
960 
LUMINOPIA is not non-inferior to PATCHING (Table 1). With an anticipated 10% loss to 
961 
follow up, the adjusted sample size to enroll is 238 total (214 ÷ 0.90). 
962 
 
963 
Table 1. Total Sample Size Estimates* 
964 
SD of 
Change in 
VA 
(logMAR) 
True Treatment Group Difference in  
Mean logMAR VA Change at 26-weeks [PATCHING – LUMINOPIA] 
-0.025 
Favoring 
PATCHING 
-0.0125  
Favoring 
PATCHING 
0 
No 
Difference 
0.0125  
Favoring 
LUMINOPIA 
0.025 
Favoring 
LUMINOPIA 
0.13 
508 
288 
184 
130 
96 
0.14 
588 
332 
214 
150 
110 
0.15 
676 
382 
246 
172 
126 
*Cells reflect total sample size unadjusted for loss to follow up with NI -0.0625 logMAR, one-
965 
sided alpha of 0.025, and 90% power.  
966 
 
967 

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Positive values for the true difference indicate greater VA improvement with LUMINOPIA 
968 
treatment as compared to PATCHING treatment. Negative values for the true difference indicate 
969 
greater VA improvement with PATCHING than LUMINOPIA (Figure 1, Table 1). 
970 
 
971 
8.3.5 Power for Superiority  
972 
If non-inferiority is declared, a two-sided test of no difference (superiority test) for LUMINOPIA 
973 
compared with PATCHING will be conducted. Superiority of LUMINOPIA over PATCHING 
974 
will be declared if the LOWER limit of the 95% CI is greater than zero. Conversely, superiority 
975 
of PATCHING over LUMINOPIA will be declared if the UPPER limit of the 95% CI is less 
976 
than zero; in this scenario, LUMINOPIA would be both inferior to PATCHING and non-inferior 
977 
to PATCHING with a margin of -0.0625 logMAR distance VA (Figure 1). 
978 
 
979 
Table 2 below shows the projected statistical power to reject a null hypothesis of no difference in 
980 
favor of an alternative hypothesis that the treatment groups differ for various true differences and 
981 
standard deviations with a two-sided alpha of 0.05 and a sample size of 214 participants 
982 
completing the primary outcome.   
983 
 
984 
If 214 participants complete the primary outcome, the study has 90% power to reject a null 
985 
hypothesis of no difference in favor of an alternative hypothesis that the treatment groups differ 
986 
if the true difference is as small as 0.0625 logMAR, assuming SD = 0.14 with a two-sided alpha 
987 
of 0.05.    
988 
 
989 
Table 2. Power for Testing Superiority of Mean Change in VA (two-sided α=0.05, N=214) 
990 
 
991 
True Difference  
0.050 logMAR 
True Difference  
0.0625 logMAR 
True Difference  
0.075 logMAR 
SD 
Power 
Power 
Power 
0.12 
85% 
96% 
99% 
0.13 
80% 
93% 
98% 
0.14 
73% 
90% 
97% 
0.15 
68% 
85% 
95% 
0.16 
62% 
81% 
92% 
 
992 
8.4 Outcome Measures 
993 
Primary Efficacy Endpoint: 
994 
• Change in amblyopic eye distance VA from baseline at 26 weeks. 
995 
 
996 
Secondary Efficacy Endpoints: 
997 
• Change in child and proxy PedEyeQ Functional Vision domain scores from baseline at 
998 
26 weeks. 
999 
• Change in child and proxy PedEyeQ Social domain scores from baseline at 13 weeks. 
1000 
• Change in child and proxy PedEyeQ Frustration/Worry domain scores from baseline at 
1001 
13 weeks.  
1002 
 
1003 

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Exploratory Efficacy Endpoints: 
1004 
• Change in amblyopic eye distance VA from baseline at 13 weeks. 
1005 
• Change in amblyopic eye distance VA over 26 weeks (area under the curve). 
1006 
• Improvement of amblyopic eye distance VA by 2 or more lines (0.2 logMAR) at 13 and 
1007 
26 weeks, respectively. 
1008 
• Resolution of amblyopia at 13 and 26 weeks, respectively as defined in section 3.3.1 and 
1009 
3.4.1. 
1010 
• Change in binocular function score from baseline at 13 and 26 weeks. 
1011 
• Child, proxy, and parent Treatment Impact Questionnaire scores at 13 weeks and 26 
1012 
weeks. 
1013 
 
1014 
8.5 Analysis Datasets and Sensitivity Analyses 
1015 
Analyses will follow the intent-to-treat principle (ITT); all participants will be analyzed 
1016 
according to their randomized treatment group, irrespective of adherence or compliance. 
1017 
However, a per protocol analysis will be performed for the primary outcome to check sensitivity 
1018 
of the results (details to be outlined in the statistical analysis plan [SAP]). The intent-to-treat 
1019 
analysis is considered primary and if the results of the per-protocol analysis and intent-to-treat 
1020 
give inconsistent results, exploratory analyses will be performed to evaluate possible factors 
1021 
contributing to the differences. 
1022 
 
