Luminopia One Amblyopia Vision Improvement Study
Phase: NA
Conditions: Amblyopia
Sponsor: Luminopia

 
Luminopia, Inc. 
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C-AM-2 Protocol 
Confidential 
 
 
 
Luminopia One Amblyopia Vision 
Improvement Study 
 (C-AM-2) 
 
 
 
 
 
 
 
Protocol Identifying Number: C-AM-2 
Version Number: v2.0 Amendment 1 
NCT03608150 
 
Oct 8, 2018 
 
 
 
 
 
 

 
Luminopia, Inc. 
C-AM-2 Amendment 1 
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C-AM-2 Protocol 
Confidential 
 
Table of Contents 
LIST OF ABBREVIATIONS ........................................................................................................................... 4 
KEY ROLES ................................................................................................................................................. 5 
1 BACKGROUND AND SUMMARY ........................................................................................................... 6 
1.1 BACKGROUND ...................................................................................................................................... 6 
1.2 RESULTS OF LUMINOPIA PILOT TRIALS ....................................................................................................... 7 
1.3 PROPOSED STUDY DESIGN ...................................................................................................................... 8 
1.4 STUDY ENDPOINTS ................................................................................................................................ 9 
1.5 SYNOPSIS OF STUDY DESIGN ................................................................................................................... 9 
1.6 STUDY ADMINISTRATION AND OVERSIGHT ............................................................................................... 10 
2 PARTICIPANT ENROLLMENT .............................................................................................................. 12 
2.1 INFORMED CONSENT ........................................................................................................................... 12 
2.2 INCLUSION AND EXCLUSION CRITERIA ...................................................................................................... 12 
2.2.1 INCLUSION CRITERIA ................................................................................................................................ 12 
2.2.2 EXCLUSION CRITERIA ................................................................................................................................ 13 
2.3 TESTING PROCEDURES AT THE ENROLLMENT VISIT ..................................................................................... 13 
2.4 RANDOMIZATION OF ENROLLED PARTICIPANTS ......................................................................................... 14 
2.5 TRAINING WITH STUDY INTERVENTIONS ................................................................................................... 14 
2.6 CONTROL PARTICIPANTS OPTIONAL STUDY EXTENSION ............................................................................... 15 
3 TREATMENT GROUPS AND FOLLOW-UP ............................................................................................ 16 
3.1 THERAPEUTIC GROUP .......................................................................................................................... 16 
3.2 CONTROL GROUP ............................................................................................................................... 16 
3.3 PHONE CALLS .................................................................................................................................... 16 
3.4 FOLLOW-UP VISIT SCHEDULE ................................................................................................................. 16 
3.5 FOLLOW-UP VISIT TESTING PROCEDURES ................................................................................................. 16 
3.5.1 MASKED EXAMINER ................................................................................................................................. 17 
3.6 ADVERSE EVENT MONITORING .............................................................................................................. 17 
3.7 NON-STUDY VISITS AND TREATMENTS .................................................................................................... 18 
4 MISCELLANEOUS CONSIDERATIONS .................................................................................................. 19 
4.1 STUDY SITES ...................................................................................................................................... 19 
4.2 PARTICIPANT WITHDRAWALS ................................................................................................................ 19 
4.3 PARTICIPANT COMPENSATION ............................................................................................................... 19 
4.4 STUDY COSTS ..................................................................................................................................... 19 
4.5 GENERAL CONSIDERATIONS .................................................................................................................. 19 

 
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5 ADVERSE EVENTS AND RISKS ............................................................................................................. 20 
5.1 DEFINITION ....................................................................................................................................... 20 
5.2 RECORDING OF ADVERSE EVENTS ........................................................................................................... 20 
5.3 SAE AND UADE REPORTING REQUIREMENTS ........................................................................................... 22 
5.4 RISKS ............................................................................................................................................... 22 
5.5 RISK ASSESSMENT ............................................................................................................................... 22 
5.6 CLINICAL MONITORING ........................................................................................................................ 23 
6 STATISTICAL CONSIDERATIONS ......................................................................................................... 24 
6.1 SAMPLE SIZE ESTIMATION .................................................................................................................... 24 
6.2 MASKED SAMPLE SIZE RE-ESTIMATION .................................................................................................... 27 
6.3 BIAS AND ERROR RATES ....................................................................................................................... 28 
6.4 ANALYSES ......................................................................................................................................... 28 
6.4.1 PRIMARY EFFICACY ANALYSIS .................................................................................................................... 28 
6.4.2 PRIMARY SAFETY ANALYSIS ....................................................................................................................... 29 
6.4.3 SUBPOPULATION ANALYSIS ....................................................................................................................... 29 
6.4.4 STUDY SUCCESS DEFINITION ...................................................................................................................... 29 
6.4.5 SECONDARY ANALYSES ............................................................................................................................. 29 
6.4.6 SAFETY REPORTING .................................................................................................................................. 30 
6.5 ANALYSIS POPULATIONS ...................................................................................................................... 30 
6.6 MISSING DATA ................................................................................................................................... 31 
6.7 SITE POOLABILITY ............................................................................................................................... 31 
6.8 DATA HANDLING AND RECORD KEEPING .................................................................................................. 31 
6.9 PUBLICATION POLICY ........................................................................................................................... 32 
7 REFERENCES ...................................................................................................................................... 33 
8 APPENDICES ...................................................................................................................................... 35 
8.1 APPENDIX 1: SCHEDULE OF EVENTS TABLE ............................................................................................... 35 
8.2 APPENDIX 2: STEREOACUITY TESTING ...................................................................................................... 36 
8.3 APPENDIX 3: DISTANCE VA TESTING ....................................................................................................... 37 
8.4 APPENDIX 4: OCULAR ALIGNMENT (SIMULTANEOUS PRISM COVER TEST) ....................................................... 39 
8.5 APPENDIX 5: INTERPUPILLARY DISTANCE ................................................................................................. 40 
8.6 APPENDIX 6: EXIT QUESTIONNAIRE ........................................................................................................ 41 
8.7 APPENDIX 7: PHONE CALL QUESTIONNAIRE AND ADVERSE EVENT QUERIES ..................................................... 42 
8.8 APPENDIX 8: SUMMARY OF AMENDMENT CHANGES .................................................................................. 44 
8.9 APPENDIX 9: INVESTIGATORS SIGNATURE ................................................................................................ 46 
 

 
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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
AE 
Amblyopic Eye 
ATS 
Amblyopia Treatment Study  
BCVA 
Best Corrected (with current refractive correction) Visual Acuity  
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
D 
Diopter 
FDA 
Food and Drug Administration 
FE 
Fellow Eye 
GCP  
Good Clinical Practice 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
NIH 
National Institutes of Health 
PI 
Principle Investigator 
PEDIG 
Pediatric Eye Disease Investigator Group 
SE  
Spherical equivalent 
SPCT 
Simultaneous Prism and Cover Test 
VA 
Visual Acuity 
 
 
 

 
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KEY ROLES 
Study Sponsor 
Luminopia, Inc. 
1 Broadway, 14th Floor 
Cambridge, MA 02142 
 
Sponsor Representatives 
Scott Xiao 
Co-Founder and Chief Scientific Officer 
Luminopia, Inc. 
scott@luminopia.com 
617-386-6506 
 
Endri Angjeli 
Clinical Development Lead 
Luminopia, Inc. 
endri@luminopia.com 
978-806-7080 
 
Medical Monitor 
Michael Xavier Repka, M.D. 
Vice Chair for Clinical Practice, Professor of Ophthalmology 
Wilmer Eye Institute 
mrepka@jhmi.edu 
410-583-2800 
 

 
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1. BACKGROUND AND SUMMARY 
 
1.1. Background 
Epidemiology and Clinical Characteristics 
Amblyopia is the most prevalent cause of reduced monocular visual acuity in children and 
young adults, with estimates of prevalence ranging from 1% to 5%.1, 2 The most common 
associated amblyogenic risk factors are uncorrected anisometropia, strabismus, or a 
combination of these. In addition to reduced visual acuity, amblyopic participants may also have 
dysfunctions of accommodation, fixation, binocularity, vergence, reading fluency, depth 
perception, and contrast sensitivity.3-10 
 
Current Treatments 
The current standard of care for amblyopia treatment is refractive correction (when there is 
uncorrected refractive error) followed by part-time patching or atropine penalization of the 
fellow eye.11-15 In younger children, aged 3 to 7 years, although current treatments with part-
time occlusion and atropine drops are somewhat effective,11-15 residual amblyopia (20/32 or 
worse) is still present in 54% of children at age 10 years16 and 40% at age 15 years.17 
 
One possible reason for failure of part-time patching treatment in some younger children and 
many older children is poor adherence with the prescribed treatment regimens.21, 22 
Nevertheless, data from studies using an occlusion dose monitor23, 24 suggest that many children 
do successfully comply with prescribed part-time patching treatment and yet fail to respond to 
treatment, suggesting that part-time patching is ineffective for treating amblyopia in some 
children. 
 
In addition, patching has negative psychosocial effects for many children, and children often 
resist wearing a patch. Some children and their parents rate patching poorly from the standpoint 
of adverse effects of treatment, treatment adherence, and social stigma.25, 26 Based on the 
prevalence of residual amblyopia with current part-time patching treatment and the challenges 
of adherence with patching, new treatments for amblyopia are needed, particularly those that are 
engaging for patients and lead to improvements in vision. 
 
Binocular Treatments 
Several past studies have demonstrated the potential of “binocular treatments” for amblyopia, 
which rebalance visual input to the eyes using various modifications and encourage proper 
binocular vision. In 2010, Hess et al27 measured dichoptic motion coherence thresholds in a 
series of sessions by adjusting fellow eye contrast levels to overcome suppression of the 
amblyopic eye. Nine adults (aged 24 to 49 years) achieved significantly improved amblyopic-
eye visual acuity (p < 0.008) and stereoacuity (p = 0.012) after repeated measurements, despite 
4 of 9 participants previously being treated with patching.  
 
Knox et al28 studied a similar paradigm with a binocular computer game using an in-office, 
head-mounted display over five 1-hour treatment sessions. Contrast was adjusted to equalize 
input from each eye. Fourteen children (aged 5 to 14 years) with prior patching treatment were 
included in the study, with initial amblyopic eye visual acuity ranging from 20/25 to 20/200. 
Following treatment, mean amblyopic eye visual acuity (p = 0.0001) and stereoacuity improved 
significantly (p = 0.02). 
 

 
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In another recent study published in 2015, Li et al29 used dichoptic movies presented through a 
passive 3D display with a fellow eye contrast reduction to treat amblyopia in 8 amblyopic 
children. After only ten hours of treatment, amblyopic eye visual acuity improved on average by 
a clinically significant 0.2 logMAR. As a comparison, the average rate of improvement for 
patching is 0.1 logMAR per 120 hours of treatment30. 
 
In 2016, Kelly et al31 compared the video game Dig Rush to patching for the treatment of 
amblyopia in 28 children. Dig Rush is played on an iPad with red-green anaglyphic glasses, and 
consists of a fellow eye contrast reduction and dichoptic presentation of game elements. The 
study employed a cross-in design, where half of the participants played the binocular game for 4 
weeks and the other half underwent patching for 2 weeks before crossing into the binocular 
group for the remaining 2 weeks. After 2 weeks, the binocular game group improved an average 
of 0.15 logMAR compared to an average improvement of 0.07 logMAR in the patching group 
(p = 0.02). At the 4-week visit after the patching group had crossed into the binocular group, no 
difference was found in average visual acuity improvement between the groups. 
 
In 2017, Bossi et al32 studied a binocular treatment which used blurring modifications to balance 
visibility between the two eyes. Participants were asked to watch dichoptic movies for an 
hour/day for either 8 or 24 weeks, and the system applied a Gaussian blur to the fellow eye image 
based on the participant’s initial interocular visual acuity difference. The mean improvement in 
visual acuity was 2.7 lines, a clinically significant gain. 
 
