Randomized Trial of Bifocal Spectacles vs. Single Vision Spectacles for Esotropia Greater at Near
Phase: PHASE3
Conditions: Esotropia
Sponsor: Jaeb Center for Health Research

 
ETS03RCT_PROTOCOL_V1.1_1JUNE2022 (CLEAN) 
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Signature Page 
Randomized Trial of Bifocal Spectacles vs. Single Vision 
Spectacles for Esotropia Greater at Near 
 
Protocol Identifying Number: ETS3 
Version Number: 1.1 
June 1, 2022 
 
Protocol Co-Chair 
Name, degree 
Kristine B. Hopkins, O.D., MSPH 
Title 
Protocol Co-chair 
Institution Name 
University of Alabama at Birmingham School of Optometry 
1716 University Blvd 
Birmingham, AL 35294 
Cell Phone:  205-243-0137 
Email:  kbhopkins@uab.edu 
Signature/ Date 
 
Protocol Co-Chair 
Name, degree 
Justin D. Marsh, M.D. 
Title 
Protocol Co-chair 
Institution Name 
Eye Physicians of Central Florida 
790 Concourse Parkway 
Maitland, FL 32751 
Cell Phone: 803-553-9486 
Email: jmarsh@eyephy.com 
Signature/ Date 
 
JCHR Lead Investigator 
Name, degree 
Danielle L. Chandler, M.S.P.H. 
Title 
Principal Investigator 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: dchandler@jaeb.org  
Signature/ Date 
 

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ETS03RCT_PROTOCOL_V1.1_1JUNE2022 (CLEAN) 
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Randomized Trial of Bifocal Spectacles vs. Single Vision 
Spectacles for Esotropia Greater at Near 
 
Protocol Identifying Number: ETS3 
Funded by: The National Eye Institute of the National Institutes of Health  
Version Number: 1.1 
June 1, 2022 
 

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KEY ROLES 
 
Protocol Co-Chair 
Name, degree 
Kristine B. Hopkins, O.D., MSPH 
Title 
Protocol Co-chair 
Institution Name 
University of Alabama at Birmingham School of Optometry 
1716 University Blvd 
Birmingham, AL 35294 
Cell Phone:  205-243-0137 
Email:  kbhopkins@uab.edu 
Protocol Co-Chair 
Name, degree 
Justin D. Marsh, M.D. 
Title 
Protocol Co-chair 
Institution Name 
Eye Physicians of Central Florida 
790 Concourse Parkway 
Maitland, FL 32751 
Cell Phone: 803-553-9486 
Email: jmarsh@eyephy.com 
JCHR Lead Investigator 
Name, degree 
Danielle L. Chandler, M.S.P.H. 
Title 
Principal Investigator 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: dchandler@jaeb.org  

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TABLE OF CONTENTS 
List of Abbreviations .............................................................................................................................. 8 
Protocol Summary ................................................................................................................................ 10 
Study Summary Flow Chart ................................................................................................................. 13 
Schedule of Study Visits and Procedures ............................................................................................. 15 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 17 
1.1 Introduction ....................................................................................................................................... 17 
1.2 Current Practice ................................................................................................................................. 17 
1.3 Potential Benefits of Treatment with Bifocal Lenses and Single Vision Lenses .............................. 17 
1.3.1 Treatment with Bifocal Lenses (BFLs) ....................................................................................... 17 
1.3.2 Treatment with Single Vision Lenses (SVLs) ............................................................................. 18 
1.4 Studies Evaluating BFLs and SVLs .................................................................................................. 18 
1.4.1 Comparative Studies of BFLs versus SVLs ................................................................................ 18 
1.4.2 Bifocal Lenses – On-Treatment Outcomes ................................................................................. 19 
1.4.3 Single Vision Lenses – On-Treatment Outcomes ....................................................................... 19 
1.4.4 Potential Risks of BFL Spectacles .............................................................................................. 20 
1.4.5 Potential Risks of Single Vision Spectacles ................................................................................ 20 
1.5 Risks of Examination or Testing Procedures..................................................................................... 20 
1.6 Risk Assessment ................................................................................................................................ 20 
1.7 Summary of Existing Data ................................................................................................................ 20 
1.8 Rationale for Present Study ............................................................................................................... 21 
1.9 Study Objectives ................................................................................................................................ 21 
1.10 General Considerations.................................................................................................................... 21 
CHAPTER 2: STUDY ENROLLMENT AND RANDOMIZATION .................................................................... 22 
2.1 Participant Recruitment and Enrollment ........................................................................................... 22 
2.1.1 Informed Consent ........................................................................................................................ 22 
2.2 Eligibility Criteria .............................................................................................................................. 22 
2.3 Exclusion Criteria .............................................................................................................................. 24 
2.4 Historical Information ....................................................................................................................... 24 
2.5 Procedures at Enrollment ................................................................................................................... 25 
2.6 Spectacle Tolerance Criteria at Enrollment ....................................................................................... 26 
2.7 Randomization ................................................................................................................................... 26 
2.8 Prescription of Randomized Treatment ............................................................................................. 26 
CHAPTER 3: STUDY FOLLOW-UP .............................................................................................................. 28 
3.1 Study Follow-up Visits ...................................................................................................................... 28 

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3.1.1 Phone Calls .................................................................................................................................. 29 
3.2 Masking Procedures .......................................................................................................................... 29 
3.2.1 Masked Examiner ........................................................................................................................ 29 
3.3 Follow-up Procedures Prior to 36 Months......................................................................................... 30 
3.4 36-Month Primary Outcome Visit ..................................................................................................... 31 
3.4.1 Prescribing Bifocal Spectacles at the 36-month Primary Outcome Visit .................................... 32 
3.5 Failure Criteria ................................................................................................................................... 33 
3.5.1 Procedures for Participants Meeting Failure Criteria at a Study Visit PRIOR 
to the 36-month Primary Outcome Visit .............................................................................................. 34 
3.5.2 Procedures for Participants Meeting Failure Criteria AT the 36-month 
Primary Outcome Visit ......................................................................................................................... 35 
3.6 Failure Confirmation Visit ................................................................................................................. 36 
3.7 Post-failure Secondary Outcome Visit (After Confirmed Failure) .................................................... 37 
3.7.1 Treatment After the Post-failure Secondary Outcome Visit........................................................ 37 
3.7.2 Follow-up After the Post-failure Secondary Outcome Visit ....................................................... 37 
3.8 38-month Secondary Outcome Visit ................................................................................................. 38 
3.9 Inability to Complete a Study Visit ................................................................................................... 39 
3.10 Initiating Non-randomized Treatment for Esotropia (ET) ............................................................... 39 
3.11 Treatment of Amblyopia ................................................................................................................. 40 
3.12 Spectacle Tolerance Criteria for Follow-up .................................................................................... 40 
3.12.1 Change in Spectacles Because Lensometry Reveals Spectacles are Out of 
Tolerance .............................................................................................................................................. 41 
3.13 Management of Refractive Error During Follow-up ....................................................................... 41 
3.13.1 Change in Spectacles Following a Change in Cycloplegic Refraction ..................................... 41 
3.13.2 Reduction of Hyperopic Correction Because of Distance Blur ................................................. 41 
3.13.3 Management of Refractive Error to Control Exodeviations ...................................................... 41 
CHAPTER 4: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 42 
4.1 Clinical Assessments ......................................................................................................................... 42 
CHAPTER 5: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING ....................................... 44 
5.1 Unanticipated Problems ..................................................................................................................... 44 
5.2 Adverse Events .................................................................................................................................. 44 
5.2.1 Reportable Adverse Events ......................................................................................................... 44 
5.3 Safety Oversight ................................................................................................................................ 44 
5.4 Stopping Criteria ............................................................................................................................... 45 
5.5 Participant Discontinuation of Study Treatment ............................................................................... 45 
CHAPTER 6: MISCELLANEOUS CONSIDERATIONS ................................................................................... 46 

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6.1 Contacts by the Jaeb Center for Health Research and Sites .............................................................. 46 
6.2 Participant Compensation .................................................................................................................. 46 
6.3 Cost of Spectacles .............................................................................................................................. 46 
6.4 Participant Withdrawal ...................................................................................................................... 46 
6.5 Confidentiality ................................................................................................................................... 46 
CHAPTER 7: STATISTICAL CONSIDERATIONS .......................................................................................... 47 
7.1 Statistical and Analytical Plans ......................................................................................................... 47 
7.2 Primary Objective and Hypothesis .................................................................................................... 47 
7.3 Sample Size ....................................................................................................................................... 47 
7.4 Interim Monitoring ............................................................................................................................ 48 
7.5 Analysis Dataset ................................................................................................................................ 49 
7.6 Analysis of Primary Outcome – Treatment Failure by 36 Months .................................................... 49 
7.6.1 Sensitivity Analyses for Primary Outcome ................................................................................. 50 
7.6.2 Contingency Plan for Primary Outcome ..................................................................................... 50 
7.7 Analysis of Secondary Outcomes ...................................................................................................... 50 
7.7.1 Binocular Function Test Score in BFLs at the Secondary Outcome Visit .................................. 50 
7.7.2 Treatment Effects on Failure by 36 Months by Subgroup .......................................................... 51 
7.8 Exploratory Analysis of Tertiary Outcomes ...................................................................................... 52 
7.8.1 Ocular Alignment at Distance and Near ...................................................................................... 52 
7.8.1.1 Comparison of Randomized Treatments at 36 Months or Confirmed Failure .................... 52 
7.8.2 Binocular Function Test Score .................................................................................................... 53 
7.8.2.1 Subgroup Analysis of Secondary Outcome Binocular Function Score .............................. 53 
7.8.2.2 Comparison of Overall Treatment Strategies at 38 Months ................................................ 53 
7.8.2.3 Comparison of Randomized Treatments at 36 Months or Confirmed Failure .................... 53 
7.8.3 Near Stereoacuity ........................................................................................................................ 53 
7.8.3.1 Comparison of Randomized Treatments at the Secondary Outcome Visit ......................... 53 
7.8.3.2 Comparison of Overall Treatment Strategies at 38 Months ................................................ 53 
7.8.3.3 Comparison of Randomized Treatments at 36 Months or Confirmed Failure .................... 54 
7.8.4 Distance Stereoacuity .................................................................................................................. 54 
7.8.4.1 Comparison of Randomized Treatments at the Secondary Outcome Visit ......................... 54 
7.8.4.2 Comparison of Overall Treatment Strategies at 38 Months ................................................ 54 
7.8.4.3 Comparison of Randomized Treatment at 36 Months or Confirmed Failure ..................... 54 
7.8.5 Short-term Effect of BFLs in SVL Group Post-failure and at 38 Months ................................... 54 
7.9 Safety Analyses ................................................................................................................................. 54 
7.9.1 Distance Motor and Near Stereoacuity Treatment Failures ........................................................ 54 
7.9.2 Diplopia ....................................................................................................................................... 54 

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7.9.3 Reduction of Distance Visual Acuity .......................................................................................... 55 
7.10 Spectacle Adherence ........................................................................................................................ 55 
7.11 Additional Tabulations and Analyses .............................................................................................. 55 
CHAPTER 8: DATA COLLECTION AND MONITORING .............................................................................. 56 
8.1 Case Report Forms and Other Data Collection ................................................................................. 56 
8.2 Study Records Retention ................................................................................................................... 56 
8.3 Quality Assurance and Monitoring .................................................................................................... 56 
8.4 Protocol Deviations ........................................................................................................................... 57 
CHAPTER 9: ETHICS/PROTECTION OF HUMAN PARTICIPANTS .............................................................. 58 
9.1 Ethical Standard ................................................................................................................................. 58 
9.2 Institutional Review Boards .............................................................................................................. 58 
9.3 Informed Consent Process ................................................................................................................. 58 
9.3.1 Consent Procedures and Documentation ..................................................................................... 58 
9.3.2 Participant and Data Confidentiality ........................................................................................... 58 
9.3.3 Future Use of Data....................................................................................................................... 59 
CHAPTER 10: REFERENCES ....................................................................................................................... 60 
 

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List of Abbreviations 
ABBREVIATION 
DEFINITION 
∆ 
Prism diopters 
AC/A 
Accommodative convergence to accommodation ratio 
ANCOVA 
Analysis of covariance 
arcsec 
Seconds of arc 
ATS 
Amblyopia Treatment Study 
ATS-HOTV 
Amblyopia Treatment Study HOTV visual acuity testing protocol 
ETS 
Esotropia Treatment Study 
CC 
Coordinating Center 
CI 
Confidence interval 
BFL 
Bifocal Lenses 
CFR 
Code of Federal Regulations 
CR 
Cycloplegic refraction 
CRF 
Case report form 
D 
Diopter 
DSMC 
Data safety and monitoring committee 
DVD 
Dissociated vertical deviation 
eCRF 
Electronic case report form  
E-ETDRS 
Electronic Early Treatment of Diabetic Retinopathy Study visual acuity protocol 
ET 
Esotropia 
EVA 
Electronic visual acuity tester 
FDA 
Food and Drug Administration 
ICH 
International Council for Harmonisation 
IOD 
Interocular difference 
IRB 
Institutional Review Board 
IXT 
Intermittent exotropia 
JCHR 
Jaeb Center for Health Research 
log arcsec 
Logarithm of seconds of arc 
logMAR 
Logarithm of the minimal angle of resolution 
ME 
Masked examiner 
NIH 
National Institutes of Health 
PACT 
Prism and alternate cover test 
PEDIG 
Pediatric Eye Disease Investigator Group  
RPS 
Randot Preschool Stereoacuity test 
SE 
Spherical equivalent refractive error (Sphere + ½ Cylinder) 
SPCT 
Simultaneous prism and cover test 
SVL 
Single-vision lenses 
TF 
Trial frames 
VA 
Visual acuity 
VT 
Vision therapy 
 

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PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL 
1 
Randomized Trial of Bifocal Spectacles vs. Single Vision Spectacles for 
2 
Esotropia Greater at Near (ETS03) 
3 
 
4 
 
5 
Each clinical site that is approved to participate in the ETS03 study will have one individual designated as the Protocol 
6 
Principal Investigator (Protocol PI) at the site for this protocol. This investigator may or may not be the same 
7 
investigator that serves as the overall Network Site Principal Investigator (Site PI) for all PEDIG studies.  
8 
  
9 
The Protocol PI and the Site PI (if different) agree to the following for the ETS03 study – They will:  
10 
 
11 
• 
Have a thorough understanding of the protocol design and study procedures.  
12 
• 
Ensure that local institutional requirements (if applicable) are satisfied for the protocol and that approvals and 
13 
assurances are obtained annually, if required. 
14 
• 
Ensure that the required protocol-certified staff, facilities, and equipment are available to conduct the study. 
15 
• 
Ensure that the required protocol staff have a thorough understanding of the protocol design and procedures.  
16 
• 
Provide adequate support and guidance to site investigators, coordinators, and other staff so that the study can 
17 
be conducted according to protocol. 
18 
• 
Respond promptly to requests from the Coordinating Center (CC), Network Chair/s, or Protocol Chair/s.  
19 
• 
Correspond and maintain accessibility via email and phone with the site’s PEDIG Protocol Monitor.  
20 
• 
Oversee local study documentation and records. 
21 
• 
Conduct periodic meetings of study personnel at their clinical site(s). 
22 
• 
Cooperate with the PEDIG Protocol Monitors by working with the site coordinator to make available study 
23 
personnel, study records, protocol binders, clinic charts for study participants, and other necessary records 
24 
needed for on-site or virtual monitoring visits. 
25 
• 
Notify the CC if any protocol adherence or data reporting problem is discovered or suspected. 
26 
• 
Attend scheduled PEDIG meetings and conference calls, including those for any PEDIG committees to which 
27 
appointed. 
28 
• 
Review study monitoring reports evaluating clinical site performance and discuss with the CC any areas 
29 
identified to be deficient. 
30 
 
31 
Given the amount of time and effort required for site personnel to become certified for the study (and for the 
32 
Coordinating Center to manage the site), the PEDIG Executive Committee is asking each interested site to declare the 
33 
number of participants meeting ETS03 protocol criteria they feel they can enroll into the study.  
34 
 
35 
After review of ETS03 eligibility criteria with participating site staff, and retrospective chart review, Site ___ ___ ___ 
36 
commits to enroll 3 new participants each year for 4 years and to follow them for the duration of the study.  
37 
 
38 
If you feel you do not see a sufficient number of eligible patients who are likely to enroll into the study each year, we 
39 
ask that you not pursue certification for the study.  
40 
 
41 
In addition to the above, the Protocol PI and the Site PI (if different) agree(s) that they:  
42 
• 
Understand the importance of successful follow-up and retention of those enrolled at our site.  
43 
• 
Agree that the site has the potential and commits to enroll the number of participants stated above per year 
44 
once certified. 
45 
 
46 
Protocol Principal Investigator’s Signature ________________________Date: _____ / _____ / _____ 
47 
 
48 
Name: ____________________________ 
49 
 
50 
To be completed only if different:  
51 
Network Site Principal Investigator’s Signature _______________________Date: ____ / ____ / ____ 
52 
 
53 
Name: ____________________________                                Site #: _____________ 
 
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Protocol Summary 
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DESCRIPTION 
Title 
Randomized Trial of Bifocal Spectacles vs. Single Vision Spectacles for Esotropia Greater at 
Near 
Précis 
The study is being conducted to compare whether an optical correction of bifocal spectacle 
lenses (BFL) or single-vision spectacle lenses (SVL) is more effective for the treatment of 
children with esotropia greater at near. Children will be randomized to be treated with BFLs or 
SVLs for 3 years and be evaluated at regular intervals throughout the study to determine 
whether their condition has worsened. Children whose condition worsens during the study will 
either start BFL treatment (if randomized to SVL group) or continue BFL treatment (if 
randomized to BFL group) for 2 months to allow assessment of outcome in BFLs, and then be 
released to treatment at investigator discretion while continuing in study follow-up. Children 
whose condition has not worsened during the study will start or continue BFL (depending on 
treatment group) for 2 months at 3 years. All children return at 38 months to assess binocular 
function. The effectiveness and safety of both treatments will be compared. 
Objectives 
• To compare the proportion of BFL and SVL participants with treatment failure by 36 months  
• To compare binocular function test scores between the BFL and SVL groups with both 
groups in BFL at 38 months after randomization (or 2 months after treatment failure)  
• To evaluate treatment failure by 36 months according to baseline factor subgroups of: 
duration of constant esotropia pre-enrollment, presence of near stereoacuity on the Randot 
Preschool Stereoacuity test, in-office response of near alignment with +3.00 D lenses, and 
gradient AC/A ratio  
Study Design 
Multicenter, randomized clinical trial 
Number of Sites 
Up to 70 PEDIG sites will participate in the study.  
Endpoint 
Primary Effectiveness Outcome: Treatment failure defined as meeting any one of the  
following criteria at any follow-up visit between 3 months to 36 months inclusive: 
1. 
Distance motor failure: Constant ET ≥15∆ by SPCT at distance. (NOTE: intermittent 
esotropia and esophoria of any magnitude are NOT considered failures). 
2. 
Near stereo failure: Decrease in near stereoacuity on the Randot Preschool Stereotest 
of 2 or more levels from baseline or from 960” at baseline to nil (criteria not 
applicable if nil near stereo at baseline)  
• 
Baseline stereoacuity is defined as the near stereoacuity performed with +3.00 D 
added to the participant’s enrollment distance spectacle correction in trial frames. 
• 
At all follow-up visits, the best of two stereo measures in the OFFICE lenses will 
be used to determine treatment failure.  
• 
Stereoacuity values are calculated for the 33 cm test distance required for testing 
through the added +3.00 D lenses at near (instead of the standard 40 cm).  
• 
NOTE: Participants without measurable near stereoacuity at baseline cannot fail 
by stereoacuity criteria. 
3. 
Binocular diplopia with a frequency of “more than 2 times per day” over the last 
week by parental report 
4. 
Nonsurgical or surgical treatment for ET, other than the randomized treatment, is 
started before a failure criterion is met  
 
Key Secondary Effectiveness Outcomes: Binocular function test score with both groups in 
BFLs 2 months following failure or at the 38-month visit, if no failure (whichever comes first).  
Key Safety Outcomes: Distance motor or near stereo failure, reduction of distance visual 
acuity of ≥0.2 logMAR 