1023 
8.6 Analysis of the Primary Efficacy Outcome 
1024 
The primary outcome, change in amblyopic eye logMAR distance VA from baseline at 26 
1025 
weeks, is a continuous outcome that will be analyzed using an analysis of covariance 
1026 
(ANCOVA) model to estimate the adjusted mean difference between PATCHING and 
1027 
LUMINOPIA. The model will adjust for baseline amblyopic-eye distance VA and prior 
1028 
treatment for amblyopia (glasses only vs other treatment in addition to glasses). The adjusted 
1029 
between-group mean difference and two-sided 95% confidence interval will be reported. If an 
1030 
imbalance of factors between treatment groups is observed, a sensitivity analysis may be 
1031 
performed, controlling for these potential confounders. 
1032 
 
1033 
Non-inferiority of LUMINOPIA compared to PATCHING will be declared if the LOWER limit 
1034 
of the two-sided 95% CI for the difference between treatment groups in mean change in logMAR 
1035 
distance VA from baseline to 26 weeks (PATCHING minus LUMINOPIA) is greater than the 
1036 
non-inferiority limit of -0.0625 logMAR favoring PATCHING. Note that the LOWER limit of a 
1037 
two-sided 95% confidence interval is equivalent to the lower limit of a one-sided 97.5% 
1038 
confidence interval. 
1039 
 
1040 
If non-inferiority is declared, superiority of LUMINOPIA over PATCHING will be declared if 
1041 
the LOWER limit of the 95% CI is greater than zero. Conversely, superiority of PATCHING 
1042 
over LUMINOPIA will be declared if the UPPER limit of the 95% CI is less than zero; in this 
1043 
scenario, LUMINOPIA would be both inferior to PATCHING and non-inferior to PATCHING 
1044 
with a margin of 0.0625 logMAR distance VA (Figure 1). 
1045 
 
1046 
Participants who do not complete the 26-week visit will have their 26-week amblyopic eye 
1047 
distance VA imputed. Markov chain Monte Carlo multiple imputation with 100 imputations will 
1048 
be used to impute missing data; variables in the imputation model will include prior treatment for 
1049 

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amblyopia and amblyopic-eye VA at baseline, 13, and 26 weeks. Imputation will be carried out 
1050 
separately for PATCHING and LUMINOPIA.47  Reasons for which a participant may not 
1051 
complete the 26-week visit are outlined in section 7.13, “Intercurrent Events.” 
1052 
 
1053 
The ANCOVA model assumptions of linearity, normality, and homoscedasticity (equal variance) 
1054 
will be verified with graphical methods. If assumptions are seriously violated, then 
1055 
transformation of dependent or independent variables, elimination or categorization of 
1056 
continuous covariates, a robust method, or a nonparametric method may be considered.  
1057 
 
1058 
As a sensitivity analysis, the primary outcome will be analyzed using complete cases rather than 
1059 
the imputed data. If the results from these analyses are discordant, then differences between 
1060 
participants with and without complete visit data will be evaluated. Additional sensitivity 
1061 
analyses will be detailed in the SAP. 
1062 
 
1063 
8.7 Analysis of the Secondary Efficacy Outcomes 
1064 
Secondary analyses will test the null hypothesis of no difference between treatment groups. Both 
1065 
p-values and confidence intervals will be reported with adjustments for multiplicity (described in 
1066 
section 8.15).  
1067 
 
1068 
8.7.1 Pediatric Eye Disease Questionnaire (PedEyeQ) 
1069 
Quality of life will be evaluated for children respondents aged 5 to 7 years in each treatment 
1070 
group using the PedEyeQ questionnaire. Additionally, the parent will answer on behalf of his/her 
1071 
child as a proxy for children 4 to 7 years of age. Scores on Functional Vision, Frustration/Worry, 
1072 
and Social domains will be assessed for both child and proxy at baseline as well as at the visit 
1073 
week indicated below (Table 3). Responses will be Rasch scored according to reference tables 
1074 
and standardized on a ratio scale ranging from 0 to 100.46  
1075 
 
1076 
Table 3. Structure of the PedEyeQ Analysis: Domains and Respondents 
1077 
  
  
Domain 
  
Participant  
Respondent 
Social 
Frustration/Worry 
Functional Vision 
Outcomes 
Age 
Level 
(13 weeks) 
(13 weeks) 
(26 weeks) 
4-7 years 
Proxy 
1 
1 
1 
3 
5-7 years 
Child 
1 
1 
1 
3 
Total = 6 
Univariate analysis of covariance (ANCOVA) will be used to assess the difference between 
1078 
treatment groups across all domains and respondents (3 domains × 2 respondents = 6 outcomes) 
1079 
as shown in Table 3. Models will be adjusted for prior treatment for amblyopia and enrollment 
1080 
scores. The treatment effect will be summarized as a mean difference and 95% confidence 
1081 
interval. Similar to the primary outcome, missing data will be imputed using multiple imputation 
1082 
with prior treatment for amblyopia and baseline and outcome scores included in the imputation 
1083 
model and stratified by treatment group. 
1084 
 