1.2. Results of Luminopia Pilot Trials 
The first version of the Luminopia One therapeutic was tested in a pilot trial for feasibility and 
safety at Boston Children’s Hospital led by Dr. David Hunter and approved by the Boston 
Children’s Hospital Institutional Review Board. The study enrolled participants aged 7+ with 
amblyopia who had failed prior treatment. All participants were prescribed a dosage of 1 hour per 
day and received either 4 or 8 weeks of treatment. Participants were able to understand the 
therapeutic well and use it at-home for treatment, and no instances of new heterotropias, diplopia, 
or other adverse events were reported. 
 
The second version of the therapeutic was tested in an open-label, single-arm pilot trial at 
Houston Eye Associates led by Dr. Malcolm Mazow and Dr. Ann Stout, and approved by Alpha 
IRB. The mean (SD) age was 5.4 (1.2) years and the mean (SD) amblyopic eye BCVA at 
enrollment was 0.42 (0.12) logMAR (approximately 20/50) (unpublished data). All participants 
except one showed improvement in amblyopic eye BCVA, with 7 out of 10 participants gaining 
0.2 logMAR (2 lines) or more and 6 out of 10 participants gaining 0.3 logMAR (3 lines) or 
more from baseline. The mean (SD) improvement in BCVA from baseline was 0.17 (0.09) 
logMAR (1.7 lines) after 4 weeks of treatment, 0.24 (0.16) logMAR (2.4 lines) after 8 weeks of 
treatment, and 0.29 (0.17) logMAR (2.9 lines) after 12 weeks of treatment. This is the largest 
known improvement in visual acuity from baseline with any binocular treatment for amblyopia 
to date. No adverse events were reported, and mean adherence to the prescribed dosage (1 hour 
per day, 7 days per week) was 77%. 
 
The final version of Luminopia One is currently being tested in an open-label, single-arm, 
multicenter study enrolling children aged 4-12 at 9 centers to use Luminopia One at home for 1 
hour/day, 6 days/week for 16 weeks. The study was reviewed and approved by Alpha IRB. Out 
of the 49 participants enrolled to date (mean age of 7.2 +/- 2.2 years), 21 participants have 

 
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completed 12 weeks of treatment with mean adherence 92% of the prescribed dose. Mean 
amblyopic eye BCVA improved 0.16 logMAR (1.6 lines; p=0.0014) after 12 weeks of treatment 
from baseline. 
 
Although the latest study is ongoing, an analysis of the data collected across pilot trials to date 
demonstrates clinically and statistically significant improvements in visual acuity after 12 weeks 
of treatment with Luminopia One, as well as high adherence over the full treatment period. 
 
1.3. Proposed Study Design 
Study Design Overview 
The proposed study is a multi-center randomized controlled clinical trial which compares mean 
change in amblyopic eye BCVA from baseline with Luminopia One (“therapeutic”) to 
refractive correction (“control”). One-hundred and forty participants (n = 140) aged 4-7 years 
will be enrolled. Participants will be randomized 1:1 to the “therapeutic group”, to use 
Luminopia One, or the “control group”, to undergo continued refractive correction, for 12 
weeks of treatment. 
 
The objective of the study is to demonstrate the safety and efficacy of Luminopia One in 
amblyopia patients with amblyopia associated with anisometropia and/or with mild strabismus. 
 
Proposed Treatment Dosage 
The proposed study prescribes a treatment dosage of 1 hour per day, 6 days per week for the 
therapeutic group and full-time refractive correction for the control group. The selected dosage 
for the therapeutic group is based on pilot trials on the therapeutic and prior research with 
binocular treatments. Studies on binocular video games by Hess et al primarily used 1 hour per 
day33, while studies on dichoptic movies and other video games used 5 hours per week29, 34. A 
treatment dosage of 1 hour per day, 6 days per week balances these two options, allowing 
participants to miss 1 day of the week while encouraging participants to undergo at least 5 hours 
of treatment per week. The selected dosage for the control group is consistent with guidelines 
recommended by the American Academy of Ophthalmology for treatment of amblyopia35. 
 
Refractive Correction Control Group 
The control group of refractive correction is most appropriate for evaluating the therapeutic’s 
safety and efficacy. Since refractive correction is the first step with all amblyopia treatments, 
refractive correction as a control group provides a robust baseline comparator for which any 
difference in effect between groups can be attributed to the therapeutic. The proposed design 
mimics the ATS5 RCT conducted by PEDIG, which established safety and efficacy of patching 
through a comparison to refractive correction36. In that study, the refractive correction group 
continued to improve, but more slowly than the patching group. 
 
Proposed Primary Endpoint Duration 
The primary endpoint duration should be sufficient to demonstrate efficacy of Luminopia One 
while minimizing the amount of time for which study participants are unable to use alternative 
amblyopia treatments. Based on these tradeoffs, a 12-week primary endpoint duration was 
deemed most appropriate for both the therapeutic and control groups. For the therapeutic group, 
pilot trials on the therapeutic have demonstrated a significant effect after 12 weeks of treatment. 
This treatment duration is also supported by prior research on other binocular treatments33, 
where 82% of the total effect was observed within 12 weeks of treatment. For the control group, 

 
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a 12-week treatment duration allows for comparison with the therapeutic at an equivalent time 
point while minimizing the delay in alternative treatment. 
 
1.4. Study Endpoints 
Primary Efficacy Endpoint: 
• The mean change in amblyopic eye BCVA from baseline to 12 weeks of treatment with 
Luminopia One compared to mean change in amblyopic eye BCVA from baseline to 12 
weeks with refractive correction alone. 
 
Primary Safety Endpoint: 
• The mean change in fellow eye BCVA from baseline to 12 weeks of treatment with 
Luminopia One compared to mean change in fellow eye BCVA from baseline to 12 
weeks with refractive correction alone.  
• Additionally, the primary safety endpoint will report the frequency and severity of all 
related Adverse Events (anticipated and unanticipated). 
 
1.5. Synopsis of Study Design 
Major Eligibility Criteria –see Section 2.2 for complete list 
• Age 4 to 7 years (inclusive) 
• Amblyopia associated with anisometropia, strabismus (≤ 5∆ at distance measured by 
SPCT in current refractive correction), or both 
• Refractive correction (if required) worn for at least 16 weeks, or until stability of VA is 
demonstrated (≤ 0.1 logMAR change by the same testing method measured on 2 exams 
at least 8 weeks apart) 
• VA in the amblyopic eye 20/40 to 20/200 
• VA in the fellow eye 20/32 or better 
• Interocular difference ≥ 3 logMAR lines 
• No prior amblyopia treatment (other than refractive correction) for > 12 months in total 
 
Treatment Groups – see Section 3.1 and 3.2 for more information 
Participants will be randomly assigned 1:1 to either: 
• Therapeutic group: Luminopia One prescribed 1 hour per day, 6 days per week with 
refractive correction 
• Control group: Refractive correction alone full-time 
 
Sample Size – see Section 6.1 for more information  
• 140 participants 
 
Visit Schedule – see Section 3.4 for more information 
• Visit 1: Screening and Enrollment exam 
• Phone Call 1: 1-week phone call ± 2 days 
• Visit 2: 4-week visit ± 1 week 
• Phone Call 2: 6-week phone call ± 1 week 
• Visit 3: 8-week visit ± 1 week  
• Phone Call 3: 10-week phone call ± 1 week 
• Visit 4: 12-week visit ± 1 week (Primary endpoint) 

 
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• Optional Phone Call 4: 16-week phone call ± 1 week (for those randomized to control 
group) 
• Optional Visit 5: 24-week visit ± 1 week (for those randomized to control group) 
 
Primary Endpoint Testing Procedure – see Section 3.5 for more information 
At each follow-up visit, best-corrected distance visual acuity will be measured in each eye using 
a standardized electronic ATS-HOTV system and protocol. The ATS-HOTV electronic visual 
acuity testing protocol inherently incorporates testing of the visual acuity limit twice in order to 
increase test-retest reliability38. All clinical sites will follow a standardized Visual Acuity 
Protocol for visual acuity testing.  
 
Statistical Analysis – see Section 6.4 for more information 
The sample size is based on a primary efficacy analysis that will compare mean change in 
amblyopic eye VA from baseline to 12 weeks in the therapeutic group with the control group. A 
group sequential design with a single interim analysis will be used to allow stopping for either 
early success or futility. The interim analysis will be conducted after 75% of subjects have 
completed their 12-week follow-up visit. The overall Type I error rate was set at 0.05. 
  
The primary safety endpoint will test if the mean change in best-corrected fellow-eye visual 
acuity in the therapeutic group is noninferior to that in the control group from baseline to 12 
weeks. Additionally, the primary safety endpoint will report the frequency and severity of all 
related Adverse Events (anticipated and unanticipated). The interim analysis will include an 
early test of the primary safety endpoint as well. 
 
Secondary endpoints will evaluate the proportion of participants who improve 2 or more 
logMAR lines from baseline to 12 weeks, the mean change in stereoacuity from baseline to 4, 8, 
and12 weeks, the mean change in amblyopic-eye VA from baseline to 4 and 8 weeks, and the 
adherence from baseline to 4, 8, and 12 weeks.  These endpoints will be summarized 
descriptively. No formal analyses are planned for secondary endpoints. 
 
1.6. Study Administration and Oversight 
Medical Monitor 
Safety oversight will fall under the direction of a Medical Monitor with the appropriate medical 
and ophthalmological expertise. A Safety Management Plan will be developed prior to first 
participant enrollment in the trial.  The Safety Management Plan will include expectations and 
the process for Medical Monitor oversight and frequency/timing of Medical Monitor review of 
safety events. 
 
Contract Research Organization (CRO) 
A contract research organization (CRO) will provide services surrounding data management and 
biostatistics for the study.  

 
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Study Summary Flow Chart (excluding Optional Visits and Calls) 
 
  
Visit 2: 4 weeks ± 1 week - Follow-up Visit  
AE monitoring 
Stereoacuity (Masked) 
Monocular distance visual acuity (Masked) 
Ocular alignment
Luminopia One 1 hour per 
day, 6 days per week plus 
refractive correction  
Visit 1: Screening and Enrollment Visit 
Informed Consent, Demographics, and Medical History  
Stereoacuity 
Monocular distance visual acuity as baseline safety and efficacy value  
Ocular alignment and IPD 
D
i
T i i
d AE M
it
i
Randomize 
Refractive correction  
full-time 
Phone Call 1: 1 Week Call ± 2 days 
AE query, Phone Call Questionnaire and encourage adherence 
Phone Call 2: 6 Week Call ± 1 week 
AE query, Phone Call Questionnaire and encourage adherence 
Major Eligibility Criteria 
Age 4 to 7 years (inclusive) 
Amblyopia associated with anisometropia, strabismus (≤5∆ at distance, measured by SPCT) or both 
No atropine treatment in the past 2 weeks 
Refractive correction worn for at least 16 weeks, or ≤ 0.1 logMAR change in amblyopic eye BCVA between 2 
visits at least 8 weeks apart with the same VA testing method 
AE VA 20/40 to 20/200 (inclusive), and FE VA 20/32 or better 
Interocular difference ≥3 logMAR lines 
No prior amblyopia treatment (other than refractive correction) for >12 months in total 
No myopia greater than -6.00D SE in either eye 
Visit 4: 12 weeks ± 1 week - Primary Endpoint Exam  
AE monitoring 
Stereoacuity (Masked) 
Monocular distance visual acuity (Masked) 
Ocular alignment 
Study Exit 
Visit 3: 8 weeks ± 1 week - Follow-up Visit  
AE monitoring 
Stereoacuity (Masked) 
Monocular distance visual acuity (Masked) 
Ocular alignment
Phone Call 3: 10 Week Call ± 1 week 
AE query, Phone Call Questionnaire and encourage adherence 

 
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2. PARTICIPANT ENROLLMENT 
 
2.1. Informed Consent 
The study plans to enroll a minimum of 140 participants.  
 
A patient is considered for the study after undergoing a routine eye examination (by a study 
investigator as part of standard of care) that identifies amblyopia appearing to meet the eligibility 
criteria. The study will be discussed with the patient’s parent(s) or guardian(s) (referred to 
subsequently as parent(s)). Parent(s) who express an interest in the study will be given a copy of the 
informed consent form to read. Written informed consent must be obtained from a parent prior to 
any study-specific procedures that are not part of routine care being performed on the patient. 
Assent must be obtained from any study participant age 7 or older at time of consent. 
 