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DESCRIPTION 
Population 
Inclusion Criteria for Enrollment: 
• Age 3 to <9 years 
• Esodeviation meeting all the following criteria is present in refractive correction (if 
required or worn) 
o 
Constant or intermittent esotropia ≥10∆ measurable by SPCT at near 
o 
Distance esotropia (constant, intermittent), esophoria, or orthophoria, with near 
esodeviation ≥10∆ larger than distance deviation by PACT 
▪ 
If constant ET at distance, then must be ≤6∆ by SPCT 
▪ 
If intermittent ET or esophoric at distance, can be any magnitude at 
distance (as long as near esodeviation is ≥10∆ larger than distance 
deviation by PACT) 
• Cycloplegic refraction within past 3 months (but not on day of exam) 
• Wearing spectacles for at least 4 weeks if refractive error is 0.75 D SE or more 
• Spectacles (if worn) must meet the following criteria: 
o SE refractive error must be corrected within ±0.625 D 
o Sphere power must be corrected within ±0.50 D  
o Anisometropia must be corrected within ±0.50 D SE 
o Cylinder power must be corrected within ±0.50 D  
o Cylinder axis must be within ±10 degrees if cylinder power is ≤1.00 D and within ±5 
degrees if cylinder power is >1.00 D. 
• Best-corrected VA meeting the following criteria:  
o Better-seeing eye VA is age-normal (see section 2.2) 
o IOD in VA within 0.2 logMAR (although previous amblyopia is allowed) 
o Worse-seeing eye VA of 20/63 or better 
• Investigator and parent willing to forgo treatment of ET other than assigned randomized 
treatment for 36 months unless failure criteria are met. 
• Investigator willing to prescribe BFL-spectacles only (in both treatment groups) for 2 
months after meeting failure criteria (if failed prior to 36 months); otherwise, between 36 
and 38 months  
 
Exclusion Criteria for Enrollment: 
• Previous BFL wear (SVL spectacle wear of any duration is allowed) 
• Current or planned contact lens wear over the next 3 years 
• Myopic refractive error of more than -6.00 D SE  
• Previous strabismus surgery (including Botox injection), intraocular surgery (e.g., laser, 
anti-VEGF injection, or cataract), extraocular surgery (e.g., scleral buckle), or refractive 
surgery  
• Previous treatment for ET using miotics, VT, or prism within prior 3 months 
• Amblyopia treatment other than refractive correction within prior 3 months 
• Vertical deviation ≥3Δ at distance or near by PACT 
• Oculomotor findings consistent with infantile ET (e.g., latent nystagmus, manifest 
nystagmus, DVD) 
• AV pattern: ≥10∆ difference between upgaze and downgaze by PACT at distance 
• Paretic or restrictive strabismus 
• Constant exotropia at near when tested through the +3.00 D add (intermittent XT and 
exophoria are allowed) 
• Diplopia “more than 2 times per day” over the last week prior to enrollment by parental 
report. The frequency of diplopia, if any, must be “2 times or less per day” to be eligible. 
• Significant developmental delay that would interfere with child’s ability to complete 
testing 
• Neurological conditions that could affect ocular motility (e.g., cerebral palsy, Down 
syndrome) 
• Immediate family member (child or sibling) of any site personnel directly affiliated with 
the study 
Sample Size 
444 participants randomized (approximately 222 per treatment group) 
Phase 
Phase 3 
Treatment Groups 
Random assignment (1:1) to: 

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DESCRIPTION 
• 
Single vision spectacles (SVLs)  
• 
Bifocal spectacles (BFLs): +3.00 D flat-top 35  
Duration of Participation 
38-40 months after randomization 
Protocol Overview/Synopsis 
Participants will be randomly assigned to treatment with a BFL or SVL spectacle correction for 
3 years. Generally, participants will be followed at 3-month intervals for the first year and every 
6 months thereafter until the primary outcome visit at 36 months. At each follow-up visit 
between 3 months and 36 months, ocular alignment and stereoacuity will be assessed to 
determine if any of the three study-specified failure criteria have been met (worsening of 
distance ET, reduction in near stereoacuity, or frequent diplopia (“more than 2 times per day” 
over the last week). The primary outcome is failure at or before 36 months. 
If a failure criterion is met between 3 to 30 months, participants randomized to SVLs will be 
prescribed BFLs and those in BFLs will be prescribed continued BFLs. Participants in both 
groups will return in BFLs 2 months after failure for a Post-failure Secondary Outcome Visit to 
determine the child’s binocular function, after which the child will be released to treatment at 
investigator discretion. Participants with confirmed failure who complete the Post-failure 
Secondary Outcome Exam will return for the 12- and 24-month follow-up visits (abbreviated 
testing) as well as the 38-month Secondary Outcome Visit (they will not return for the 36-
month Primary Outcome visit).  
If a failure criterion is not met between 3 to 30 months, participants without confirmed failure 
will complete the 36-month Primary Outcome Visit, After the 36-month visit, SVL group 
participants will be prescribed BFLs and BFL participants will continue using BFLs.  
All participants (i.e., regardless of failure status) will return for a 38-month Secondary Outcome 
Visit to assess binocular function. 
 
 
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Study Summary Flow Chart   
58 
 
59 
Randomization 1:1 
Bifocal (+3.00 D) Spectacles 
Single Vision Spectacles 
 
Enrollment Exam Test Procedures  
 Lensometry 
 Diplopia assessment 
 VA in spectacle correction (if worn): measured by ATS-HOTV; e-ETDRS; OR crowded single-optotype or single-
line HOTV, LEA SYMBOLS, or Snellen letters 
 Randot Preschool Stereoacuity Test in spectacles (if worn) 
 Distance Randot Stereotest in spectacles (if worn) 
 Randot Preschool Stereoacuity Test in TF with +3.00 added lenses  
 Random Dot Stereo Butterfly Test in TF with +3.00 added lenses 
 Preschool Worth 4-Shape test in TF with +3.00 added lenses 
 Near ocular alignment in TF with +3.00 added lenses 
 Distance and near ocular alignment in spectacles (if worn)   
Exclusion Criteria for Enrollment 
 Previous BFL wear (SVL wear of any duration is 
allowed) 
 Current or planned contact lens wear over the next 3 
years 
 Myopia more than -6.00 D SE  
 Previous strabismus surgery (including Botox), 
intraocular surgery, extraocular surgery, or refractive 
surgery  
 Previous treatment for ET using miotics, VT or prism 
within prior 3 months 
 Amblyopia treatment other than refractive correction 
within prior 3 months 
 Vertical deviation ≥3∆ at distance or near by PACT 
 Oculomotor findings consistent with infantile ET (e.g., 
latent nystagmus, manifest nystagmus, DVD) 
 AV pattern ≥10∆ difference between upgaze and 
downgaze by PACT at distance 
 Constant exotropia at near during enrollment visit 
when tested through +3.00 D add (intermittent XT and 
exophoria are allowed) 
 Paretic or restrictive strabismus 
 Diplopia “more than 2 times per day” over the last 
week prior to enrollment by parental report 
 Significant developmental delay that would interfere 
with child’s ability to complete testing 
 Neurological condition that could affect ocular motility 
(e.g., cerebral palsy, Down syndrome) 
 Immediate family member (child or sibling) of any 
investigative site personnel directly affiliated with the 
study 
3-, 6-, 9-, 12-, 18-, 24-, and 30-Month Visits (± 2 weeks) 
 Lensometry (HOME and OFFICE spectacles) 
 Diplopia assessment 
 VA (monocular at distance) through top of HOME spectacles* 
 Randot Preschool Stereoacuity Test #1 in OFFICE spectacles (masked)  
 Ocular alignment at near in OFFICE spectacles: cover/uncover, SPCT, PACT (masked) 
 Ocular alignment at distance / near through top of HOME spectacles: cover/uncover, SPCT, PACT (masked) 
 Randot Preschool Stereoacuity Test #2 in OFFICE spectacles (masked) 
 Cycloplegic refraction (12-, 24-, and 30-month visits only) – and performed after additional testing if failure criteria met at 
any visit 
* HOME spectacles are the spectacles prescribed at randomization that are worn full-time when not in the office. OFFICE 
spectacles are the SVL spectacles with +3.00 D over CR – kept in the office and used for masked testing only. 
Eligibility Criteria for Enrollment 
 Age 3 to < 9 years 
 
Esodeviation meeting all the following criteria in refractive 
correction (if required or worn) 
o Constant or intermittent esotropia ≥10∆ measurable by SPCT at 
near 
o Distance esotropia (constant, intermittent), esophoria, or 
orthophoria, with near esodeviation ≥10∆ larger than distance 
deviation by PACT 
 If constant ET at distance, then must be ≤6∆ by SPCT 
 If intermittent ET or esophoric at distance, can be any 
magnitude at distance (as long as near esodeviation is ≥10∆ 
larger than distance deviation by PACT) 
 Better-seeing eye VA is age normal 
o 3 years: 20/50 or better  
o 4 years: 20/40 or better  
o 5-6 years: 20/32 or better  
o 7-12 years: 20/25 or better 
 IOD in VA within 0.2 logMAR 
 Worse-seeing eye VA is 20/63 or better 
 Cycloplegic refraction within 3 months (but not on day of exam) 
 Wearing spectacles if refractive error is  
0.75 D SE or more 
 Current spectacles (if worn) meeting all the following: 
o Worn for at least 4 weeks 
o SE refractive error must be corrected within ±0.625 D  
o Sphere power must be corrected within ±0.50 D  
o Anisometropia must be corrected within ±0.50 D SE 
o Cylinder power must be corrected within ±0.50 D  
o Cylinder axis must be within ±10 degrees if cylinder power is 
≤1.00 D and within ±5 degrees if cylinder power is >1.00 D. 
Phone Call: 1 month ± 1 week 

JAEB CENTER FOR HEALTH RESEARCH 
ETS03RCT_PROTOCOL_V1.1_1JUNE2022 (CLEAN) 
14  
60 
Yes 
Additional testing after meeting failure criteria (unless previously failed) 
 Random Dot Stereo Butterfly Test in OFFICE spectacles (masked) 
 Preschool Worth 4-Shape test in OFFICE spectacles (masked) 
 Distance Randot Stereotest through TOP of HOME spectacles (masked) 
 Randot Preschool Stereoacuity Test #3 through TOP of HOME spectacles (masked) 
 Cycloplegic refraction 
No 
Yes 
Do spectacles 
require a change? 
No 
Prescribe BFL to SVL group; All return in 2 months for 38-Month Visit 
No 
Yes 
Are failure criteria 
confirmed at Failure 
Confirmation Visit? 
Has the participant met ANY of the following FAILURE criteria?* 
1. Constant esotropia ≥15∆ by SPCT at distance 
2. Decrease in Randot Preschool stereoacuity of 2 or more levels from baseline (or a 
decrease from 960” at baseline to nil) based on comparing the best of two stereo 
measures in OFFICE spectacles to baseline stereo in +3.00 D trial frames 
3. Diplopia “more than 2 times per day” over the last week, by parental report  
*Participants with previously confirmed failure do not need to complete additional testing at this visit 
Failure Confirmation Visit 
Perform all testing for 36-Month Visit (below) 
Update spectacles and return for Failure 
Confirmation Visit in 2 months 
Failure is confirmed.  Prescribe BFL to SVL Group and continue BFL in BFL 
Group: Return in 2 months for Post-Failure Secondary Outcome Visit  
Post-Failure Secondary Outcome Visit 
Perform all testing for 38-Month Secondary Outcome Visit (below) 
Not Failure 
Spectacle change NOT required 
36-Month Primary Outcome (± 2 weeks) 
 Lensometry (HOME and OFFICE spectacles) 
 Diplopia assessment 
 VA (monocular at distance) through TOP of HOME spectacles  
 Randot Preschool Stereoacuity Test #1 in OFFICE spectacles (masked) 
 Random Dot Stereo Butterfly Test in OFFICE spectacles (masked) 
 Preschool Worth 4-Shape test in OFFICE spectacles (masked) 
 Randot Preschool Stereoacuity Test #2 in OFFICE spectacles (masked) 
 Ocular alignment at near through OFFICE spectacles: cover/uncover, SPCT, PACT (masked) 
 Ocular alignment at distance / near through TOP of HOME spectacles by cover/uncover, SPCT, 
PACT (masked) 
 Distance Randot Stereotest through top of HOME spectacles (masked) 
 Randot Preschool Stereoacuity Test #3 through TOP of HOME spectacles (masked) 
Spectacle change required 
Prescribe new spectacles and return for a 
Failure Confirmation Visit in 2 months 
Failure 
Perform 
cycloplegic 
refraction 
Failure Confirmation 
Visit 
Perform all testing for 36-
Month Visit (above) 
Study 
Ends 
38-Month Secondary Outcome Visit (± 2 weeks)  
 Lensometry (HOME) 
 Diplopia assessment 
 VA (monocular at distance) through TOP of HOME spectacles (masked) 
 Cover/uncover test at near to determine optical correction (for participants not wearing BFLs--section 3.8)  
 Distance Randot Stereotest through TOP of HOME spectacles (masked) 
 Randot Preschool Stereoacuity Test #1 through BOTTOM of HOME spectacles (masked) 
 Random Dot Stereo Butterfly Test through BOTTOM of HOME spectacles (masked) 
 Preschool Worth 4-Shape through BOTTOM of HOME spectacles (masked) 
 Randot Preschool Stereoacuity Test #2 through TOP of HOME spectacles (masked) 
 Ocular alignment at distance / near through HOME spectacles by cover/uncover, SPCT, PACT (masked) 
Return to 
regular 
follow-up 
 
If <30-
month 
visit  
If 30-
month 
visit  
Return to 
follow-up 
at 12 and 
24 months 
(but with 
less testing)  
  
If <24-
month 
visit  
If 24-
month 
visit or 
later 

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Schedule of Study Visits and Procedures 
 
Enrollment / 
Randomization 
Visit 
3 to 30-month 
Visits (3, 6, 9, 12, 
18, 24, and 30)c 
36-Month Visit 
(Primary 
Outcome)f 
Failure 
Confirmation 
Visit 
Post-failure 
Secondary 
Outcome Visith 
38-Month 
Secondary 
Outcome Visitg 
Consent/Assent 
X 
---- 
---- 
---- 
---- 
---- 
Demographic Information / Ocular History 
X 
X 
X 
X 
X 
X 
Lensometry 
X 
Home and Office 
Home and Office 
Home and Office 
Home 
Home 
Diplopia Assessment 
X 
X 
X 
X 
X 
X 
Visual Acuity (monocular distance)a 
X 
Hometop 
Hometop 
Hometop 
Home top 
Home top 
Cover-uncover Test at Near (if not wearing 
BFLs at 38 months)g 
 
 
 
 
 
ME 
Homebot 
Randot Preschool Stereoacuity Test (33 cm) #1 
X 
ME 
Office 
ME 
Office 
ME 
Office 
ME 
Home bot 
ME 
Home bot i 
Distance Randot Stereotest (3 m) 
X 
if failsd 
ME 
Hometop  
ME 
Hometop 
ME 
Hometop 
ME 
Home top 
ME 
Home top 
Randot Preschool Stereoacuity Test (33 cm) #2 
TF+3 
ME 
Office 
ME 
Office 
ME 
Office 
ME 
Hometop 
ME 
Hometop 
Random Dot Stereo Butterfly Test (33 cm) 
TF+3 
if failsd 
ME 
Office 
ME 
Office 
ME 
Office 
ME 
Home bot 
ME 
Home bot g 
Preschool Worth 4-Shape (at 33 cm) 
TF+3 
if failsd 
ME  
Office 
ME 
Office 
ME 
Office 
ME 
Home bot 
ME 
Home bot g 
Ocular Alignment at distance and near  
(in study spectacles as specified) 
X 
ME 
Hometop 
ME 
Hometop 
ME 
Hometop 
ME 
Home 
ME 
Home 
Ocular Alignment at near through +3.00 D 
TF+3 
ME 
Office 
ME 
Office 
ME 
Office 
---- 
---- 
Randot Preschool Stereoacuity Test (33 cm) #3 
---- 
If failsd 
ME 
Hometop 
ME 
Hometop 
ME 
Hometop 
---- 
---- 
Cycloplegic Refraction  
---- 
12, 24, 30-mos, 
and if fail 
If fail 
 
---- 
---- 
Prescribe Spectacles 
Xb 
 
Xe 
Xg 
 
 

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TF + 3.00 = trial frames with current refractive correction worn at enrollment (or plano, if emmetropia) with +3.00 
D. The two sphere powers should be added and a single lens used for the spherical power component of the trial 
frames.   
BFLtop = participant viewing through top portion of bifocal lenses (looking over BFL segment) 
BFLbot = participant viewing through the BFL segment situated at the bottom of the lenses 
Home = randomized spectacles worn full-time when not in the office 
Hometop = randomized spectacles worn full-time when not in the office with participant viewing through top 
(distance) portion with bottom half taped (for masking)  
ME = masked examiner 
Office = SVLs comprised of cycloplegic refraction with +3.00 D added (to be kept at clinic for testing) 
 
a Visual acuity can be completed at the end of the visit, if desired. 
b Prescribe assigned spectacles per randomization (BFLs or SVLs) 
c Participants with confirmed failure prior to the 36-month Primary Outcome visit and completing their Post-failure Secondary 
Outcome Visit will only return for interim follow-up visits at 12 and 24 months with abbreviated testing (monocular distance 
VA, near stereoacuity, and ocular alignment). 
d Additional testing is completed if a failure criterion is met prior to the 36-month visit (and failure has not been met and 
confirmed at a prior visit). Additional testing must be done prior to the cycloplegic refraction. 
e At the 36-month visit, prescribe BFLs for participants randomized to the SVL group; continue BFLs for those randomized to the 
BFL group. The exceptions are: 1) participants who met confirmed failure criteria at a previous visit, who underwent 2 months 
of BFL spectacle wear and the Post-Failure Secondary Outcome Visit, and who now continue with treatment (or no treatment) 
at investigator discretion; and 2) participants who have unconfirmed failure at 36 months, who have their randomized 
treatment spectacles updated and return to have failure confirmed/not confirmed at the Failure Confirmation Visit.  
f 36-month Primary Outcome Visit not required for participants with previously confirmed failure. 
g For visits prior to 36 months:  
• 
If failure NOT CONFIRMED, continue current randomized spectacle correction 
• 
If failure CONFIRMED, prescribe BFL spectacles for participants in the SVL group; continue BFL spectacles for the 
BFL group. 
For the 36-month Visit, prescribe BFL spectacles for participants in the SVL group; continue BFL spectacles for the BFL 
spectacles group regardless of whether failure is confirmed. 
h At the Post-Failure Secondary Outcome Visit, all participants are expected to be wearing HOME spectacles that are BFL.  
i All participants will have a 38-month Secondary Outcome Visit, even if they have had a previous Post-failure Secondary 
Outcome Visit. Regarding the timing of the visit, note that participants who meet failure criteria at 36 months (and have not 
failed previously) and need their spectacles updated will have a Failure Confirmation Visit 2 months later (4-12 weeks) and 
return at 40 months for their 38-month Secondary Outcome Visit. Most participants are expected to be wearing HOME spectacles 
that are BFLs, in which case participants should look through the top portion (distance correction) of their HOME spectacles for 
all tests requiring distance viewing and look through the bottom of their HOME spectacles for all near testing done at 33 cm. For 
participants who are not wearing BFLs, a cover/uncover test at near should be performed to determine the optical correction to be 
used for testing. If the participant has an esotropia at near on cover/uncover testing, then most near testing (section 3.8) must be 
completed through added +3.00 lenses at near.  This can be done by 1) placing +3.00 lenses in Halberg/Janelli clips over their 
current HOME SVL lenses or 2) using a trial frame with a lens power that is +3.00D more than their HOME spectacle correction; 
if no esotropia is present, near testing must be completed through the HOME spectacles. 
   