1085 
8.8 Intervention Adherence 
1086 
At 13, and 26-weeks, the investigator will assess participant adherence to the assigned treatment. 
1087 
For each participant randomized to LUMINOPIA, the number of dichoptic treatment hours will 
1088 
be categorized according to percentage of prescribed treatment time as 75-100%, 50-75%, or 
1089 

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<50%.  PATCHING calendar data will not be analyzed other than a subjective assessment by the 
1090 
investigator of adherence at 13, and 26-weeks as Excellent, Good, Fair, or Poor after review of 
1091 
calendar and interview with parent. The tabulation of data related to treatment adherence is 
1092 
intended for exploratory purposes only, and therefore formal comparisons between treatment 
1093 
groups will not be performed. 
1094 
8.9 Protocol Adherence and Retention 
1095 
Protocol deviations and visit completion rates (excluding participants who die before the end of 
1096 
the visit window) will be tabulated for each treatment group. 
1097 
 
1098 
8.10 Intercurrent Events 
1099 
If any of the following events take place before the 26-week outcome, missing follow-up data 
1100 
will be imputed for the participant experiencing the event in the primary ITT analysis. 
1101 
• Death 
1102 
• Lost to follow up 
1103 
• Withdrawal 
1104 
 
1105 
If any of the following events occur before the 26-week outcome, data will not be imputed for 
1106 
participants experiencing these events, since the event itself does not preclude completion of 
1107 
study visits. Thus, the observed data at the 26-week outcome visit will be utilized.   
1108 
• Treatment discontinuation 
1109 
• Treatment crossover 
1110 
• Receipt of non-protocol treatment 
1111 
 
1112 
8.11 Safety Analyses 
1113 
The cumulative proportions of each of the following adverse events by treatment group will be 
1114 
assessed at the initial study phase (enrollment to 26 weeks) and during the LUMINOPIA 
1115 
treatment phase for those originally randomized to PATCHING (26 weeks to 52 weeks). During 
1116 
the initial study phase, the proportions will be compared statistically with Barnard’s 
1117 
Unconditional Exact Test considering the number of participants per group as fixed. As type II 
1118 
error (false negative) is more of a concern than type I error (false positive) in safety analyses, we 
1119 
will use p ≤ 0.05, without adjustment for multiplicity, to define statistical significance in all 
1120 
safety analyses. It is noted that this study is not powered for safety analyses and that absence of a 
1121 
significant effect cannot be taken as evidence that a difference does not exist. The proportion of 
1122 
adverse events occurring during the LUMINOPIA treatment phase for original PATCHING 
1123 
participants will be tabulated.    
1124 
 
1125 
• Worsening of best-corrected fellow-eye distance VA of 0.2 logMAR or more 
1126 
• New onset strabismus >5 ∆ by SPCT in participants with no strabismus at baseline  
1127 
• Strabismus >10 ∆ by SPCT in participants with strabismus at baseline 
1128 
• Parental report of diplopia occurring more than once per week 
1129 
• Skin irritation  
1130 
• Headache 
1131 
• Seizures 
1132 
• Eyestrain 
1133 
• Dizziness 
1134 

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• Night terrors 
1135 
• Eye twitching 
1136 
• Facial redness 
1137 
 
1138 
The PEDIG DSMC will review safety data tabulated by treatment group at each of its semi-
1139 
annual meetings and can request formal statistical comparison of any safety outcome at any time 
1140 
if they have cause for concern.  
1141 
 
1142 
8.12 Baseline Descriptive Statistics 
1143 
Baseline demographic and clinical characteristics will be tabulated by randomized treatment 
1144 
group, and summary statistics appropriate to their distributions will be reported. 
1145 
 
1146 
8.13 Planned Interim Analyses 
1147 
There is no plan for formal interim analyses. The Data and Safety Monitoring Committee will 
1148 
review tabulated and graphical displays of interim safety data at approximately 6-month intervals 
1149 
and will have the option to recommend stopping the study. 
1150 
 
1151 
8.14 Subgroup Analyses 
1152 
Subgroup analyses, i.e., assessments of effect modification, will be conducted for the primary 
1153 
outcome. These analyses will be considered exploratory. Missing data will be imputed like the 
1154 
primary analyses except that the subgroup factors of interest, specified below, will be included in 
1155 
the imputation model, which will be stratified by treatment group. Within-subgroup mean 
1156 
differences for the treatment effects with 95% confidence intervals will be estimated for each 
1157 
subgroup by adding an interaction term to the primary analysis models. Results will be presented 
1158 
as forest plots; p-values will not be presented.  
1159 
 
1160 
The baseline factors to be evaluated in pre-planned exploratory subgroup analyses include 
1161 
amblyopic-eye distance VA (categorized), type of amblyopia, prior treatment for amblyopia, age 
1162 
4 to 5 or >5 to 7), and binocularity. The SAP will provide specific details on categorizations. The 
1163 
subgroup analysis by amblyopic-eye distance VA is considered of greatest interest. 
1164 
 