2.2. Inclusion and Exclusion Criteria 
2.2.1. Inclusion Criteria 
A participant may be enrolled in the study if all of the following criteria are met: 
1. Signed and dated informed consent form. 
2. Parent and participant understand and are willing to comply with study procedures, and will 
be available for the duration of the study. 
3. Age 4 to 7 years at the time of consent (inclusive). 
4. Amblyopia associated with anisometropia and/or with mild strabismus, previously treated or 
untreated. 
• Criteria for mild strabismus: At least one of the following must be met: 
o Presence of a heterotropia on examination at distance or near fixation  
o Documented history of strabismus or strabismus surgery which is no longer present 
(which in the judgment of the investigator could have caused amblyopia) 
• Criteria for anisometropia: At least one of the following criteria must be met: 
o ≥ 1.00 D difference between eyes in spherical equivalent 
o ≥ 1.50 D difference in astigmatism between corresponding meridians in the two eyes 
5. Must have refractive error correction (based on a cycloplegic refraction completed within 
the last 7 months) if any of the following are true: 
• Hypermetropia of 2.50 D or more by spherical equivalent (SE) 
• Myopia of amblyopic eye of 0.50D or more SE 
• Astigmatism of 1.00D or more  
• Anisometropia of more than 0.50D SE 
6. Current refractive correction must be worn: 
• For at least 16 weeks OR 
• Until 2 consecutive BCVA measurements at least 8 weeks apart do not change by more 
than 0.1 logMAR lines  

 
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Note: Since this determination is a pre-study procedure, the method of 
measuring VA is not mandated. 
7. Visual acuity (VA), measured in each eye without cycloplegia in current refractive 
correction (if required) within 7 days prior to randomization using the electronic ATS-
HOTV visual acuity protocol, as follows: 
• VA in the amblyopic eye 20/40 to 20/200 inclusive 
• VA in the fellow eye 20/32 or better 
• Interocular difference ≥ 3 logMAR lines 
8. Heterotropia with a distance deviation of ≤ 5∆ in current refractive correction measured by 
SPCT. 
9. Interpupillary distance ≥ 52mm. 
10. Participant understands how to use Luminopia One and wear refractive correction and has 
access to wireless internet at home which is able to support the therapeutic – See Section 
2.5. 
 
2.2.2. Exclusion Criteria 
A participant will be excluded from the study if any of the following criteria are met: 
1. Atropine treatment in the past 2 weeks. 
2. Prior amblyopia treatment (other than refractive correction) for > 12 months in total. 
3. Myopia greater than -6.00D spherical equivalent in either eye. 
4. Previous intraocular or refractive surgery. 
5. Any other condition which could be a potential cause for reduced BCVA according to the 
Investigator. 
o Note: Nystagmus does not exclude the participant if the above VA criteria are met. 
6. Severe developmental or cognitive delay that would interfere with treatment or evaluation 
according to the Investigator. 
o Note: Participants with mild speech delay or reading and/or learning disabilities are 
not excluded. 
7. History of low adherence with amblyopia treatment as assessed informally by the 
investigator. 
8. History of light-induced seizures. 
 
2.3. Testing Procedures at the Enrollment Visit 
All examination procedures must be conducted within 7 days prior to the date of enrollment, except 
the cycloplegic refraction and the ocular examination, which may be performed within 7 months 
prior to enrollment.  
 
All examination procedures at enrollment should be performed in the participant’s current 
refractive correction (testing in trial frames is not permitted), and without cycloplegia: 
 

 
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1. Demographics and Medical History 
• The study personnel will collect demographic information from the participant and/or 
parent including: date of birth, sex, ethnicity, and race. 
• The study personnel will collect medical history information from the participant and/or 
parent including: ocular/non-ocular medical history, length of refractive correction wear, 
amblyopia treatment history, strabismus surgery history, and concomitant medications. 
 
2. Stereoacuity – see Section 8.2 
• Stereoacuity testing will be performed in current refractive correction by an examiner 
using the Titmus Fly and Randot Preschool tests. 
 
3. Distance VA Testing – see Section 8.3 
• Monocular distance VA testing will be performed in current refractive correction in 
each eye by an examiner using the electronic ATS-HOTV visual acuity protocol. 
 
4. Ocular Alignment Testing – see Section 8.4 
• Ocular alignment will be assessed in current refractive correction by the simultaneous 
prism and cover test (SPCT) at distance. 
 
5. Additional Clinical Testing 
• Ocular examination as per investigator’s clinical routine (if not performed within 7 
months). 
• Interpupillary distance – see Section 8.5. 
 
6. Demonstration of Ability to Use Interventions 
• The participant must be able to use Luminopia One and be able to wear refractive 
correction properly. 
 
7. AE Monitoring – see Section 5.1 
• The study personnel will query the participant and parent(s) to assess the occurrence 
of known and unknown adverse events during the screening visit. 
 
2.4. Randomization of Enrolled Participants 
Participants will be randomly assigned in a 1:1 allocation to one of the following treatment groups 
for 12 weeks:  
1. Therapeutic group: Luminopia One therapeutic for 1 hour per day, 6 days per week with 
refractive correction 
2. Control group: Refractive correction alone full-time 
 
2.5. Training with Study Interventions 
During the enrollment visit, but prior to enrollment and randomization, study personnel will train all 
participants on using the therapeutic. Training will consist of the participant and parent(s) watching 
an IRB-approved explainer video. In addition, study personnel will ask all participants to use the 
therapeutic which will be in “demonstration mode” and ensure that the participant understands how 
to complete the following activities: 
 
1. Select a video to begin the therapeutic modifications 

 
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2. Pause/play the video 
3. Change the volume of the video, and 
4. Return to the menu to select a different video, 
 
The participant will also be instructed how to put on their refractive correction. Once the participant 
and parent have watched the explainer video, and the participant has shown the ability to complete 
the aforementioned tasks within the therapeutic and to wear refractive correction properly, the 
participant is eligible for randomization and enrollment. As per the Inclusion Criteria (see Section 
2.2.1), the participant must understand how to use both interventions to be eligible for 
randomization and enrollment. 
 
In addition, participants must have access to wireless internet at home which is able to support the 
therapeutic to be eligible for the study. The participant will be withdrawn from the study if they find 
that videos buffer and don’t play, and will be asked to return for a final follow-up visit. The 
participant will not count towards the study’s enrollment target (see Section 6.1) and will not be 
included in the primary analysis population (see Section 6.5). 
 
Study personnel will have access to a Study Coordinator Portal, which allows for enrollment of new 
participants. The Study Coordinator Portal takes in the age and amblyopic eye and produces a 
unique access code for each new participant. When the participant enters the access code into a 
device, the software application will apply the participant’s prescription to their therapeutic.  
 
2.6. Control Participants Optional Study Extension  
Prior studies have indicated that parents may not be interested in being part of a trial if not all study 
participants will have the opportunity to use the investigational therapeutic. This creates a risk that 
parents may withdraw their child from the study after randomization if they are randomized to the 
control group, creating unbalanced randomization, or may decide not to participate at all. In order to 
mitigate this risk, and in line with studies published by PEDIG with other binocular treatments for 
amblyopia, the control group participants will be offered the opportunity to use the Luminopia One 
therapeutic for 12 weeks after the primary endpoint visit (Visit 4). Study measurements will be 
recorded at the end of the additional 12 weeks (Visit 5); however, only safety analysis will be 
conducted on data collected during this optional visit for control group participants only. 
Participants randomized to Luminopia One will exit the study after Visit 4 and will discuss options 
for continued treatment of amblyopia with their clinician.  

 
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3. TREATMENT GROUPS AND FOLLOW-UP 
 
3.1. Therapeutic Group 
Participants assigned to the therapeutic group will be prescribed Luminopia One for 1 hour per day, 
6 days per week for 12 weeks. Parents will be instructed that the 1 hour of daily treatment should be 
completed in a single 60-minute session. Participants will be provided with the Luminopia One 
Directions For Use and Luminopia One Quick Start Guide, which contain instructions on how to 
use the therapeutic. 
 
3.2. Control Group 
Participants assigned to the control group will wear their current refractive correction full-time for 
12 weeks. 
 
3.3. Phone Calls   
Unmasked study staff will call all participants at 1, 6 and 10 (and an optional call at 16) weeks to 
encourage adherence with the interventions, administer the phone call questionnaire and to query 
for Adverse Events in accordance with the Phone Call Adverse Event Query – see Section 8.7. 
 
3.4. Follow-up Visit Schedule 
The follow-up schedule is timed from randomization as follows: 
• Phone Call 1: 1-week phone call ± 2 days 
• Visit 2: 4-week visit ± 1 week 
• Phone Call 2: 6-week phone call ± 1 week 
• Visit 3: 8-week visit ± 1 week  
• Phone Call 3: 10-week phone call ± 1 week 
• Visit 4: 12-week visit ± 1 week (Primary endpoint) 
• 
Control group participants offered therapeutic 
• Optional Phone Call 4: 16-week phone call ± 1 week (for control group participants only) 
• Optional Visit 5: 24-week visit ± 1 week (for control group participants only) 
  
3.5. Follow-up Visit Testing Procedures 
Participants will be seen at follow-up visits as outlined in Section 3.4. All procedures will be 
performed with the participant’s current refractive correction. Visit 1 and Visit 4 visual acuity 
must ONLY be performed in current refractive correction glasses (not trial frames).  
 
The following procedures should be performed at each visit: 
1. Medical History Update 
• The study personnel will inquire about any updates to medical history information from 
the participant and/or parent(s) at Visit 2, 3, and 4. 
 
2. AE Monitoring – see Section 5.1 
• The study personnel will query the participant and parent(s) to assess the occurrence of 
known and unknown adverse events, in accordance with the In Person Adverse Event 
Query – see Section 8.7. 

 
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• The study personnel will also follow-up with any adverse events identified at previous 
study visits. 
 
3. Stereoacuity – see Section 8.2 
• Stereoacuity testing will be performed in current refractive correction by a Masked 
Examiner using the Titmus Fly and Randot Preschool tests. 
 
4. Distance VA Testing – see Section 8.3 
• Monocular distance VA testing will be performed in current refractive correction in 
each eye by a Masked Examiner using the electronic ATS-HOTV visual acuity protocol. 
 
5. Ocular Alignment Testing – see Section 8.4 
• Ocular alignment will be assessed in current refractive correction by the simultaneous 
prism and cover test (SPCT) at distance. 
 
6. Exit Questionnaire – see Section 8.6 
• Participants will be asked a questionnaire about their experience with the Luminopia 
One therapeutic at Visit 4 only, and at optional Visit 5 if applicable. 
 
3.5.1. Masked Examiner 
Stereoacuity and distance visual acuity testing must be completed by a Masked Examiner at follow-
up visits. Prior to the Masked Examiner entering the room, participants and parents will be 
instructed not to discuss their treatment with the Masked Examiner. Masked Examiners will not 
have access to the treatment groups of participants. Whenever possible, stereoacuity and distance 
visual acuity testing should be completed by the same Masked Examiner at each visit for a given 
participant. 
 