 

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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
Childhood-onset esotropia (ET) affects between 0.9% and 2.3% of children in the United 
3 
States.1-4 In some types of ET, the near angle of deviation exceeds the distance deviation. This 
4 
type of esodeviation was first described by Duane in 18975 and has subsequently been referred to 
5 
as either near-distance disparity ET,6 non-refractive accommodative ET,7 high accommodative 
6 
convergence/accommodation (AC/A) ratio ET,8, 9 or convergence excess ET.10-13 Different 
7 
approaches have been employed when classifying and sub-classifying this type of esodeviation, 
8 
resulting in considerable inconsistency across studies, with added confusion arising from the 
9 
same terminology being used to describe different clinical entities. Notwithstanding differing 
10 
opinions regarding classification and terminology, there is common recognition of a distinct type 
11 
of esodeviation, characterized by manifest ET at near fixation, but with less esodeviation 
12 
(including orthophoria or intermittent ET) at distance fixation.6-8, 10-14 For the purpose of this 
13 
study, we refer to this type of esodeviation as “ET greater at near.” 
14 
By most definitions, ET greater at near is characterized by orthotropia or microesotropia at 
15 
distance fixation, often with some evidence of motor fusion and stereoacuity,11 with the ET at 
16 
near measuring at least 10 prism diopters (∆) greater than the esodeviation at distance fixation.6-8, 
17 
10-14 When the esodeviation is manifest at near, suppression typically occurs, or (more rarely) the 
18 
patient may experience diplopia.12 While different sub-types of ET greater at near have been 
19 
described, differentiated primarily by the presence or absence of a high AC/A ratio,7, 10, 11, 15 few 
20 
previous studies have evaluated the effects of treatment in these potential diagnostic sub-groups. 
21 
The average age at onset of ET greater at near is reported to be between 2 and 3 years of age.11, 16 
22 
1.2 Current Practice 
23 
Initial treatment for ET greater at near usually includes full (or nearly full) correction of 
24 
hyperopic refractive error measured by cycloplegic refraction. There is debate, however, over 
25 
whether additional treatment should be implemented, and if so, what form that treatment should 
26 
take.10, 17 Some practitioners monitor the patient in single vision lenses (SVLs) (where needed for 
27 
correction of refractive error), whereas others prescribe additional treatment out of concern that 
28 
persistent near ET may cause decompensation of the distance ET, loss of stereoacuity and 
29 
binocularity, and/or symptoms including diplopia. Possible treatment options are bifocal lenses 
30 
(BFLs), strabismus surgery, or miotic eye drops, with BFLs being the most commonly prescribed 
31 
treatment in the US.10, 11  
32 
1.3 Potential Benefits of Treatment with Bifocal Lenses and Single Vision Lenses 
33 
1.3.1 Treatment with Bifocal Lenses (BFLs) 
34 
Bifocal spectacle lenses have added plus power in the lower portion of the lenses that is designed 
35 
to be used for near viewing. These lenses reduce the amount of accommodation exerted at near, 
36 
with the aim of reducing the associated convergence response. The strength of the BFLs 
37 
prescribed for young children with ET greater at near is often +3.00 D or the minimum amount 
38 
of plus power required to achieve near motor alignment or improved stereoacuity at near.18, 19 
39 
For some eyecare providers, the aim of BFL treatment is to eventually achieve motor alignment 
40 
at near without the BFLs, and thus they attempt to gradually reduce the strength of the BFL until 
41 
motor alignment can be maintained without the BFLs. Others use a BFL prescription to facilitate 
42 

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18 
alignment of the eyes at near with improved stereopsis to delay or avoid strabismus surgery, 
43 
sometimes keeping the child in BFLs for years provided the BFLs continue to facilitate straight-
44 
eye alignment and normal sensory fusion. The reported duration of BFL treatment varies 
45 
considerably and can continue for many years.20 
46 
1.3.2 Treatment with Single Vision Lenses (SVLs) 
47 
Those who prescribe SVLs for ET greater at near (if needed for the correction of refractive error) 
48 
believe there is no functional advantage to BFLs when the child’s eyes are aligned (or nearly 
49 
aligned if a small-angle ET is present) at distance and the child does not experience diplopia or 
50 
other bothersome symptoms at near. Subjectively, such a child is asymptomatic, and may have 
51 
binocular alignment for considerable portions of the day (i.e., when not viewing at near), and in 
52 
such cases, providing reassurance that the capacity for binocular single vision is being retained. 
53 
Indeed, some proponents of SVLs have hypothesized that SVLs allow fusional divergence 
54 
amplitudes to increase over time, thereby enabling better control of the esodeviation, whereas 
55 
development of fusional divergence amplitudes with BFLs may be limited.8 SVLs also have the 
56 
advantage of lower cost, and (at least anecdotally) may be preferred by some children over BFLs 
57 
for psychosocial reasons. 
58 
1.4 Studies Evaluating BFLs and SVLs 
59 
1.4.1 Comparative Studies of BFLs versus SVLs 
60 
There are few previous studies comparing BFL and SVL treatments for ET greater at near.8, 13 Of 
61 
those available, outcomes are sometimes reported “on-treatment” (i.e., still wearing BFLs) and 
62 
sometimes after discontinuation of treatment (often considering the inability to successfully 
63 
wean the child off of BFLs as a failure of BFLs). The following review of previous studies 
64 
focuses primarily on outcomes while on treatment.  
65 
We are aware of two previous studies reporting on-treatment outcomes for both BFLs and SVLs 
66 
for ET greater at near. In the first study, Pratt-Johnson & Tillson13 performed a retrospective 
67 
review of children with ET greater at near whose parents had been offered the choice of BFL 
68 
treatment or SVL treatment. In all cases, the treatment of choice started before 4 years of age and 
69 
the outcome was assessed after 6 years of age (majority older than 8 years of age), with an 
70 
average of 4 years of follow-up (range 4 to 16 years). Eighty patients were identified with less 
71 
than 10∆ of ET at distance and with an ET of 30∆ or greater at near. Of these 80, 40 chose SVLs 
72 
and 40 chose treatment with BFLs. Sensory outcomes, while wearing the chosen lenses, were 
73 
classified as either: central fusion (positive fusion using central fusion slides on the synoptophore 
74 
and having 60 arcsec or better on the Titmus stereotest), peripheral fusion (using peripheral 
75 
fusion slides on synoptophore and having at least 8∆ of peripheral motor fusion), or no fusion. At 
76 
final follow-up, there were no differences in the proportions of participants with each of the three 
77 
sensory outcomes: central fusion: 3/40 (7.5%) with BFLs vs 2/40 (5%) with SVLs; peripheral 
78 
fusion: 32/40 (80%) vs 34/40 (85%) respectively; no fusion: 5/40 (12.5%) vs 4/40 (10%), 
79 
respectively. There was also no difference in the proportion of participants decompensating 
80 
(increasing in distance eso magnitude) and going on to surgery: 9/40 (22.5%) in the BFL group 
81 
and 5/40 (12.5%) in the SVL group. Similar findings were reported in a smaller study by the 
82 
same authors, published the previous year.17  
83 
In the second, more recent study, Whitman et al8 retrospectively reviewed the charts of 180 
84 
children with ET greater at near, with the aim of comparing on-treatment stereopsis outcomes in 
85 

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those prescribed BFLs (mean age 5.1±2.1 years) versus SVLs (mean age 5.4±2.2 years). All 
86 
patients had less than a 10∆ ET at distance (by PACT), more than 10∆ ET at near, with the near 
87 
ET measuring at least 10Δ greater than the distance. At baseline, all patients also had either 
88 
fusion on the Worth 4-dot, stereopsis, or improvement in the near angle to less than 10∆ when 
89 
tested through +3.00 D lenses. Treatment was at practitioner discretion: 77/180 were treated with 
90 
BFLs and 103/180 were treated with SVLs. Of note, patients treated with BFLs had a larger 
91 
magnitude of ET at near at baseline, but stereopsis at baseline was similar between groups. After 
92 
approximately 4 years of follow-up, stereoacuity was found to be similar between those wearing 
93 
BFLs and those wearing SVLs (5.94±2.3 log arcsec [379 arcsec] in the BFL group vs 5.59±2.1 
94 
log arcsec [268 arcsec] in SVL group). An additional primary outcome reported by the authors 
95 
was the risk of surgery, which in all cases was performed due to an increase in the distance angle 
96 
of deviation to greater than 10∆ (average increase from baseline was 25∆ in the BFL group and 
97 
20.5∆ in the SVL group). More patients prescribed BFLs went on to have surgery (12 of 77; 
98 
15.6%; 95% CI = 9.2% to 25.3%) compared with those wearing SVLs (4 of 103; 3.9%; 95% CI 
99 
= 1.5% to 9.6%) (difference: 11.7%, 95% CI = 3.1% to 21.7%), but it is important to note that 
100 
the BFL group had a larger angle of deviation at baseline. In addition, the authors acknowledged 
101 
that some investigators may have put patients in BFLs as a “last ditch” attempt at treatment 
102 
before going to surgery, which could ostensibly be responsible for the higher risk of surgery in 
103 
the BFL group.8 
104 
1.4.2 Bifocal Lenses – On-Treatment Outcomes 
105 
Other studies have reported on-treatment outcomes for BFLs with regard to treatment failure. 
106 
Arnoldi11 reported on 22 patients with ET greater at near treated with BFLs (age not reported) 
107 
who were initially aligned through the BFL segment; 7 (35%) later developed an ET through the 
108 
BFLs and 2 (10%) developed an ET at distance and underwent surgery. Von Noorden et al21 
109 
retrospectively reviewed 84 patients with convergence excess ET (some of whom had undergone 
110 
previous surgery), who were treated with BFLs with the aim of weaning the BFL power over 
111 
time. They reported that 14/84 (17%) who showed initial control of the near ET through the 
112 
BFLs subsequently lost fusional control at near through the BFLs despite having been prescribed 
113 
a bifocal add up to +3.50 D.  
114 
1.4.3 Single Vision Lenses – On-Treatment Outcomes 
115 
Gerling and Arnoldi19 retrospectively evaluated the effectiveness of SVLs in 23 children (mean 
116 
2.9, range 0.5 to 8 years) with ET greater at near, all of whom had a high AC/A ratio (>5.6:1). 
117 
After 5 years of follow-up they classified the near magnitude of deviation, control of the 
118 
deviation (categorized as either: phoria, intermittent, or tropia), change in refractive error, and 
119 
stereopsis as either: 1) stable (near angle measurements within 5∆ of baseline, no change in 
120 
control [implied at distance or near], no change in refraction [within 0.50 D of baseline 
121 
refraction], and no change in near stereopsis category [fine stereo: better or equal to 60 arcsec; 
122 
gross stereopsis 70 arcsec or worse; no stereopsis]), 2) improved (near angle decreased more 
123 
than 5∆, control improved [implied at distance or near], refraction decreased more than 0.50 D, 
124 
and near stereopsis improved), or 3) deteriorated (increase in near angle of more than 5∆, 
125 
deterioration in control [implied at distance or near], an increase in refraction of more than 0.50 
126 
D, and a loss of near stereopsis). The near angle of deviation improved in 15/23 (65%), was 
127 
stable in 8/23 (35%), and deteriorated in none (distance angle not reported). Control, categorized 
128 
as improvement, stable, or deterioration over follow-up improved in 13/23 (56%) and was stable 
129 
in 10/23 (44%). Stereopsis category improved at some point during follow-up in 8 of the 18 
130 

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(44%) for whom there were repeated stereopsis measurements, and stereopsis remained stable in 
131 
10/18 (56%).  
132 
1.4.4 Potential Risks of BFL Spectacles  
133 
The possibility of harm from BFL wear has been raised in some previous studies. Fresina et al7 
134 
prospectively evaluated potential harm (defined as a deficiency in accommodation) from BFLs in 
135 
28 children with ET greater at near, all of whom were prescribed BFLs. Near point of 
136 
accommodation was measured at baseline (before the BFL prescription was prescribed) and 
137 
measured again after 4 years of wearing BFLs. Near point of accommodation was found to be 
138 
below normal in 10/28 at baseline with no significant changes at the 4-year outcome, leading the 
139 
authors to conclude that while some patients with ET greater at near have a baseline 
140 
accommodation deficit, BFL wear does not reduce the ability to accommodate. 
141 
The other potential harm from BFL wear is a higher likelihood of surgery. Although Pratt-
142 
Johnson and Tillman13 found there was no higher likelihood of surgery, Whitman et al8 
143 
concluded that there was a higher likelihood of surgery in their patients treated with BFLs. 
144 
Nevertheless, the Whitman et al8 conclusions are confounded by the presence of a larger angle of 
145 
deviation in those being prescribed BFLs. In addition, there is a possibility of practitioner bias, 
146 
with those more likely to prescribe BFLs also being those more likely to perform surgery. It 
147 
remains unclear whether BFL wear is associated with an increased risk of the need for surgical 
148 
correction. 
149 
Although unlikely, it is possible that participants treated with BFL spectacles may experience 
150 
blurry vision, eye discomfort, or impaired depth perception when looking downward through the 
151 
BFLs when ambulating on foot.  
152 
1.4.5 Potential Risks of Single Vision Spectacles 
153 
Although unlikely, it is possible that participants treated with single vision spectacles may 
154 
experience blurry vision and/or eye discomfort. It is also unknown and thus possible that 
155 
treatment with SVLs alone for ET greater at near may lead to loss of stereoacuity and/or loss of 
156 
fusion.  
157 
1.5 Risks of Examination or Testing Procedures 
158 
The procedures in this study are part of daily eye care practice in the United States and pose no 
159 
known risks. As part of a routine usual-care exam, the participant may receive 
160 
cycloplegic/dilating eye drops. 
161 
1.6 Risk Assessment 
162 
There are no risks involved in this study that would not be part of usual care when treating the 
163 
participants with either SVL or BFL spectacles. The sponsor (Jaeb Center for Health Research) 
164 
has determined that the protocol’s level of risk is consistent with 45 CFR 46.404 and 21 CFR 
165 
50.52, which indicates research not involving greater than minimal risk for the individual child 
166 
involved in the research.  
167 
1.7 Summary of Existing Data 
168 
Existing studies have failed to demonstrate a benefit of BFLs over SVLs for ET greater at near 
169 
and, interestingly, some data appear to support the use of SVLs.19 The Whitman et al study8 
170 
created new uncertainty regarding the benefit of BFLs, in addition to suggesting that BFL wear 
171 

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may be harmful (i.e., increased likelihood of surgery). Nevertheless, BFLs remain the treatment 
172 
of choice for most practitioners. In a recent poll of investigators at the recent PEDIG investigator 
173 
meeting (February 2020) at least 75% of PEDIG care providers use BFLs to treat ET greater at 
174 
near. There is a pressing need for a randomized clinical trial evaluating the effectiveness of BFLs 
175 
versus SVLs for ET greater at near. 
176 
1.8 Rationale for Present Study  
177 
BFLs are commonly used in the treatment of ET greater at near, but their effectiveness is 
178 
unknown, and has been questioned, particularly since the publication of the study by Whitman 
179 
and colleagues.8 BFLs are more costly than SVLs, with a recent study estimating the annual 
180 
health care expenditures related to BFL treatment in children with ET greater at near, to be 
181 
$800,000 to $2.8 million in the US alone (2015 data).8 We are not aware of data that estimate 
182 
health care expenditures related to subsequently needed treatments and office visits for children 
183 
with ET greater at near who are not provided BFL treatment. 
184 
If SVLs are found to be a superior treatment for ET greater at near, BFL treatment with its 
185 
related additional costs can be avoided. On the other hand, if BFL treatment is found to be 
186 
superior to SVLs, this study will have provided the evidence necessary for establishing BFLs as 
187 
beneficial for reducing the likelihood of motor decompensation and/or for improving binocular 
188 
alignment and function at near.  
189 
In summary, providing reliable evidence of the effectiveness of BFLs versus SVLs for the 
190 
treatment of ET greater at near would help standardize the currently divergent management 
191 
practices and enable more efficient utilization of healthcare resources.  
192 
1.9 Study Objectives 
193 
1. To compare the proportion of participants with failure by 36 months between BFL and 
194 
SVL groups (failure = worsening of distance ET, reduction in near stereoacuity, frequent 
195 
diplopia (“more than 2 times per day” over the last week), or undergoing non-study 
196 
treatment) 
197 
2. To compare binocular function scores in BFLs 2 months following failure or at 38 
198 
months if no failure (whichever comes first) between the BFL and SVL spectacles groups  
199 
3. To compare the proportion of participants with failure by 36 months between BFL and 
200 
SVL groups according to baseline factor subgroups of: pre-enrollment duration of 
201 
constant ET, presence of near stereoacuity on the Randot Preschool Stereoacuity test, in-
202 
office response of near motor alignment to +3.00 D lenses, and gradient AC/A ratio  
203 
1.10 General Considerations 
204 
The study is being conducted in compliance with the policies described in the PEDIG network 
205 
policies document, with the ethical principles that have their origin in the Declaration of 
206 
Helsinki, with the protocol described herein, and with the standards of Good Clinical Practice 
207 
(GCP). 
208 
When feasible, data will be directly collected in electronic case report forms, which will be 
209 
considered the source data. 
210 

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Chapter 2: Study Enrollment and Randomization 
211 
2.1 Participant Recruitment and Enrollment 
212 
The study plans to enroll up to 444 children for whom informed consent will be obtained. 
213 
As the recruitment goal approaches completion, sites will be notified of the end date for 
214 
recruitment into the study. Participants who have signed informed consent forms can be enrolled 
215 
into the study until the end date, which means the expected recruitment number might be 
216 
exceeded.  
217 
There is no restriction on the number of participants to be enrolled by each site towards the 
218 
overall recruitment goal. 
219 
2.1.1 Informed Consent 
220 
Children with ET who are aged 3 to < 9 years attending ophthalmology or optometry outpatient 
221 
visits will be identified.  
222 
Families who qualify for the study will be approached by a research team member. The study 
223 
will be discussed with the child’s parent(s) or guardian(s) [referred to subsequently as parent(s)]. 
224 
Parent(s) who express an interest in the study will be given a copy of the informed consent form 
225 
to read. Written informed consent will be obtained from a parent and written or verbal assent 
226 
from the child (depending on age and IRB requirements) prior to collecting any study data or 
227 
performing any study-specific procedures that are not part of the child’s routine care. 
228 
A child is considered enrolled into the study when the informed consent form has been signed by 
229 
the parent, the assent form has been signed by the child (when applicable), and the investigator 
230 
has signed the appropriate forms.  
231 
2.2 Eligibility Criteria 
232 
Children under the care of a pediatric optometrist or pediatric ophthalmologist, who are 
233 
identified during a standard-of-care outpatient visit or from a referral from another provider, will 
234 
be eligible for the study if all of the following criteria are met: 
235 
• Age 3 to <9 years 
236 
• Esodeviation meeting all the following criteria in refractive correction (if required or 
237 
worn) 
238 
o 
Constant or intermittent esotropia ≥10∆ measurable by SPCT at near (duration of 
239 
esotropia sufficient to be measured by SPCT) 
240 
o 
Distance esotropia (constant, intermittent), esophoria, or orthophoria, with near 
241 
esodeviation ≥10∆ larger than distance deviation by PACT 
242 
▪ If constant ET at distance, then must be ≤6∆ by SPCT 
243 
▪ If intermittent ET or esophoric at distance, can be any magnitude at 
244 
distance (as long as near esodeviation is ≥10∆ larger than distance 
245 
deviation by PACT) 
246 
• Cycloplegic refraction within past 3 months (but not on day of exam)  
247 
• Wearing spectacles if cycloplegic refractive error is 0.75 D SE or more in either eye 
248 
• Current spectacles (if worn) must meet the following criteria based on the most recent 
249 
cycloplegic refraction within 3 months: 
250 
o Worn for at least 4 weeks 
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o SE refractive error must be corrected within ±0.625 D 
252 
o Sphere power must be corrected within ±0.50 D 
253 
o Anisometropia must be corrected within ±0.50 D SE 
254 
o Cylinder power must be corrected within ±0.50 D  
255 
o Cylinder axis must be within ±10 degrees if cylinder power is ≤1.00 D and within 
256 
±5 degrees if cylinder power is >1.00 D. 
257 
• Best-corrected VA meeting the following criteria:  
258 
o Better-seeing eye VA is age-normal22, 23  
259 
• 3 years: 20/50 or better  
260 
• 4 years: 20/40 or better  
261 
• 5-6 years: 20/32 or better  
262 
• 7-12 years: 20/25 or better 
263 
o Worse-seeing eye VA is 20/63 or better 
264 
o IOD in VA within 0.2 logMAR according to conversion shown in Table 1 
265 
below: 
266 
 