1165 
There are no data to suggest that the treatment effect will vary by sex, race, or ethnicity. 
1166 
However, each of these factors will be evaluated in exploratory subgroup analyses as mandated 
1167 
by National Institutes of Health (NIH) guidelines. 
1168 
 
1169 
8.15 Multiple Comparison/Multiplicity 
1170 
For the primary outcome, a 95% confidence interval for the treatment group difference will be 
1171 
constructed and used to evaluate the primary hypothesis of non-inferiority and also the 
1172 
possibility of superiority or inferiority (Figure 1).48 
1173 
 
1174 
For the PedEyeQ questionnaire secondary outcomes, the adaptive false discovery rate (FDR) 
1175 
method with two-stage testing will control the FDR at 5% to adjust p-values and CIs for 
1176 
multiplicity.49  
1177 
 
1178 

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8.16 Exploratory Analyses 
1179 
Exploratory analyses will test the null hypothesis of no difference between treatment groups. 
1180 
Both p-values and confidence intervals will be reported without adjustment for multiplicity. 
1181 
 
1182 
8.16.1 Mean Change in Distance VA at 13 Weeks 
1183 
Change in amblyopic eye VA from baseline to 13 weeks is a continuous outcome. Analyses, 
1184 
including imputation of missing data, will mirror the primary outcome.  
1185 
 
1186 
8.16.2 Mean Change in Distance VA over 26 weeks (area under the curve) 
1187 
The change in amblyopic eye distance VA from baseline over 26 weeks (area under the curve) 
1188 
will be calculated for each participant using the trapezoidal rule. The analysis, including 
1189 
imputation of missing data, will mirror the primary outcome.  
1190 
 
1191 
8.16.3 Improvement of Amblyopic-eye Distance VA by 2 or More Lines 
1192 
Improvement of amblyopic-eye distance VA of 2 or more lines (reduction of 0.2 logMAR) at 13 
1193 
and 26 weeks, respectively, will be analyzed as binary outcomes. For each time point, the 
1194 
proportions with improvement ≥ 2 lines and 95% confidence interval will be calculated. The risk 
1195 
difference will be calculated using logistic regression with conditional standardization and 
1196 
adjusted for amblyopic-eye VA at baseline and prior treatment of amblyopia. The delta method 
1197 
will be implemented to construct a 95% CI on the risk difference and the model-based two-sided 
1198 
p-value will be reported. Missing data will be imputed as described for the primary outcome.  
1199 
 
1200 
8.16.4 Binocular Function 
1201 
The change in binocular function score from enrollment to the 13- and 26-week visit is an 
1202 
ordinal outcome. Components of binocularity include results from the following 3 tests: Randot 
1203 
Preschool Stereoacuity (RPS), Random Dot Butterfly, and Preschool Worth 4-shape (W4S) at 
1204 
near. These tests will create a composite ordinal score of binocularity with 9 levels.51  
1205 
 
1206 
The difference between LUMINOPIA and PATCHING for the change in binocularity from 
1207 
baseline to 13 and 26 weeks will be evaluated with the nonparametric Wilcoxon Rank-Sum test. 
1208 
The difference between groups will be estimated using the Hodges-Lehmann estimator with 95% 
1209 
CI. Analyses for binocular function score will be limited to complete case data at each respective 
1210 
outcome visit (13 weeks or 26 weeks). 
1211 
 
1212 
In a sensitivity analysis, binocular function scores will be analyzed using ANCOVA with 
1213 
adjustment for prior treatment for amblyopia and baseline binocular function score and 
1214 
imputation of missing data. The baseline-adjusted mean difference and 95% CI in binocularity 
1215 
between the treatment groups will be presented. 
1216 
 
1217 
8.16.5 Resolution of Amblyopia at 13 weeks and 26 weeks 
1218 
The cumulative probability of amblyopia resolution at 13 and 26 weeks will be calculated using 
1219 
Cox proportional hazards regression with adjustment for baseline IOD and prior treatment for 
1220 
amblyopia. For each visit, the rate of resolution (estimated using the survivor function) and 95% 
1221 
CI will be presented for each group using direct adjustment along with the difference in rates, 
1222 
95% CI, and p-value (based on a Z test). Participants who are lost to follow up will be censored 
1223 
on the day of the last completed visit.  
1224 

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8.16.6 Treatment Impact Questionnaire 
1225 
The Treatment Impact Questionnaire (TIQ) will be used as a quantitative measure to evaluate 
1226 
opinions regarding the burdens and impact of the randomized treatment at 13 weeks and 26 
1227 
weeks (as questions for the child – the Child TIQ, for the parent about the child – the Proxy TIQ, 
1228 
and the parent themselves – the Parent TIQ.   
1229 
 