Masked Examiners will be certified during the site initiation process and will be trained on the 
Visual Acuity Protocol and Masking Plan which ensure that these individuals remain properly 
masked for the duration of the study. 
 
3.6. Adverse Event Monitoring 
All adverse events which occur during the study will be reported, regardless of whether or not they 
are considered to be related to treatment. The following adverse events will be specifically 
monitored in both the therapeutic and control groups: 
 
1. Risks relating to amblyopia treatment 
o Diplopia 
o New/worsening heterotropia of greater than 10 prism diopters 
o Worsening of BCVA in either eye of 2 logMAR lines or greater from baseline 
2. Risks relating to technological usage 
o Headaches 
o Nausea 
o Eye strain 
3. New risks 
 
See Section 5: Adverse Events and Risks for details relating to safety monitoring. 
1.  

 
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3.7. Non-Study Visits and Treatments 
Investigators may schedule additional non-study visits at their own discretion.  Participants will 
continue to follow the study-specified follow-up schedule regardless of any non-study visits. All 
concomitant medications taken during the study will be recorded into the appropriate Case Report 
Form. Participants must not undergo any additional amblyopia treatment other than the assigned 
study treatment prior to study completion (either Visit 4 or Visit 5 if applicable). Refractive 
correction may not be changed during the study. Because of the short duration of the study, 
strabismus surgery is not allowed prior to the end of the study.  If surgery is performed, the 
occurrence will be recorded in the appropriate Case Report Form and the participant will be 
discontinued from the trial. 

 
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4. MISCELLANEOUS CONSIDERATIONS 
4.1. Study Sites 
The study will include at least 10 clinical sites located throughout the US.  Each clinical site will 
enroll at maximum 20% of the entire enrolled population.  The randomization of participants at 
each site will be 1:1. 
 
4.2. Participant Withdrawals 
Parents or participants may withdraw from the study at any time. If the parents indicate that they 
want to withdraw their child from the study, the participant should be asked to come in for a study 
exit visit and to return the therapeutic (if applicable). 
 
In addition, the Investigator may decide to discontinue a participant from the study for safety 
reasons or when it is in the best interest of the subject. Reasons for participant withdrawal may 
include but are not limited to the following: 
• At the participant’s request for any reason. 
• At the Investigator's request due to safety concerns, AEs, or other medical reasons. 
• Due to non-compliance (e.g., failure to follow application instructions, missing visits) or 
other protocol violation. 
• When a participant is lost to follow-up.  
• When a participant is erroneously enrolled into the study or does not meet eligibility criteria. 
 
Participants who do not complete the entire study should be fully evaluated when possible. If, for 
any reason, a participant is discontinued before completing the primary endpoint visit, the subject 
should return and perform all the assessments scheduled for the primary endpoint visit. Notification 
of a participant discontinuation and the reason for discontinuation will be clearly documented on the 
participant’s CRF. 
 
4.3. Participant Compensation 
Parents/participants will be compensated $25 by Amazon gift card at each visit for Visits 1 through 
4, up to a total of $100. 
 
4.4. Study Costs  
The participant or their insurance provider will be responsible for costs incurred during the study 
that are considered standard of care, whereas procedures and visits not considered standard of care 
will be paid for by the study. The cost of the Luminopia One therapeutic and associated equipment 
will be paid for by the study; however, the therapeutic will need to be returned upon study 
completion.  The cost of refractive correction will not be paid for by the study as refractive 
correction is standard care. 
 
4.5. General Considerations 
The study will be conducted in compliance with the ethical principles that have their origin in the 
Declaration of Helsinki, with the protocol described herein, with ICH E6 and the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and with the standards of Good 
Clinical Practice. 
 

 
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5. ADVERSE EVENTS AND RISKS 
 
The following section outlines the Adverse Events and Risks for the study. For more information, 
please refer to the Safety Management Plan. 
 
5.1. Definition 
An AE is any untoward medical occurrence, unfavorable and unintended sign (including an 
abnormal lab finding), symptom, or disease in a clinical investigation associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
 
The following specific adverse events will be monitored throughout the study: 
1. Risks relating to amblyopia treatment 
o Diplopia 
o New/worsening heterotropia 
§ New heterotropia: any new ocular deviation in a participant without a tropia 
at baseline 
§ Worsening heterotropia: an increase in ocular deviation ≥ 10∆ in a participant 
with a tropia at baseline 
o Worsening of BCVA in either eye 
§ A decrease ≥ 2 logMAR lines from baseline 
2. Risks relating to technological usage 
o Headaches 
o Nausea 
o Eye strain 
 
5.2. Recording of Adverse Events 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events. The first concern will be the safety of the study participants, and appropriate medical 
intervention will be made accordingly. 
 
All reportable adverse events, whether discovered by study personnel during AE monitoring, 
through physical examination, laboratory tests, or other means will be recorded on an Adverse 
Event Case Report Form. 
 
Study personnel will also capture the following information for each adverse event: 
o Eye (OD, OS, OU, or non-ocular) 
o Relatedness to study interventions 
o Intensity 
o Onset Date 
o Serious or Non-Serious 
o Action Taken 
o Resolution Date 
 
Relatedness 
The study investigator will assess the relationship of any adverse event to treatment to determine if 
there is a reasonable possibility that the adverse event may have been caused by treatment. To 
ensure consistency of adverse event assessments, investigators should apply the following general 
guidelines when evaluating whether an adverse event is related to treatment: 

 
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Definite: A clear cut causal relationship with the study device and no other possible cause; 
Probable: A causal relationship with the study device is likely although alternate etiologies are also 
possible; 
Possible: A causal relationship with the study device is not definite, and alternate etiologies are also 
possible; 
Not related: The AE has no causal relationship to the study device and/or there is evidence of 
alternative etiology such as concurrent medication or illness; 
Not applicable: The participant has not been exposed to the study device. 
 
Intensity 
The maximum intensity that occurred since the onset of an adverse event will be rated on a three-
point scale: (1) mild, (2) moderate, or (3) severe, categorized as follows:  
 
Mild: Symptom(s) barely noticeable to participant or does not make participant uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptom(s). 
Moderate: Symptom(s) of sufficient severity to make participant uncomfortable; performance of 
daily activity is influenced; participant is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe: Symptom(s) cause severe discomfort; severity may cause cessation of treatment with study 
medication or device; treatment for symptom(s) may be given and/or participant hospitalized 
 
It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event is not 
necessarily serious. For example, itching for several days may be rated as severe, but may not be 
clinically serious. 
 
Serious or Non-Serious 
A serious adverse event (SAE) is any untoward occurrence that: 
• Results in death. 
• Is life-threatening (a non-life-threatening event which, had it been more severe, might have 
become life-threatening, is not necessarily considered a serious adverse event). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions (sight-threatening). 
• Is considered a significant medical event by the investigator based on medical judgment (ex. 
may jeopardize the participant or may require medical/surgical intervention to prevent one 
of the outcomes listed above). 
 
A non-serious adverse event is any adverse event which is not categorized as a serious adverse 
event. 
 
An unanticipated adverse device event (UADE) is defined as a serious adverse event caused by, or 
associated with, a device, if that effect was not previously identified in nature, severity, or degree of 
incidence. 
 
Resolution Date 

 
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Adverse events that occur during the study will be followed until resolution. Adverse events which 
continue after the participant’s discontinuation or completion of the study will be followed until 
their medical outcome is determined or until no further change in the condition is expected.   
 
5.3. SAE and UADE Reporting Requirements 
Study investigators are required to report any instance of an SAE or UADE to the study sponsor, 
reviewing IRBs, and Medical Monitor no later than 10 working days after the Investigator first 
learns of the effect. The study sponsor is responsible for conducting an evaluation of the UADE and 
will report the results of the evaluation to FDA, the Medical Monitor, all reviewing IRBs, and 
participating Investigators within 10 working days after the sponsor first receives notice of the 
effect. Thereafter, the sponsor shall submit such additional reports concerning the effect as FDA 
requests. 
 
5.4. Risks 
Standard of care treatment for amblyopia comes with the accepted risks of developing a 
new/worsening heterotropia or diplopia. However, the risk of developing new/worsening 
heterotropias or developing diplopia from the Luminopia One therapeutic is expected to be no greater 
than it would be with standard of care. In a 2016 study comparing binocular treatment to patching, 
the rate of new heterotropias was 8.8% in the binocular group and 5.9% in the patching group, a 
statistically and clinically insignificant difference33. The same study showed that diplopia was rare 
after both treatments33.  
 
The procedures to be conducted in the study during visits are part of daily eye-care practice and 
pose no known risks. As part of a routine eye-care exam, the participant may receive cycloplegic 
eye drops. 
 
The participants in both groups will be unable to perform any amblyopia treatment other than the 
intervention they are prescribed for the duration the study. Given the relatively short study duration 
of 12 weeks, we believe the risk of delaying standard of care treatment is minimal and justified. 
 
Extended screen time with technological products in general are associated with the risks of nausea, 
headaches, and eye-strain. Prevalence of these symptoms will be monitored throughout the study, and 
the Luminopia One Directions For Use provide additional warnings for these symptoms. More 
information can be found in the Clinical Risk Benefit Analysis (CRBA) and the Investigator’s 
Brochure for Luminopia One. 
 
5.5. Risk Assessment  
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.404 which is 
research not involving greater than minimal risk. It is also believed that the Luminopia One is a 
non-significant risk (NSR) device as per FDA 21 CFR 812.66 because: 
 
• by design it is NOT intended as an implant and does NOT presents a potential for serious 
risk to the health, safety, or welfare of a subject; 
 
• based on the device’s Indication For Use it is NOT purported or represented to be for use 
supporting or sustaining human life and does NOT present a potential for serious risk to the 
health, safety, or welfare of a subject; 

 
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• based on the device’s Indication For Use it is NOT for a use of substantial importance in 
diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of 
human health and presents a potential for serious risk to the health, safety, or welfare of a 
subject;  
 
• by design it does NOT present a potential for serious risk to the health, safety, or welfare of 
a subject. 
 
Please refer to the Study Risk Determination and the Clinical Risk Benefit Analysis for 
additional justification. 
 
5.6. Clinical Monitoring 
The sponsor is responsible for ensuring that adequate monitoring at each site is completed to 
guarantee protection of the rights and safety of participants and the quality and integrity of the data 
collected and submitted. Monitors must be appropriately trained and qualified to check for 
adherence to the investigational plan and the signed Investigator agreement, compliance to the IRB 
conditions and guidelines, and compliance to applicable regulations.  Any non-compliance with 
these items that is not adequately addressed by the Investigator and/or study personnel is cause for 
the sponsor to put the site on hold or withdraw the Investigator site or study personnel from 
participation in the study. 
 
During a monitoring visit, the monitor may review source documents, CRFs, and informed consent 
forms for a representative number of participants.  Frequency of monitoring visits will be based 
upon enrollment, study duration, compliance and any suspected inconsistency in data that requires 
investigation.  Both on-site monitoring and remote monitoring will be conducted.  
 
A separate detailed Monitoring Plan will be prepared prior to the start of the study and maintained 
in the Trial Master File with the sponsor and CRO. 

 
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6. STATISTICAL CONSIDERATIONS 
 
The approach to sample size and statistical analyses are summarized below. A detailed 
Statistical Analysis Plan will be written and finalized without knowledge of study data. The 
analysis plan synopsis in this chapter contains the framework of the anticipated final analysis 
plan. 
 