267 
Table 1: Snellen to LogMAR Conversion  
268 
Snellen Equivalent  
LogMAR 
<20/800 
1.7 
20/800 
1.6 
20/640 
1.5 
20/500 
1.4 
20/400 
1.3 
20/320 
1.2 
20/250 
1.1 
20/200 
1.0 
20/160 
0.9 
20/125 
0.8 
20/100 
0.7 
20/80 
0.6 
20/70 
0.55 
20/63 
0.5 
20/60 
0.5 
20/50 
0.4 
20/40 
0.3 
20/32 
0.2 
20/30 
0.2 
20/25 
0.1 
20/20 
0.0 
20/16 
-0.1 
20/15 
-0.1 
20/12 
-0.2 
 
269 
 
 
270 

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Examples for eligibility with respect to Snellen Equivalent and IOD:  
271 
• 
OD = 20/20, OS = 20/30 
272 
• 
IOD in VA logMAR from Table 1= 0.0 logMAR (20/20) minus 0.2 logMAR (20/30) = -0.2. 
273 
o 
Because -0.2 logMAR is within 0.2, the participant is ELIGIBLE.  
274 
• 
OD = 20/40, OS = 20/70 
275 
• 
IOD in VA logMAR from Table 1= 0.3 logMAR (20/40) minus 0.55 (20/70) logMAR = -0.25. 
276 
o 
Because -0.25 is NOT within 0.2, the participant is NOT ELIGIBLE.  
277 
 
278 
• Investigator and parent are willing to forgo treatment of ET other than randomized 
279 
treatment for 38-40 months unless failure criteria are met. 
280 
• Investigator is willing to prescribe BFLs only (in both treatment groups) between 36 to 
281 
38 months or for 2 months after meeting failure criteria (if failed). 
282 
2.3 Exclusion Criteria 
283 
Individuals meeting any of the following criteria will be excluded from study participation: 
284 
• Previous BFL wear (SVL wear of any duration is allowed) 
285 
• Current or planned contact lens wear over the next 3 years 
286 
• Myopic refractive error more than -6.00 D SE 
287 
• Previous strabismus surgery (including Botox), intraocular surgery (e.g., laser, anti-
288 
VEGF injection, or cataract), extraocular surgery (e.g., scleral buckle), or refractive 
289 
surgery  
290 
• Previous amblyopia treatment other than refractive correction within prior 3 months 
291 
• Previous treatment for ET using miotics, vision therapy, or prism treatment for ET within 
292 
prior 3 months 
293 
• Vertical deviation ≥3∆ at distance or near by PACT 
294 
• Oculomotor findings consistent with infantile ET (e.g., latent nystagmus, manifest 
295 
nystagmus, DVD) 
296 
• AV pattern ≥10∆ difference between upgaze and downgaze by PACT at distance 
297 
• Paretic or restrictive strabismus 
298 
• Constant exotropia at near during enrollment visit testing through the +3.00 D add 
299 
(intermittent XT or exophoria allowed) 
300 
• Diplopia “more than 2 times per day” over the last week prior to enrollment by parental 
301 
report. Any report of diplopia must have a frequency of “2 times or less per day” to be 
302 
eligible. 
303 
• Significant developmental delay that would interfere with child’s ability to complete 
304 
testing 
305 
• Neurological condition that could affect ocular motility (e.g., cerebral palsy, Down 
306 
syndrome) 
307 
• Immediate family member (child or sibling) of any investigative site personnel directly 
308 
affiliated with this study 
309 
2.4 Historical Information 
310 
Historical information elicited will include the following: date of birth, sex, race, ethnicity, 
311 
clinical diagnosis, prior esotropia therapy, prior amblyopia therapy, cycloplegic refraction, 
312 
history of SVL and BFL spectacle wear, and duration of constant ET (if applicable).  
313 

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2.5 Procedures at Enrollment 
314 
The test procedures will be done in the order specified below within 7 days of enrollment 
315 
through the child’s pre-study refractive correction and without cycloplegia. Any spectacle 
316 
correction worn must meet the criteria specified in section 2.2. For the testing to be performed in 
317 
trial frames, the two sphere powers should be added and a single lens used for the spherical 
318 
power component of the trial frames.  
319 
 
320 
1. Lensometry (if wearing spectacles)  
321 
2. Diplopia Assessment: Assess diplopia presence and frequency over the last week, by parental 
322 
report. If present, classify diplopia frequency as “2 times or less per day” or “more than 2 
323 
times per day.” 
324 
3. Monocular Visual Acuity Testing: Distance visual acuity (VA) testing will be performed 
325 
(right eye first) with the child wearing their spectacles (if worn). Testing method is at 
326 
investigator discretion, but must meet the following criteria:  
327 
• ATS-HOTV; e-ETDRS; OR crowded single-optotype or single-line HOTV, LEA 
328 
SYMBOLS, or Snellen letters  
329 
o Allen pictures and Tumbling E’s are NOT allowed  
330 
• NOTE: VA testing may instead be performed at the end of the visit 
331 
4. Randot Preschool Stereoacuity Test #1: in spectacles at 33 cm* (see ETS3 Procedures 
332 
Manual) 
333 
5. Distance Randot Stereoacuity Test: in spectacles at 3 m (see ETS3 Procedures Manual) 
334 
6. Randot Preschool Stereoacuity Test #2: in trial frames with +3.00 D added lenses at 33 cm* 
335 
(see ETS3 Procedures Manual) 
336 
7. Random Dot Butterfly Test: in trial frames with +3.00 D added lenses at 33 cm* (see ETS3 
337 
Procedures Manual) 
338 
8. Preschool Worth 4-Shape Test: in trial frames with +3.00 D added lenses at 33 cm* (see 
339 
ETS3 Procedures Manual) 
340 
9. Near Ocular Alignment: in trial frames with +3.00 D added lenses at 33 cm 
341 
• Near alignment will be assessed in trial frames with +3.00 D added lenses by the 
342 
cover/uncover test, simultaneous prism and cover test (SPCT), and prism and 
343 
alternate cover test (PACT) in primary gaze at near (1/3 meter) as outlined in the 
344 
ETS3 Procedures Manual. 
345 
10. Distance and Near Ocular Alignment Testing: 
346 
• Ocular alignment will be assessed in spectacles by the cover/uncover test, SPCT, and 
347 
PACT in primary gaze at distance (3 meters) and at near (33 cm) as outlined in the 
348 
ETS3 Procedures Manual. 
349 
* Test distance for near stereoacuity and other binocular testing is 33 cm rather than 40 cm because of the focal length of the 
350 
+3.00 D add 
351 
 
 
352 

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2.6 Spectacle Tolerance Criteria at Enrollment 
353 
Spectacles worn at enrollment [whether required (refractive error of 0.75 D or more – see section 
354 
2.2) or at investigator discretion] must be worn for 4 or more weeks and must meet the following 
355 
spectacle tolerance criteria based on lensometry and the cycloplegic refraction performed within 
356 
the prior 3 months (but not on the day of the exam) which is used to assess eligibility: 
357 
• SE refractive error must be corrected within ±0.625 D  
358 
• Sphere power must be corrected within ±0.50 D  
359 
• Anisometropia must be corrected within ±0.50 D SE 
360 
• Cylinder power must be corrected within ±0.50 D  
361 
• Cylinder axis must be within ±10 degrees if cylinder power is ≤1.00 D and within ±5 
362 
degrees if cylinder power is >1.00 D 
363 
2.7 Randomization 
364 
Eligible participants will be randomized 1:1 to the following: 
365 
1. Single vision spectacles (SVLs) 
366 
2. Bifocal spectacles (BFLs): +3.00 D flat-top bifocal add  
367 
The Jaeb Center will construct a separate Master Randomization List using a permuted block 
368 
design stratified by presence/absence of stereoacuity of at least 960 arcsec or better on the 
369 
Randot Preschool Stereoacuity Test conducted at near (33 cm) in a trial frame with +3.00 D 
370 
added lenses.  
371 
A child is officially enrolled in the randomized trial when the website randomization process is 
372 
completed. 
373 
2.8 Prescription of Randomized Treatment 
374 
Spectacles prescribed at enrollment will be referred to as the HOME spectacles for both 
375 
treatment groups. These are the spectacles that the participants will have at home and be 
376 
instructed to wear every day for all waking hours (at home, school, outside, etc.).  
377 
 
378 
Single-vision lens (SVL) group:  
379 
Participants randomized to treatment with SVLs will be prescribed HOME spectacles meeting 
380 
the following criteria based on their cycloplegic refraction:  
381 
• Full correction of hyperopia/myopia  
382 
• Full correction of astigmatism  
383 
• Full correction of anisometropia 
384 
Children in the SVL group with no refractive error (emmetropia or plano refraction) will be 
385 
prescribed spectacles with plano lenses. 
386 
 
387 
Bifocal lens (BFL) group:  
388 
Participants randomized to treatment with BFLs will be prescribed HOME spectacles meeting 
389 
the following criteria based on their cycloplegic refraction: 
390 
• Full correction of hyperopia/myopia  
391 
• Full correction of astigmatism  
392 
• Full correction of anisometropia 
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• +3.00 D bifocal add (flat top, 35 mm with segment height set at mid-pupil - see ETS3 
394 
Manual of Procedures)  
395 
o Progressive addition lenses (PALs) are NOT allowed to be worn during the study. 
396 
 
397 
Children in the BFL group with no refractive error (emmetropia or plano refraction) will be 
398 
prescribed spectacles with plano lenses and the +3.00 D bifocal add. 
399 
Both treatment groups:  
400 
The refractive error correction prescribed at the time of randomization must follow the 
401 
requirements outlined for each group above. However, if the participant is having problems with 
402 
blurred vision, then the prescription may be adjusted when the child returns for follow-up as 
403 
described in section 3.13.2. If the participant develops constant exotropia at near or any type of 
404 
exodeviation at distance (constant XT, IXT, or exophoria), the prescription may be adjusted as 
405 
described in section 3.13.3, AFTER calling one of the Protocol Chairs. 
406 
Participants in both treatment groups (SVLs and BFLs) will also be prescribed a pair of single-
407 
vision spectacles to be used for near testing and to facilitate in-office masking of examiners. 
408 
These spectacles are referred to as the OFFICE spectacles and will be sent to the enrolling site 
409 
where they will be stored on site and used only for testing purposes at study visits (see ETS3 
410 
Manual of Procedures). The lens power will be +3.00 D more than the full distance correction 
411 
(i.e., same refractive correction as measured through the BFL add, but made as single-vision 
412 
spectacles). These OFFICE spectacles will be used for masking purposes during follow-up visits; 
413 
they will not be sent home with the participant. Throughout the study, any prescription changes 
414 
that are made to the HOME spectacles for any reason (see sections 3.12.1, 3.13.2 and 3.13.3) 
415 
will also be made to the OFFICE spectacles at the same time. 
416 
 
417 

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Chapter 3: Study Follow-up  
418 
3.1 Study Follow-up Visits 
419 
Participants randomized in the study generally* will return for follow-up according to the 
420 
following schedule (timed from randomization, unless otherwise specified): 
421 
 
422 
Protocol-
specified 
Visit/Call 
Target Day 
Target Window 
(around target day) 
Allowable Window 
(around target day) 
1-month call 
Randomization+30 
days 
± 1 week 
23 to 37 days 
1 to 76 days 
3-month visit 
Randomization+91 
days 
± 2 weeks 
77 to 105 days 
± 1.5 months 
46 to 137 days 
6-month visit 
Randomization+183 
days 
± 2 weeks 
169 to 197 days 
± 1.5 months 
138 to 228 days 
9-month visit 
Randomization+274 
days 
± 2 weeks 
260 to 288 days 
± 1.5 months 
229 to 320 days 
12-month visit 
Randomization+365 
days 
± 2 weeks 
351 to 379 days 
-1.5 to +3 months 
321 to 457 days 
18-month visit 
Randomization+548 
days 
± 2 weeks 
534 to 562 days 
± 3 months 
458 to 639 days 
24-month visit 
Randomization+731 
days 
± 2 weeks 
717 to 745 days 
± 3 months 
640 to 822 days 
30-month visit 
Randomization+913 
days 
± 2 weeks 
899 to 927 days 
± 3 months 
823 to 1004 days 
36-month 
Primary 
Outcome Visitb 
Randomization+1096 
days 
± 2 weeks 
1068 to 1124 days 
-3 to +6 months 
1005 to 1278 days 
38-month 
Secondary 
Outcome Visitc,d 
36-month visit +60 
days (or 38-months 
from randomization 
for confirmed 
failures occurring 
before 36 months).  
± 4 weeks 
32 to 88 days 
-1 month to +6.5 months 
30 to 258 days from 36-
month Visit (from 38 months 
following randomization for 
confirmed failures) 
Additional if 
needed 
Target Day 
Target Window 
(around target day) 
Allowable Window 
(around target day) 
1-month call 
after new 
spectaclese 
Visit at which 
spectacles changed 
+30 days 
± 1 week 
23 to 37 days 
1 to 76 days 
Failure 
Confirmation 
Visitf 
Visit at which failure 
criteria met and 
spectacles updated + 
60 days 
± 4 weeks 
46 to 88 days 
30 days to open end (must be 
completed) 
Post-failure 
Secondary 
Outcome Visitg 
Visit at which failure 
confirmed +60 days 
± 4 weeks 
32 to 88 days 
-1 month to +6.5 months 
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b SVL group is prescribed BFLs at end of the 36-month Primary Outcome Visit. The exception is participants who 
423 
previously failed, had the post-failure secondary outcome visit, and been released to treatment.  
424 
c Note that participants who meet failure criteria at 36 months (and have not failed previously) and need their spectacles 
425 
updated will have a Failure Confirmation Visit 2 months later (4-12 weeks) and return at 40 months for the 38-month 
426 
Secondary Outcome Visit. 
427 
d At the 38-month Secondary Outcome Visit, both groups are now in BFLs. 
428 
e Phone calls from site 1 month ± 1 week from the time spectacles are prescribed or changed (section 3.1.1). 
429 
f Failure Confirmation Visit: If a participant meets failure criteria at the 12-month visit or later and needs a change in 
430 
refractive correction, new spectacles will be prescribed, and the participant will return in 4 to 12 weeks to determine 
431 
(confirm) whether the participant meets failure criteria.  
432 
g Post-failure Secondary Outcome Visit: If a participant meets failure criteria prior to 36 months, BFLs will be 
433 
prescribed to the SVL group (BFLs continued in the BFL group) and a Post-failure Secondary Outcome Visit will be 
434 
scheduled 4 to 12 weeks after the visit at which failure criteria was confirmed (i.e., at a regularly-scheduled study 
435 
visit or at a separate Failure Confirmation Visit, if one is required).  
436 
 
437 
*Participants who meet confirmed failure criteria (section 3.5) and complete the Post-failure 
438 
Secondary Outcome Exam will return for the 12- and 24-month follow-up visits (if they have not 
439 
already been completed) and the 38-month Secondary Outcome Visit as outlined in section 3.7.1; 
440 
all other remaining visits will be skipped.  
441 
3.1.1 Phone Calls 
442 
Site personnel will call the parents 1 month ± 1 week following the prescription of any new 
443 
spectacles or after a change in spectacles. The purpose of the call is to determine whether the 
444 
new spectacles have been received and are being worn, to determine whether there are any 
445 
problems / symptoms with wearing the spectacles, and to determine whether the parent has any 
446 
questions about the study.  
447 
3.2 Masking Procedures 
448 
Participants will not be masked to their treatment group, given that their spectacles either will or 
449 
will not have a visible flat-top bifocal. The investigator treating each participant also will not be 
450 
masked to treatment group. Therefore, an examiner masked to treatment group will measure eye 
451 
alignment and stereoacuity at all follow-up visits and conduct the binocular function testing at 
452 
the required follow-up visits. Masking of examiners will be accomplished in two ways. First, 
453 
unmasked personnel will place painter’s tape (provided to sites) over the entire lower half of the 
454 
HOME spectacle lenses such that the tape covers the entire bottom half and top line of the BFL 
455 
segment or where the BFL segment would be located (upper edge at mid-pupil) if the SVLs were 
456 
BFLs (see ETS3 Procedures Manual). All distance testing and some near testing will be done 
457 
through the distance correction using the top portion (above the tape) of the HOME spectacle 
458 
lenses. Second, where specified, some near testing will be performed with the participant 
459 
wearing their OFFICE spectacles; these spectacles remain at the study site. Masked exams will 
460 
be completed at all study visits unless otherwise specified.   
461 
3.2.1 Masked Examiner 
462 
The masked examiner must be a pediatric optometrist, pediatric ophthalmologist, or certified 
463 
orthoptist who is not aware of the participant’s assigned treatment.  
464 

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3.3 Follow-up Procedures Prior to 36 Months 
465 
The following procedures will be performed in the order specified below at each interim follow-
466 
up visit occurring at 3, 6, 9, 12, 18, 24, and 30 months, with participants wearing their HOME 
467 
spectacles or their OFFICE spectacles as specified by the protocol. Participants who present for a 
468 
follow-up visit without their HOME spectacles, or whose HOME or OFFICE spectacles do not 
469 
meet the spectacle tolerance criteria as determined by lensometry (see below) will be tested in 
470 
trial frames with the appropriate randomized refractive correction (based on the most recent 
471 
cycloplegic refraction and with any allowed adjustments to the most recent prescription as 
472 
outlined in sections 3.13.2 and 3.13.3) and either with or without +3.00 D added power (to 
473 
substitute for OFFICE and HOME spectacles, respectively). The two sphere powers should be 
474 
added and a single lens used for the spherical power component of the trial frames.  
475 
 
476 
NOTE: Participants with confirmed failure status (sections 3.5 and 3.6) who have 
477 
completed a Post-failure Secondary Outcome Visit will return for interim follow-up at 12 
478 
months and 24 months with abbreviated testing (section 3.7.2). 
479 
 
480 
1. Lensometry:  
481 
• Spectacles (HOME and OFFICE) must meet the following spectacle tolerance criteria 
482 
as compared with the participant’s last prescribed refractive correction (NOTE: if the 
483 
hyperopic sphere and/or bifocal add power have been reduced per protocol [see 
484 
sections 3.13.2 and 3.13.3], the sphere and add power must meet the spectacle 
485 
tolerance criteria as compared with what was last prescribed): 
486 
• SE refraction must be corrected within ±0.625 D 
487 
• Sphere power must be corrected within 0.50 D 
488 
• Anisometropia must be corrected within ±0.50 D SE  
489 
• Cylinder power must be corrected within ±0.50 D  
490 
• Cylinder axis must be within ±10 degrees if cylinder power is ≤1.00 D, and 
491 
within ±5 degrees if cylinder power is >1.00 D. 
492 
• If bifocals, bifocal must be a flat-top 35 and meet the following criteria: 
493 
• Height must be within ±2 mm of mid-pupil  
494 
• Power must be within ±0.50 D of that prescribed  
495 
• Total sphere power of the bifocal segment must be corrected within 
496 
±0.50 D of the sum of the prescribed bifocal power and distance 
497 
sphere power 
498 
• Measured bifocal add power (i.e., dioptric difference between 
499 
distance sphere power and bifocal sphere power) must be within 
500 
±0.50 D of prescribed bifocal add power. 
501 
• If at any follow-up visit the participant’s spectacles (HOME or OFFICE) do not meet 
502 
these spectacle tolerance criteria (above) based on the most recent cycloplegic 
503 
refraction and with allowed adjustments to the most recent prescriptions as outlined in 
504 
sections 3.13.2 and 3.13.3, then the spectacles must be remade. NOTE that if the 
505 
spectacles are found to be out of tolerance at any follow-up visit, testing should be 
506 
performed in trial frames rather than requiring the participant to return for another 
507 
visit. 
508 