1230 
The Child-TIQ, Proxy-TIQ, and Parent-TIQ will undergo separate factor analysis to determine 
1231 
the number of domains for each TIQ. Each domain will be refined through the evaluation of 
1232 
misfitting items and will then be Rasch scored.  
1233 
 
1234 
Note that because the TIQ is not administered at baseline (because treatment has not been 
1235 
started), there will be no adjustment for baseline score in any analysis.  
1236 
 
1237 
Additional methods to score and analyze the Treatment Impact Questionnaire will be detailed in 
1238 
a separate SAP. 
1239 
 
1240 
8.16.7 Improvement with Dichoptic Therapy after PATCHING 
1241 
Participants who were randomized to PATCHING who have 1 line or more IOD residual 
1242 
amblyopia will be offered dichoptic treatment with LUMINOPIA after 26 weeks. These 
1243 
participants will have visits at 39 weeks and 52 weeks to evaluate safety and efficacy. The same 
1244 
safety, binocular function, and VA outcomes evaluated at 13 and 26 weeks will be evaluated at 
1245 
39 and 52 weeks with 26 weeks considered the baseline visit for the extended follow-up.  
1246 

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Chapter 9: Data Collection and Monitoring 
1247 
 
1248 
9.1 Case Report Forms and Other Data Collection 
1249 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1250 
collected in real-time in electronic case report forms, this will be considered the source data. For 
1251 
any data points for which the eCRF is not considered source (e.g., lab results that are transcribed 
1252 
from a printed report into the eCRF; data not entered in real-time; etc.), the original source 
1253 
documentation must be maintained in the participant’s study chart or medical record. This source 
1254 
must be readily verifiable against the values entered into eCRF. Even where all study data are 
1255 
directly entered into the eCRFs at office visits, evidence of interaction with a live participant 
1256 
must be recorded (e.g., office note, visit record, etc.)  
1257 
 
1258 
Electronic device data files are obtained from the study software and individual hardware 
1259 
components. These electronic device files are considered the primary source documentation. 
1260 
Each participating site will maintain appropriate medical and research records for this trial, in 
1261 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1262 
confidentiality of participants. 
1263 
 
1264 
9.2 Study Records Retention 
1265 
Study documents should be retained for a minimum of 3 years after completion of the final grant 
1266 
reporting. These documents should be retained for a longer period, however, if required by local 
1267 
regulations. No records will be destroyed without the written consent of the sponsor, if 
1268 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
1269 
no longer need to be retained. 
1270 
 
1271 
9.3 Quality Assurance and Monitoring 
1272 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1273 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1274 
conducted appropriately, and the data are generated, documented, and reported in compliance 
1275 
with the protocol that adheres to Good Clinical Practice (GCP) and the applicable regulatory 
1276 
requirements. In addition, QC systems will be in place to ensure that the rights and well-being of 
1277 
trial participants are protected, and that the reported trial data are accurate, complete, and 
1278 
verifiable. Adverse events will be prioritized for monitoring. 
1279 
 
1280 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1281 
consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1282 
Based Approach to Monitoring” (August 2013). This plan describes in detail who will conduct 
1283 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
1284 
will be performed, and the distribution of monitoring reports. 
1285 
 
1286 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1287 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1288 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1289 
veracity and completeness of the key site data.  
1290 
 
 
1291 

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Elements of the RBM may include: 
1292 
 
1293 
• Qualification assessment, training, and certification for sites and site personnel 
1294 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1295 
procedures 
1296 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1297 
review of entered data and edits, statistical monitoring, study closeout 
1298 
• On-site monitoring (site visits): source data verification, site visit report 
1299 
• Agent/Device accountability 
1300 
• Communications with site staff 
1301 
• Participant retention and visit completion 
1302 
• Quality control reports 
1303 
• Management of noncompliance 
1304 
• Documenting monitoring activities 
1305 
• Adverse event reporting and monitoring 
1306 
 
1307 
Coordinating Center representatives or their designees may visit the study site facilities at any 
1308 
time to maintain current and personal knowledge of the study through medical record review, 
1309 
comparison with source documents, observation and discussion of the conduct and progress of 
1310 
the study. The investigational site will provide direct access to all trial related sites, source 
1311 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1312 
inspection by local and regulatory authorities. 
1313 
 
1314 
9.4 Protocol Deviations 
1315 
A protocol deviation is any instance of noncompliance with the clinical trial protocol, GCP, or 
1316 
clinical procedure requirements. The noncompliance may be either on the part of the participant, 
1317 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
1318 
developed by the site and implemented promptly. 
1319 
 
1320 
The site PI, protocol PI (if different) and all study staff are responsible for knowing and adhering 
1321 
to their IRB requirements. Further details about the handling of protocol deviations will be 
1322 
included in the monitoring plan. 
1323 

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Chapter 10: Ethics/Protection of Human Participants 
1324 
 
1325 
10.1 Ethical Standard 
1326 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1327 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1328 
21 CFR Part 56, and/or the ICH E6. 
1329 
 
1330 
10.2 Institutional Review Boards 
1331 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1332 
be submitted to the JCHR IRB for review and approval as the IRB of Record. Approval of both 
1333 
the protocol and the consent form must be obtained from the IRB before any participant is 
1334 
enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
1335 
changes are implemented to the study. All changes to the consent form will be IRB approved; the 
1336 
IRB will determine whether previously consented participants need to be re-consented. 
1337 
 
1338 
10.3 Informed Consent Process 
1339 
 
1340 
10.3.1 Consent Procedures and Documentation 
1341 
Informed consent is a process that is initiated prior to an individual agreeing to participate in the 
1342 
study and continues throughout that individual’s study participation. Written IRB-approved 
1343 
consent materials and consent discussions must be in a language understandable to the 
1344 
participants and their parent(s). For example, if the parent(s) primary language is Spanish, then 
1345 
the Spanish consent form, as well as other participant/parent facing materials (e.g., 
1346 
questionnaires) must be in Spanish. Also, the use of a translator approved by the Coordinating 
1347 
Center is required to support not only the consent process, but also the participants and their 
1348 
parent(s) understanding and communication for the duration of the study.  
1349 
 
1350 
Extensive discussion of risks and possible benefits of participation will be provided to 
1351 
participants and their families. Consent forms will be approved by the IRB and the parent/legal 
1352 
guardian will be asked to read and review the document. The investigator will explain the 
1353 
research study to the parent and participant and answer any questions that may arise. All parents 
1354 
and participants will receive a verbal explanation in terms suited to their comprehension of the 
1355 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
1356 
Parents and participants (old enough to sign per IRB) will have the opportunity to carefully 
1357 
review the written consent form and ask questions prior to signing. 
1358 
 
1359 
Parents should have the opportunity to discuss the study with their partner or family physician or 
1360 
think about it prior to agreeing to participate. Written informed consent will be obtained from a 
1361 
parent and written or verbal assent from the child (depending on age and IRB requirements) prior 
1362 
to performing any study-specific procedures that are not part of the child’s routine care. 
1363 
Participants may withdraw consent at any time throughout the course of the trial. A copy of the 
1364 
informed consent document will be given to the family for their records. The rights and welfare 
1365 
of the participants will be protected by emphasizing to them and their parent(s) that the quality of 
1366 
their medical care will not be adversely affected if they decline to participate in this study. 
1367 

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10.4 Participant and Data Confidentiality 
1368 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1369 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1370 
samples and genetic tests in addition to the clinical information relating to participants. 
1371 
Therefore, the study protocol, documentation, data, and all other information generated will be 
1372 
held in strict confidence. No information concerning the study or study data will be released to 
1373 
any unauthorized third party without prior written approval of the sponsor. 
1374 
 
1375 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1376 
regulatory agencies or company supplying study product may inspect all documents and records 
1377 
required to be maintained by the investigator, including but not limited to, medical records 
1378 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
1379 
study site will permit access to such records. 
1380 
 
1381 
The study participant’s contact information will be securely stored at each clinical site for 
1382 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1383 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1384 
sponsor requirements. 
1385 
 
1386 
Study participant research data, which is for purposes of statistical analysis and scientific 
1387 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research. This will not 
1388 
include the participant’s contact or identifying information. Rather, individual participants and 
1389 
their research data will be identified by a unique study identification number. The study data 
1390 
entry and study management systems used by clinical sites and by Jaeb Center for Health 
1391 
Research staff will be secured and password protected.  
1392 
 
1393 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1394 
for Health Research. 
1395 
 
1396 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1397 
obtained from the NIH. This certificate protects identifiable research information from forced 
1398 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1399 
disclose identifying information on research participation in any civil, criminal, administrative, 
1400 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1401 
researchers and institutions from being compelled to disclose information that would identify 
1402 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1403 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1404 
 
1405 
10.5 Future Use of Data 
1406 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research. 
1407 
After the study is completed, the de-identified, archived data will be made available to the 
1408 
public. 
1409 