6.1. Sample Size Estimation 
Sample size estimates were based on data from previous PEDIG studies (ATS320, ATS536, 
ATS1833 and ATS20) and data from participants in Luminopia One pilot trials who would meet 
the eligibility criteria for the current protocol. 
 
Control Group –Refractive Correction 
To estimate the mean change in amblyopic eye visual acuity for the primary efficacy endpoint, 
data were reviewed from participants aged 4 to 6 years who were randomly assigned to continue 
refractive correction alone in a previous PEDIG study (ATS5, see Table 1). The mean change in 
VA at 5 weeks was 0.55 logMAR lines (95% CI: 0.19 to 0.90 logMAR lines) with standard 
deviation 1.28 logMAR lines (95% CI: 1.07 to 1.58 logMAR lines). 
 
Given the more stringent eligibility criteria in the proposed study as compared to the previous 
study, we anticipate that the magnitude and standard deviation of mean change in visual acuity 
after 12 weeks with refractive correction in the current study will be smaller than those in Table 
1. 
 
To estimate the mean change in fellow eye visual acuity for the primary safety endpoint, data 
were reviewed from participants who were randomly assigned to continue refractive correction 
alone in a previous PEDIG study (ATS5, see Table 2).  The mean change in VA at 5 weeks was 
0.02 logMAR lines (95% CI: 0.00 to 0.04 logMAR lines) with standard deviation 0.10 logMAR 
lines (95% CI: 0.08 to 0.12 logMAR lines). 
 
Therapeutic Group – Luminopia One 
To estimate the mean change in amblyopic eye visual acuity for the primary efficacy endpoint, 
data from 3 studies were reviewed: (1) data for participants randomly assigned to a similar 
treatment of “Dig Rush” on an iPad device (E. Birch Study); (2) data from a previous PEDIG 
trial (ATS18) for participants randomly assigned to a similar treatment of “Hess falling blocks” 
on an iPad device; and (3) data from Luminopia One pilot trials (Table 1). 
 
To estimate the mean change in fellow eye visual acuity for the primary safety endpoint, data 
were reviewed from participants aged 4 to 7 years enrolled in Luminopia One pilot trials.  The 
mean change in VA at 12 weeks was 0.05 logMAR lines (95% CI: 0.02 to 0.08 logMAR lines) 
with standard deviation 0.10 logMAR lines (95% CI: 0.08 to 0.13 logMAR lines).   
 
 

 
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Table 1: Previous Study Data (Primary Efficacy Endpoint Reference) 
Cohort 
N 
Change in Amblyopic Eye VA 
at the 4 or 5 Week Visit 
(logMAR Lines) 
N 
Change in Amblyopic Eye VA 
at 8-12 Week Visit 
(logMAR Lines) ‡ 
Mean Change  
(95% CI) 
SD Change  
 (95% CI) 
Mean Change  
(95% CI) 
SD Change  
(95% CI) 
Refractive Correction Alone: 
 
 
 
 
 
 
ATS5: Age 3 to 6 years 1 
53 
0.55  
(0.20 to 0.89) 
1.28  
(1.07 to 1.58) 
 
n/a 
n/a 
Binocular Therapeutic: 
 
 
 
 
 
 
E. Birch Study (Age 4 to 6 years) 2 
9 
1.67  
(0.89 to 2.45) 
1.19  
(0.80 to 2.28) 
 
n/a 
n/a 
Luminopia Pilot Trials  
(Age 4 to 7 years) 3 
34 
1.36  
(0.96 to 1.76) 
1.18  
(0.95 to 1.55) 
35 
1.64  
(1.09 to 2.19) 
1.66 
(1.34 to 2.17) 
ATS18 (Age 5 to 6 years) 4 
39 
1.15 
(0.73 to 1.57) 
1.35 
(1.10 to 1.74) 
39 
1.23  
(0.79 to 1.67) 
1.39 
(1.14 to 1.79) 
Patching Therapeutic: 
 
 
 
 
 
 
ATS18 (Age 5 to 6 years) 4 
50 
0.90 
(0.50 to 1.30) 
1.45 
(1.21 to 1.81) 
48 
1.43 
(0.98 to 1.88) 
1.62  
(1.35 to 2.02) 
1 ATS5 data were limited to randomized participants with an amblyopic-eye VA of 20/40 to 20/200 inclusive with ≥ 3 lines of interocular 
difference and a fellow-eye VA of 20/25 or better who had stabilized with refractive correction prior to randomization.  The baseline magnitude 
of tropia at near (as measured by SPCT) was limited to <5pd.  The outcome data reported were based on the 5-week primary masked outcome 
visit.  
2 E. Birch study enrolled children aged 4 to <7 years of age.  Change in VA after 4 weeks of binocular therapy was computed for participants 
randomly assigned to receive binocular  the Dig Rush game on an iPad device for 4 weeks (prescribed 1 hour per day, 5 days per week without 
patching).  Participants with >4pd magnitude of strabismus (measured by PACT) were excluded from the study  
3 Data from Luminopia pilot trials are limited to participants 4 to 7 years old with ocular alignment ≤5pd.   
4 ATS18 study participants were prescribed binocular therapy for 1 hour per day, 7 days per week vs 2-hours per day of patching.  The binocular 
game, Hess falling blocks, was played on an iPad device.  The outcome data reported are from the 4-week and 8-week masked outcome visits.   
 
Table 2: Previous Study Data (Primary Safety Endpoint Reference) 
Cohort 
N 
Change in Fellow Eye VA 
at the 4 or 5 Week Visit 
(logMAR Lines) 
N 
Change in Fellow Eye VA 
at 12 Week Visit 
(logMAR Lines) ‡ 
Mean Change  
(95% CI) 
SD Change  
 (95% CI) 
Mean Change  
(95% CI) 
SD Change  
(95% CI) 
Refractive Correction Alone: 
  
  
  
  
  
  
ATS5: Age 3 to 6 years 1 
68 
0.02 
(0.00 to 0.04) 
0.10 
(0.08 to 0.12) 
  
  
  
Binocular : 
  
  
  
  
  
  
Luminopia Pilot Trials  
(Age 4 to 7 years) 3 
36 
0.00 
(-0.02 to 0.02) 
0.05 
(0.04 to 0.06) 
35 
0.05 
(0.02 to 0.08) 
0.10 
(0.08 to 0.13)  
 
 
Effect Size Estimates 
Efficacy: 
Based on Luminopia One pilot trials (Table 1), the estimate for mean change in amblyopic eye 
visual acuity for the primary efficacy endpoint is 1.64 logMAR lines in the therapeutic group and 
0.45 logMAR lines in the control group, with a pooled standard deviation of 1.40 logMAR lines. 
 
The true difference between the therapeutic and refractive correction might be as large as 1.19 
logMAR lines; however, a conservative approach was taken to detect a true difference as small 

 
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as 0.75 logMAR, and therefore a group difference of 0.75 logMAR will be used to estimate 
sample size.  
 
Safety: 
Safety will be measured as change of visual acuity in the fellow eye.  This is a noninferiority 
analysis to demonstrate that change of VA in the fellow eye when using Luminopia One is not 
worse than that observed in the control group.   
 
Based on previous studies (Table 2), the estimate for mean change in fellow eye visual acuity for 
the primary safety endpoint is 0.05 logMAR lines in the therapeutic group and 0.02 logMAR 
lines in the control group, with a pooled standard deviation of 0.10 logMAR lines. 
 
A noninferiority margin of 1.0 logMAR lines was determined to be most appropriate, given that 
1.0 logMAR line is the minimum detectable difference in clinical practice with a standard eye 
chart for this age group38. Consequently, 1.0 logMAR line would be the smallest unacceptable 
difference in fellow eye visual acuity change between the therapeutic and control groups, and 
therefore the most appropriate noninferiority margin. 
 
Additionally, the primary safety endpoint will report the frequency and severity of all related 
Adverse Events (anticipated and unanticipated). 
 
Group Sequential Design: 
The sample size for this trial will be based on a group sequential design with a single interim 
analysis to allow for stopping due to either early success (rejecting the null hypothesis) or 
futility. The goal of the group sequential design is to conserve precious time and resources and 
prevent unnecessary enrollment of participants if there is no observed difference in effect 
between groups or if there is a significant effect in favor of Luminopia One. It is important to 
allow for early stopping for success since there is a real possibility the therapeutic could perform 
significantly better than expected. 
 
Boundaries for both alpha and beta will be calculated using a power cumulative error spending 
function. The mathematical form of this spending function is: 
 
 
 
where ρ is the power parameter and t is the information fraction. 
 
For beta spending, rho was set to 1.0 which results in a spending function much like the Pocock 
method (i.e. equal spending between the interim and final analyses). For alpha spending, rho was 
set to 2.0 resulting a spending function somewhere between that found for the O’Brien-Fleming 
method and the Pocock method. 
 
otherwise
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The planned interim analysis will also involve an analysis of the primary safety endpoint, 
including both the test of noninferiority in mean fellow eye BCVA change between groups and a 
report of the frequency and severity of all related Adverse Events (anticipated and 
unanticipated). 
 
Sample Size Estimation 
The sample size was calculated using the SEQDESIGN procedure in SAS version 9.3.  The 
alternative reference was set to 0.75. As part of the design statement, the number of analyses was 
set to 2 where the first analysis was planned after 75% of the expected participants complete 
their 12-week primary outcome visit and the second after all participants complete their 12-week 
primary outcome visit.  The method of alpha spending was set to “errfuncpow(rho=2.0)” and the 
method of beta spending was set to “errfuncpow(rho=1.0).”  The “alt” parameter was set to 
“upper” to indicate a one-sided test, alpha was set to 0.05, and beta was set to 0.10 in order to 
achieve 90% power.  The “stop” parameter was set to “both” in order to have boundaries for both 
success and futility.  
 
This specification results in an effective sample size of 132 participants (66 per arm) providing 
90% power to detect a 0.75 logMAR line difference between the therapeutic and control groups 
using a one-sided test (primary efficacy endpoint). 
 
With an equal beta-spending function, if there truly is no treatment effect favoring Luminopia 
One, the chance of stopping the study early for futility at the interim analysis is approximately 
89%. 
 
The primary safety endpoint will test noninferiority in fellow eye visual acuity change from 
baseline to 12 weeks endpoint. The sample size required to achieve 90% power, for a non-
inferiority window of 1.0 logMAR line with Type I error rate of 0.05, is fewer than 132 
participants. Therefore, the primary efficacy endpoint will be used to drive sample size. 
 
Adjusting the effective sample size for a 5% loss to follow-up results in a target enrollment of 
140 subjects. 
 
6.2. Masked Sample Size Re-estimation 
The sample size estimates are based on previous studies of refractive correction and binocular 
treatments. Although we believe that our estimates of variance are reasonable, a sample size re-
estimation will be performed once 50% of the pre-planned number of participants have 
completed the primary endpoint visit.  A pooled estimate of variance without respect to treatment 
group will be calculated and used to re-estimate sample size using a procedure that maintains 
masking and has a negligible effect on the Type I error rate, as the data of treatment effect will 
remain masked. If the observed standard deviation is larger than the pre-study estimate, the 
sample size will be increased to maintain adequate power.  The masked sample size re-
estimation will be conducted separately from the interim analysis. 
 

 
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6.3. Bias and Error Rates 
Minimizing Bias 
The interim analysis will be designed to optimize usage of time and resources while controlling 
the Type I and II error rates and minimizing operational bias, in accordance with FDA’s 
guidance on Adaptive Designs for Medical Devices. 
 
Type I and II Error Rates 
Analyzing interim data during the study can lead to Type I error inflation and increase the chance 
of a false positive conclusion. The proposed group sequential design controls for Type I error 
inflation by using the well-established statistical method of alpha-spending, so the Type I error 
for the overall study is controlled at an acceptable level. A similar approach of a beta-spending 
function is used to keep the Type II error for the overall study at an acceptable level. 
 