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2. Diplopia Assessment: Assess diplopia presence and frequency over the last week by parental 
509 
report. If present, classify diplopia frequency as “2 times or less per day” or “more than 2 
510 
times per day.” 
511 
3. Monocular Visual Acuity Testing: Distance VA will be measured (right eye first) with the 
512 
participant wearing their HOME spectacles and without cycloplegia, using the same test 
513 
method used at enrollment.  
514 
• ATS-HOTV; e-ETDRS; OR crowded single-optotype or single-line HOTV, LEA 
515 
SYMBOLS, or Snellen letters (Allen pictures and Tumbling E optotypes are NOT 
516 
allowed) 
517 
• NOTE: VA testing may be performed at the end of the visit. 
518 
4. Randot Preschool Stereoacuity Test with OFFICE spectacles #1 (masked): 
519 
• Tested in OFFICE spectacles at 33 cm (see ETS3 Procedures Manual) 
520 
5. Ocular Alignment Testing – cover/uncover test, SPCT, and PACT (masked):  
521 
• Wearing OFFICE spectacles and testing at near (33 cm) only 
522 
• Wearing HOME spectacles with participant viewing through the TOP of the lenses 
523 
(with bottom half of lenses taped) at both distance (3 m) and near (33 cm) (see ETS3 
524 
Procedures Manual) * 
525 
6. Randot Preschool Stereoacuity Test in OFFICE spectacles #2 (masked): 
526 
• Tested a second time in OFFICE spectacles at 33 cm.* 
527 
7. Additional Testing: if failure criteria are met (section 3.5) (masked) 
528 
8. Cycloplegic Refraction (at all 12-, 24-, and 30-month visits, and only if failure is met at any 
529 
other visit):  
530 
• NOTE: If failure criteria are met, the additional procedures in section 3.5.1 must be 
531 
completed prior to the cycloplegic refraction. 
532 
• The cycloplegic refraction must be performed 30 to 45 minutes following at least one 
533 
application of cyclopentolate 1%.  
534 
• If the cycloplegic refraction reveals uncorrected refractive error outside the spectacle 
535 
tolerance criteria (above), the spectacle correction must be updated (see section 3.12). 
536 
(Smaller refractive changes may be prescribed at investigator discretion). Any changes 
537 
that are made to the HOME spectacles will be made to the OFFICE spectacles at the 
538 
same time. 
539 
*Test distance for near stereoacuity and other binocular testing is 33 cm rather than 40 cm because of the focal length of the 
540 
+3.00 D add 
541 
3.4 36-Month Primary Outcome Visit 
542 
At the 36-month primary outcome visit, participants will complete the following test procedures 
543 
in the order specified below (1-9) while wearing their HOME spectacles or OFFICE spectacles, 
544 
as specified. Participants who present without their HOME spectacles or whose HOME or 
545 
OFFICE spectacles do not meet the spectacle tolerance criteria (section 3.12) as determined by 
546 
lensometry, should be tested in trial frames. The trial lenses should be the appropriate 
547 
randomized refractive correction (based on the most recent cycloplegic refraction and with the 
548 
allowed adjustments to the most recent prescriptions as outlined in sections 3.13.2 and 3.13.3) 
549 
either with or without the added +3.00 D power to substitute for the OFFICE and HOME 
550 
spectacles, respectively. The two sphere powers should be added and a single lens used for the 
551 
spherical power component of the trial frames.  
552 

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1. Lensometry (HOME and OFFICE spectacles) 
553 
2. Diplopia Assessment: Assess diplopia presence and frequency over the last week by 
554 
parental report. If present, classify diplopia frequency as “2 times or less per day” or “more 
555 
than 2 times per day.” 
556 
3. Monocular Visual Acuity Testing: Distance VA will be measured (right eye first) with the 
557 
participant wearing their HOME spectacles and without cycloplegia, using the same test 
558 
method used at enrollment.  
559 
4. Randot Preschool Stereoacuity Test wearing OFFICE spectacles #1 (masked): Tested in 
560 
OFFICE spectacles at 33 cm (see ETS3 Procedures Manual).* 
561 
5. Random Dot Stereo Butterfly Test wearing OFFICE spectacles (masked): Tested in 
562 
OFFICE spectacles at 33 cm (see ETS3 Procedures Manual).*  
563 
6. Preschool Worth 4-Shape test wearing OFFICE spectacles (masked): Tested in OFFICE 
564 
spectacles using the hand-held Preschool Worth 4-Shape test held at 33 cm (see ETS3 
565 
Procedures Manual).* 
566 
7. Randot Preschool Stereoacuity Test wearing OFFICE spectacles #2 (masked): tested in 
567 
OFFICE spectacles at 33 cm (see ETS3 Procedures Manual)* 
568 
8. Ocular Alignment Testing - cover/uncover test, SPCT, and PACT (masked): 
569 
• Wearing OFFICE spectacles and testing at near (33 cm) only 
570 
• Wearing HOME spectacles with participant viewing through the TOP of the lenses 
571 
(with bottom half of lenses taped) at both distance (3 m) and near (33 cm) (see ETS3 
572 
Procedures Manual) 
573 
9. Distance Randot Stereotest (masked): tested through TOP of HOME spectacles at 3 m 
574 
(with bottom half taped) 
575 
10. Randot Preschool Stereoacuity Test wearing HOME spectacles (masked): Tested in HOME 
576 
spectacles with participant viewing through the TOP of the lenses at 33 cm* (with bottom 
577 
half of lenses taped; see ETS3 Procedures Manual)* 
578 
*Test distance for near stereoacuity and other binocular testing is 33 cm rather than 40 cm because of the focal length of the 
579 
+3.00 D add 
580 
NOTE: Participants who meet confirmed failure criteria (section 3.5) and complete the Post-
581 
failure Secondary Outcome Exam do not complete the 36-month visit.  
582 
3.4.1 Prescribing Bifocal Spectacles at the 36-month Primary Outcome Visit  
583 
For participants who HAVE NOT failed prior to or by the end of the 36-month Primary Outcome 
584 
Visit: 
585 
• Participants in the SVL group will be prescribed BFLs to be worn until the 38-month 
586 
Secondary Outcome Visit.  
587 
• Participants in the BVL group will continue to wear BFLs until the 38-month Secondary 
588 
Outcome Visit. 
589 
 
590 
For participants who FAIL AT the 36-month Primary Outcome Visit: 
591 

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• SVL participants who meet CONFIRMED failure criteria at the 36-month visit (i.e., fail 
592 
and do not require a change in spectacles) will be prescribed BFLs to be worn until the 
593 
38-month Secondary Outcome Visit. 
594 
• BFL participants who meet CONFIRMED failure criteria at the 36-month visit (i.e., fail 
595 
and do not require a change in spectacles) will continue to wear their BFLs until the 38-
596 
month Secondary Outcome Visit. 
597 
• Participants in both treatment groups who meet failure criteria at the 36-month visit and 
598 
require a Failure Confirmation Visit (see section 3.6) because their spectacles are NOT 
599 
within study tolerance will be prescribed updated spectacles according to their respective 
600 
treatment group and return for a Failure Confirmation Visit. 
601 
 
602 
BFL spectacles that are being prescribed per protocol at the 36-month Primary Outcome Visit (as 
603 
opposed to being prescribed at investigator discretion) should meet the following criteria based 
604 
on the participant’s most recent cycloplegic refraction:  
605 
 
606 
• Full correction of hyperopia/myopia  
607 
• Full correction of astigmatism 
608 
• Full correction of anisometropia 
609 
• +3.00 D bifocal add (flat top, 35 mm, segment height set mid-pupil, see ETS3 Manual of 
610 
Procedures).  
611 
• Children with no refractive error (emmetropia or plano refraction) will be prescribed 
612 
spectacles with plano lenses and the +3.00 D bifocal add. 
613 
 
614 
Progressive addition lenses (PALs) are NOT allowed during the study. SVL participants will 
615 
wear their newly prescribed BFL spectacles until their 38-month Secondary Outcome Visit.  
616 
Regardless of the correction worn, all participants return for the 38-month Secondary Outcome 
617 
Visit. 
618 
3.5 Failure Criteria 
619 
Treatment failure is defined as meeting one or more of the following criteria at any follow-up 
620 
visit between 3 months to 36 months inclusive: 
621 
1. Constant ET ≥15∆ by SPCT at distance. (NOTE: intermittent ET and esophoria of any 
622 
magnitude are NOT considered failures). 
623 
2. Decrease in near stereoacuity on the Randot Preschool Stereoacuity Test (at 33 cm) of 2 
624 
or more levels from baseline (see levels below) stereo or from 960” (equivalent to 800” 
625 
when measured at 40 cm) at baseline to nil (criteria not applicable if nil near stereo at 
626 
baseline) 
627 
• Baseline stereoacuity is defined as the near stereoacuity performed with +3.00 D 
628 
added to the participant’s enrollment distance spectacle correction in trial frames. 
629 
• At all follow-up visits, the best of two stereo measures in the OFFICE lenses will be 
630 
used to determine treatment failure.  
631 
• Stereoacuity values are calculated for the 33 cm test distance required for testing 
632 
through the added +3.00 D lenses at near (instead of the standard 40 cm). NOTE: 
633 
Participants without measurable near stereoacuity at baseline cannot fail by 
634 
stereoacuity criteria.   
635 

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636 
Table 2. Baseline and Follow-up Randot Preschool Stereoacuity Test Levels 
637 
for Defining Treatment Failure 
638 
Baseline Stereoacuity  
(in trial frames with lens power 
that is +3.00D more than distance 
correction)a 
Follow-up Stereoacuity  
for Treatment Failure 
(best of two tests in 
OFFICE spectacles) 
48” (40” at 40 cm) 
120” or worse 
72” (60” at 40 cm) 
240” or worse 
120” (100” at 40 cm) 
480” or worse 
240” (200” at 40 cm) 
960” or worse 
480” (400” at 40 cm) 
Nil 
960” (800” at 40 cm) 
Nil 
Nil  
Not applicable 
aThe two sphere powers should be added and a single lens used for the spherical power component 
639 
of the trial frames.  
640 
 
641 
3. Binocular diplopia with a frequency of “more than 2 times per day” over the last week by 
642 
parental report. 
643 
4. If any nonsurgical or surgical treatment for ET other than the randomized treatment is 
644 
started before the participant meets failure criteria, the participant will be considered a 
645 
failure at the visit at which the non-randomized treatment is prescribed.  
646 
 
647 
If treatment failure occurs, proceed according to whether the participant failed PRIOR to the 36-
648 
month Primary Outcome Visit (section 3.5.1) or AT the 36-month Primary Outcome Visit 
649 
(section 3.5.2).  
650 
If failure has been CONFIRMED previously in the study, there is no need to confirm failure at 
651 
subsequent visits. Participants with previously CONFIRMED failure will continue in follow-up 
652 
as outlined in section 3.7.1 regardless of whether they meet failure criteria again on subsequent 
653 
visits. 
654 
3.5.1 Procedures for Participants Meeting Failure Criteria at a Study Visit PRIOR to the 
655 
36-month Primary Outcome Visit 
656 
All participants who meet failure criteria PRIOR to the 36-month Primary Outcome Visit will 
657 
undergo the following additional testing in the order specified below (1-5) at the visit when the 
658 
failure criterion is met:  
659 
1. Random Dot Stereo Butterfly test (masked): tested in OFFICE spectacles at 33 cm.* 
660 
2. Preschool Worth 4-Shape test (masked): tested in OFFICE spectacles at 33 cm.* 
661 
3. Distance Randot Stereotest (masked): tested through TOP of HOME spectacles at 3 
662 
meters (with bottom half of lenses taped). (See ETS3 Procedures Manual for taping 
663 
instructions) 
664 
4. Randot Preschool Stereoacuity Test (masked): tested through TOP of HOME spectacles 
665 
at 33 cm (with bottom half of lenses taped) (See ETS3 Procedures Manual)* 
666 
5. Cycloplegic Refraction (after the testing above is completed)  
667 

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• The cycloplegic refraction must be performed 30 to 45 minutes following at least 
668 
one application of cyclopentolate 1%. 
669 
• If the cycloplegic refraction reveals that the spectacles no longer meet the spectacle 
670 
tolerance criteria according to section 3.12, the spectacle correction must be 
671 
updated (both HOME and OFFICE spectacles). 
672 
*Test distance for near stereoacuity and other binocular testing is 33 cm rather than 40 cm because of the focal 
673 
length of the +3.00 D add. 
674 
If based on the cycloplegic refraction performed at this visit: 
675 
• The spectacle correction IS within tolerance (section 3.12) and does not need to be 
676 
updated: 
677 
1. Failure is CONFIRMED at this visit. 
678 
2. The participant should be prescribed BFLs (if in the SVL group) or continued in 
679 
BFLs (if in the BFL group) (section 2.8)  
680 
3. The participant should return in 2 months (window: 4 to 12 weeks) for their Post-
681 
failure Secondary Outcome Visit (section 3.7).  
682 
 
683 
• The spectacle correction is NOT within tolerance (section 3.12) and needs to be updated: 
684 
1. Failure is NOT CONFIRMED at this visit.  
685 
2. The participant should be prescribed new spectacles (according to the criteria in 
686 
section 2.8) consistent with the participant’s randomized group assignment to SVL 
687 
or BFL spectacles. 
688 
3. The participant will return for a Failure Confirmation Visit (section 3.6) in 2 
689 
months (window: 4 to 12 weeks).  
690 
3.5.2 Procedures for Participants Meeting Failure Criteria AT the 36-month Primary 
691 
Outcome Visit 
692 
All participants who meet failure criteria AT the 36-month visit must have a cycloplegic 
693 
refraction at the end of this study visit (after eye alignment, stereoacuity, and other binocular 
694 
function testing, etc.): 
695 
• The cycloplegic refraction must be performed 30 to 45 minutes following at least 
696 
one application of cyclopentolate 1%.  
697 
• If cycloplegic refraction reveals that the spectacles are no longer within the 
698 
spectacle tolerance criteria according to section 3.12, then both HOME and 
699 
OFFICE spectacle corrections must be updated. 
700 
 
701 
NOTE: All eye alignment, stereoacuity, and other binocular function testing must 
702 
already have been completed as part of the 36-month Primary Outcome visit (for all 
703 
participants) before instilling cyclopentolate drops.  
704 
 
705 
If the spectacle correction IS within tolerance (section 3.12) and does not need to be updated: 
706 
1. Failure is CONFIRMED at this 36-month visit. 
707 
2. SVL group participants should be prescribed BFLs and BFL group participants continued 
708 
in BFLs (section 3.4.1)  
709 
3. Both groups should return in 2 months (window: 4 to 12 weeks) for their 38-month 
710 
Secondary Outcome Visit (section 3.8).  
711 

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36 
 
712 
If the spectacle correction is NOT within tolerance (section 3.12) and needs to be updated: 
713 
1. Failure is NOT CONFIRMED at this 36-month visit.  
714 
2. Participants should be prescribed new spectacles (according to the criteria in section 2.8) 
715 
consistent with their randomized group assignment.  
716 
3. Participants should return for a Failure Confirmation Visit in 2 months (window: 4 weeks 
717 
to 12 weeks).  
718 
4. Regardless of whether study failure criteria are confirmed or not confirmed at the Failure 
719 
Confirmation Visit, all SVL participants will be prescribed BFLs and all BFL participants 
720 
will continue with BFL wear (section 3.4.1).  
721 
5. Both groups return in 2 months (window: 4 to 12 weeks) following the Failure 
722 
Confirmation Visit for their 38-month Secondary Outcome Visit. In this specific 
723 
situation, the 38-month Secondary Outcome Visit will be scheduled at 40 months after 
724 
randomization (section 3.8).  
725 
3.6 Failure Confirmation Visit  
726 
Failure Confirmation Visits occur 2 months (window: 4 to 12 weeks) after suspected failures that 
727 
occurred for participants who were found to need a change in spectacles at that time. The 
728 
purpose of the Failure Confirmation Visit is to determine whether failure criteria are met after 
729 
the participant has been wearing the updated randomized treatment spectacles. Note that meeting 
730 
any failure criteria in updated spectacles will be considered a CONFIRMED failure. It is not 
731 
required that the participant fail the same criterion that was initially failed before the spectacles 
732 
were updated (e.g., could have failed distance motor criterion initially but now fails near stereo 
733 
criterion; this is still failure).  
734 
NOTE: The Failure Confirmation Visit (if required) is not allowed to be missed regardless of 
735 
timing. If the timing of the Failure Confirmation Visit overlaps with a subsequent follow-up 
736 
visit, the Failure Confirmation Visit must be completed in lieu of the follow-up visit (or 
737 
before the 38-month visit). Regardless of whether any regularly scheduled follow-up visits 
738 
have been missed, the Failure Confirmation Visit must be completed when the participant 
739 
returns at the next study visit. 
740 
All testing in section 3.4 (same as 36-month Primary Outcome Visit) must be repeated at the 
741 
Failure Confirmation Visit, with participants wearing their HOME spectacles or OFFICE 
742 
spectacles (or appropriate trial frames) as specified.   
743 
• If failure criteria are NOT CONFIRMED at a Failure Confirmation Visit occurring 
744 
before the 36-month visit, no changes are made to treatment and the participant 
745 
continues with the next scheduled follow-up visit for which the participant is not 
746 
currently in the window, regardless of how soon. 
747 
 
748 
• If failure criteria are NOT CONFIRMED at a Failure Confirmation Visit occurring after 
749 
the 36-month Primary Outcome Visit, participants will:  
750 
o Be prescribed BFLs (if in SVL group) or continued in BFLs (if in the BFL group) 
751 
(section 3.4.1)  
752 
o Return in 2 months (window: 4 to 12 weeks) for their 38-month Secondary 
753 
Outcome Visit (section 3.8).  
754 
 
755 

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• If failure criteria are CONFIRMED at ANY Failure Confirmation Visit (regardless of 
756 
timing), participants will:  
757 
o Be prescribed BFLs if in the SVL group or continued in BFLs if in the BFL group 
758 
(section 3.4.1)  
759 
o Return in 2 months (window: 4 to 12 weeks) for their: 
760 
• Post-failure Secondary Outcome Visit (section 3.7) if failure occurred prior to 
761 
the 36-month Primary Outcome Visit or  
762 
• 38-month Secondary Outcome Visit if failure occurred at the 36-month 
763 
Primary Outcome Visit (section 3.8).  
764 
3.7 Post-failure Secondary Outcome Visit (After Confirmed Failure) 
765 
Post-failure Secondary Outcome Visits occur 2 months (window: 4 to 12 weeks) after a 
766 
CONFIRMED failure at either a protocol-specified visit or a Failure Confirmation Visit. All 
767 
testing procedures completed at the 38-month Secondary Outcome Visit (section 3.8) will be 
768 
completed at this Post-failure Secondary Outcome Visit. 
769 
After a Post-failure Secondary Outcome Visit is completed:  
770 
• Further treatment is at investigator discretion (including whether to continue BFL or 
771 
SVL spectacles).  
772 
3.7.1 Treatment After the Post-failure Secondary Outcome Visit 
773 
Participants with confirmed failure status (sections 3.5 and 3.6) who have completed a Post-
774 
failure Secondary Outcome Visit prior to 36 months may be prescribed treatment at investigator 
775 
discretion. Note that office spectacles will no longer be prescribed. 
776 
3.7.2 Follow-up After the Post-failure Secondary Outcome Visit 
777 
Participants with confirmed failure status (sections 3.5 and 3.6) who have completed a Post-
778 
failure Secondary Outcome Visit prior to 36 months will return for follow-up at 12 months and 
779 
24 months (with reduced testing as described below), and for the 38-month Secondary Outcome 
780 
Visit (as described in section 3.8); all other study visits will be skipped.  
781 
 
782 
At the 12- and 24-month visits, these participants will undergo the following (reduced) testing 
783 
while wearing their habitual correction: 
784 
1. Monocular Visual Acuity Testing: Distance VA will be measured (right eye first) with the 
785 
participant wearing habitual correction and without cycloplegia, using the same test method 
786 
used at enrollment.  
787 
• ATS-HOTV; e-ETDRS; OR crowded single-optotype or single-line HOTV, LEA 
788 
SYMBOLS, or Snellen letters (Allen pictures and Tumbling E optotypes are NOT 
789 
allowed) 
790 
• NOTE: VA testing may be performed at the end of the visit. 
791 
2. Randot Preschool Stereoacuity Test with habitual correction  
792 
• Tested in habitual correction at 33 cm (see ETS3 Procedures Manual)* 
793 
3. Ocular Alignment Testing – cover/uncover test, SPCT, and PACT:  
794 
• Wearing habitual correction at both distance (3 m) and near (33 cm) (see ETS3 
795 
Procedures Manual)* 
796 
4. Cycloplegic Refraction (required only if not completed within the past 12 months):  
797 