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Chapter 11: References 
1410 
1. 
Holmes JM, Clarke MP. Amblyopia. Lancet. 2006;367:1343-51. 
1411 
2. 
Webber AL, Wood J. Amblyopia: prevalence, natural history, functional effects and 
1412 
treatment. Clin Exp Optom. 2005;88(6):365-75. 
1413 
3. 
Abraham SV. Accommodation in the amblyopic eye. Am J Ophthalmol. 1961;52:197-
1414 
200. 
1415 
4. 
Agrawal R, Conner IP, Odom JV, Schwartz TL, Mendola JD. Relating binocular and 
1416 
monocular vision in strabismic and anisometropic amblyopia. Arch Ophthalmol. 2006;(124):844-
1417 
50. 
1418 
5. 
Ciuffreda KJ, Hokoda SC, Hung GK, Semmlow JL, Selenow A. Static aspects of 
1419 
accommodation in human amblyopia. Am J Optom Physiol Opt. 1983;60(6):436-49. 
1420 
6. 
Kelly KR, Jost RM, De La Cruz A, Birch EE. Amblyopic children read more slowly than 
1421 
controls under natural, binocular reading conditions. J AAPOS. 2015;19(6):515-20. 
1422 
7. 
McKee SP, Levi DM, Movshon JA. The pattern of visual deficits in amblyopia. J Vis. 
1423 
2003;3(5):380-405. 
1424 
8. 
Repka MX, Kraker RT, Beck RW, et al. Monocular oral reading performance after 
1425 
amblyopia treatment in children. Am J Ophthalmol. 2008;146(6):942-7. 
1426 
9. 
Rutstein RP, Corliss D. Relationship between anisometropia, amblyopia, and 
1427 
binocularity. Optom Vis Sci. 1999;76(4):229-33. 
1428 
10. 
Weakley DR, Jr. The association between nonstrabismic anisometropia, amblyopia, and 
1429 
subnormal binocularity. Ophthalmology. 2001;108(1):163-71. 
1430 
11. 
Birch EE, Kelly KR. Pediatric ophthalmology and childhood reading difficulties: 
1431 
Amblyopia and slow reading. J AAPOS. 2017;21(6):442-444. doi: 10.1016/j.jaapos.2017.06.013. 
1432 
Epub 2017 Sep 1. 
1433 
12. 
Kelly KR, Jost RM, De La Cruz A, et al. Slow reading in children with anisometropic 
1434 
amblyopia is associated with fixation instability and increased saccades. J AAPOS. 
1435 
2017;21(6):447-451. 
1436 
13. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 
1437 
treatment of moderate amblyopia in children. Arch Ophthalmol. 2002;120(3):268-78. 
1438 
14. 
Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized 
1439 
trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 
1440 
2005;123(2):149-157. 
1441 
15. 
Pediatric Eye Disease Investigator Group. A comparison of atropine and patching 
1442 
treatments for moderate amblyopia by patient age, cause of amblyopia, depth of amblyopia, and 
1443 
other factors. Ophthalmology. 2003;110(8):1632-8. 
1444 
16. 
Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for 
1445 
treatment of moderate amblyopia in children. Arch Ophthalmol. 2003;121(5):603-611. 
1446 
17. 
Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching 
1447 
regimens for treatment of severe amblyopia in children. Ophthalmology. 2003;110(11):2075-87. 
1448 
18. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine regimens for 
1449 
treatment of moderate amblyopia in children. Ophthalmology. 2004;111(11):2076-2085. 
1450 
19. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 
1451 
treatment of moderate amblyopia: follow-up at age 10 years. Arch Ophthalmol. 
1452 
2008;126(8):1039-44. 
1453 

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20. 
Repka MX, Kraker RT, Holmes JM, et al. Atropine vs patching for treatment of moderate 
1454 
amblyopia: follow-up at 15 years of age of a randomized clinical trial. JAMA Ophthalmology. 
1455 
2014;132(7):799-805. 
1456 
21. 
Oliver M, Neumann E, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and 
1457 
results of treatment for amblyopia in children more than 8 years old. Am J Ophthalmol. 
1458 
1986;102(3):340-5. 
1459 
22. 
Pritchard C. Why won't you treat my 10 year old's lazy eye? Am Orthopt J. 1990;40:15-
1460 
18. 
1461 
23. 
Loudon SE, Polling JR, Simonsz HJ. Electronically measured compliance with occlusion 
1462 
therapy for amblyopia is related to visual acuity increase. Graefes Arch Clin Exp Ophthalmol. 
1463 
2003;241(3):176-180. 
1464 
24. 
Stewart CE, Moseley MJ, Stephens DA, Fielder AR, MOTAS Cooperative. Treatment 
1465 
dose-response in amblyopia therapy: The Monitored Occlusion Treatment of Amblyopia Study 
1466 
(MOTAS). Invest Ophthalmol Vis Sci. 2004;45(9):3048-3054. 
1467 
25. 
Tailor V, Bossi M, Bunce C, Greenwood JA, Dahlmann-Noor A. Binocular versus 
1468 
standard occlusion or blurring treatment for unilateral amblyopia in children aged three to eight 
1469 
years. Cochrane Database Syst Rev. 2015;2015(8)(CD011347 ) 
1470 
26. 
Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of 
1471 
amblyopia in adults well beyond the critical period of visual development. Restor Neurol 
1472 
Neurosci. 2010;28(6):793-802. 
1473 
27. 
Baker DH, Meese TS, Mansouri B, Hess RF. Binocular summation of contrast remains 
1474 
intact in strabismic amblyopia. Invest Ophthalmol Vis Sci. 2007;48(11):5332-8. 
1475 
28. 
Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of 
1476 
amblyopia in adults well beyond the critical period of visual development. Restor Neurol 
1477 
Neurosci. 2010;28(6):793-802. 
1478 
29. 
Knox PJ, Simmers AJ, Gray LS, Cleary M. An Exploratory Study: Prolonged Periods of 
1479 
Binocular Stimulation Can Provide an Effective Treatment for Childhood Amblyopia. 
1480 
Investigative Ophthalmology & Visual Science. 2012;53(2):817-824. 
1481 
30. 
Li J, Thompson B, Deng D, Chan LY, Yu M, Hess RF. Dichoptic training enables the 
1482 
adult amblyopic brain to learn. Current Biology. 2013;23(8):R308-R309. 
1483 
31. 
Holmes JM, Manh VM, Lazar EL, et al. Effect of a binocular iPad game vs part-time 
1484 
patching in children aged 5 to 12 years with amblyopia: a randomized clinical trial. JAMA 
1485 
Ophthalmol. 2016;134(12):1391-1400. 
1486 
32. 
Manny RE, Holmes JM, Kraker RT, et al. A Randomized Trial of Binocular Dig Rush 
1487 
Game Treatment for Amblyopia in Children Aged 4 to 6 Years. Optom Vis Sci. 2022;99(3):213-
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227  
1489 
33. 
Roy S, Saxena R, Dhiman R, Phuljhele S, Sharma P. Comparison of Dichoptic Therapy 
1490 
Versus Occlusion Therapy in Children With Anisometropic Amblyopia: A Prospective 
1491 
Randomized Study. J Pediatr Ophthalmol Strabismus. 2022;8:1-8. 
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34. 
Jin L, Fang Y, Jin C. Binocular treatment for individual with amblyopia: A systematic 
1493 
review and meta-analysis. Medicine (Baltimore). 2022;101(27)(e28975) 
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35. 
Kadhum A, Tan ETC, Levi DM, et al. Barriers to successful dichoptic treatment for 
1495 
amblyopia in young children. Graefes Arch Clin Exp Ophthalmol. 2021;259(10):3149-3157. 
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36. 
Xiao S, Angjeli E, Wu HC, et al. Randomized Controlled Trial of a Dichoptic Digital 
1497 
Therapeutic for Amblyopia. Ophthalmology. 2022;129(1):77-85  
1498 