Operational Bias 
The details of the group sequential design will be included in the full Statistical Analysis Plan 
and approved prior to collection of study data. To avoid any change in behavior between study 
personnel and participants before and after the interim analysis, the interim analysis will be 
conducted by the CRO and Sponsor without the involvement of participating investigators.  The 
Medical Monitor will be informed of the interim analysis findings. 
 
In the event that the study is stopped early for success or futility, randomization will be halted 
and the Medical Monitor will be asked to make a recommendation as to whether follow-up 
exams for existing participants should continue. 
 
6.4. Analyses 
6.4.1. Primary Efficacy Analysis 
The primary analysis of efficacy will compare the mean change in amblyopic eye BCVA from 
baseline after 12 weeks (Visit 4) of treatment with Luminopia One compared to continued 
refractive correction. The 12-week visit in the therapeutic and control groups will determine 
success and failure of this endpoint. An analysis of variance will be performed to compare the 
therapeutic and control groups at 12 weeks.  The mean change in amblyopic-eye VA for the 
therapeutic and control will be used as the dependent variable. The independent predictors will 
be the randomized treatment group (therapeutic/control). A standard F-test will be used to 
determine if significant differences exist in mean change from baseline between groups.  A 95% 
confidence interval on the difference between groups will also be provided.  If the mean change 
from baseline in VA is significantly larger for the therapeutic group over the control group then 
the primary efficacy endpoint will have been successfully passed.  
 
The linear model used for this analysis is as follows: 
 
 
 
where α is the intercept, ßi is the coefficient associated with treatment group, coded 1 for the 
therapeutic group and 0 for the control group.    
ijk
i
ijk
Group
e
b
a
µ
+
+
=
*

 
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The formal hypothesis being tested is: 
 
 
 
Testing will be done at the 0.05 level of significance. 
 
6.4.2. Primary Safety Analysis 
The coprimary analysis of safety will test if the mean change in fellow eye visual acuity of the 
therapeutic group from baseline to 12 weeks is noninferior to the mean change in fellow eye 
visual acuity of control group within a margin of 1.0 logMAR lines.  The formal hypotheses 
being tested are: 
 
 
 
where µ is the change from baseline for both the control and therapeutic subjects and δ is the 
non-inferiority window.  The statistical test is a two-sample T-test which will be done at the 0.05 
level of significance. In addition to the formal test on the mean change in fellow eye visual 
acuity, the primary safety endpoint will report the frequency and severity of all related Adverse 
Events (anticipated and unanticipated). 
 
6.4.3. Subpopulation Analysis 
The primary efficacy analysis will be redone on various subpopulations.  Those subpopulations 
are type of amblyopia (anisometropia without vs with strabismus) , age (≤5, >5), and baseline 
VA where the range of baseline VA is split into two groups (better than 20/100, 20/100 or 
worse).  The proportion of amblyopic eyes demonstrating each number of lines of improvement 
in BCVA at each study visit will also be reported. These analyses are not powered and are only 
supportive in nature. 
 
6.4.4. Study Success Definition 
The overall trial will be deemed a success if both the primary efficacy and primary safety 
endpoints are passed. 
 
6.4.5. Secondary Analyses 
6.4.5.1. VA Improvement at 12 Weeks of 2.0 or more logMAR Defined as a Binary 
Outcome 
A secondary analysis will estimate the proportion of participants with amblyopic eye BCVA 
improvement of ≥ 2 logMAR lines at 12 weeks (Visit 4) after baseline.  An exact 95% 
confidence interval will also be given along with the estimate. 
0
:
0
:
>
£
i
i
Ha
Ho
b
b
d
µ
µ
d
µ
µ
>
-
£
-
c
therapeuti
control
c
therapeuti
control
Ha
Ho
;
:

 
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6.4.5.2.  
6.4.5.3. Stereoacuity Improvement at 4, 8 and 12 Weeks 
A secondary analysis will report the mean change in stereoacuity from baseline to 4, 8 and 12 
weeks along with 95% confidence intervals about the mean change. 
 
6.4.5.4. VA Improvement at 4 and 8 Weeks 
A secondary analysis will repeat the primary analysis except for the 4 and 8 week visit instead.  
Ninety-five percent confidence intervals will also be given. 
 
6.4.5.5. Adherence at 4, 8, and 12 Weeks 
A secondary analysis will report the mean adherence from baseline to 4, 8, and 12 weeks along 
with 95% confidence intervals about the mean adherence in the therapeutic group. 
 
6.4.6.  Safety Reporting 
6.4.6.1. Adverse Events 
The participant and parent(s) will be asked about known and unknown adverse events at each 
visit and phone call.  The frequency of known and unknown adverse events will be summarized 
for all subjects. 
 
6.5. Analysis Populations 
The intent to treat (ITT) population will be those participants enrolled and randomized. For the 
purposes of analysis of the primary endpoints, subjects will be analyzed in the group to which 
they were assigned regardless of the treatment actually received. The ITT population will not 
include participants who do not meet eligibility criteria and are ultimately deemed ineligible for 
the study, including participants who are withdrawn from the study due to insufficient internet. 
 
The as treated population (AT) will be those participants enrolled and randomized; however, 
treatment group assignment for the purposes of analysis will be based on the actual treatment 
type received.   
 
The per protocol population (PP) is defined as those participants enrolled, randomized, who have 
adherence > 25%, and who have no major protocol deviations that could affect the endpoints of 
interest. The 25% adherence threshold for the PP population was determined from the first pilot 
trial on Luminopia One, in which all enrolled participants with > 25% adherence and no major 
protocol deviations showed improvements from using the therapeutic. The adherence data will 
be captured during follow-up visits and calls for the control group and with electronic tracking in 
the therapeutic group.  Adherence will be captured while maintain masking of the study in 
accordance with the Masking Plan.  
 
The ITT population will be the population used for analysis and interpretation of the primary and 
secondary efficacy endpoints.  The analysis for the primary and secondary efficacy endpoints 
will also be conducted on the PP population and the AT population and these analyses will be 
considered supportive in nature. The AT population will be used to assess and characterize all 
safety endpoints. 
 

 
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Additional approaches to the primary analysis will also include participants who completed the 
primary endpoint visit outside of the pre-defined visit window. These will be considered 
supportive in nature. 
 
6.6. Missing Data 
Multiple imputation for missing data will be performed as a secondary approach with the ITT 
population, and results of the analysis with imputation of missing data will be considered 
supportive in nature and assessed for consistency with the primary analysis.  Imputation will be 
based on regression methods using baseline covariates as independent predictors.  If no 
significant predictors can be found, the following method will be used.  Those subjects 
completing the study will be categorized by age, sex, and treatment received.  For a subject with 
missing data, the imputed value will be a random draw from those subjects with data that have 
the same age, sex, and treatment. 
 
6.7. Site Poolability 
Data from this trial will be pooled across study site for the purposes of analysis.  To demonstrate 
poolability of the primary endpoint data, the change in amblyopic eye BCVA between baseline 
and 12 weeks will be calculated for each subject. This value will be used as the dependent 
variable in a linear model. The independent predictors will be study site, treatment group, and a 
study site by treatment group interaction.  If the interaction term is considered non-significant 
then the data will be pooled across site for the purposes of analysis. If the interaction term is 
considered significant then the analysis of the primary endpoint will have to be adjusted for 
study site. A significance level of 0.15 will be used for this analysis. 
 
6.8. Data Handling and Record Keeping 
Source documentation is defined as the first place where data is recorded.  This includes, but is 
not limited to, medical records (paper and electronic), test results and reports, and study 
worksheets. Original source documentation must be maintained at each site to substantiate data 
entered on case report forms. Source data must be made available by the Investigator to facilitate 
monitoring and audits. Monitors must have access to medical records sufficient to ensure the 
completeness and accuracy of reported data. 
 
Investigators are required to maintain complete and accurate records pertaining to the study. 
Relevant records include: 
1. IRB approvals, renewals, and withdrawals; 
2. Records of interventions used in the study, including traceability to the participant that 
received the intervention; 
3. Records of any intervention returned to the sponsor; 
4. Signed informed consent form(s) for each enrolled participant; 
5. Completed case report forms; 
6. Records of all adverse events and supporting documentation; 
7. Copies of the current approved version of the protocol. 
 

 
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Case Report Forms should be submitted within 10 business days after the corresponding visit. 
However, adverse events should be reported according to the timelines in Section 5.3. 
Investigators are responsible for notifying the sponsor of any changes to previously reported 
data. 
 
Records should be maintained for at least 2 years following the completion or termination of the 
investigation or the time dictated by national guidelines if longer. 
 
6.9. Publication Policy 
This study is designed to gather and report clinically relevant information for the advancement of 
patient care.  It is intended that peer-reviewed publications/abstracts will be generated to report 
the primary study results.  The study’s investigators and sponsor will have priority to author the 
primary manuscript(s) and initial abstract(s) related to overall study results.  At the discretion of 
the sponsor, contributors to the writing of these pieces may be sought from Investigators who 
have contributed most significantly to the study.  Contribution considerations include but are not 
limited to protocol compliance, data accuracy/completeness, number of participants enrolled, and 
willingness to adhere to established guidelines outlined in the International Committee of 
Medical Journal Editors (ICMJE).  
 
Sites shall be prohibited from individually publishing any reports, abstracts, articles or data 
compilations concerning the study until its termination or a notification from the sponsor that the 
main study manuscript and/or abstract(s) have been accepted for publication/presentation.  
Additionally, the sponsor shall be provided a period of time for prior written notice to review and 
comment on any publications by a site concerning the study data. If the sponsor, in its reasonable 
judgment, needs additional time to seek patent protection for the information or to remove 
confidential information, the sponsor can have the submission or publication deferred for an 
agreed upon period of time.  The sponsor alone reserves ownership of all data collected during 
this study and publication rights regarding any endpoints or hypotheses not specifically outlined 
in this investigational plan. 