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38 
• The cycloplegic refraction must be performed 30 to 45 minutes following at least one 
798 
application of cyclopentolate 1%.  
799 
If the cycloplegic refraction reveals uncorrected refractive error, spectacle changes may 
800 
be prescribed at investigator discretion.  
801 
3.8 38-month Secondary Outcome Visit 
802 
All participants will complete a 38-month Secondary Outcome Visit, including participants who 
803 
had a Post-failure Secondary Outcome Visit earlier in the study. The 38-month Secondary 
804 
Outcome Visits will occur at one of the following times:   
805 
• 2 months (±4 weeks) after the 36-month Primary Outcome Visit if: 
806 
o failure has not been met by 36 months, OR 
807 
o failure is met at 36 months and does not require confirmation 
808 
• 2 months (±4 weeks) after the Failure Confirmation Visit (40 months) following 
809 
failure which requires confirmation at the 36-month Primary Outcome Visit  
810 
• At 38 months (±4 weeks) after randomization if failure was confirmed prior to 36 
811 
months 
812 
At the 38-month Secondary Outcome Visit, most participants will be wearing HOME spectacles 
813 
that will be bifocals; however, some participants who have previously met failure criteria may 
814 
not be wearing BFLs. A cover/uncover test at near will be performed for participants who are not 
815 
wearing BFLs to determine whether they have esotropia (see test procedure #5); if esotropia is 
816 
present, then +3.00D lenses will be required for near testing (except for the second Randot 
817 
Preschool Stereotest measure, which is performed through the distance correction only). If any 
818 
participant presents to the visit without their HOME spectacles (if prescribed) or if the spectacles 
819 
do not meet the spectacle tolerance criteria as determined by lensometry, trial frames will be 
820 
used for testing.   
821 
The following test procedures are to be performed in the order specified below; procedures 4-9 
822 
must be performed by an examiner masked to original treatment assignment: 
823 
1. Lensometry (HOME spectacles) 
824 
2. Diplopia Assessment: Assess diplopia presence and frequency over the last week, by 
825 
parental report. If present, classify diplopia frequency as “2 times or less per day” or 
826 
“more than 2 times per day.” 
827 
3. Monocular VA Testing: through TOP of HOME spectacles (if wearing)  
828 
Items 4-10 will be performed by an examiner masked to original treatment assignment (SVLs or 
829 
BFLs); most participants are measured in a BFL lens correction at this visit (unless previously 
830 
released to treatment at investigator discretion). 
831 
4. Distance Randot Stereotest: through TOP of HOME spectacles (if wearing) at 3 m 
832 
(masked) 
833 
5. Cover/uncover test at near (for participants NOT currently wearing BFLs) to determine 
834 
the optical correction to be used for Randot Preschool Stereoacuity #1, Randot Butterfly, 
835 
Worth 4-Shape, and ocular alignment at near (cover/uncover, SPCT, and PACT testing) 
836 
(tests #6, 7, 8 and 10 below):  
837 

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39 
• Perform a cover/uncover test at near through the HOME spectacles (or without 
838 
spectacles, if none were prescribed)  
839 
• If an esotropia is present on the cover/uncover test at near, the specified testing must 
840 
be completed in either 1) +3.00 lenses placed in Halberg or Janelli clips attached to 
841 
the HOME spectacles or 2) a trial frame with a lens power that is +3.00D more than 
842 
the HOME spectacles. 
843 
• If no esotropia is present on the cover/uncover test at near, the specified testing must 
844 
be completed through the HOME spectacles (or without spectacles, if none were 
845 
prescribed).     
846 
6. Randot Preschool Stereoacuity Test #1: through BOTTOM of HOME spectacles if 
847 
currently wearing BFLs (otherwise, see step #5) at 33 cm* (masked)  
848 
7. Random Dot Stereo Butterfly test: through BOTTOM of HOME spectacles if currently 
849 
wearing BFLs; (otherwise, see step #5) at 33 cm* (masked) 
850 
8. Preschool Worth 4-Shape test: through BOTTOM of HOME spectacles if currently 
851 
wearing BFLs (otherwise, see step #5) at 33 cm* (masked). 
852 
9. Randot Preschool Stereoacuity Test #2: through TOP of HOME spectacles for at 33 cm* 
853 
(masked)  
854 
10. Ocular Alignment Testing: in HOME spectacles (masked) 
855 
• Cover/uncover test, SPCT, and PACT at 3 m through TOP of HOME spectacles 
856 
• Cover/uncover test, SPCT, and PACT through BOTTOM of HOME spectacles if 
857 
currently wearing BFLs (otherwise, see step #5)  
858 
*Test distance for near stereoacuity/binocularity testing is 33 cm rather than 40 cm because of 
859 
the focal length of the +3.00 D add. 
860 
Study follow-up will end for all participants after the 38-month Secondary Outcome Visit is 
861 
completed.  
862 
3.9 Inability to Complete a Study Visit  
863 
If a child is not sufficiently cooperative (for any reason) for valid study data to be collected at a 
864 
study visit, the child may return for continuation of the study visit on another day. This visit 
865 
should be scheduled within 10 days or before the end of the study-visit window, whichever is 
866 
sooner. The decision to have the child return on a subsequent day must be made by the masked 
867 
examiner prior to the end of the masked exam. Any test procedures or measurements in question 
868 
because of participant fatigue will be repeated at the return visit (all testing does not need to be 
869 
repeated).  
870 
If the participant’s family does not have sufficient time to complete a study visit and must leave 
871 
prior to completing all required study testing (e.g., not able to stay for a cycloplegic refraction 
872 
when meeting failure criteria), the participant must be brought back to complete testing within 10 
873 
days or before the end of the study-visit window, whichever is sooner. 
874 
3.10 Initiating Non-randomized Treatment for Esotropia (ET) 
875 
Non-randomized treatment for ET is NOT permitted during the study unless the following 3 
876 
conditions have been met:  
877 
1. Participant has met failure criteria (section 3.5)  
878 

JAEB CENTER FOR HEALTH RESEARCH 
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40 
2. Failure was confirmed either at the initial visit (section 3.5) or at the Failure 
879 
Confirmation Visit (section 3.6)  
880 
3. Participant has completed their Post-failure Secondary Outcome Visit (section 3.7).  
881 
If none of the failure criteria are met but the participant is experiencing overwhelming social 
882 
concerns or significant symptoms (other than frequent or constant diplopia at distance or near, 
883 
which is a failure criterion) associated specifically with the ET, the investigator must call one of 
884 
the Protocol Chairs to discuss the case and obtain approval for an exception prior to initiating 
885 
any non-randomized treatment for ET.  
886 
To the extent possible, participants for whom non-study treatment is planned (after discussion 
887 
with Protocol Chair) should proceed as if one of the three protocol-specified failure criteria were 
888 
met. Thus, they should complete the additional testing in section 3.5.1 (including the cycloplegic 
889 
refraction) and a Post-failure Secondary Outcome Visit (section 3.7) prior to initiating any non-
890 
study treatment. The SVL participants will be prescribed BFL spectacles to be worn prior to the 
891 
Post-failure Secondary Outcome Visit and the BFL participants should continue wearing BFLs.  
892 
3.11 Treatment of Amblyopia 
893 
Patching, Bangerter foils, and binocular treatment for amblyopia are allowed at investigator 
894 
discretion during the study. However, atropine and other cycloplegic drops, and/or bifocal lenses 
895 
prescribed for treating amblyopia are not allowed. 
896 
3.12 Spectacle Tolerance Criteria for Follow-up 
897 
The following spectacle tolerance criteria will apply throughout the study (unless previously 
898 
released to treatment at investigator discretion): 
899 
a. Spectacles (HOME and OFFICE) must meet the following spectacle tolerance 
900 
criteria as compared with the participant’s most recent cycloplegic refraction 
901 
(NOTE: if hyperopic sphere and/or the bifocal add power has been reduced per 
902 
protocol, sphere and add power must be within tolerance of what was prescribed): 
903 
• SE refraction must be corrected within ±0.625 D 
904 
• Sphere power must be corrected within ±0.50 D 
905 
• Anisometropia must be corrected within ±0.50 D SE  
906 
• Cylinder power must be corrected within ±0.50 D  
907 
• Cylinder axis must be within ±10 degrees if cylinder power is ≤1.00 D, and 
908 
within ±5 degrees if cylinder power is >1.00 D. 
909 
• Bifocal must be a flat-top 35 and meet the following tolerance criteria: 
910 
o Height must be within ±2 mm of mid-pupil 
911 
o Power must be within ±0.50 D of that prescribed  
912 
o Total sphere power of the bifocal segment must be corrected within 
913 
± 0.50 D of the sum of the prescribed bifocal power and distance 
914 
sphere power 
915 
o Measured bifocal add power (lensometry difference between 
916 
distance sphere power and bifocal sphere power) must be within 
917 
±0.50 D of prescribed bifocal add power 
918 

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3.12.1 Change in Spectacles Because Lensometry Reveals Spectacles are Out of Tolerance 
919 
When lensometry reveals that the spectacles do not meet spectacle tolerance criteria (section 
920 
3.12) based on the most recent spectacle prescription (which includes any reduction in hyperopic 
921 
sphere and bifocal add power) and the most recent cycloplegic refraction, the spectacles must be 
922 
remade. 
923 
3.13 Management of Refractive Error During Follow-up 
924 
3.13.1 Change in Spectacles Following a Change in Cycloplegic Refraction 
925 
If a cycloplegic refraction during follow-up reveals a change in refractive error such that the 
926 
current spectacles do not correct the refractive error to within spectacle tolerance criteria (section 
927 
3.12) then both HOME and OFFICE spectacle corrections must be updated (new lenses 
928 
prescribed).  
929 
The new spectacles must be prescribed based on the most recent cycloplegic refraction and the 
930 
full correction for hyperopia, myopia, and astigmatism is to be prescribed. Those randomized to 
931 
the BFL group also will be prescribed a +3.00 D add.  
932 
• NOTE: No reduction in hyperopic correction or bifocal add is permitted when initially 
933 
prescribing required new spectacles during follow-up; however, a reduction in hyperopic 
934 
correction or bifocal add can be made at a subsequent visit, if warranted (see sections 
935 
3.13.2 and 3.13.3).  
936 
3.13.2 Reduction of Hyperopic Correction Because of Distance Blur  
937 
The initial study spectacles will be prescribed with the full-plus hyperopic correction. However, 
938 
if one of the following occurs at any time during follow-up, the investigator may reduce the 
939 
distance hyperopic correction (sphere) symmetrically by 0.25 D or 0.50 D from the original 
940 
randomized prescription. Hyperopic correction may be reduced if the participant:  
941 
 
942 
(1) has a decrease in VA of 0.2 logMAR or more (based on conversion of Snellen 
943 
equivalent to logMAR. (See Table 1 in section 2.2),  
944 
(2) complains of distance blur (even if VA has not decreased), or  
945 
(3) resists wearing the spectacles and the investigator believes the resistance may be from an 
946 
inability to relax accommodation fully 
947 
3.13.3 Management of Refractive Error to Control Exodeviations 
948 
If at any time during follow-up a participant develops a constant exotropia at NEAR, the 
949 
investigator should determine the amount of reduced hyperopic correction in the reading portion 
950 
of the lens (bifocal add for the BFL group and spherical component of the entire lens for the SVL 
951 
group) necessary to reduce the frequency of the exotropia such that it is no longer constant AND 
952 
contact one of the Protocol Chairs prior to making any changes.  
953 
If at any time during follow-up the child develops an exodeviation at DISTANCE (constant, 
954 
intermittent, or phoria), the investigator should determine the amount of reduced hyperopic 
955 
correction necessary to reduce the exodeviation to ortho or a small amount of esodeviation AND 
956 
contact one of the Protocol Chairs prior to making any changes. 
957 
 
958 

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Chapter 4: Testing Procedures and Questionnaires 
959 
4.1 Clinical Assessments 
960 
The following test procedures as described in the ETS3 Procedures Manual will be completed 
961 
for both treatment groups at each visit as specified by the protocol.  
962 
1. Monocular Visual Acuity Testing: Monocular distance VA will be tested in both eyes with 
963 
the participant wearing their study-specified spectacle correction. The right eye is tested, with 
964 
the left eye occluded with an adhesive patch. The left eye is tested after the right eye. The 
965 
testing method is at investigator discretion provided the following are used: ATS-HOTV; e-
966 
ETDRS protocol; OR crowded single-optotype or single-line HOTV, LEA SYMBOLS or 
967 
Snellen letters. (Allen pictures and tumbling E optotypes are NOT allowed). Testing does not 
968 
need to be performed by a study-certified tester and it is not required to be measured on a 
969 
PEDIG-certified VA testing system, but the chart used needs to be appropriately calibrated. 
970 
The same testing method must be used throughout the study. Testing time for both eyes 
971 
typically is in the range of 5 to 7 minutes. 
972 
2. Lensometry: The distance correction and the bifocal add (where applicable) will be 
973 
measured. Measurement time takes between 1 and 3 minutes and does not involve the 
974 
participant. 
975 
3. Randot Preschool Stereoacuity Test: The Randot Preschool Stereoacuity Test measures 6 
976 
levels (40 to 800 arcsec) of stereoacuity at near (40 cm). Corresponding levels range from 48 
977 
to 960 arcsec when tested at 33 cm. The test consists of 3 booklets, each designed to test 2 
978 
levels of stereoacuity, and each level consisting of 4 panels, 3 of which contain a random dot 
979 
stereogram. The participant wears polarized lenses over their spectacle correction. The 
980 
examiner asks the participant if they can identify a specific black and white shape in the 
981 
booklet and then asks the participant to point to the panel containing the corresponding 
982 
stereogram image, as outlined in the ETS3 Procedures Manual. The test must be 
983 
administered by a certified examiner. Testing time is approximately 2-4 minutes. 
984 
4. Distance Randot Stereotest: The Distance Randot Stereotest measures 4 levels (60, 100, 200, 
985 
and 400 arcsec) of stereoacuity at 3 meters. The test consists of a booklet designed to display 
986 
2 pages at a time, each page containing a panel with a single random dot stereogram. The 
987 
participant wears polarized lenses over their spectacle correction and identifies the 
988 
stereogram images they see, as outlined in the ETS3 Procedures Manual. The test must be 
989 
administered by a certified examiner. Testing time is approximately 2-4 minutes.  
990 
5. Random Dot Stereo Butterfly Test: The Random Dot Stereo Butterfly Test measures 2000 
991 
arcsec of stereoacuity at 40 cm (2400 arcsec at 33 cm). The test consists of a booklet with a 
992 
single stereogram of a butterfly. The participant wears polarized lenses over their spectacle 
993 
correction and is asked to pinch the tip of the butterfly’s wings, which will appear to float off 
994 
the page if the participant has stereoacuity. The test must be administered by a certified 
995 
examiner. Testing time is approximately 1-2 minutes. 
996 
6. Preschool Worth 4-Shape Test: The Preschool Worth-4-Shape test is used to assess a 
997 
participant’s second-degree sensory fusion. The test utilizes a flashlight with 4 back-lit 
998 

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shapes: red heart, green circle, green moon, and white star. The participant views the shapes 
999 
at approximately 33 cm while wearing red/green filter glasses and identifies the shapes that 
1000 
are seen as outlined in the ETS3 Procedures Manual. The test can determine whether the 
1001 
participant has second-degree fusion, suppression, or diplopia. The test must be administered 
1002 
by a pediatric ophthalmologist, pediatric optometrist, or certified orthoptist. Testing time is 
1003 
approximately 3-5 minutes. 
1004 
7. Ocular Alignment Testing: 
1005 
Ocular alignment will be assessed by the cover/uncover test, simultaneous prism and cover 
1006 
test (SPCT), and the prism and alternate cover test (PACT) in primary gaze at distance (3 
1007 
meters) and at near (33 cm) as outlined in the ETS3 Procedures Manual. Testing must be 
1008 
done by a pediatric ophthalmologist, pediatric optometrist, or certified orthoptist. Testing 
1009 
time is approximately 3-5 minutes. 
1010 
 
1011 
8. Cycloplegic Refraction: The cycloplegic refraction must be/have been performed 30 to 45 
1012 
minutes following at least one application of cyclopentolate 1%. The cycloplegic refraction 
1013 
may be done with spectacles off or as an over-refraction in front of the spectacles. Subjective 
1014 
refinement is allowed. Testing time is approximately 1-5 minutes (following 30-45 minutes 
1015 
of waiting for the cycloplegic drops to take effect). 
1016 
 
1017 
The following information will be collected by interviewing the parent(s): 
1018 
 
1019 
1) Assessment of Diplopia: An estimate of the frequency of diplopia (if any) will be determined 
1020 
by asking the parent whether “your child has complained of double vision over the last 
1021 
week.” If yes, the parent is asked how frequently the child has complained of double vision: 
1022 
“2 times or less per day,” “or “more than 2 times per day.” Any study personnel may ask the 
1023 
parent to rate diplopia. Testing time is approximately 1 minute. 
1024 
 
1025 

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Chapter 5: Unanticipated Problem and Adverse Event Reporting 
1026 
5.1 Unanticipated Problems 
1027 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
1028 
problems meeting the criteria below. Sites must report Unanticipated Problems to the IRB within 
1029 
seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
1030 
experience, or outcome that meets all three (3) of the following criteria: 
1031 
 
1032 
1. Is unexpected (in terms of nature, severity, or frequency) given (a) the research 
1033 
procedures that are described in the protocol-related documents, such as the IRB-
1034 
approved research protocol and informed consent document and (b) the characteristics of 
1035 
the subject population being studied 
1036 
2. Is related or possibly related to participation in the research (possibly related means 
1037 
there is a reasonable possibility that the incident, experience, or outcome may have been 
1038 
caused by the procedures involved in the research) 
1039 
3. Suggests that the research places participants or others at a greater risk of harm than was 
1040 
previously known or recognized (including physical, psychological, economic, or social 
1041 
harm)  
1042 
 
1043 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
1044 
involving a specific site such as unanticipated problems that occur at the Coordinating Center. 
1045 
These instances must be reported to the JCHR IRB within seven (7) calendar days of recognition. 
1046 
The Director of the Human Research Protection Program will report to the appropriate regulatory 
1047 
authorities if the IRB determines that the event indeed meets the criteria of an Unanticipated 
1048 
Problem that requires further reporting.  
1049 
5.2 Adverse Events 
1050 
5.2.1 Reportable Adverse Events 
1051 
Because study treatment with bifocal or single-vision spectacles is non-invasive and consistent 
1052 
with usual care, it is not expected that there would be any significant adverse events other than 
1053 
those already being captured as part of clinical outcome assessments (e.g., treatment failure 
1054 
criteria).  For this reason, only serious, related adverse events shall be reported to the 
1055 
Coordinating Center, on the applicable eCRF, within seven (7) days of identification. 
1056 
Furthermore, investigators must still abide by IRB reporting requirements. If covered by the 
1057 
JCHR IRB, investigators are required to report all serious, related adverse events to the JCHR 
1058 
IRB within seven (7) calendar days of identification of the event.  
1059 
5.3 Safety Oversight 
1060 
A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
1061 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to 
1062 
the study protocol or suspension or outright stoppage of the study if deemed necessary based on 
1063 
the totality of safety data available. Details regarding DSMC review will be documented in a 
1064 
separate DSMC charter.  
1065 
The objective of the DSMC review is to decide whether the study (or study treatment for an 
1066 
individual or study cohort) should continue per protocol, proceed with caution, be further 
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investigated, be discontinued, or be modified and then proceed. Suspension of enrollment (for a 
1068 
particular group, a particular study site, or for the entire study) is a potential outcome of a DSMC 
1069 
safety review. 
1070 
5.4 Stopping Criteria 
1071 
The study may be discontinued by the Steering Committee (with approval of DSMC) prior to the 
1072 
preplanned completion of follow-up for all study participants. No formal guidelines for stopping 
1073 
the study for futility or efficacy are pre-specified (section 7.4). 
1074 
5.5 Participant Discontinuation of Study Treatment 
1075 
Rules for discontinuing study treatment use are one of the following:  
1076 
• The investigator believes it is unsafe for the participant to continue to receive the 
1077 
treatment.  
1078 
• The participant or parent requests that the treatment be stopped. 
1079 
Even if the study treatment is discontinued, the participant will be encouraged to remain in the 
1080 
study through the 38-month Secondary Outcome Visit. 
 