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37. 
Jost RM, Hudgins LA, Dao LM, et al. Randomized clinical trial of streaming dichoptic 
1499 
movies versus patching for treatment of amblyopia in children aged 3 to 7 years. Sci Rep. 
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2022;12(1):4157  
1501 
38. 
Xiao S, Gaier ED, Wu HC, et al. Digital therapeutic improves visual acuity and 
1502 
encourages high adherence in amblyopic children in open-label pilot study. J AAPOS. 
1503 
2021;25(2):e1-6. . 
1504 
39. 
Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on 
1505 
the child and family in the amblyopia treatment study. Arch Ophthalmol. 2003;121(11):1625-32. 
1506 
40. 
Felius J, Chandler DL, Holmes JM, et al. Evaluating the burden of amblyopia treatment 
1507 
from the parent and child's perspective. J AAPOS. 2010;14(5):389-95. 
1508 
41. 
Koklanis K, Abel LA, Aroni R. Psychosocial impact of amblyopia and its treatment: a 
1509 
multidisciplinary study. Clin Exp Ophthalmol. 2006;34(8):743-750. 
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42. 
Dixon-Woods M, Awan M, Gottlob I. Why is compliance with occlusion therapy for 
1511 
amblyopia so hard? A qualitative study. Arch Dis Child. 2006;91(6):491-494. 
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43. 
Horwood J, Waylen A, Herrick D, Williams C, Wolke D. Common visual defects and 
1513 
peer victimization in children. Invest Ophthalmol Vis Sci. 2005;46(4):1177-1181. 
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44. 
Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric 
1515 
visual acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester 
1516 
following the Amblyopia Treatment Study protocol. J AAPOS. 2008;12(2):145-9. 
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45. 
Pan Y, Tarczy-Hornoch K, Cotter SA, et al. Visual acuity norms in pre-school children: 
1518 
the Multi-Ethnic Pediatric Eye Disease Study. Optom Vis Sci. 2009;86(6):607-12. 
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46. 
Hatt SR, Leske DA, Castañeda YS, et al. Development of pediatric eye questionnaires for 
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children with eye disease. Am J Ophthalmol. 2019;200:201-217. 
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47. 
Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the 
1522 
method of choice for handling missing data in randomized trials? Stat Methods Med Res. 
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2018;27(9):2610-2626. 
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US Food and Drug Administration. Non-inferiority clinical trials to establish 
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effectiveness: Guidance for industry 2016. FDA-2010-D-0075. Accessed June 28, 2023. 
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Benjamini Y, Krieger AM, Yekutieli D. Adaptive linear step-up procedures that control 
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the false discovery rate. Biometrika. 2006;93(3):491-507. 
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Kleinman LC, Norton EC. What's the Risk? A simple approach for estimating adjusted 
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risk measures from nonlinear models including logistic regression. Health Serv Res. 
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2009;44(1):288-302. 
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Webber AL, Wood JM, Thompson B, E. BE. From suppression to stereoacuity: a 
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composite binocular function score for clinical research. Ophthalmic Physiol Opt. 2019;39:53-
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1537