 
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7. REFERENCES 
1. Holmes JM, Clarke MP. Amblyopia. Lancet 2006;367:1343-51.  
2. Webber AL, Wood J. Amblyopia: prevalence, natural history, functional effects and treatment. 
Clin Exp Optom 2005;88:365-75.  
3. Agrawal R, Conner IP, Odom JV, Schwartz TL, Mendola JD. Relating binocular and monocular 
vision in strabismic and anisometropic amblyopia. Arch Ophthalmol 2006;124:844-50.  
4. Rutstein RP, Corliss D. Relationship between anisometropia, amblyopia, and binocularity. Optom 
Vis Sci 1999;76:229-33.  
5. Ciuffreda KJ, Hokoda SC, Hung GK, Semmlow JL, Selenow A. Static aspects of accommodation 
in human amblyopia. Am J Optom Physiol Opt 1983;60:436-49.  
6. Abraham SV. Accommodation in the amblyopic eye. Am J Ophthalmol 1961;52:197-200.  
7. Weakley DR, Jr. The association between nonstrabismic anisometropia, amblyopia, and 
subnormal binocularity. Ophthalmol 2001;108:163-71.  
8. McKee SP, Levi DL, Movshon JA. The pattern of visual deficits in amblyopia. J Vis 2003;3:380-
405.  
9. Repka MX, Kraker RT, Beck RW, et al. Monocular oral reading performance after amblyopia 
treatment in children. Am J Ophthalmol 2008;146:942-7.  
10. Birch EE, Cheng C, Vu C, Stager DR, Jr. Oral reading after treatment of dense congenital 
unilateral cataract. J AAPOS 2010;14:227-31. 
11. Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs. patching for 
treatment of moderate amblyopia in children. Arch Ophthalmol 2002;120:268-78.  
12. Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized trial of 
atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol 
2005;123:149-57.  
13. Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for 
treatment of moderate amblyopia in children. Arch Ophthalmol 2003;121:603-11.  
14. Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching regimens 
for treatment of severe amblyopia in children. Ophthalmol 2003;110:2075-87.  
15. Pediatric Eye Disease Investigator Group. A randomized trial of atropine regimens for treatment 
of moderate amblyopia in children. Ophthalmol 2004;111:2076-85.  
16. Pediatric Eye Disease Investigator Group. A randomized trial of atropine versus patching for 
treatment of moderate amblyopia: follow-up at age 10 years. Arch Ophthalmol 2008;126:1039-44.  
17. Repka MX, Kraker RT, Holmes JM, et al. Atropine vs Patching for Treatment of Moderate 
Amblyopia: Follow-up at 15 Years of Age of a Randomized Clinical Trial. JAMA Ophthalmol 
2014:10.1001/jamaophthalmol.2014.392.  
18. Pediatric Eye Disease Investigator Group. Patching vs atropine to treat amblyopia in children 
aged 7 to 12 years: a randomized trial. Arch Ophthalmol 2008;126:1634-42.  
19. Repka MX, Kraker RT, Beck RW, et al. Treatment of severe amblyopia with weekend atropine: 
results from 2 randomized clinical trials. J AAPOS 2009;13:258-63.  
20. Pediatric Eye Disease Investigator Group. Randomized trial of treatment of amblyopia in 
children aged 7 to 17 years. Arch Ophthalmol 2005;123:437-47.  
21. Oliver M, Neumann R, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and results of 
treatment for amblyopia in children more than 8 years old. Am J Ophthalmol 1986;102:340- 5.  
22. Pritchard C. Why won't you treat my 10 year old's lazy eye? American Orthoptic Journal 
1990;40:15-8. A18ProtV2 0_10-21-14(11-5-14) (3) 6-2  
23. Loudon SE, Polling JR, Simonsz HJ. Electronically measured compliance with occlusion 
therapy for amblyopia is related to visual acuity increase. Graefes Archive for Clinical and 
Experimental Ophthalmology 2003;241:176-80.  

 
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24. Stewart CE, Moseley MJ, Stephens DA, Fielder AR. Treatment dose-response in amblyopia 
therapy: The Monitored Occlusion Treatment of Amblyopia Study (MOTAS). Invest Ophthalmol 
Vis Sci 2004;45:3048-54.  
25. Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on the 
child and family in the amblyopia treatment study. Arch Ophthalmol 2003;121:1625-32.  
26. Felius J, Chandler DL, Holmes JM, et al. Evaluating the burden of amblyopia treatment from 
the parent and child's perspective. Journal of AAPOS: American Association for Pediatric 
Ophthalmology & Strabismus 2010;14:389-95.  
27. Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of amblyopia in 
adults well beyond the critical period of visual development. Restor Neurol Neurosci 2010;28:793-
802.  
28. Knox PJ, Simmers AJ, Gray LS, Cleary M. An exploratory study: prolonged periods of 
binocular stimulation can provide an effective treatment for childhood amblyopia. Invest 
Ophthalmol Vis Sci 2012;53:817-24.  
29. Li, S. L., Reynaud, A., Hess, R. F., Wang, Y.-Z., Jost, R. M., Morale, S. E., … Birch, E. E. 
(2015). Dichoptic movie viewing treats childhood amblyopia. Journal of AAPOS: American 
Association for Pediatric Ophthalmology & Strabismus 19(5), 401–405. 
30. De Zárate BR, Tejedor J. Current concepts in the management of amblyopia. Clinical 
ophthalmology (Auckland, NZ) 2007;1(4):403-414. 
31. Kelly KR, Jost RM, Dao L, Beauchamp CL, Leffler JN, Birch EE. Binocular iPad Game vs 
Patching for Treatment of Amblyopia in Children: A Randomized Clinical Trial. JAMA 
Ophthalmol 2016;134(12):1402-1408.  
32. Bossi M, Tailor VK, Anderson EJ, et al. Binocular therapy for childhood amblyopia improves 
vision without breaking interocular suppression. Invest Ophthalmol Vis Sci. 2017;58:3031–3043. 
DOI:10.1167/ iovs.16-20913 
33. Holmes JM, Manh VM, Lazar EL, Beck RW, Birch EE, Kraker RT, Crouch ER, Erzurum SA, 
Khuddus N, Summers AI, Wallace DK, for the Pediatric Eye Disease Investigator Group. Effect of 
a Binocular iPad Game vs Part-time Patching in Children Aged 5 to 12 Years With 
Amblyopia. JAMA Ophthalmol 2016;134(12):1391-1400. 
34. Kelly KR, Jost RM, Dao L, Beauchamp CL, Leffler JN, Birch EE. Binocular iPad Game vs 
Patching for Treatment of Amblyopia in Children. JAMA Ophthalmol 2016;134(12):1402-1408. 
35. American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. Preferred 
Practice Pattern®Guidelines. Amblyopia. San Francisco, CA: American Academy of 
Ophthalmology; 2012. Available at: www.aao.org/ppp. 
36. Pediatric Eye Disease Investigator Group. A Randomized Trial to Evaluate Two Hours of Daily 
Patching for Amblyopia in Children. Ophthalmology. 2006;113(6):904-912. 
doi:10.1016/j.ophtha.2006.01.069. 
37. American Academy of Pediatrics Announces New Recommendations for Children's Media Use. 
American Academy of Pediatrics. https://www.aap.org/en-us/about-the-aap/aap-press-
room/pages/american-academy-of-pediatrics-announces-new-recommendations-for-childrens-
media-use.aspx. Published October 21, 2016. Accessed April 10, 2017. 
 

 
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8. APPENDICES 
8.1. Appendix 1: Schedule of Events Table 
Procedures 
Visit 1: 
Screening 
and 
Enrollment 
Phone 
Call 1: 
Week 
1 Call 
Visit 
2: 
Week 
4 
Visit 
Phone 
Call 
2: 
Week 
6 Call 
Visit 
3: 
Week 
8 
Visit  
Phone 
Call 
3: 
Week 
10 
Call 
Visit 
4: 
Week 
12 
Visit  
Optional 
Phone Call 
4: Week 16  
(Control 
participants 
only) 
Optional 
Visit 5: 
Week 24 
(Control 
participants 
only) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
Demographics 
& Medical 
history 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Therapeutic 
administration 
and training 
X 
 
 
 
 
 
 
 
 
Refraction (if 
applicable) 
X 
 
 
 
 
 
 
 
 
Phone call 
questionnaire 
 
X 
 
X 
 
X 
 
X 
 
Concomitant Tx 
X 
 
X 
 
X 
 
X 
 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
update 
 
 
X 
 
X 
 
X 
 
X 
Adherence 
 
 
X 
 
X 
 
X 
 
X 
Distance visual 
acuity 
X 
 
X 
 
X 
 
X 
 
X 
Stereoacuity 
X 
 
X 
 
X 
 
X 
 
X 
Ocular 
alignment 
X 
 
X 
 
X 
 
X 
 
X 
Interpupillary 
distance 
X 
 
 
 
 
 
 
 
 
Exit 
questionnaire  
 
 
 
 
 
 
X* 
 
X 
Compensation 
X 
 
X 
 
X 
 
X 
 
 
Recollect 
therapeutic 
 
 
 
 
 
 
X* 
 
X 
*Luminopia One active group only  
 
 

 
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8.2. Appendix 2: Stereoacuity Testing 
Titmus Fly 
The Titmus Fly test is to be conducted with current refractive correction. The testing distance is 40 
cm. If the participant identifies the fly correctly, their stereoacuity is presumed to be 3000 seconds 
of arc or better. If the participant does not identify the fly correctly their stereoacuity is presumed to 
be 10000 seconds of arc or worse. 
 
Procedure 
• Place Polaroid glasses on subject (over prescription glasses or contact lenses, if worn) before 
opening the test booklet. 
• Display the fly. Ask the subject to pinch the tips of the wings. 
 
Randot Preschool 
The Randot Preschool test measures random dot stereoacuity from 800 to 40 arc seconds (800, 400, 
200, 100, 60, 40). The Randot Preschool test consists of 3 booklets each with 2 sets of 4 random dot 
shapes, which can be matched to non-stereo shapes on the opposite side of the booklets. There are 
six levels (seconds of arc) in the test with two levels in each book. Each level has 4 rectangles that 
contain 3 shapes and one blank. Testing order is Book 3, Book 1, Book 2. 
 
Procedure 
1. As a pretest, use Book 3. 
2. Point to the top 4 panels on the non-stereo side (black on white shapes) and ask, “Can you 
point to the duck?” If the child does not correctly identify the duck, do not proceed with the 
rest of the test. 
3. Starting with Book 3, turn to the Randot side of the test booklet starting with the top level, 
point to one of the boxes containing a Randot shape, and ask the subject what shape is in the 
box. The child should be encouraged to match one of the black and white shapes to the 
Randot shape. 
4. Continue by pointing to another shape at the same level. For each shape, indicate whether 
the patient identified correctly or incorrectly by tapping the image. 
5. If 2 shapes are identified correctly at a level, testing will proceed to the next level. 
6. If 2 shapes are identified incorrectly at a level, testing will stop at the current level. 
7. The final score will be calculated as the lowest level of seconds of arc measured at which 2 
shapes were correctly identified. 
 
The final stereoacuity measurement used for analysis for each visit is the higher measurement 
between the Titmus Fly and the Randot Preschool tests. 
 

 
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8.3. Appendix 3: Distance VA Testing 
Visual acuity testing is to be performed using the ATS-HOTV testing protocol with single 
surrounded optotypes on an electronic visual acuity (EVA) system supported by the EMMES 
Corporation or obtained from M&S Technologies. The Visual Acuity Protocol contains further 
details on the conduct of this procedure.  
 
The examiner will test the participant’s amblyopic eye visual acuity first, followed by the 
participant’s fellow eye visual acuity. 
 
The ATS-HOTV electronic visual acuity testing protocol inherently incorporates testing of the 
visual acuity limit twice in order to increase test-retest reliability38. The ATS-HOTV programs on 
the EVA system automatically execute the following Visual Acuity Testing Protocol: 
 
Single letters with surround bars are presented in four phases:  
 
Screening  Phase I  Reinforcement Phase II 
 
• In Phase I and II, up to 4 single letters are sequentially presented at each logMAR level 
that is tested. 
• LogMAR levels are: 20/800, 20/640, 20/500, 20/400, 20/320, 20/250, 20/200, 20/160, 
20/125, 20/100, 20/80, 20/63, 20/50, 20/40, 20/32, 20/25, 20/20, 20/16, 20/12 
• A level is “passed” if 3 of 3 or 3 of 4 letters are correct and “failed” if 2 letters are 
missed. 
• Testing of a level stops as soon as criteria are met for either “pass” or “fail”. 
 
Screening Phase 
1. Tester selects 20/100 or 20/400 size letter to present as a starting point, based on prior 
knowledge about the participant’s visual acuity. 
2. If response is correct, letter at next smallest logMAR level is presented and testing continues 
sequentially with one letter per logMAR level towards 20/20 until there is an incorrect 
response. 
3. If starting point was 20/100 and response is incorrect at either 20/100 or 20/80, screening is 
restarted at 20/400. 
4. If screening starts at 20/400 and response is incorrect, testing continues sequentially with 
one letter per logMAR level towards 20/800 until there is a correct response. 
5. If 20/800 is missed, 20/800 becomes the starting level for phase I. 
 
Phase I 
1. Up to 4 single letters are sequentially presented 2 logMAR levels above the level missed in 
screening. 
a. Exception: If 20/20 was correct in Screening, phase I starts at 20/30. 
b. Exception: If 20/800 or 20/640 was missed in Screening, phase I starts at 20/800. 
2. If the first level tested is failed, testing continues at sequentially larger logMAR levels until 
a level is passed. 
a. If 20/800 is failed, phase I ends, the Reinforcement phase is skipped, and 20/800 is 
retested in phase II. 
3. If the first level tested is passed, testing continues at sequentially smaller logMAR levels 
until a level is failed. 
 