1081 

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Chapter 6: Miscellaneous Considerations 
1082 
6.1 Contacts by the Jaeb Center for Health Research and Sites 
1083 
The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided the 
1084 
parents’ contact information. The Jaeb Center may contact the parents of the participants. 
1085 
Permission for such contacts will be included in the Informed Consent Form. The principal 
1086 
purpose of the contacts will be to develop and maintain rapport with the participant’s family and 
1087 
to help coordinate the scheduling of study visits, when needed.  
1088 
6.2 Participant Compensation 
1089 
Participant compensation will be specified in the informed consent form. 
1090 
6.3 Cost of Spectacles 
1091 
Spectacles required as part of the study will be paid for by the study. Spectacle changes are 
1092 
required following a cycloplegic refraction that indicates the spectacles are out of study tolerance 
1093 
limits, at the time of failure for children in the SVL group, and at the 36-month Primary 
1094 
Outcome Visit for the SVL group. Spectacles may be updated and paid for by the study 
1095 
whenever a spectacle change is required or made at investigator discretion for both treatment 
1096 
groups. Spectacles may be replaced and paid for by the study if in poor condition (e.g., 
1097 
significantly scratched lenses, broken frame) at any time during follow-up.  
1098 
At the parent’s request, a separate prescription for SVL sports glasses may be provided for wear 
1099 
during sports. Sports glasses will not be paid for by the study. Sports glasses must only be worn 
1100 
when playing sports. 
1101 
6.4 Participant Withdrawal 
1102 
Participation in the study is voluntary and a participant may withdraw at any time. For 
1103 
participants who withdraw, their data collected prior to their withdrawal will be used. This 
1104 
stipulation is specified in the consent form. 
1105 
6.5 Confidentiality 
1106 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1107 
used instead of their name. Protected health information gathered for this study will be shared 
1108 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1109 
participant information may also be provided to research sites involved in the study.
1110 

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Chapter 7: Statistical Considerations 
1111 
7.1 Statistical and Analytical Plans 
1112 
The approach to sample size calculation and statistical analyses are summarized below.  
1113 
 
1114 
7.2 Primary Objective and Hypothesis 
1115 
The primary objective is to determine if participants with ET greater at near who are prescribed 
1116 
SVLs and BFLs have different failure probabilities by 36 months.  
1117 
The primary outcome is treatment failure by 36 months, defined as meeting any one of the 
1118 
following criteria at any follow-up visit from 3 months to 36 months inclusive: 
1119 
1. Constant ET ≥15∆ by SPCT at distance. (NOTE: intermittent ET and esophoria of any 
1120 
magnitude are NOT considered failures.) 
1121 
2. Decrease in near stereoacuity on the Randot Preschool Stereoacuity (RPS) Test of 2 or 
1122 
more levels from baseline, or from 960” at baseline to nil (see Table 2 in section 3.5 for 
1123 
reference). 
1124 
• 
At follow-up visits, the best of two stereoacuity measures in OFFICE spectacles 
1125 
will be used. 
1126 
• 
Baseline stereoacuity is defined as the near stereoacuity recorded with +3.00 D 
1127 
power added to the participant’s enrollment distance spectacle correction in trial 
1128 
frames. 
1129 
• 
Approximately 50% of participants are expected to have nil near stereoacuity at 
1130 
baseline; it is acknowledged that these participants will not be able to meet the 
1131 
near stereoacuity failure criteria. 
1132 
3. Binocular diplopia with a frequency of “more than 2 times per day” over the last week at 
1133 
distance or near, by parental report. 
1134 
If nonsurgical or surgical treatment for ET other than the randomized treatment is before meeting 
1135 
failure criteria, that participant will be considered a failure at the visit that such treatment is 
1136 
prescribed. 
1137 
 
1138 
The study is designed as a superiority study to evaluate a 2-sided primary null hypothesis that the 
1139 
failure probability by 36 months is the same between the SVL and BFL groups versus the 
1140 
alternative hypothesis that it is different: 
1141 
 
1142 
 
Hnull   
BFL% of failure by 36 months = SVL% of failure by 36 months 
1143 
            Halternative  
BFL% of failure by 36 months ≠ SVL% of failure by 36 months 
1144 
 
1145 
The composition of the treatment failures (i.e., whether due to distance motor failure, near 
1146 
stereoacuity failure, or diplopia “more than 2 times per day” over the last week) is also of 
1147 
primary interest. However, the failure criteria may be interrelated and thus there is no specific 
1148 
hypothesis for each criterion. 
1149 
 
1150 
7.3 Sample Size 
1151 
Sample size estimation is based on data from the retrospective cohort study conducted by 
1152 
Whitman et al.24 After approximately 4 years of follow-up, 15.6% of the BFL group and 3.9% of 
1153 

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the SVL group underwent strabismus surgery, all of whom had an increase in the distance angle 
1154 
of deviation to more than 10∆ by PACT (average increase from baseline was 25∆ in the BFL 
1155 
group and 20.5∆ in the SVL group). In the current study, the primary outcome is based on 
1156 
distance motor failure (based on SPCT), near stereoacuity failure, or diplopia “more than 2 times 
1157 
per day” over the last week by 36 months. Given a shorter follow-up, the proportion of distance 
1158 
motor failures may be less than that found in the Whitman et al. study. The proportion of near 
1159 
stereoacuity failures is believed to be less in the BFL group than the SVL group, but no data are 
1160 
available to provide estimates of the failure proportion for each group. 
1161 
 
1162 
Table 4 shows the sample size estimates under various assumptions for the primary outcome in 
1163 
the SVL group and the difference in the primary outcome between the BFL and SVL groups. To 
1164 
be conservative, the total sample size needed to detect a treatment group difference is calculated 
1165 
using a two-sided Pearson chi-square test with a type I error rate of 5% and 90% power. Power is 
1166 
expected to increase slightly using a time-to-event approach for the primary outcome analysis. 
1167 
 
1168 
Table 4. Total sample size needed to detect a treatment group difference in proportions of 
1169 
failure by 36 months under various assumptions 
1170 
% of Failure in 
SVL Group 
Treatment Group Difference in % of Failures (BFL – SVL) 
5% 
6% 
7% 
8% 
9% 
10% 
15% 
20% 
3% 
870 
656 
518 
424 
356 
306 
172 
116 
4% 
1018 
756 
592 
480 
400 
342 
186 
124 
5% 
1164 
856 
664 
534 
442 
376 
202 
130 
6% 
1304 
954 
734 
588 
484 
408 
214 
138 
7% 
1442 
1140 
802 
640 
524 
440 
228 
146 
8% 
1576 
1140 
870 
690 
564 
472 
242 
152 
9% 
1708 
1230 
936 
740 
602 
502 
254 
158 
10% 
1836 
1318 
998 
788 
640 
532 
266 
164 
11% 
1960 
1402 
1060 
834 
676 
562 
278 
172 
12% 
2082 
1486 
1120 
880 
712 
590 
290 
178 
13% 
2198 
1566 
1178 
924 
746 
618 
302 
182 
14% 
2314 
1644 
1236 
966 
780 
644 
312 
188 
15% 
2424 
1720 
1290 
1008 
812 
670 
322 
194 
 
1171 
Assuming a failure probability of 5% in the SVL group and 15% in the BFL group, a sample size 
1172 
of 376 (188 per group) provides 90% power to detect a treatment group difference with a two-
1173 
sided type I error rate of 5%. The total sample size is increased to 444 (222 per group) to account 
1174 
for up to a 15% loss to follow-up over 36 months. 
1175 
7.4 Interim Monitoring 
1176 
An interim sample size re-estimation based on 12-month treatment failure outcome was 
1177 
considered because of uncertainty in the assumed proportions of failure by 36 months in the 
1178 

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treatment groups. However, it is unclear how well the 12-month outcome will predict the 36-
1179 
month outcome. Because of this additional uncertainty, this approach will likely increase the bias 
1180 
in the estimation of the 36-month primary outcome. To minimize this bias, sample size re-
1181 
estimation would have to be performed based on the partial 36-month outcome data, but it would 
1182 
be too late to affect recruitment since recruitment is expected to be completed within 3 years. In 
1183 
addition, the estimated total sample size of 444 is close to the maximum number of eligible 
1184 
participants that could potentially be recruited. Therefore, a sample size re-estimation will not be 
1185 
performed. 
1186 
Interim monitoring for futility and/or efficacy was also considered. For the same reasons, interim 
1187 
monitoring would have to be conducted based on the partial 36-month outcome data when 
1188 
recruitment is likely completed. Even if there is evidence for futility and/or efficacy for the 
1189 
primary outcome at that time, the remaining follow-up visits would likely be continued to collect 
1190 
data on all the outcomes including binocular function at 38 months. Therefore, there will be no 
1191 
formal guidelines for stopping the trial for futility or efficacy. The DSMC will review safety and 
1192 
efficacy data periodically.  
1193 
7.5 Analysis Dataset 
1194 
The primary efficacy analysis will follow an intent-to-treat (ITT) principle. All randomized 
1195 
participants will be included in the primary analysis dataset and analyzed according to the group 
1196 
they were originally assigned, regardless of what treatment (if any) they received. 
1197 
7.6 Analysis of Primary Outcome – Treatment Failure by 36 Months 
1198 
There may be participants who are lost to follow-up before their 36-month primary outcome data 
1199 
are collected. To use the data collected from these participants before they are lost to follow-up, 
1200 
a time-to-event analysis will be performed for the primary outcome. For participants who meet 
1201 
failure criteria before or at the 36-month Primary Outcome Visit, time to treatment failure will be 
1202 
defined as the time from randomization to the visit at which the failure is confirmed (either at the 
1203 
initial visit or later at a Failure Confirmation Visit because the spectacle correction must be 
1204 
updated [section 3.6]). If a participant is prescribed non-randomized treatment for ET before 
1205 
meeting failure criteria, they will be considered a failure at the time when such treatment is 
1206 
prescribed. Participants lost to follow-up are considered censored at the time of their last 
1207 
recorded visit. If a participant is lost to follow-up before failure is confirmed, they will be 
1208 
censored at their last visit for the primary analysis.  
1209 
The hazard ratio of treatment failure for treatment with BFLs versus SVLs and a two-sided 95% 
1210 
confidence interval (CI) will be estimated with a Cox proportional hazards model. The model 
1211 
will be adjusted for baseline near stereoacuity by the Randot Preschool Stereotest (RPS) in +3.00 
1212 
D trial frames and baseline magnitude of the distance esodeviation by SPCT. The treatment 
1213 
group difference in the probability of failure and a two-sided 95% CI will be estimated using the 
1214 
direct adjustment method. The proportional hazards and functional form assumptions will be 
1215 
evaluated.  
1216 
The timing and composition of failures (distance motor, near stereoacuity, diplopia, starting non-
1217 
protocol treatment) will be tabulated by treatment group to aid in the interpretation of the 
1218 
treatment group difference for failure probability by 36 months.  
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7.6.1 Sensitivity Analyses for Primary Outcome 
1220 
As a sensitivity analysis, if a participant meets the failure criteria prior to a required spectacle 
1221 
update but is lost to follow-up before the failure is confirmed, the participant will be treated as a 
1222 
failure at the time when they initially met the failure criteria (suspected failure). The primary 
1223 
analysis will be repeated with these unconfirmed failures being counted as failures.  
1224 
As an additional sensitivity analysis, treatment crossovers (BFL group participants who have 
1225 
bifocals formally discontinued and begin to wear SVL; SVL group participants prescribed 
1226 
bifocals) that occur before meeting any of the clinical measures for failure will be censored at the 
1227 
visit date when treatment crossover occurred. 
1228 
7.6.2 Contingency Plan for Primary Outcome 
1229 
If the assumptions for the Cox model are not satisfied, an exact logistic regression model with 
1230 
the same covariates will be attempted. If the adjusted model fails to converge, a model will be fit 
1231 
without the adjustment for covariates. If the exact logistic regression still fails to converge, 
1232 
Barnard’s exact test will be performed.  
1233 
7.7 Analysis of Secondary Outcomes 
1234 
7.7.1 Binocular Function Test Score in BFLs at the Secondary Outcome Visit 
1235 
A secondary outcome is the binocular function test score at the Secondary Outcome Visit (Post-
1236 
failure Secondary Outcome visit if failed or 38-month Secondary Outcome Visit if not failed). 
1237 
The test score is assigned on an ordinal scale that combines the results of the RPS test, Random 
1238 
Dot Stereo Butterfly test, and Preschool Worth 4-shape (W4S) test that were measured using the 
1239 
bottom portion of the participants’ BFLs. Given that BFLs can potentially reduce the magnitude 
1240 
of near ET, which might in turn improve near stereoacuity, it was felt critical to measure 
1241 
binocular function after a period of BFL wear in both treatment groups. Consequently, after 36 
1242 
months of SVL or BFL wear, the SVL group will be prescribed BFLs, the BFL group will 
1243 
continue wearing their BFLs, and both groups will be re-assessed at the 38-month Secondary 
1244 
Outcome Visit. Because participants who meet failure criteria for the primary outcome at a prior 
1245 
visit must be released to treatment at investigator discretion, these participants will be prescribed 
1246 
BFLs (if in the SVL group) or continue in BFL (if in the BFL group) and return within 2 months 
1247 
after meeting failure criteria for a Post-failure Secondary Outcome Visit.  
1248 
The possible levels of binocular function will be 48, 72, 120, 240, 480, 960 arcsec (RPS test), 
1249 
2400 arcsec (Random Dot Stereo Butterfly test), and 10,000 or 100,000 arcsec (fusion or 
1250 
suppression, respectively, indicated by Preschool W4S test). The binocular function test score 
1251 
will be calculated by converting binocular function to a log value ranging from 1.68 (log of 48 
1252 
arcsec) to 5.0 (log of 100,000 arcsec). Baseline near stereoacuity on the RPS test that was 
1253 
measured through +3.00 D lenses will be used in the calculation of the binocular function test 
1254 
score at baseline, and the Random Dot Stereo Butterfly and Preschool W4S tests that were also 
1255 
measured through +3.00 lenses. The score at the Secondary Outcome Visit (Post-failure 
1256 
Secondary Outcome visit if failed or 38-month Secondary Outcome Visit if not failed) and the 
1257 
change from baseline will be tabulated for each treatment group. A treatment group comparison 
1258 
of the scores will be performed using the exact Wilcoxon rank sum test to determine whether the 
1259 
treatment groups have different distributions of the score. If the hypothesis test for the primary 
1260 
outcome is significant, an alpha of 0.05 will be passed down to this test. If not, this outcome will 
1261 
be exploratory with no P-value reported. 
 
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7.7.2 Treatment Effects on Failure by 36 Months by Subgroup 
1263 
This study has liberal inclusion/exclusion criteria. It is possible that the treatment effect is not 
1264 
consistent across different subgroups of the population. With potentially small numbers of 
1265 
participants in subgroups, results of subgroup analyses will be interpreted with caution and the 
1266 
interpretation may depend on whether the primary analysis demonstrates a significant overall 
1267 
treatment group difference.  
1268 
The subgroup analyses will be performed by modifying the primary analysis to adjust for the 
1269 
subgroup factor and an interaction between the subgroup factor and treatment group.  
1270 
Baseline subgroups of interest are: 
1271 
1. Duration of ET prior to enrollment: <6 months vs. ≥ 6 months 
1272 
2. Stereoacuity 
1273 
a. Distance Randot Stereotest: nil vs. not nil 
1274 
b. Near RPS Test through +3.00 D lenses: nil vs. not nil 
1275 
3. Intermittent ET (or esophoria) vs. constant ET  
1276 
4. Motor response at near to +3.00 D trial frames testing classified as follows:  
1277 
a. No response (tropia ≥10∆ by SPCT) 
1278 
b. Microtropia (<10Δ) 
1279 
c. Phoria or orthophoria 
1280 
5. Near stereoacuity response vs. no near stereo response through +3.00 D trial frames 
1281 
a. Stereoacuity response is defined as near stereoacuity improvement of at least 2 
1282 
levels (for participants who have stereoacuity in SVLs) or presence (any level) of 
1283 
near stereoacuity in +3.00 D lenses (for participants who do not have stereoacuity 
1284 
in SVLs). 
1285 
b. Participants who have 48” or 72” of near stereopsis in SVLs cannot meet the 
1286 
stereoacuity response criteria and will be excluded from this subgroup analysis   
1287 
6. Gradient AC/A ratio  
1288 
a. By tertiles  
1289 
b. <2.5 vs. 2.5 to 6 vs. >6  
1290 
7. Age: 3 to <6 years vs. 6 to <9 years 
1291 
 
1292 
The proportion of participants that fall into each of the subgroups is unknown. Table 5 shows the 
1293 
expected half-width of the 95% CI for the treatment group difference in the primary outcome in 
1294 
subgroups of various sizes. For example, if the observed proportions of failure by 36 months are 
1295 
5% with SVLs and 15% with BFLs in a subgroup with 100 participants per treatment group, the 
1296 
expected half-width of the 95% CI for the treatment group difference would be 8%.  
1297 
 
 
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Table 5. Expected half-width of 95% CI* for treatment group difference in the proportion 
1299 
of failures by 36 months in subgroups with various sizes 
1300 
Observed % 
of Failure in 
SVL Group 
(p1) 
Observed 
% of 
Failure in 
BFL 
Group 
(p2) 
Observed 
Treatment 
Difference 
in % of 
Failure 
(p2 – p1) 
Number Per Treatment Group in Subgroup  
25 
50 
75 
100 
125 
150 
175 
200 
5% 
5% 
0% 
12% 
9% 
7% 
6% 
5% 
5% 
5% 
4% 
5% 
10% 
5% 
15% 
10% 
8% 
7% 
7% 
6% 
5% 
5% 
5% 
15% 
10% 
16% 
12% 
9% 
8% 
7% 
7% 
6% 
6% 
5% 
20% 
15% 
18% 
13% 
10% 
9% 
8% 
7% 
7% 
6% 
5% 
25% 
20% 
19% 
13% 
11% 
10% 
8% 
8% 
7% 
7% 
10% 
10% 
0% 
17% 
12% 
10% 
8% 
7% 
7% 
6% 
6% 
10% 
15% 
5% 
18% 
13% 
11% 
9% 
8% 
7% 
7% 
6% 
10% 
20% 
10% 
20% 
14% 
11% 
10% 
9% 
8% 
7% 
7% 
10% 
25% 
15% 
21% 
15% 
12% 
10% 
9% 
8% 
8% 
7% 
10% 
30% 
20% 
21% 
15% 
12% 
11% 
10% 
9% 
8% 
8% 
15% 
15% 
0% 
20% 
14% 
11% 
10% 
9% 
8% 
7% 
7% 
15% 
20% 
5% 
21% 
15% 
12% 
11% 
9% 
9% 
8% 
7% 
15% 
25% 
10% 
22% 
16% 
13% 
11% 
10% 
9% 
8% 
8% 
15% 
30% 
15% 
23% 
16% 
13% 
11% 
10% 
9% 
9% 
8% 
15% 
35% 
20% 
23% 
17% 
13% 
12% 
10% 
10% 
9% 
8% 
*Half-width of a 2-sided 95% CI = 1.96*sqrt[p1*(1-p1)/n1 + p2*(1-p2)/n2] 
1301 
 
1302 
7.8 Exploratory Analysis of Tertiary Outcomes  
1303 
All tertiary outcomes will be considered exploratory. Point estimates and 95% CIs for treatment 
1304 
group differences will be reported (where applicable) with no adjustment for multiplicity. 
1305 
Binocularity and stereoacuity outcomes that are better suited to non-parametric methods will be 
1306 
described using the median and interquartile range for each treatment group. 
1307 
7.8.1 Ocular Alignment at Distance and Near  
1308 
7.8.1.1 Comparison of Randomized Treatments at 36 Months or Confirmed Failure 
1309 
At the time of the primary outcome (36 months or confirmed failure), the magnitude of deviation 
1310 
by PACT and the change from baseline will be tabulated and described with summary statistics 
1311 
for each treatment group. The treatment group difference in the magnitude of deviation and the 
1312 
95% CI will be estimated using an analysis of covariance (ANCOVA) adjusting for the baseline 
1313 
PACT magnitude.  
1314 
The magnitude of deviation by SPCT and the change from baseline will also be tabulated and 
1315 
described with summary statistics for each treatment group. The proportions with constant ET of 
1316 
≥10Δ, constant ET of <10Δ, intermittent ET, esophoria, and orthophoria will be tabulated by 
1317 
treatment group. 
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The above analyses will be performed separately for distance and near deviations as measured 
1319 
through distance correction, to assess the magnitude of the underlying angle of deviation. In 
1320 
addition, the near deviations as measured through OFFICE spectacles (i.e., SVLs with 
1321 
cycloplegic refraction and +3.00 D power) will be analyzed similarly, to assess the impact of 
1322 
+3.00 D lenses on the near deviation.  
1323 
7.8.2 Binocular Function Test Score 
1324 
7.8.2.1 Subgroup Analysis of Secondary Outcome Binocular Function Score 
1325 
The secondary outcome of binocular function test score in BFLs at the Secondary Outcome Visit 
1326 
(Post-failure Secondary Outcome visit if failed or 38-month Secondary Outcome Visit if not 
1327 
failed) as defined in section 7.7.1 will be further evaluated in subgroups specified in section 
1328 
7.7.2. 
1329 
7.8.2.2 Comparison of Overall Treatment Strategies at 38 Months 
1330 
To evaluate real-world effectiveness of the overall treatment strategies the binocular function test 
1331 
score at the 38-month Secondary Outcome Visit and the change from baseline will be tabulated 
1332 
by treatment group. Distinct from the secondary outcome binocular function score (sections 7.7 
1333 
and 7.8.2.1), this analysis will utilize the 38-month data for all participants, regardless of whether 
1334 
they met failure criteria at a prior visit. Scores will be calculated using the same algorithm as 
1335 
described in section 7.7.1 for combining the results of the RPS, Random Dot Butterfly, and W4S 
1336 
tests that are measured through the bottom of the HOME spectacles for most participants (see 
1337 
section 3.8 for exceptions). Results of the individual tests will also be tabulated separately for 
1338 
each treatment group.  
1339 
7.8.2.3 Comparison of Randomized Treatments at 36 Months or Confirmed Failure 
1340 
The binocular function score will be evaluated at the primary outcome (36 months or prior 
1341 
failure) (before the BFLs are prescribed) and compared between the SVL group and the BFL 
1342 
group. At these visits, the best of two near stereoacuity measures by the RPS test in OFFICE 
1343 
spectacles will be used when calculating the binocular function score. The binocular function 
1344 
score at the time of treatment failure (if failed) or the 36-month Primary Outcome Visit (if not 
1345 
failed) and the change from baseline will be tabulated by treatment group.  
1346 
7.8.3 Near Stereoacuity  
1347 
At baseline, near RPS stereoacuity measured in +3.00 D trial frames will be used for analysis. At 
1348 
regular follow-up visits between 3 months and 36 months, the best of the two RPS measures in 
1349 
OFFICE spectacles will be used for analysis. 
1350 
7.8.3.1 Comparison of Randomized Treatments at the Secondary Outcome Visit 
1351 
Near stereoacuity measured using the bottom portion of the participants’ BFLs at the Secondary 
1352 
Outcome Visit (Post-failure Secondary Outcome visit if failed or 38-month Secondary Outcome 
1353 
Visit if not failed) and the change from baseline will be tabulated for each treatment group.   
1354 
7.8.3.2 Comparison of Overall Treatment Strategies at 38 Months 
1355 
To evaluate real-world effectiveness of the overall treatment strategies, near RPS stereoacuity at 
1356 
the 38-month Secondary Outcome Visit and the change from baseline will be tabulated for each 
1357 
treatment group, regardless of whether failure criteria were met at a prior visit. The analysis will 
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use the same RPS stereoacuity measurement (in arcsec) that is taken through the bottom of the 
1359 
HOME spectacles for most participants (see section 3.8 for exceptions).  
1360 
7.8.3.3 Comparison of Randomized Treatments at 36 Months or Confirmed Failure 
1361 
Near RPS stereoacuity at the time of the primary outcome (36 months or prior failure) and the 
1362 
change from baseline will be tabulated for each treatment group. 
1363 
7.8.4 Distance Stereoacuity 
1364 
Scores from the Distance Randot Stereotest will be collected at enrollment, at 36 months using 
1365 
the top portion of the HOME spectacles, and at 38 months using the top portion of the BFLs. 
1366 
Distance stereoacuity will also be measured if a failure criterion is met before the 36-month visit. 
1367 
7.8.4.1 Comparison of Randomized Treatments at the Secondary Outcome Visit 
1368 
The Distance Randot Stereotest measured in BFLs at the Secondary Outcome Visit (Post-failure 
1369 
Secondary Outcome visit if failed or 38-month Secondary Outcome Visit if not failed) and the 
1370 
change from baseline will be tabulated for each treatment group.  
1371 
7.8.4.2 Comparison of Overall Treatment Strategies at 38 Months 
1372 
To evaluate real-world effectiveness of the overall treatment strategies, distance stereoacuity at 
1373 
the 38-month Secondary Outcome Visit and the change from baseline will be tabulated for each 
1374 
treatment group, regardless of whether failure criteria were met at a prior visit.  
1375 
7.8.4.3 Comparison of Randomized Treatment at 36 Months or Confirmed Failure 
1376 
The Distance Randot Stereotest measured at the time of the primary outcome (36 months or 
1377 
confirmed failure) and the change from baseline will be tabulated for each treatment group using 
1378 
the participant’s HOME spectacles. 
1379 
7.8.5 Short-term Effect of BFLs in SVL Group Post-failure and at 38 Months 
1380 
In the SVL group, the changes in near RPS stereoacuity, distance stereoacuity, and the binocular 
1381 
function test score from the time of the primary outcome (36 months or confirmed failure) to the 
1382 
Secondary Outcome Visit (Post-failure Secondary Outcome visit if failed or 38-month 
1383 
Secondary Outcome Visit if not failed) will be tabulated and described with summary statistics to 
1384 
evaluate the short-term effect of BFL wear.  
1385 
 
1386 
7.9 Safety Analyses 
1387 
7.9.1 Distance Motor and Near Stereoacuity Treatment Failures 
1388 
The occurrences of distance motor failure and near stereoacuity failure, as each is defined under 
1389 
“treatment failure” (section 7.2) will be tabulated for each treatment group as safety outcomes.  
1390 
The risk of undergoing strabismus surgery is not included as a safety outcome given that surgery 
1391 
is at the discretion of the investigator provided failure criteria have been met, with biases 
1392 
expected to vary considerably among investigators.   
1393 
7.9.2 Diplopia  
1394 
Any new cases of diplopia will be tabulated for each treatment group. In addition, diplopia 
1395 
occurring “more than 2 times per day” over the last week will also be tabulated for each 
1396 
treatment group.  
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55 
7.9.3 Reduction of Distance Visual Acuity 
1398 
Any cases of inter-ocular difference not within 0.2 logMAR and reduced visual acuity in best 
1399 
refractive correction (≥0.2 logMAR) in either eye will be tabulated by treatment group.  
1400 
7.10 Spectacle Adherence 
1401 
Spectacle adherence assessed by a parental estimate at the start of each visit will be tabulated 
1402 
over time for each treatment group over the 36 months in the study. Separately, spectacle 
1403 
adherence for each treatment group will be tabulated for the 36- to 38-month window for non-
1404 
failures, and for the time window from prior treatment failure (i.e., Failure Confirmation Visit, if 
1405 
required; otherwise, from the failure visit) to the Post-failure Secondary Outcome Visit if failed. 
1406 
7.11 Additional Tabulations and Analyses 
1407 
The following tabulations and analyses will be performed: 
1408 
• A flow chart accounting for all participants according to treatment group for all visits 
1409 
• Visit completion rates for each follow-up visit according to treatment group 
1410 
• Baseline demographics and clinical characteristics overall and by treatment group at 
1411 
randomization 
1412 
• Protocol deviations according to treatment group 
1413 
• Number of and reasons for non-study treatment according to treatment group 
1414 
 
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Chapter 8: Data Collection and Monitoring 
1416 
8.1 Case Report Forms and Other Data Collection 
1417 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1418 
collected in electronic case report forms, this will be considered the source data. For any data 
1419 
points for which the eCRF is not considered source (e.g., lab results that are transcribed from a 
1420 
printed report into the eCRF), the original source documentation must be maintained in the 
1421 
participant’s study chart or medical record. This source must be readily verifiable against the 
1422 
values entered into eCRF. Even where all study data are directly entered into the eCRFs at office 
1423 
visits, evidence of interaction with a live participant must be recorded (e.g., office note, visit 
1424 
record, etc.)  
1425 
Electronic device data files are obtained from the study software and individual hardware 
1426 
components. These electronic device files are considered the primary source documentation. 
1427 
Each participating site will maintain appropriate medical and research records for this trial, in 
1428 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1429 
confidentiality of participants. 
1430 
8.2 Study Records Retention 
1431 
Study documents should be retained for a minimum of 3 years after completion of the final grant 
1432 
reporting. These documents should be retained for a longer period, however, if required by local 
1433 
regulations. No records will be destroyed without the written consent of the sponsor, if 
1434 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
1435 
no longer need to be retained. 
1436 
8.3 Quality Assurance and Monitoring 
1437 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1438 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1439 
conducted appropriately, and the data are generated, documented, and reported in compliance 
1440 
with the protocol that adheres to Good Clinical Practice (GCP) and the applicable regulatory 
1441 
requirements. In addition, QC systems will be in place to ensure that the rights and well-being of 
1442 
trial participants are protected, and that the reported trial data are accurate, complete, and 
1443 
verifiable. Adverse events will be prioritized for monitoring. 
1444 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1445 
consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1446 
Based Approach to Monitoring” (August 2013). This plan describes in detail who will conduct 
1447 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
1448 
will be performed, and the distribution of monitoring reports. 
1449 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1450 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1451 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1452 
veracity and completeness of the key site data.  
1453 
 
 
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Elements of the RBM may include: 
1455 
• Qualification assessment, training, and certification for sites and site personnel 
1456 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1457 
procedures 
1458 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1459 
review of entered data and edits, statistical monitoring, study closeout 
1460 
• On-site monitoring (site visits): source data verification, site visit report 
1461 
• Agent/Device accountability 
1462 
• Communications with site staff 
1463 
• Patient retention and visit completion 
1464 
• Quality control reports 
1465 
• Management of noncompliance 
1466 
• Documenting monitoring activities 
1467 
• Adverse event reporting and monitoring 
1468 
 
1469 
Coordinating Center representatives or their designees may visit the study site facilities at any 
1470 
time to maintain current and personal knowledge of the study through medical record review, 
1471 
comparison with source documents, observation and discussion of the conduct and progress of 
1472 
the study. The investigational site will provide direct access to all trial related sites, source 
1473 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1474 
inspection by local and regulatory authorities. 
1475 
8.4 Protocol Deviations 
1476 
A protocol deviation is any instance of noncompliance with the clinical trial protocol, GCP, or 
1477 
clinical procedure requirements. The noncompliance may be either on the part of the participant, 
1478 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
1479 
developed by the site and implemented promptly. 
1480 
The site PI, protocol PI (if different) and all study staff are responsible for knowing and adhering 
1481 
to their IRB requirements. Further details about the handling of protocol deviations will be 
1482 
included in the monitoring plan. 
1483 

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Chapter 9: Ethics/Protection of Human Participants 
1484 
9.1 Ethical Standard 
1485 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1486 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1487 
21 CFR Part 56, and/or the ICH E6. 
1488 
9.2 Institutional Review Boards 
1489 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1490 
be submitted to the JCHR IRB for review and approval as the IRB of Record. Approval of both 
1491 
the protocol and the consent form must be obtained from the IRB before any participant is 
1492 
enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
1493 
changes are implemented to the study. All changes to the consent form will be IRB approved; the 
1494 
IRB will determine whether previously-consented participants need to be re-consented. 
1495 
9.3 Informed Consent Process 
1496 
9.3.1 Consent Procedures and Documentation 
1497 
Informed consent is a process that is initiated prior to an individual agreeing to participate in the 
1498 
study and continues throughout that individual’s study participation. Written IRB-approved 
1499 
consent materials and consent discussions must be in a language understandable to the 
1500 
participants and their parent(s). For example, if the parent(s) primary language is Spanish, then 
1501 
the Spanish consent form, as well as other participant/parent facing materials (e.g., 
1502 
questionnaires) must be in Spanish. Also, the use of a translator approved by the Coordinating 
1503 
Center is required to support not only the consent process, but also the participants and their 
1504 
parent(s) understanding and communication for the duration of the study.  
1505 
Extensive discussion of risks and possible benefits of participation will be provided to 
1506 
participants and their families. Consent forms will be approved by the IRB and the parent/legal 
1507 
guardian will be asked to read and review the document. The investigator will explain the 
1508 
research study to the parent and participant and answer any questions that may arise. All parents 
1509 
and participants will receive a verbal explanation in terms suited to their comprehension of the 
1510 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
1511 
Parents and participants (old enough to sign per IRB) will have the opportunity to carefully 
1512 
review the written consent form and ask questions prior to signing. 
1513 
Parents should have the opportunity to discuss the study with their partner or family physician or 
1514 
think about it prior to agreeing to participate. Written informed consent will be obtained from a 
1515 
parent and written or verbal assent from the child (depending on age and IRB requirements) prior 
1516 
to performing any study-specific procedures that are not part of the child’s routine care. 
1517 
Participants may withdraw consent at any time throughout the course of the trial. A copy of the 
1518 
informed consent document will be given to the family for their records. The rights and welfare 
1519 
of the participants will be protected by emphasizing to them and their parent(s) that the quality of 
1520 
their medical care will not be adversely affected if they decline to participate in this study. 
1521 
9.3.2 Participant and Data Confidentiality 
1522 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1523 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1524 

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59 
samples and genetic tests in addition to the clinical information relating to participants. 
1525 
Therefore, the study protocol, documentation, data, and all other information generated will be 
1526 
held in strict confidence. No information concerning the study or study data will be released to 
1527 
any unauthorized third party without prior written approval of the sponsor. 
1528 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1529 
regulatory agencies or company supplying study product may inspect all documents and records 
1530 
required to be maintained by the investigator, including but not limited to, medical records 
1531 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
1532 
study site will permit access to such records. 
1533 
The study participant’s contact information will be securely stored at each clinical site for 
1534 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1535 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1536 
sponsor requirements. 
1537 
Study participant research data, which is for purposes of statistical analysis and scientific 
1538 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research. This will not 
1539 
include the participant’s contact or identifying information. Rather, individual participants and 
1540 
their research data will be identified by a unique study identification number. The study data 
1541 
entry and study management systems used by clinical sites and by Jaeb Center for Health 
1542 
Research staff will be secured and password protected.  
1543 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1544 
for Health Research. 
1545 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1546 
obtained from the NIH. This certificate protects identifiable research information from forced 
1547 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1548 
disclose identifying information on research participation in any civil, criminal, administrative, 
1549 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1550 
researchers and institutions from being compelled to disclose information that would identify 
1551 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1552 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1553 
9.3.3 Future Use of Data 
1554 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research. 
1555 
After the study is completed, the de-identified, archived data will be made available to the 
1556 
public. 
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Chapter 10: References 
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1. Greenberg AE, Mohney BG, Diehl NN, Burke JP. Incidence and types of childhood 
1559 
esotropia: a population-based study. Ophthalmology 2007;114:170-174. 
1560 
2. Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of amblyopia and strabismus in 
1561 
African American and Hispanic children ages 6 to 72 months. The Multi-ethnic Pediatric Eye 
1562 
Disease Study. Ophthalmology 2008;115:1229-1236. 
1563 
3. Friedman DS, Repka MX, Katz J, et al. Prevalence of amblyopia and strabismus in white and 
1564 
African American children aged 6 through 71 months. The Baltimore Pediatric Eye Disease 
1565 
Study. Ophthalmology 2009;116:2128-2134. 
1566 
4. McKean-Cowdin R, Cotter SA, Tarczy-Hornoch K, et al. Prevalence of amblyopia or 
1567 
strabismus in Asian and non-Hispanic white preschool children: Multi-ethnic Pediatric Eye 
1568 
Disease Study. Ophthalmology 2013;120:2117-2124. 
1569 
5. Duane A. A New Classification of the Motor Anomalies of the Eye. Based Upon 
1570 
Physiological Principles, Together with their Symptoms, Diagnosis and Treatment. The Prize 
1571 
Assay of the Alumni Association of the College of Physicians and Surgeons, New York for 
1572 
1896. New York: J. H. Vail; 1897. 
1573 
6. Burke JP. Distance-near disparity esotropia: can we shrink the gap? Eye (Lond) 2015;29:208-
1574 
213. 
1575 
7. Fresina M, Schiavi C, Campos EC. Do bifocals reduce accommodative amplitude in 
1576 
convergence excess esotropia? Graefes Arch Clin Exp Ophthalmol 2010;248:1501-1505. 
1577 
8. Whitman MC, MacNeill K, Hunter DG. Bifocals fail to improve stereopsis outcomes in high 
1578 
AC/A accommodative esotropia. Ophthalmology 2016;123:690-696. 
1579 
9. Olitsky SE. High AC/A ratio esotropia: do we really need to be using bifocals? Am Orthopt J 
1580 
2016;66:5-9. 
1581 
10. Vivian AJ, Lyons CJ, Burke J. Controversy in the management of convergence excess 
1582 
esotropia. Br J Ophthalmol 2002;86:923-929. 
1583 
11. Arnoldi KA. Convergence excess: characteristics and treatment. Am Orthopt J 1999;49:37-
1584 
47. 
1585 
12. Garretty T. Convergence excess accommodative esotropia: A descriptive review of patients 
1586 
presenting over a period of 10 years. Br Ir Orthopt J 2011;8:23-28. 
1587 
13. Pratt-Johnson JA, Tillson G. The management of esotropia with high AC/A ratio 
1588 
(convergence excess). J Pediatr Ophthalmol Strabismus 1985;22:238-242. 
1589 
14. Arnoldi K, Shainberg M. High AC/A ET: Bifocals? surgery? or nothing at all? Am Orthopt J 
1590 
2005;55:62-75. 
1591 
15. von Noorden GK, Avilla CW. Nonaccommodative convergence excess. Am J Ophthalmol 
1592 
1986;101:70-73. 
1593 
16. Parks MM. Abnormal accommodative convergence in squint. AMA Arch Ophthalmol 
1594 
1958;59:364-380. 
1595 
17. Pratt-Johnson JA, Tillson G. Sensory outcome with nonsurgical management of esotropia 
1596 
with convergence excess (a high accommodative convergence/accommodation ratio). Can J 
1597 
Ophthalmol 1984;19:220-223. 
1598 
18. American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. 
1599 
Esotropia and exotropia preferred practice pattern. San Francisco, CA: American Academy 
1600 
of Ophthalmology; 2017:Available at: http://www.aao.org/ppp. 
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19. Gerling A, Arnoldi K. Single-vision lenses: a comparison of management of high AC/A 
1602 
esotropia and refractive esotropia. Strabismus 2013;21:106-109. 
1603 
20. Ludwig IH, Parks MM, Getson PR. Long-term results of bifocal therapy for accommodative 
1604 
esotropia. J Pediatr Ophthalmol Strabismus 1989;26:264-270. 
1605 
21. von Noorden GK, Morris J, Edelman P. Efficacy of bifocals in the treatment of 
1606 
accommodative esotropia. Am J Ophthalmol 1978;85:830-834. 
1607 
22. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual 
1608 
acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester 
1609 
following the Amblyopia Treatment Study protocol. J AAPOS 2008;12:145-149. 
1610 
23. Pan Y, Tarczy-Hornoch K, Cotter SA, et al. Visual acuity norms in pre-school children: the 
1611 
Multi-Ethnic Pediatric Eye Disease Study. Optom Vis Sci 2009;86:607-612. 
1612 
24. Whitman MC, MacNeill K, Hunter DG. Bifocals fail to improve stereopsis outcomes in high 
1613 
AC/A accommodative esotropia. Ophthalmology 2016;123:690-696. 
1614 
 
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