 
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Reinforcement Phase 
1. Starting 3 levels larger than the level missed in phase I, 3 successively smaller single letters 
are presented. 
a. Exception: If the level failed in phase I is 20/500 or 20/640, 3 20/800 letters are 
shown for reinforcement. 
b. Note: The reinforcement phase responses do not contribute to the visual acuity score 
and even if the responses are incorrect, the test proceeds to phase II. 
 
Phase II 
1. Up to 4 single letters are sequentially presented at the last level missed in phase I. 
2. If the level is failed, testing stops. 
3. If the level is passed, testing continues at sequentially smaller logMAR levels until a level is 
failed. 
 
Final Visual Acuity Score 
The visual acuity score is the smallest logMAR level passed in Phase I or Phase II. 
 
 

 
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8.4. Appendix 4: Ocular Alignment (Simultaneous Prism Cover Test) 
The Simultaneous Prism Cover Test (SPCT) is to be conducted with current refractive correction. 
The SPCT is used to measure a tropia. The SPCT is performed at distance (3m) fixation using an 
accommodative target (never a fixation light). 
 
Procedure 
1. Determine the fixating eye by inspection and/or a cover test. 
2. Rapidly and simultaneously, position a cover before the fixating eye while placing a prism 
before the deviating eye. 
3. Watch for movement of the nonfixating eye. The cover and prism are quickly removed and 
the binocular state reestablished. 
4. Repeat steps #2 and #3, increasing the power of the prism until a reversal of the movement 
of the deviating eye is seen, where the prism is overcorrecting the deviation. Record the 
magnitude of prism that either neutralized the deviation or was closest to neutralizing the 
deviation. 
 
 

 
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8.5. Appendix 5: Interpupillary Distance 
Interpupillary Distance (IPD) can either be measured by a ruler or by a pupilometer. The procedure 
for measuring IPD with a ruler is as follows: 
 
Procedure 
1. Examiner stands at 40 cm (16 inches). 
2. Examiner closes right eye, participant fixes on examiner’s left eye. 
3. Examiner lines up the ruler zero point on the participant’s right pupil, left pupillary border, 
or left limbus. 
4. Examiner closes left eye, participant fixes on examiner’s right eye. 
5. Examiner reads scale directly in line with participant’s life pupil center, left pupillary 
border, or left limbus. 
6. Examiner closes right eye, participant fixes on examiner’s left eye. 
7. Examiner checks to make sure that zero point is still correct. 
Common Difficulties and Solutions 
8. If participant cannot close one eye, the eye can be occluded with a free hand. 
9. If participant has strabismus, cover the participant’s eye which is not being observed. 
10. If participant is uncooperative, take a canthus-to-canthus measurement. 
 
The procedure for measuring IPD with a pupilometer is as follows: 
Pupilometer 
1. Rest the instrument lightly on the nose with the child looking into the instrument. Move the 
slide so that the vertical line bisects the pupil and read the value from the instrument. 
 
 

 
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8.6. Appendix 6: Exit Questionnaire 
For parent to complete during primary endpoint visit (Visit 4) or Visit 5 (if applicable). 
 
1. On a scale of 0 (not likely at all) to 10 (extremely likely), how likely is it that you would recommend the 
Luminopia therapeutic to someone else with lazy eye? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
2. How likely would you be to choose the Luminopia therapeutic over eye-patching to treat your child’s 
amblyopia in the future? 
Very unlikely 
Unlikely 
Neutral 
Likely 
Very likely 
 
3. Do you have any suggestions on how to make the therapeutic more comfortable or more captivating 
for your child? 
4. How did Luminopia One fit into your daily routine? 
Very disruptive 
Disruptive 
Neutral 
Easily 
Very easily 
5. What was the most enjoyable part of you and/or your child’s experience with Luminopia One? 
6. What was the most frustrating part of you and/or your child’s experience with Luminopia One? 
7. How valuable did you find the ability to review your child’s usage data on the Patient Portal? 
Not valuable at all 
Not valuable 
Neutral 
Valuable 
Very valuable 
 
8. How valuable did you find the ability to curate content for your child on the Patient Portal? 
Not valuable at all 
Not valuable 
Neutral 
Valuable 
Very valuable 
 
9. Do you have any suggestions on how to make the Patient Portal more useful? 
10. The average cost of braces for children’s teeth is just under $5000. Given that, if your child 
continued to need an amblyopia therapeutic, how likely would you be to purchase Luminopia One at 
$1500? 
Very unlikely 
Unlikely 
Neutral 
Likely 
Very likely 
 
11. If your child continued to need an amblyopia therapeutic, how likely would you be to purchase 
Luminopia One at $950? 
Very unlikely 
Unlikely 
Neutral 
Likely 
Very likely 
 
 
 
 
 

 
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8.7. Appendix 7: Phone Call Questionnaire and Adverse Event Queries 
 
Phone Call Questionnaire 
For study personnel to ask parent/guardian during phone calls. 
 
1. What are your general thoughts about you and/or your child’s experience using Luminopia 
One so far? 
2. Have you and/or your child encountered any issues with the usability of Luminopia One? 
3. How long does your child use Luminopia One for each day? (If less than an hour) What 
stops your child from using Luminopia One for an hour each day? 
4. What are your child’s favorite shows in Luminopia One? 
5. What shows does your child wish were available in Luminopia One? 
 
Phone Call Adverse Event Query 
For study personnel to ask parent/guardian during phone calls. 
 
1. Have you noticed any change in your child’s health since the last visit?  
O No        O Yes  → Explain and record AE 
2. Has your child reported Double Vision (Diplopia)?  
O No        O Yes  → Explain and record AE 
3. Has your child reported or have you noticed any worsened Eye Turn (Ocular 
Misalignment)?  
O No        O Yes  → Explain and record AE 
4. Has your child reported Headaches?  
O No        O Yes  → Explain and record AE 
5. Has your child reported Nausea?  
O No        O Yes  → Explain and record AE 
6. Has your child reported Eye Strain?  
O No        O Yes  → Explain and record AE 
 
In Person Adverse Event Query 
For study personnel to ask parent/guardian and participant during study visits. 
 
1. Have you noticed any change in your child’s health since the last visit?  
O No        O Yes  → Explain and record AE 
2. Has your child reported Double Vision (Diplopia)?  
O No        O Yes  → Explain and record AE 
3. (To the child) Have you seen “two Moms or two Dads” at any time? 
O No        O Yes  → Explain and record AE 

 
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4. Has your child reported or have you noticed any worsened Eye Turn (Ocular 
Misalignment)?  
O No        O Yes  → Explain and record AE 
5. Has your child reported Headaches?  
O No        O Yes  → Explain and record AE 
6. (To the Child) Has your head hurt at all? 
O No        O Yes  → Explain and record AE 
7. Has your child reported Nausea?  
O No        O Yes  → Explain and record AE 
8. Has your child reported Eye Strain?  
O No        O Yes  → Explain and record AE 
9. (To the Child) Have your eyes hurt or felt blurry at all? 
O No        O Yes  → Explain and record AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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8.8. Appendix 8: Summary of Amendment Changes 
Page 1-3 
• Background and Summary  Current Treatments 
o Paragraph beginning with “In teenagers…” since that information is irrelevant to 
study population age of 4-7 years. 
Page 1-4 
• Background and Summary  Results of Luminopia One Pilot Trials 
o Results from pilot trials updated 
Page 1-5 
• Proposed Study Design 
o Change of N from 130 to 140 following statistics evaluation, change of age group 
from 4-6 to 4-7 years old and change of study duration to 12 weeks, in paragraph 1 
o Added exclusion for > 12 months of prior amblyopia treatment 
Page 1-6 
• Study Objective  
o Study objectives section revised to specify study endpoints – specifically, primary 
efficacy and primary safety endpoint 
• Synopsis of Study Design  Major Eligibility Criteria –see Section 2.2 for complete list 
o Upper age changed limit changed from 6 to 7 years of age 
• Treatment Groups – see Section 3.1 and 3.2 for more information 
o Therapeutic group prescription refined  
o Control group prescription refined  
• Sample Size 
o Study N changed from 130 to 140 and age upper bound changed from 6 to 7 years  
• Visit Schedule – see Section 3.4 for more information 
o Visit 4 added as primary endpoint visit after 12 weeks.  
o Call 3 added 
Page 1-7 
• “Testing Procedure” paragraph changed to “Primary Endpoint Treatment Procedure” to 
further describe the VA procedure 
• “Statistical Analysis” section updated and expanded after statistician review 
• Steering committee section eliminated 
Page 1-9 
• Visit 4 information added to flow chart 
• Flow Chart updated  
• Call 3 added 
Page 2-1 
• Informed Consent updated to include Assent procedures of 7 year old participants and 
updating study N 
• Inclusion 3 updated from 6 to 7 years 
• Inclusion 4a refined 
• Inclusion 5, cycloplegic refraction changed from 9 to 7 months, and the “Note” eliminated 
as it caused covered by inclusion/exclusion 
Page 2-2 
• Inclusion 5a and 5b refined 
• Inclusion 5b of Fellow Eye requirement eliminated 
• Inclusion 9, refined  

 
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• Exclusion 1 eliminated as a discontinuation of prism would require stability in new 
refraction and is contradictory with other criteria 
• Added exclusion for > 6 months of prior amblyopia treatment 
• Exclusion 4 refined  
Page 2-4 
• Update of study duration from 8 to 12 weeks 
• Therapeutic and Control prescription refined 
• Section 2.4.1 on Luminopia One Therapeutic Administration refined and expanded to 
describe use of both Therapy and Controls 
• Section of Optional Crossover for participants in control group placed from page 3-3 in 
protocol  
Page 3-1 
• Therapeutic group restricted to use of 60 continuous minutes 
• Study duration updated to 12 weeks and usage updated from 7 days to 6 days.  
• Study calls refined 
• Change in Follow-up visit Testing Procedure refining requirement of corrective glasses in 
VA testing 
• Inclusion of Phone Call Questionnaire  
Page 3-2 
• Clarification that all comparator group will have refraction 
• Restriction of Masked Examiner access to treatment information and training.  
• Inclusion of Exit Questionnaire  
Page 3-3 
• Section of Optional Crossover for participants in control group removed from page 3-3 in 
protocol and moved to page 2-4 
• Corrective Refraction restriction added. 
Page 4-1 
• Participant Compensation updated 
• Study Costs Refined 
• Inclusion of study sites and enrollment limitation   
• Elimination of Adherence procedures to prevent bias between active and control groups  
• Elimination of Management of Refractive Error section, refraction will be kept the same 
during the study. 
• Elimination of Discontinuation of Study, as there is no steering committee 
Page 5-5 
• Risk assessment expanded 
Page 6-1  
• Statistics section – Extensive Rewrite 
Page 8-3 
• Schedule of Events Table updated 
Page 8-5 
• Distance VA Testing procedure updated 
Page 8-9 
• Inclusion of Appendix 6 
Page 8-10 
• Inclusion of Appendix 7 
 
 

 
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8.9. Appendix 9: Investigators Signature 
 
Protocol Title: Luminopia One Amblyopia Vision Improvement Study 
 
Protocol Number: C-AM-2 Amendment 1 
 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
conditions of the IRB, ICH Guidelines for Good Clinical Practice (GCP) and all applicable laws and 
regulations, to supervise all usage of the device involving human subjects, and to ensure that the 
requirements for obtaining informed consent are met. 
 
 
 
Printed Name:  
 
 
 
Signed: 
 
 
Date: