Randomized Trial of Full-Time Occlusion Therapy for Intermittent Exotropia in Children
Phase: PHASE3
Conditions: Intermittent Exotropia
Sponsor: Jaeb Center for Health Research

 
 
Signature Page 
Randomized Trial of Full-Time Occlusion Therapy for 
Intermittent Exotropia in Children 
Funded by: The National Eye Institute of the National Institutes of Health  
 
Protocol Identifying Number: IXT7 
Version Number: 1.0 
19 April 2022 
Protocol Co-Chair 
Name, degree 
Stephen P. Christiansen, MD 
Title 
Protocol Co-Chair 
Institution Name 
Department of Ophthalmology 
Boston Medical Center, Boston University School of Medicine 
85 East Concord St, 8th Fl 
Boston, MA 02116 
Phone: 617-638-4589 
Cell: 617-735-5688 
Email:Stephen.Christiansen@bmc.org 
Signature/ Date 
 
Protocol Co-Chair 
Name, degree 
Erin C Jenewein, OD, MS, FAAO 
Title 
Protocol Co-Chair 
Institution Name 
The Eye Institute 
1200 West Godfrey 
Philadelphia, PA 19141 
Cell: 920-456-9105 
Email: ejenewein@salus.edu 
Signature/ Date 
 
JCHR Lead Investigator 
Name, degree 
Raymond T. Kraker, M.S.P.H. 
Title 
Principal Investigator, PEDIG Director 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: rkraker@jaeb.org  
Signature/ Date 
 

JAEB CENTER FOR HEALTH RESEARCH 
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Randomized Trial of Full-Time Occlusion Therapy for 
Intermittent Exotropia in Children 
Funded by: The National Eye Institute of the National Institutes of Health  
 
Protocol Identifying Number: IXT7 
Version Number: 1.0 
19 April 2022 
 

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KEY ROLES 
Protocol Co-Chair 
Name, degree 
Stephen P. Christiansen, MD 
Title 
Protocol Co-Chair 
Institution Name 
Department of Ophthalmology 
Boston Medical Center, Boston University School of Medicine 
85 East Concord St, 8th Fl 
Boston, MA 02116 
Phone: 617-638-4589 
Cell: 617-735-5688 
Email:Stephen.Christiansen@bmc.org 
Protocol Co-Chair 
Name, degree 
Erin C Jenewein, OD, MS, FAAO 
Title 
Protocol Co-Chair 
Institution Name 
The Eye Institute 
1200 West Godfrey 
Philadelphia, PA 19141 
Cell: 920-456-9105 
Email: ejenewein@salus.edu 
JCHR Lead Investigator 
Name, degree 
Raymond T. Kraker, M.S.P.H. 
Title 
Principal Investigator, PEDIG Director 
Institution Name 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
Phone: 1-888-797-3344 
Fax: 1-888-697-3344 
Email: rkraker@jaeb.org  

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 14 
1.1 Epidemiology and Clinical Characteristics ....................................................................................... 14 
1.2 Current Management Strategies ........................................................................................................ 14 
1.2.1 Observation ................................................................................................................................. 14 
1.2.2 Surgery ........................................................................................................................................ 15 
1.2.3 Nonsurgical treatments ................................................................................................................ 15 
1.3 Patching ............................................................................................................................................. 16 
1.3.1 Current clinical practice .............................................................................................................. 16 
1.3.2 Previous Randomized Trials of Patching Treatment ................................................................... 16 
1.3.3 Previous Non-randomized Studies of Patching Treatment .......................................................... 17 
1.4 Mechanism of Patching Treatment Effect ......................................................................................... 18 
1.4.1 Suppression ................................................................................................................................. 18 
1.4.2 Fusional Vergence Amplitudes ................................................................................................... 18 
1.4.3 Magnitude of Deviation ............................................................................................................... 18 
1.5 Measuring Patch Wear Time ............................................................................................................. 18 
1.6 Unanswered Questions Regarding Patching Treatment for IXT ....................................................... 19 
1.7 Rationale for Present Study ............................................................................................................... 19 
1.8 Study Objectives ................................................................................................................................ 19 
1.9 Potential Risks and Benefits of Study Treatment .............................................................................. 20 
1.9.1 Known Potential Risks ................................................................................................................ 20 
1.9.2 Known Potential Benefits ............................................................................................................ 20 
1.10 Risks of Examination or Testing Procedures ................................................................................... 20 
1.11 Risk Assessment .............................................................................................................................. 20 
1.12 General Considerations.................................................................................................................... 20 
CHAPTER 2: STUDY ENROLLMENT AND RANDOMIZATION .................................................................... 21 
2.1 Participant Recruitment and Enrollment ........................................................................................... 21 
 Informed Consent ........................................................................................................................ 21 
2.2 Eligibility Criteria .............................................................................................................................. 21 
 Inclusion Criteria ......................................................................................................................... 21 
 Exclusion Criteria ........................................................................................................................ 23 
2.3 Historical Information ....................................................................................................................... 23 
2.4 Screening and Baseline Procedures ................................................................................................... 23 
2.5 Randomization ................................................................................................................................... 25 
 Observation Group ...................................................................................................................... 25 
 Full-Time Patching Group ........................................................................................................... 25 

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2.6 Monitoring of Adherence .................................................................................................................. 25 
CHAPTER 3: STUDY FOLLOW-UP .............................................................................................................. 26 
3.1 Study Visits ....................................................................................................................................... 26 
3.2 Phone Call at 4-weeks ....................................................................................................................... 26 
3.3 Masking Procedures .......................................................................................................................... 26 
 Masked Examiner ........................................................................................................................ 26 
3.4 Testing Procedures at 3-Month Outcome Visit ................................................................................. 26 
3.5 IXT Treatment Changes During Follow-up ...................................................................................... 27 
3.6 Management of Refractive Error During Follow-up ......................................................................... 27 
CHAPTER 4: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 29 
4.1 Clinical Assessments ......................................................................................................................... 29 
CHAPTER 5: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING ....................................... 33 
5.1 Unanticipated Problems ..................................................................................................................... 33 
5.2 Adverse Events .................................................................................................................................. 33 
5.3 Safety Oversight ................................................................................................................................ 33 
5.4 Stopping Criteria ............................................................................................................................... 34 
5.5 Participant Discontinuation of Study Treatment ............................................................................... 34 
CHAPTER 6: MISCELLANEOUS CONSIDERATIONS ................................................................................... 35 
6.1 Contacts by the Jaeb Center for Health Research and Sites .............................................................. 35 
6.2 Participant Compensation .................................................................................................................. 35 
6.3 Participant Withdrawal ...................................................................................................................... 35 
6.4 Confidentiality ................................................................................................................................... 35 
CHAPTER 7: STATISTICAL CONSIDERATIONS .......................................................................................... 36 
7.1 Statistical and Analytical Plans ......................................................................................................... 36 
7.2 Primary Objective and Hypothesis .................................................................................................... 36 
7.3 Sample Size ....................................................................................................................................... 36 
7.4 Interim Monitoring ............................................................................................................................ 38 
7.5 Analysis Datasets ............................................................................................................................... 38 
7.6 Analysis of the Primary Efficacy Endpoints ..................................................................................... 38 
 Sensitivity Analyses .................................................................................................................... 39 
7.7 Analysis of the Secondary Endpoints ................................................................................................ 39 
 Near Control ................................................................................................................................ 39 
 Angle of Deviation ...................................................................................................................... 40 
 Level of Suppression ................................................................................................................... 40 
 Proportion with Anomalous Retinal Correspondence ................................................................. 40 

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 Convergence and Divergence Fusional Amplitudes ................................................................... 40 
 IXT Symptom Survey Score ....................................................................................................... 40 
 PedEyeQ Score ............................................................................................................................ 40 
 Binocular Diplopia by Parental Report ....................................................................................... 40 
7.8 Exploratory Analyses ........................................................................................................................ 41 
 Actual Patch Wear Time ............................................................................................................. 41 
 Outcome of Retinal Correspondence Testing .............................................................................. 41 
 Subgroup Analysis of Distance Control ...................................................................................... 42 
7.9 Safety Analyses ................................................................................................................................. 42 
 Deterioration ................................................................................................................................ 42 
 Reduction of Distance Visual Acuity .......................................................................................... 42 
 Diplopia ....................................................................................................................................... 42 
7.10 Patching Adherence ......................................................................................................................... 42 
7.11 Additional Tabulations and Analyses .............................................................................................. 42 
CHAPTER 8: DATA COLLECTION AND MONITORING .............................................................................. 43 
8.1 Case Report Forms and Other Data Collection ................................................................................. 43 
8.2 Study Records Retention ................................................................................................................... 43 
8.3 Quality Assurance and Monitoring .................................................................................................... 43 
8.4 Protocol Deviations ........................................................................................................................... 44 
CHAPTER 9: ETHICS/PROTECTION OF HUMAN PARTICIPANTS .............................................................. 45 
9.1 Ethical Standard ................................................................................................................................. 45 
9.2 Institutional Review Boards .............................................................................................................. 45 
9.3 Informed Consent Process ................................................................................................................. 45 
 Consent Procedures and Documentation ..................................................................................... 45 
 Participant and Data Confidentiality ........................................................................................... 45 
 Future Use of Data....................................................................................................................... 46 
CHAPTER 10: REFERENCES ....................................................................................................................... 47 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
∆ 
Prism diopters 
ANCOVA 
Analysis of covariance 
ATS 
Amblyopia Treatment Study 
ATS-HOTV 
Amblyopia Treatment Study HOTV visual acuity testing protocol 
CI 
Confidence interval 
CFR 
Code of Federal Regulations 
CR 
Cycloplegic refraction 
CRF 
Case report form 
D 
Diopter 
DHHS 
Department of Health and Human Services 
DSMC 
Data safety and monitoring committee 
eCRF 
Electronic case report form  
E-ETDRS 
Electronic Early Treatment of Diabetic Retinopathy Study visual acuity protocol 
EVA 
Electronic visual acuity tester 
FDA 
Food and Drug Administration 
FDR 
False discovery rate 
FT 
Full-time patching 
GCP  
Good clinical practice 
ICH 
International Council for Harmonisation 
IOD 
Interocular difference 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IXT 
Intermittent exotropia 
JCHR 
Jaeb Center for Health Research 
logMAR 
Logarithm of the minimal angle of resolution 
log sec arc 
Logarithm of the seconds of arc 
MCMC 
Monte Carlo Markov chain 
NIH 
National Institutes of Health 
Obs 
Observation 
PACT 
Prism and alternate cover test 
PEDIG 
Pediatric Eye Disease Investigator Group  
QA 
Quality assurance 
QC 
Quality control 
RBM 
Risk-based monitoring 
RCT 
Randomized clinical trial 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Spherical equivalent refractive error (Sphere + ½ Cylinder) 
sec arc 
Seconds of arc 
SPCT 
Simultaneous prism and cover test 
VA 
Visual acuity 

 
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PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL 
 
Randomized Trial of Full-Time Occlusion Therapy for 
Intermittent Exotropia in Children (IXT7) 
Site Number: ________ 
 
Each clinical site that is approved to participate in the IXT7 study will have one individual designated as the Protocol 
Principal Investigator (Protocol PI) at the site for that protocol. This may or may not be the same investigator that 
serves as the overall Site Principal Investigator (Site PI) for all PEDIG studies.  
  
The Protocol PI and the Site PI (if different) agrees to the following for the IXT7 study. They will: 
 
• 
Have a thorough understanding of the protocol design and study procedures.  
• 
Ensure that local institutional requirements (if applicable) are satisfied for the protocol and that approvals and 
assurances are obtained annually if required. 
• 
Ensure that the required protocol-certified staff, facilities, and equipment are available to conduct the 
protocol. 
• 
Ensure that the required protocol staff have a thorough understanding of the protocol design and procedures.  
• 
Provide adequate support and guidance to site investigators, coordinators, and other staff so that the study can 
be conducted according to protocol. 
• 
Respond promptly to requests from the Coordinating Center (CC), Network Chair/s, or Protocol Chair/s.  
• 
Correspond and maintain accessibility via email and phone with their PEDIG protocol monitor.  
• 
Oversee local study documentation and records. 
• 
Conduct periodic meetings of study personnel at their site. 
• 
Cooperate with protocol monitors by working with the site coordinator to make available study personnel, 
study records, protocol binders, clinic charts for study participants, and other necessary records needed for 
on-site or virtual clinic monitoring visits. 
• 
Notify the CC if any protocol adherence or data reporting problem is discovered or suspected. 
• 
Attend scheduled PEDIG meetings and conference calls, including those for any PEDIG committees to which 
appointed. 
• 
Review study monitoring reports evaluating clinical site performance and discuss with the CC any areas 
identified to be deficient. 
 
The Protocol and PI shall exert diligent efforts to enroll at least three (3) study 
subjects.                                                                                                                                                                                                           
 
In addition to the above, the Protocol PI and the Site PI (if different) agree(s) to the following:   
• 
I/we understand the importance of successful follow-up of participants enrolled at my/our site.  
• 
I/we agree as a site that we have the potential and commitment to as a site to enroll at least 3 subjects once 
certified. 
 
Protocol Principal Investigator’s Signature  
Date: _____ / _____ / _____ 
 
Name: ____________________________ 
 
To be completed only if different:  
 
Site Principal Investigator’s Signature ___________________ 
_____Date: _____ / _____ / _____ 
 
Name: ____________________________ 

 
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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Randomized Trial of Full-Time Occlusion Therapy for Intermittent 
Exotropia in Children 
Précis 
Understanding the effectiveness of intensive patching has important 
implications for managing children with IXT. If full-time patching is 
associated with improvement in distance control vs an observation group, 
then future studies can be conducted to evaluate different durations of 
full-time patching treatment, whether the effect is maintained off-
treatment, and how full-time patching compares to other treatment 
strategies.  
Objectives 
Determine whether full-time patching is more effective than observation 
for improving distance control of IXT after 3 months of treatment (on-
treatment outcome). 
Study Design 
Randomized clinical trial. 
Number of Sites 
The study is open to all clinical sites approved to participate in the PEDIG 
network.  
Endpoint 
Primary Efficacy Outcome:  
Change in control of IXT at distance after 3 months based upon the 
average of three measures of control at distance.  
Key Safety Outcomes:  
1. Deterioration is defined as meeting one of the following criteria at the 
3 months follow-up visit:  
• 
Constant exotropia >= 10Δ at distance AND near by SPCT. 
Constant is defined as an exotropia present throughout the 
examination and determined by at least three cover/uncover 
tests performed at various times during the exam. 
• 
Decrease in near stereoacuity on the Randot Preschool 
Stereotest of at least 2 levels from baseline, or to nil. 
2. Decrease in distance visual acuity 3 or more logMAR lines from 
baseline in either eye or IOD 3 or more logMAR lines. 
3. Diplopia ‘More than 2 times per day’ by parental report 
4. Diplopia ‘All the Time’ by child symptom survey 
Population 
Inclusion Criteria: 
Children under the care of a pediatric optometrist or pediatric 
ophthalmologist will be eligible for the study if they meet all the 
following criteria: 
1. Age 3 to < 9 years 
2. IXT meeting all of the following criteria: 
• 
Intermittent or constant XT at distance (mean distance control 
2.0 or more) with at least 1 control measure of 3, 4 or 5 (i.e., 
indicating spontaneous tropia) 
• 
Either IXT, exophoria, or orthophoria at near (cannot have 
control score of 5 on all 3 near assessments) 
• 
Distance exodeviation between 15∆ and 50∆ by PACT 
• 
Near exodeviation between 0∆ and 50∆ by PACT 
• 
Near exodeviation does not exceed distance by more than 10∆ 
by PACT (convergence insufficiency-type IXT excluded) 
3. 
Age-normal visual acuity in both eyes:  
• 
3 years: 20/50 or better (>=63 letters) 
• 
4 years: 20/40 or better (>=68 letters) 

 
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PARTICIPANT AREA 
DESCRIPTION 
• 
5-6 years: 20/32 or better (>=73 letters) 
• 
7-<9 years: 20/25 or better (>=78 letters) 
4. Interocular difference in distance VA of 2 logMAR lines or less (10 
letters or less on E-ETDRS for patients ≥7 years old). Testing by 
ATS HOTV for participants 3 to < 7 years old and by E-ETDRS for 
participants ≥7 years old. 
5. Cycloplegic refraction within the last 7 months. 
6. Refractive error between -6.00 D SE and +2.00 D SE (inclusive) 
based on a cycloplegic refraction within 7 months 
7. Participants with refractive error meeting any of the following based 
on a cycloplegic refraction within 6 months must be wearing 
spectacles for at least 2 weeks: 
• 
Myopia > -0.50 D spherical equivalent (SE) in either eye 
• 
Anisometropia > 1.00 D SE 
• 
Astigmatism in either eye > 1.00 D  
8. Any refractive correction worn at enrollment (required or not) must 
meet the following guidelines based on a cycloplegic refraction 
within 7 months: 
• Anisometropia SE must be within 0.50 D of the full 
anisometropic difference correction 
• Astigmatism must be corrected within 0.50 D 
• Axis must be within ±10 degrees if cylinder power is ≤1.00 D and 
within ±5 degrees if cylinder power is >1.00 D. 
• For hyperopia, the spherical component can be reduced at 
investigator discretion provided the reduction is symmetrical and 
does not meet the definition of deliberate overminus (see below).  
• For myopia, the intent is to fully correct, but the spherical 
component can be undercorrected at investigator discretion 
provided the reduction is symmetrical and results in no more than 
-0.50 D SE residual (i.e., uncorrected) myopia. Deliberate 
overminus is not allowed. 
• Deliberate overminus is defined for this protocol as any refractive 
correction prescribed to yield lenses that are overminused by 
more than -0.50D SE than cycloplegic refraction SE 
▪ 
Less than the full cycloplegic hyperopic correction (i.e., 
prescribing reduced plus) is not considered the same as 
overminusing for this protocol (because most patients 
without IXT but with hyperopic SE refractions up to +2.00 
D SE would not typically be prescribed a refractive 
correction.) 
• For refractive errors with an emmetropic or myopic SE, the intent 
is to fully correct, but the spherical component can be 
undercorrected at investigator discretion provided the reduction is 
symmetrical and results in no more than -0.50 D SE residual (i.e., 
uncorrected) myopia. Prescribing a correction that yields more 
than 0.50 D more minus SE than the cycloplegic refraction SE is 
considered deliberate overminus and is not allowed. 
• Note that the refractive correction guidelines and the requirement 
to wear refractive correction for at least 2 weeks apply not only to 
participants who require refractive correction under the above 
criteria but also to any other participant who is wearing refractive 
correction. 
9. Gestational age > 30 weeks 
10. Birth weight > 1500 grams 
11. Patient and/or parent understands protocol, is willing to enroll, and is 
willing to accept that other (i.e., nonrandomized) treatment for IXT 
will not be offered by the investigator for 3 months 
12. Parent has phone and is willing to be contacted by Jaeb Center staff 
13. Relocation outside of area of an active PEDIG site within 3 months 

 
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PARTICIPANT AREA 
DESCRIPTION 
not anticipated 
 
Exclusion Criteria: 
Individuals meeting any of the following criteria at baseline will be 
excluded from study participation: 
1. Prior strabismus, intraocular, or refractive surgery (including 
BOTOX injection) 
2. Prior nonsurgical treatment for IXT (e.g., patching, vergence therapy, 
vision therapy/orthoptics, base-in prism, or deliberate overminus 
(more than 1.00 D) spectacles of >1week duration within the past 
year 
3. Previous amblyopia treatment other than refractive correction  
4. Diplopia more than 2 times per day by parental assessment 
5. Paretic or restrictive strabismus 
6. Craniofacial malformations affecting the orbits 
7. Ocular disorders which would reduce VA (except refractive error) 
8. Severe developmental delay that would interfere with treatment or 
evaluation (in the opinion of the investigator). Participants with mild 
speech delay or reading and/or learning disabilities or ADHD are not 
excluded. 
9. Neurological anomaly that could affect ocular motility (e.g., cerebral 
palsy, Down syndrome) 
10. Immediate family member (child or sibling) of any investigative site 
personnel directly affiliated with this study. 
11. Known allergy to adhesive patches.  
12. Known allergy to silicone.  
Sample Size 
72 (36 observation, 36 full-time patching) 
Phase 
Phase 3 
Treatment Groups 
Random assignment to: 
• Observation  
• Full-time patching (all waking hours, 7 days/week) 
Participant Duration 
3 months after randomization  
Protocol Overview/Synopsis 
Participants will be randomly assigned to observation or full-time 
patching. All parents will receive a phone call at 4 weeks to answer any 
questions about observation or patching treatment. Participants will be 
followed for 3 months.  
 

 
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STUDY SUMMARY FLOW CHART 
 
Enrollment/Baseline Visit 
Informed consent 
Pediatric Eye Questionnaire (PedEyeQ) 
IXT Symptom Survey 
Diplopia Assessment by Parent 
Randot Preschool Stereoacuity (40 cm) 
Exotropia control #1 (distance and near) 
Divergence and convergence fusional amplitudes  
Exotropia control #2 (distance and near) 
Ocular alignment (cover/uncover, SPCT, PACT) 
Exotropia control #3 (distance and near) 
Suppression  
Retinal correspondence (ages 6-8 years) 
Assessment of eligibility  
Randomize 
Major Eligibility Criteria 
Children aged 3 to <9 years  
Intermittent exotropia meeting all the following criteria: 
Intermittent or constant XT at distance (mean distance control 2.0 or more, with at least 1 measure of 3, 4 or 5 
IXT or exophoria or orthophoria at near (cannot have control score of 5 on all 3 near assessments) 
Distance deviation between 15∆ and 50∆ by PACT 
Near deviation between 0∆ and 50∆ by PACT 
Near deviation does not exceed distance by more than 10∆ by PACT 
No prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
No previous nonsurgical treatment of >1 week duration within the past year 
No amblyopia treatment other than refractive correction 
No diplopia more than 2 times per day by parental report 
Refractive error between -6.00 D SE and +2.00 D SE (inclusive) based on a cycloplegic refraction within 7 months 
Age-normal VA (3 yrs = 20/50 or better; 4 yrs = 20/40 or better; 5-6 yrs = 20/32 or better; 7-8 yrs = 20/25 or better) 
No interocular VA difference more than 0.2 logMAR  
Wearing appropriate refractive correction for at least 2 weeks 
No abnormality of the cornea, lens, or central retina  
No known allergy to adhesive patches or silicone. 
3 months (±2 weeks) Primary Outcome  
Patch adherence monitoring (patching group only) 
Pediatric Eye Questionnaire (PedEyeQ) 
IXT Symptom Survey 
Diplopia Assessment by Parent 
Randot Preschool Stereoacuity (40 cm) (masked) 
Exotropia control #1 (distance and near) (masked) 
Divergence and convergence fusional amplitudes (masked) 
Exotropia control #2 (distance and near) (masked) 
Ocular alignment (cover/uncover, SPCT, PACT) (masked) 
Exotropia control #3 (distance and near) (masked) 
Suppression (masked) 
Retinal correspondence (ages 6-8 years) (masked) 
Observation 
Patching All 
waking hours 
4 weeks (± 1 week): Phone Call 

 
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SCHEDULE OF STUDY VISITS AND PROCEDURES 
a Retinal correspondence to be measured only in children 6, 7, or 8 years of age at randomization 
.
 
Enrollment 
4-Week 
Call 
3-Month 
Visit 
Consent 
X 
 
 
Demographics / Medical History 
X 
 
 
Treatment Compliance  
 
X 
X 
Quality of Life Survey 
X 
 
X 
IXT Symptom Survey 
X 
 
X 
Diplopia Assessment by Parent 
X 
 
X 
Distance Visual Acuity 
X 
 
X 
Randot Preschool Stereoacuity 
X 
 
X 
Exotropia Control (distance and near) 
X 
 
X 
Amplitude Testing (Divergence and Convergence) 
X 
 
X 
Ocular Alignment (distance and near) 
X 
 
X 
Suppression (distance) 
X 
 
X 
Retinal Correspondence* 
X 
 
X 

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Chapter 1: Background Information 
1 
1.1 Epidemiology and Clinical Characteristics 
2 
Intermittent exotropia (IXT) is the most common form of childhood-onset exotropia,1,2 with an 
3 
incidence of 32.1 per 100,000 in children under 19 years of age,1 and occurring more frequently 
4 
in females3 and in Asian populations.4-6 Onset of IXT is thought to be in the first year of life.7 
5 
Etiology is unknown although anatomical, innervational, sensory, and genetic factors have been 
6 
proposed.8,9 
7 
IXT is characterized by an exodeviation present predominantly at distance fixation with or 
8 
without deviation at near fixation. Pseudonyms include periodic exotropia and exotropia of 
9 
inattention. In addition to being present for distance viewing, exotropia may also occur at near 
10 
and with inattention, in bright sunlight, or when tired. Closure of one eye in bright sunlight and 
11 
sensitivity to sunlight10-12 are also characteristic features. Normal binocular single vision is 
12 
typically present at near when the eyes are aligned, with normal (occasionally subnormal) 
13 
stereoacuity.13,14 Diplopia is rarely reported.15 
14 
IXT is characterized by unique sensory adaptations:16 suppression mechanisms prevent diplopia 
15 
when the exodeviation is manifest, but normal binocular single vision with normal stereoacuity is 
16 
reestablished when the deviation is controlled (albeit with persistent temporal retinal suppression 
17 
in some children17). In addition, some children with IXT are thought to covary between normal 
18 
and anomalous retinal correspondence (ARC)16,18 and may also experience panoramic 
19 
viewing.7,19 However. the true nature of these adaptations, how often they occur, and how they 
20 
respond to treatment are poorly characterized having not been previously studied in large 
21 
numbers of children with IXT. 
22 
1.2 Current Management Strategies  
23 
IXT is currently managed by observation alone, or with surgical correction or non-surgical 
24 
treatment.14 Despite a plethora of studies evaluating treatments for IXT, there are relatively few 
25 
data on treatment effectiveness14 and current practice patterns are fragmented.20,21  
26 
In addition, long-term success following treatment appears elusive, and specific reasons for 
27 
treatment failure are unclear. Popular explanations include the possibility that persistent sensory 
28 
maladaptations (suppression and/or anomalous retinal correspondence), as well as inadequate 
29 
fusional amplitudes, may be responsible for recurrence of the exotropia following treatment. 
30 
To provide context for the proposed randomized clinical trial (RCT), the following summary 
31 
briefly describes commonly used management strategies along with data from previous RCTs.  
32 
1.2.1 Observation 
33 
We are aware of two previous RCTs in which subjects with IXT were randomized to 
34 
observation. The PEDIG IXT2 studies22,23 randomized children to observation versus part-time 
35 
patching. In the older cohort randomized to observation (3 to < 10 years at enrollment), 
36 
deterioration of IXT (constant exotropia ≥10Δ at distance and near or ≥2-octave decrease in near 
37 
stereoacuity from the best previous measure, or being prescribed treatment despite not having 
38 
met motor or stereo deterioration) was met in 25 of 183 by 3 years (15%, 95% confidence 
39 
interval = 10%-22%), 12 of whom were prescribed treatment without meeting motor or 
40 
stereoacuity criteria.24 However, of the 132 who completed the 3-year visit and had not been 
41 

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treated during the study, only 1 (<1%) met motor or stereoacuity deterioration criteria at 3 
42 
years.24 Of those older children randomized to observation who remained untreated over the 3 
43 
years, “complete or near complete resolution” (exodeviation <10Δ at distance and near, no 
44 
reduction in stereoacuity, and no other nonsurgical treatment for IXT, having never met 
45 
deterioration criteria) was met in 6 (7%) of 86.25  
46 
In the younger cohort randomized to observation (12-35 months at enrollment), deterioration of 
47 
IXT (constant exotropia ≥10 prism diopters at distance and near or treatment prescribed despite 
48 
not having met motor deterioration) occurred in 28% (95% CI = 20%–39%) by 3 years.26 Of the 
49 
24 participants meeting the primary outcome of deterioration, seven met motor deterioration and 
50 
17 were prescribed treatment without meeting motor deterioration.26 The cumulative probability 
51 
of motor deterioration by 3 years was 10% (95% CI = 5%–19%). 
52 
In a pilot RCT of surgery versus observation for IXT, Clarke et al27 found 2 (9%) of 22 in the 
53 
observation group showed significant improvement in control (improved 3 and 4 points on the 
54 
office control scale) after 9 months of follow-up. 
55 
1.2.2 Surgery 
56 
The aim of surgery for IXT is to reduce the magnitude of the exodeviation (or eliminate it 
57 
completely) such that any residual deviation can be easily compensated by existing convergence 
58 
and divergence motor fusion mechanisms. Two RCTs have evaluated surgery for IXT.14 PEDIG 
59 
(IXT1)28 compared bilateral and unilateral surgery and found complete or near-complete 
60 
resolution of IXT in 30% of participants overall at 3 years postoperatively (complete or near 
61 
complete resolution defined as exodeviation <10Δ at distance and near, reduction of ≥10 Δ by 
62 
PACT, esotropia <6Δ by SPCT at distance and near, no ≥2 octave reduction in stereoacuity, no 
63 
reoperation, no nonsurgical treatment for recurrent or residual exodeviation, and having never 
64 
met failure criteria [exotropia ≥10Δ by SPCT at distance or near, constant esotropia ≥6Δ by 
65 
SPCT at distance or near, and ≥2 octave reduction in stereoacuity]). In a separate RCT, 
66 
Kushner29 also compared unilateral versus bilateral surgery and found a satisfactory outcome 
67 
(aligned within 10Δ of exophoria and 5Δ of esophoria) in 82% and 52% respectively, but 
68 
outcomes were evaluated at only one year postoperatively. In IXT1,30 younger age (3 to <5 
69 
years) was associated with a lower risk of failure by 3 years (28% vs 50%); however, reasons for 
70 
failure versus success were not explored in Kushner’s RCT.  
71 
1.2.3 Nonsurgical treatments 
72 
The aim of nonsurgical treatment for IXT is to improve the strength and/or quality of binocular 
73 
single vision (reducing suppression, increasing fusional amplitudes), thereby improving control 
74 
of the exodeviation. Commonly utilized non-surgical management strategies include, vision 
75 
therapy, overminus lenses, relieving or correcting base-in prism, and part-time patching.  
76 
Vision therapy: 
77 
There are no published RCTs of vision therapy, but a multicenter pilot RCT is planned and due 
78 
to commence in 2021 (NCT04487249).  
79 
Overminus optical correction: 
80 
A recently published RCT (IXT5; NCT02807350) conducted by PEDIG,31 randomized 3- to 10-
81 
years old with IXT to overminus spectacles (−2.50 D over cycloplegic refraction for 12 months) 
82 
vs non-overminus spectacles and found better mean distance control at 12 months (in correction) 
83 

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for participants treated with overminus spectacles (n=196) than those with non-overminus 
84 
spectacles (n=190) (1.8 vs 2.8 points; adjusted difference, −0.8; 95% CI, −1.0 to −0.5; P< 0.001). 
85 
Factors associated with better versus worse control at outcome were not evaluated. However, a 
86 
greater myopic shift occurred in those with overminus vs non-overminus treatment (−0.42 D vs 
87 
−0.04 D; adjusted difference, −0.37 D; 95% CI, −0.49 to −0.26 D; P<0.001), resulting in the 
88 
overminus spectacles being discontinued before follow-up was complete in some participants.31  
89 
Prism correction: 
90 
Relieving base-in prism correction was evaluated in an 8-week pilot RCT conducted by PEDIG 
91 
(IXT6; NCT03998670). The primary outcome was change in exodeviation control score, but 
92 
factors associated with success versus failure of treatment were not evaluated. Results are due to 
93 
be published later this year.  
94 
Patching: 
95 
Patching is one of the most frequently prescribed nonsurgical treatments for IXT and is described 
96 
in detail below (section 1.3).  
97 
 
98 
1.3 Patching 
99 
1.3.1 Current clinical practice 
100 
Prevailing clinical practice is to prescribe a low dose of 2-4 hours/day, and to either patch 
101 
alternate eyes, alternate days, or patch the eye preferred for fixation (if present). Some clinicians 
102 
prescribe for longer periods of time such as 6-8 hours/day or full-time (all waking hours) based 
103 
on their clinical experience or outcomes from previous full-time patching studies,32,33 but there is 
104 
no evidence to support whether full-time patching has additional benefit to part-time patching. 
105 
Patching may be prescribed over a short duration of weeks or months or may be utilized on and 
106 
off over a period of years. It is currently prescribed either to improve exodeviation control to the 
107 
point where other treatments are not necessary, or to maintain reasonable control until the child 
108 
and family are ready for other treatments such as surgery or vision therapy. While patching 
109 
therapy is thought to improve exodeviation control and potentially reduce the size of the 
110 
exodeviation, there are few data on the magnitude of such effects or whether any benefit persists 
111 
long-term.  
112 
1.3.2 Previous Randomized Trials of Patching Treatment 
113 
Akbari et al 202034: Akbari et al recently published a RCT34 comparing part-time patching (2 
114 
hours a day, alternating eyes) to observation in 76 children who were 3- to 8-years-old with IXT. 
115 
The primary outcome was a single measure of control, using a modification of the Office Control 
116 
Score35 at 3 and 6 months (on treatment). Control scores ranged from 0 (phoria) to 6 (constant 
117 
exotropia) and were better (lower score) in the patching group at 3 months (distance: 2.3±1.0 
118 
points vs 2.7±1.1 points; P=0.03; near: 1.2±0.7 points vs 1.5±0.6 points; P=0.003), and at 6 
119 
months (distance: 2.4±1.1 points vs 2.8±1.2 points; P=0.03; near: 1.0±0.6 points vs 1.6±0.9 
120 
points; P=0.003). Nevertheless, post-treatment outcomes, as well as effects on suppression, angle 
121 
of deviation, and fusional amplitudes were not evaluated. In addition, while control improved 
122 
with patching, control scores reflect that many participants had persistent intermittent exotropia.  
123 
PEDIG 201422 and PEDIG 201523: Two PEDIG RCTs evaluated part-time patching (3 hours a 
124 
day for 5 months) versus observation in 12- to 35-month-olds23 and 3- to <11-year-olds22 with 
125 
IXT. In published secondary analyses of 6-month outcomes (1-month post cessation of patching 
126 

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treatment), mean control scores and mean angle of deviation were compared between patching 
127 
and observation groups. For 12- to 35-month-olds, mean distance control scores were better 
128 
(lower) in the patching group compared with the observation group (2.3 points vs 2.8 points; 
129 
P=0.02) (near control scores were similar: 1.1 points vs 1.4 points; P=0.26).23 In addition, mean 
130 
distance angle of deviation (PACT) was significantly smaller in the patched group (24.9Δ vs 
131 
27.9Δ, P=0.02)(near angle was similar: 17.0Δ vs 19.3Δ, P=0.10). For 3- to <11-year-olds, 
132 
distance control scores were similar between groups (2.0 points patching vs 2.3 points 
133 
observation; P=0.094) but near control scores were lower in the patching group (0.9 points vs 1.2 
134 
points; P=0.013).22 Mean angle of deviation by PACT was 22.2Δ in the patching group vs 23.8Δ 
135 
in the observation group (P=0.012) at distance and 15.4Δ vs 17.6Δ (P=0.11) at near.  
136 
The studies were designed primarily to evaluate deterioration rates, but in post hoc analyses 
137 
(publication in process) of 3- to <11-year-olds with a control score of 2 or more at enrollment 
138 
and a 3-month on-treatment examination (matching current study inclusion criteria and primary 
139 
outcome time-point) distance control improved 0.4 points in the observation group (n=147) and 
140 
0.8 points in the patching group (n=125) (mean difference 0.41 points (95% CI, 0.12 to 0.70 
141 
points). Angle of deviation improved 0.2Δ in the observation group and 2.3Δ in the patching 
142 
group (mean difference 2.1Δ (0.6 to 3.6Δ). 
143 
Nevertheless, in both the 12- to 35-month and 3- to <11-year-old cohorts, many participants had 
144 
persistent intermittent exotropia post-treatment. Changes in suppression or fusional amplitudes, 
145 
and relationships with better versus worse control, were not evaluated. 
146 
1.3.3 Previous Non-randomized Studies of Patching Treatment 
147 
A small number of non-randomized studies have evaluated patching for IXT.16,36,37 While there 
148 
are intrinsic challenges when interpreting data from non-randomized studies, the following are 
149 
selected for more detailed review either because they provide additional information on potential 
150 
effects of full-time patching, and/or provide some insight regarding how patching may impact 
151 
sensory adaptations, the angle of deviation, or fusional amplitudes. 
152 
Full-time Patching 
153 
Iacobucci & Henderson 196533: Twenty-eight children with IXT, scheduled for surgery, were 
154 
selected (“at random”) for full-time patching for 3 months. IXT control and angle of deviation 
155 
were compared with a control group of 38 children undergoing anti-suppression and diplopia 
156 
therapy. Distance angle of deviation by PACT reduced by a mean of 5.8±1.1Δ from baseline to 3 
157 
months in the patching group, compared with an increase of 1.8±0.4Δ in the control group. Near 
158 
angle of deviation by PACT reduced by a mean of 4.6±1Δ from baseline to 3 months in the 
159 
patching group, compared with an increase of 1.3±0.5Δ in the control group. Eleven of 28 
160 
patched patients and 20 of 38 control patients were constant exotropia at distance at baseline; of 
161 
these, 8 (73%) of 11 in the patching group and 0 of 20 in the control group became intermittent 
162 
or phoric at 3 months. 
163 
Flynn et al 197632: In a prospective study, Flynn and colleagues prescribed full-time patching for 
164 
4-12 weeks to 31 children (mean age 7.6 years, range 3 to 13 years) with IXT. Mean angle of 
165 
deviation pre-treatment was 20±7Δ at distance and 15±12Δ at near. Nine of 31 had undergone 
166 
previous surgery. Following patching treatment, 7 (23%) of 31 showed dramatic improvement 
167 
such that “the deviation became almost completely phoric, fusion improved, and all evidence of 
168 
suppression on the synoptophore or in free space disappeared.” Fourteen of 31 patients had a 
169 
reduction in angle of deviation and a change from tropia to intermittent tropia or phoria. In 12 of 
170 

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31 patients there was a measurable improvement in suppression with disappearance of the 
171 
suppression scotoma. Increase in the range of fusional amplitudes occurred in 9 of these 12 
172 
patients. Of note, Flynn et al32 report that some patients did not respond positively to patching, 
173 
with 12 showing an increase in angle of deviation (mean 5Δ, range 2Δ to 15Δ) and 6 showing 
174 
worsening control. Long-term follow-up was not reported. 
175 
1.4 Mechanism of Patching Treatment Effect 
176 
Patching is considered “anti-suppression” therapy, affecting exodeviation control by reducing or 
177 
eliminating the suppression that occurs when the exodeviation is manifest.32,33,38,39  
178 
1.4.1 Suppression 
179 
Previous studies have attempted to evaluate the presence versus absence of suppression, as well 
180 
as the size and location of the suppression scotoma when the exodeviation is manifest,15,18,40-44 
181 
but few have evaluated changes in suppression with treatment or the relationship between 
182 
suppression status and treatment success. In fact, although patching is designated “anti-
183 
suppression” treatment, there are few data demonstrating that changes in suppression occur with 
184 
patching. 
185 
It has been suggested that, left untreated, suppression in many children with IXT will increase,41 
186 
making it harder to remediate and leading to poorer treatment outcomes, but this has not been 
187 
studied. It has also been suggested that eradication of suppression is required for successful 
188 
treatment,15 but this deserves further study. 
189 
1.4.2 Fusional Vergence Amplitudes 
190 
Motor fusion mechanisms are responsible for maintaining binocular alignment, and in IXT, both 
191 
convergence and divergence are thought to be important for enabling motor control of the 
192 
exodeviation.45,46 In previous studies,32,38,47,48 data suggest that patching results in an increase in 
193 
convergence amplitudes, but further study is needed to verify whether such changes truly occur 
194 
and if they do, whether they are directly related to changes in suppression or occur 
195 
independently. It is also unknown how such changes relate to improvement or successful 
196 
treatment of IXT. 
197 
1.4.3 Magnitude of Deviation 
198 
Previous studies22,23,32,33,39,48-50 have shown that the magnitude of the deviation may reduce with 
199 
patching treatment. Nevertheless, there are few data that support this notion, and the mechanism 
200 
by which patching might alter ocular alignment remains unclear.  
201 
1.5 Measuring Patch Wear Time 
202 
Adherence with a prescribed patching dose is often problematic and limits the interpretation of 
203 
findings when attempting to correlate dose to outcome. In studies of patching treatment for 
204 
amblyopia, some research groups have used occlusion dose monitors (ODMs) to record actual 
205 
patch wear time.51-54 In general these previous studies concluded that dose is a significant factor 
206 
in determining amblyopia treatment outcome, although there remains considerable individual 
207 
variability. We are unaware of previous studies that have analyzed actual patch wear time when 
208 
treating IXT, and such data are important for understanding whether there is a dose effect 
209 
relationship.  
210 
Recently, a new method of monitoring patching adherence has become available and is being 
211 
used in a concurrent PEDIG amblyopia study (ATS22, NCT04378790). TheraMon®, a 
212 

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thermosensor device, appears to work well for monitoring adherence with amblyopia patching 
213 
treatments in children.51 We propose utilizing the TheraMon® in the current study to enable 
214 
important secondary analyses of outcome in relation to actual (rather than prescribed) wear time. 
215 
 
216 
1.6 Unanswered Questions Regarding Patching Treatment for IXT 
217 
While previous data confirm an effect of patching on control of IXT, and even on angle of 
218 
deviation, there remain many unanswered questions regarding treatment effectiveness. Such 
219 
questions include: 
220 
- 
Is prescribed full-time patching more effective for improving control and/or reducing 
221 
angle of deviation than observation alone? 
222 
- 
Does patching alter suppression, angle of deviation, fusional amplitudes, or 
223 
anomalous retinal correspondence, and are such changes related to exodeviation 
224 
control? 
225 
- 
Is there a dose-response relationship (greater improvement with more actual patching 
226 
time)? 
227 
- 
Which clinical and demographic characteristics, if any, are associated with 
228 
improvement in exodeviation control and/or treatment success?  
229 
1.7 Rationale for Present Study  
230 
IXT is a common eye condition, but long-term surgical treatment outcomes are disappointing, 
231 
with high failure rates due to recurrence or undercorrection of the exodeviation. Patching is a 
232 
commonly used nonsurgical treatment for which there is some evidence of short-term treatment 
233 
benefit (improved exodeviation control and reduced angle of deviation) when prescribed 2-3 
234 
hours/day. Nevertheless, the extent to which patching is effective if worn for long periods of 
235 
time per day or if any treatment effect is sustained once treatment is discontinued is unknown.  
236 
Understanding the effectiveness of patching treatment and whether there is a benefit from full-
237 
time patching versus observation alone has important implications for managing children with 
238 
IXT. If full-time patching is associated with more improvement in distance control compared to 
239 
observation alone, then future studies can be conducted to evaluate different durations of full-
240 
time patching treatment, whether the effect is maintained off-treatment, and how full-time 
241 
patching compares to other treatment strategies. 
242 
In addition, this study would provide evidence of the ability of patching to alter suppression, 
243 
anomalous retinal correspondence, and fusional amplitudes, and the relationships of these 
244 
clinical characteristics with treatment success, failure, and improvement of IXT. This study 
245 
provides an opportunity to explore such relationships, and data are expected to create hypotheses 
246 
for future studies.  
247 
1.8 Study Objectives 
248 
Determine whether full-time patching is more effective than observation for improving distance 
249 
control of IXT after 3 months of treatment (on-treatment outcome). 
250 
 
251 

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1.9 Potential Risks and Benefits of Study Treatment  
252 
1.9.1 Known Potential Risks 
253 
There is a risk that patching may create diplopia that then becomes troublesome to the patient, 
254 
but this complication is seldom reported. It is possible that some patients will show worsening of 
255 
IXT control or increase in magnitude with patching32 or observation,22 but deterioration criteria 
256 
will be assessed after 3 months and the short 3-month duration allows for cessation of patching 
257 
treatment and/or commencement of other treatment should deterioration of the IXT occur. Skin 
258 
irritation may occur. If persistent skin irritation occurs due to the adhesive patch, the participant 
259 
will be provided with a fabric patch to wear on their glasses (plano glasses will be provided for 
260 
children who are not already wearing glasses). Patching could potentially cause a decrease of VA 
261 
in the patched eye, but that is very unlikely since alternating patching is prescribed, and any 
262 
decrease in VA is almost always reversible. One potential risk with observing IXT without 
263 
treatment is that suppression may increase in density over time. An increase in the density of 
264 
suppression may predispose the child to worse motor and sensory outcomes in the long term, but 
265 
with a 3-month study duration there is unlikely to be a significant change, and furthermore this 
266 
has not been previously studied to know if and when this occurs. 
267 
1.9.2 Known Potential Benefits  
268 
The potential benefits of patching are improved exodeviation control, reduced angle of deviation, 
269 
reduced suppression, and/or increased fusional amplitudes. 
270 
There are no direct benefits of observation, however, in a previous RCT, approximately 7% of 
271 
patients55 resolved spontaneously over 3 years. Therefore, avoiding the need for treatment of 
272 
IXT and any associated risks of IXT treatment may be considered an indirect benefit of 
273 
observation. 
274 
1.10 Risks of Examination or Testing Procedures 
275 
The procedures in this study are part of daily eye care practice in the United States and pose no 
276 
known risks. As part of a routine usual-care exam, the participant may receive 
277 
cycloplegic/dilating eye drops. 
278 
 
279 
1.11 Risk Assessment 
280 
There are no risks involved in this study that would not be part of usual care when treating with 
281 
either patching or by observation alone. The protocol’s level of risk is consistent with 45 CFR 
282 
46.404 and 21 CFR 50.51, which indicates research not involving greater than minimal risk for 
283 
the individual child involved in the research.  
284 
 
285 
1.12 General Considerations 
286 
The study is being conducted in compliance with the policies described in the PEDIG network 
287 
policies document, with the ethical principles that have their origin in the Declaration of 
288 
Helsinki, with the protocol described herein, and with the standards of Good Clinical Practice 
289 
(GCP). 
290 

 
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Chapter 2: Study Enrollment and Randomization 
291 
2.1 Participant Recruitment and Enrollment 
292 
The study plans to enroll enough participants, for whom informed consent will be obtained, in 
293 
order to randomize a minimum of 72 participants.  
294 
 
295 
As the randomization goal approaches attainment, sites will be notified of the end date for 
296 
recruitment into the study. Participants who have signed informed consent forms are enrolled and 
297 
can be randomized until the end date, which means the expected recruitment number might be 
298 
exceeded. The maximum number randomized will be 82. 
299 
 
300 
There is no restriction on the number of participants to be enrolled by each site toward the 
301 
overall recruitment goal. The overall number of participants with an interocular difference in 
302 
distance VA of 2 logMAR lines (10 letters on E-ETDRS for patients ≥7 years old) will be 
303 
limited to 14. 
304 
 
305 
 Informed Consent  
306 
Children with IXT who are 3 to <9 years of age attending ophthalmology or optometry 
307 
outpatient visits will be identified.  
308 
 
309 
Families who qualify for the study will be approached by one of the research team members. The 
310 
study will be discussed with the child’s parent(s) or guardian(s) [referred to subsequently as 
311 
parent(s)]. Parent(s) who express an interest in the study will be given a copy of the informed 
312 
consent form to read. Written informed consent must be obtained from a parent and written or 
313 
verbal assent from the child (depending on age and local IRB requirements) prior to performing 
314 
any study-specific procedures that are not part of the child’s routine care. 
315 
 
316 
A child is considered enrolled into the study when the informed consent form has been signed by 
317 
the parent, the assent form has been signed by the child (when applicable), and the investigator 
318 
has also signed the appropriate forms.  
319 
 
320 
2.2 Eligibility Criteria 
321 
 Inclusion Criteria 
322 
Children under the care of a pediatric optometrist or pediatric ophthalmologist, who are 
323 
identified during a standard-of-care outpatient visit or from a referral from another provider, will 
324 
be eligible for the study if they meet all the following criteria: 
325 
1. Age 3 to < 9 years 
326 
2. IXT meeting all the following criteria: 
327 
• Intermittent or constant XT at distance (mean distance control 2.0 or more) with at 
328 
least 1 measure of 3, 4 or 5 (i.e., indicating spontaneous tropia) on control testing 
329 
• Either IXT, exophoria, or orthophoria at near (cannot have control score of 5 on all 3 
330 
near assessments) 
331 
• Distance exodeviation between 15∆ and 50∆ by PACT 
332 
• Near exodeviation between 0∆ and 50∆ by PACT 
333 
• Near exodeviation does not exceed distance by more than 10∆ by PACT 
334 
3. Age-normal visual acuity in both eyes:56-58 
335 

 
IXT7PROTV1.0_19APR2022 
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• 3 years: 20/50 or better (>=63 letters) 
336 
• 4 years: 20/40 or better (>=68 letters) 
337 
• 5-6 years: 20/32 or better (>=73 letters) 
338 
• 
7-<9 years: 20/25 or better (>=78 letters) 
339 
4. Interocular difference in distance VA of 2 logMAR lines or less (10 letters or less on E-
340 
ETDRS for patients ≥7 years old). Testing by ATS HOTV for participants 3 to < 7 years 
341 
old and by E-ETDRS for participants ≥7 years old. 
342 
o The overall number of participants with an interocular difference in distance VA 
343 
of 2 logMAR lines (10 letters on E-ETDRS for patients ≥7 years old) will be 
344 
limited to 14. 
345 
5. Refractive error between -6.00 D SE and +2.00 D SE (inclusive) based on cycloplegic 
346 
refraction performed within 7 months 
347 
6. Participants with refractive error meeting any of the following based on cycloplegic 
348 
refraction performed within the prior 7 months must be wearing spectacles for at least 2 
349 
weeks: 
350 
• Myopia > -0.50 D spherical equivalent (SE) in either eye 
351 
• Anisometropia > 1.00 D SE 
352 
• Astigmatism in either eye > 1.00 D  
353 
7. Any refractive correction worn at enrollment (required or not) must meet the following 
354 
guidelines based on cycloplegic refraction performed within the prior 7 months: 
355 
• Anisometropia SE must be within 0.50 D of the full anisometropic difference 
356 
correction 
357 
• Astigmatism must be corrected within 0.50 D  
358 
• Axis must be within ±10 degrees if cylinder power is ≤1.00 D and within ±5 
359 
degrees if cylinder power is >1.00 D. 
360 
• For hyperopia, the spherical component can be reduced at investigator discretion 
361 
provided the reduction is symmetrical and does not meet the definition of 
362 
deliberate overminus (see below).  
363 
• For refractive errors with an emmetropic or myopic SE, the intent is to fully 
364 
correct, but the spherical component can be undercorrected at investigator 
365 
discretion provided the reduction is symmetrical and results in no more than  
366 
-0.50 D SE residual (i.e., uncorrected) myopia. Deliberate overminus is not 
367 
allowed. 
368 
• Deliberate overminus is defined for this protocol as any refractive correction 
369 
prescribed to yield lenses that are overminused by more than -0.50D SE than 
370 
cycloplegic refraction SE.  
371 
▪ Less than the full cycloplegic hyperopic correction (i.e., prescribing 
372 
reduced plus) or no correction for a hyperopic SE refractive error is 
373 
not considered the same as overminusing for this protocol (because 
374 
most patients without IXT but with hyperopic SE refractions up to 
375 
+2.00 D SE would not typically be prescribed a refractive correction.) 
376 
• Note that the refractive correction guidelines and the requirement to wear 
377 
refractive correction for at least 2 weeks apply not only to participants who 
378 
require refractive correction under the above criteria but also to any other 
379 
participant who is wearing refractive correction. 
380 
8. Gestational age > 30 weeks 
381 

 
IXT7PROTV1.0_19APR2022 
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9. Birth weight > 1500 grams 
382 
10. Patient and/or parent understands protocol, is willing to enroll, and is willing to accept 
383 
that other treatment for IXT will not be offered for 3 months 
384 
11. Parent has phone and is willing to be contacted by Jaeb Center staff 
385 
12. Relocation outside of area of an active PEDIG site within next 3 months not anticipated 
386 
 
387 
 Exclusion Criteria 
388 
Individuals meeting any of the following criteria at baseline will be excluded from study 
389 
participation. 
390 
1. Prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
391 
2. Prior nonsurgical treatment for IXT (e.g., patching, vergence therapy, vision 
392 
therapy/orthoptics, base-in prism, or deliberate overminus with spectacles more than 
393 
1.00 D) for >1 week duration within the past 1 year 
394 
3. Previous amblyopia treatment other than refractive correction  
395 
4. Diplopia more than 2 times per day by parental assessment 
396 
5. Paretic or restrictive strabismus 
397 
6. Craniofacial malformations affecting the orbits 
398 
7. Ocular disorders which would reduce VA (except refractive error) 
399 
8. Severe developmental delay that would interfere with treatment or evaluation (in the 
400 
opinion of the investigator). Participants with mild speech delay or reading and/or 
401 
learning disabilities or ADHD are not excluded. 
402 
9. Neurological anomaly that could affect ocular motility (e.g., cerebral palsy, Down 
403 
syndrome) 
404 
10. Immediate family member (child or sibling) of any investigative site personnel directly 
405 
affiliated with this study. 
406 
11. Known allergy to adhesive patches. 
407 
12. Known allergy to silicone.  
408 
 
409 
2.3 Historical Information 
410 
Historical information elicited will include the following: date of birth, sex, race, ethnicity, 
411 
spectacle correction, and prior treatment for IXT and amblyopia.  
412 
 
413 
2.4 Screening and Baseline Procedures  
414 
Testing will be done in the order specified below on a single day following enrollment in the 
415 
child’s current refractive correction if worn (any spectacle correction worn must meet the criteria 
416 
specified in section 2.2) and without cycloplegia: 
417 
1. Eye-Related Quality of life: Pediatric Eye Questionnaire (PedEyeQ) 
418 
• Child questionnaire: Completed by children 5 years and older 
419 
• Parent questionnaire: Completed by the parent for all children regardless of age 
420 
(includes parent and proxy questions) 
421 
2. Symptom Survey:  
422 
• Intermittent Exotropia Symptom Survey completed by children 5 years or older.  
423 
• Single diplopia question to be completed by children 3 or 4 years.  
424 

 
IXT7PROTV1.0_19APR2022 
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3. Diplopia Assessment by Parent: Assess diplopia presence and frequency over the last week, 
425 
by parental report. If present, classify diplopia frequency as “2 times or less per day” or 
426 
“more than 2 times per day.” 
427 
4. Monocular Distance VA Testing: Distance VA testing will be performed by a certified 
428 
examiner on a certified VA system (EVA or M&S), using the ATS single surround HOTV 
429 
for participants 3 to <7 years old and using the E-ETDRS for participants ≥ 7 years. The 
430 
same VA testing method used at enrollment will be used again at 3 months.  
431 
5. Stereoacuity Testing: Assessed using the Randot Preschool Stereotest at near (performed at 
432 
40 cm) as outlined the IXT7 Procedures Manual  
433 
6. Control of the Exodeviation #1: Control of the exodeviation at distance (6 meters) then near 
434 
(1/3 meter) will be assessed using the standardized IXT control scale,35 as outlined in the 
435 
IXT7 Procedures Manual. 
436 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
437 
certified orthoptist. 
438 
• The same examiner must assess control for all three assessments of control at each 
439 
visit.  
440 
8. Divergence Amplitude Testing: Measured at distance (6 meters) using the PEDIG-approved 
441 
prism bar as described in the IXT7 Procedures Manual 
442 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
443 
certified orthoptist. 
444 
• Record the break and recovery points. 
445 
9. Convergence Amplitude Testing: Measured at distance (6 meters) using the PEDIG-approved 
446 
prism bar as described in the IXT7 Procedures Manual 
447 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
448 
certified orthoptist. 
449 
10. Control of the Exodeviation #2 (repeat) (see item #7). 
450 
11. Ocular Alignment Testing:  
451 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
452 
certified orthoptist. 
453 
• Ocular alignment will be assessed by the cover/uncover test, simultaneous prism and 
454 
cover test (SPCT), and prism and alternate cover test (PACT) in primary gaze at 
455 
distance (3 meters) and near (1/3 meter) as described in the IXT7 Procedures Manual.  
456 
12. Control of the Exodeviation #3 (repeat) (see item #7) 
457 
13. Suppression: Assessment of suppression at distance (6 meters) using the Office Suppression 
458 
Test59 as described in the IXT7 Procedures Manual 
459 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
460 
certified orthoptist. 
461 
14. Retinal Correspondence (children 6 to <9 years only): Assessment of retinal correspondence 
462 
will be made when aligned and also when tropic using the Hering-Bielschowsky After Image 
463 
Test60 as described in the IXT7 Procedures Manual using the PEDIG-supplied flash unit.  
464 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
465 
certified orthoptist.  
466 
 
467 

 
IXT7PROTV1.0_19APR2022 
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2.5 Randomization 
468 
Eligible participants will be randomly assigned on the study website to the following treatment: 
469 
 
470 
1. Observation for 3 months – no treatment other than refractive correction 
471 
2. Full-time patching (all waking hours) for 3 months (right eye on even days, left eye on odd 
472 
days), in addition to refractive correction  
473 
 
474 
The Jaeb Center will construct a Master Randomization List stratified by mean distance control 
475 
score at enrollment (2 to <3, 3 to <4, 4 to 5). A participant is officially randomized when the 
476 
website randomization process is completed.  
477 
 Observation Group 
478 
Participants randomized to observation alone will not be allowed to receive any other treatment 
479 
for IXT, except refractive correction, for 3 months.  
480 
 Full-Time Patching Group 
481 
Participants randomized to the full-time patching group will patch full-time (all waking hours) 
482 
for 3 months up until the day before the 3-month primary outcome visit. Daily alternate patching 
483 
will be prescribed (right eye on even days, left eye on odd days). No other treatment for IXT will 
484 
be used, except for refractive correction. 
485 
2.6 Monitoring of Adherence 
486 
Site staff will activate and distribute occlusion dose monitors (ODMs) for participants 
487 
randomized to patching (patching adherence is not applicable to the observation group). 
488 
• Adherence with patching will be monitored throughout the study by an ODM worn on the 
489 
inside of the patch for participants randomized to patching.  
490 
• In addition, parents will be asked to record patching wear time and which eye was 
491 
patched on a study calendar.
492 

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Chapter 3: Study Follow-up 
493 
3.1 Study Visits 
494 
Study follow up for participants randomized in the study is (timed from randomization): 
495 
 
496 
• 4-week phone call: 4 weeks ± 1 week 
497 
• 3-month (on treatment) primary outcome visit: 3 months ± 2 weeks 
498 
• Parents will be instructed to not patch on the day of the visit 
499 
 
500 
3.2 Phone Call at 4-weeks 
501 
Study personnel will call the parent of each participant 4 weeks ± 1 week following 
502 
randomization. The purpose of the call for the patching groups is to determine whether patching 
503 
is being done, and if so, how it is being done. If patching is not being done correctly, patching 
504 
instructions will be reviewed with the parents. Parents in the patching groups will be asked if 
505 
they have had any problems using the ODM. If ODMs have been lost, replacement ODMs may 
506 
be sent to the parent. Parents in both treatment groups will be asked if they have any questions or 
507 
concerns about the study. 
508 
3.3 Masking Procedures 
509 
Participants will not be masked to their treatment group, given that they will be asked to patch all 
510 
waking hours/day (full-time patching group) or not at all (observation group). The investigator 
511 
treating each participant also will not be masked to treatment group. An examiner masked to 
512 
treatment group will perform all clinical testing (with the exception of VA testing and 
513 
administration of questionnaires, which may be performed by unmasked, certified personnel) at 
514 
the 3-month visit.  
515 
 Masked Examiner 
516 
The masked examiner must be a pediatric optometrist, pediatric ophthalmologist, or certified 
517 
orthoptist who is not aware of the participant’s assigned treatment. Because the enrolling 
518 
investigator will be unmasked to treatment group, they will not be allowed to serve as their own 
519 
masked examiner. 
520 
3.4 Testing Procedures at 3-Month Outcome Visit 
521 
The following procedures will be performed in the order specified below at the 3-month outcome 
522 
visit with the participant wearing their current refractive correction (if worn), and without 
523 
cycloplegia. If unable to complete the entire masked exam during the office visit, the participant 
524 
can return with 10 days to complete all masked testing (# 6-14 below). Testing procedures #1-5 
525 
below do not need to be repeated if completed at the initial office visit. 
526 
 
527 
1. Adherence Monitoring (for patching group): 
528 
• Evaluate compliance by review of study calendar 
529 
• Download adherence data from ODM 
530 
2. Eye-Related Quality of life: Pediatric Eye Questionnaire (PedEyeQ) 
531 
• Child questionnaire: Completed by children 5 years and older 
532 
• Parent questionnaire: Completed by the parent for all children regardless of age 
533 
(includes parent and proxy questions) 
534 
3. Symptom Survey:  
535 

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• Intermittent Exotropia Symptom Survey completed by children 5 years or older. 
536 
• Single diplopia question to be completed by children 3 or 4 years. 
537 
4. Diplopia Assessment by Parent: Assess diplopia presence and frequency over the last week, 
538 
by parental report. If present, classify diplopia frequency as “2 times or less per day” or 
539 
“more than 2 times per day.” 
540 
5. Monocular Distance VA Testing: Distance VA testing in each eye using the same test 
541 
method used at enrollment. 
542 
6. Stereoacuity Testing (masked): Randot Preschool Stereoacuity at 40 cm.  
543 
7. Control of the Exodeviation #1 (masked):  
544 
• Distance (6 meters) 
545 
• Near (1/3 meter) 
546 
• The same examiner must assess control for all three assessments of control for each visit.  
547 
8. Divergence Amplitude Testing (masked): Measured at distance (6 meters) using a PEDIG-
548 
approved prism bar as described in the IXT7 Procedures Manual 
549 
• Record the break and recovery points 
550 
9. Convergence Amplitude Testing (masked): Measured at distance (6 meters) using a PEDIG-
551 
approved prism bar as described in the IXT7 Procedures Manual 
552 
• Record the blur, break, and recovery points 
553 
10. Control of the Exodeviation #2 (masked) (repeat) (see item #7) 
554 
11. Ocular Alignment Testing (masked):  
555 
• Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
556 
certified orthoptist. 
557 
• Ocular alignment will be assessed by the cover/uncover test, simultaneous prism and 
558 
cover test (SPCT), and prism and alternate cover test (PACT) in primary gaze at 
559 
distance (3 meters) and near (1/3 meter) as described in the IXT7 Procedures Manual.   
560 
12. Control of the Exodeviation #3 (masked) (repeat) (see item #7) 
561 
13. Suppression (masked): Assessment at distance using the Office Suppression Test at distance 
562 
(6 meters) as described in the IXT7 Procedures Manual 
563 
14. Retinal correspondence (masked): In children aged 6, 7, or 8 years of age at randomization, 
564 
assessment of retinal correspondence will be made using the Hering-Bielschowsky After- 
565 
Image Test as described in the IXT7 Procedures Manual using the PEDIG-supplied flash 
566 
unit. 
567 
 
568 
3.5 IXT Treatment Changes During Follow-up 
569 
Changes in treatment are not allowed prior to the 3-month outcome visit.  
570 
If the participant is experiencing overwhelming social concerns or significant symptoms 
571 
associated specifically with IXT, the investigator must call one of the Protocol Chairs to 
572 
discuss the case and obtain approval for an early 3-month outcome visit (if not already in 
573 
window) prior to initiating any non-randomized treatment for IXT.  
574 
3.6 Management of Refractive Error During Follow-up 
575 
Because of the short duration of the study, the spectacles prescribed at randomization may not be 
576 
changed or discontinued without contacting a Protocol Chair.  
577 

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In the event that spectacles are lost or damaged after randomization but before the 3-month 
578 
outcome visit, the spectacles may only be replaced with the same spectacle prescription that was 
579 
prescribed at randomization. 
 
580 

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Chapter 4: Testing Procedures and Questionnaires 
581 
4.1 Clinical Assessments 
582 
The following test procedures will be completed for all three treatment groups at each visit as 
583 
defined in the IXT Procedures Manual:  
584 
1. Monocular VA Testing: Distance VA will be tested in both eyes with the participant wearing 
585 
their study-specified spectacle correction. The right eye is tested, with the left eye occluded 
586 
with an adhesive patch. The left eye is tested after the right eye. Testing must be performed 
587 
by a certified examiner on a certified VA system (EVA or M&S), using the ATS single 
588 
surround HOTV for participants 3 to <7 years old and using the E-ETDRS for participants ≥ 
589 
7 years. The same testing method must be used throughout the study. Testing time for both 
590 
eyes typically is in the range of 5 to 10 minutes. 
591 
2. Randot Preschool Stereoacuity Test: The Randot Preschool Stereoacuity Test measures 6 
592 
levels (40 to 800 seconds of arc) of stereoacuity at near (40 cm). The test consists of 3 
593 
booklets, each designed to test 2 levels of stereoacuity, and each level consisting of 4 panels, 
594 
3 of which contain a random dot stereogram. The participant wears polarized lenses over 
595 
their spectacle correction. The examiner asks the participant if they can identify a specific 
596 
black and white shape in the booklet and then asks the participant to point to the panel 
597 
containing the corresponding stereogram image, as outlined in the IXT7 Procedures Manual. 
598 
The test must be administered by a certified examiner. The certified examiner will be 
599 
required to be masked to treatment group. Testing time is approximately 2-4 minutes. 
600 
3. Ocular Alignment: Ocular alignment will be assessed by the cover/uncover test, simultaneous 
601 
prism and cover test when tropia present by cover/uncover test (SPCT), and prism and 
602 
alternate cover test (PACT), using the PEDIG-approved IXT7 prism bar, in primary gaze at 
603 
distance (6 meters) and at near (33 cm) as outlined in the IXT7 Procedures Manual. The 
604 
examiner will be required to be masked to treatment group. Testing time is approximately 2-
605 
4 minutes. 
606 
4. Cycloplegic Refraction: A cycloplegic refraction will be done prior to enrollment and only if 
607 
clinically indicated thereafter. After administration of eye drops, it typically takes 30 minutes 
608 
to achieve cycloplegia, and testing time for refraction of both eyes is in the range of 2 to 10 
609 
minutes. 
610 
5. Suppression Testing: Suppression will be assessed using the Office Suppression Test which 
611 
grades the level of suppression while tropic on a 4-level scale. Testing will be performed at 6 
612 
meters as outlined in the IXT7 Procedures Manual. Testing must be performed by a pediatric 
613 
ophthalmologist, pediatric optometrist, or certified orthoptist. The examiner will be required 
614 
to be masked to treatment group. Testing time is approximately 3-5 minutes. 
615 
6. Retinal Correspondence Testing: In children 6, 7, or 8 years old at time of randomization, 
616 
retinal correspondence status will be assessed by the Hering-Bielschowky after-image test, 
617 
using a PEDIG-provided flash unit. Correspondence will be assessed when aligned and when 
618 
tropic to record overall status as either: 
619 

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Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or certified 
620 
orthoptist as outlined in the IXT7 Procedures Manual. The examiner will be required to be 
621 
masked to treatment group. Testing time is approximately 3-5 minutes. 
622 
 
623 
7. Control of IXT: Assessment of IXT control will be performed using the Office Control 
624 
Scale35 at both distance (6 meters) and near (1/3 meter), fixating an accommodative target. 
625 
Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or certified 
626 
orthoptist as outlined in the IXT7 Procedures Manual. The examiner will be required to be 
627 
masked to treatment group. Testing time is approximately 3-5 minutes. 
628 
The scale below applies to both distance and near test distance separately.  
629 
Intermittent Exotropia Control Scale 
630 
5 = Constant Exotropia 
631 
4 = Exotropia > 50% of the 30-second period before dissociation 
632 
3 = Exotropia < 50% of the 30-second period before dissociation 
633 
2 = No exotropia unless dissociated, recovers in >5 seconds 
634 
1 = No exotropia unless dissociated, recovers in 1-5 seconds 
635 
0 = No exotropia unless dissociated, recovers in <1 second (phoria) 
636 
Not applicable = No exodeviation present  
637 
 
638 
Directions:  
639 
Step1: Assessment before any dissociation: Eye alignment is observed for a 30-second period 
640 
with distance fixation. The time in seconds that a spontaneous IXT is observed is 
641 
counted, and the appropriate control score (3, 4, or 5) is assigned for distance fixation. 
642 
This is then repeated for near fixation for another 30-second period; if an exotropia is 
643 
observed, then the time in seconds that an eye is observed to be exotropic is counted 
644 
and the appropriate score of 3, 4, or 5 is assigned. If a score of ≥3 is present, then Step 
645 
2 (dissociation) is not required for that test distance. First distance and then near 
646 
fixation are assessed before any dissociation (i.e., before step 2). 
647 
Step 2: Assessment with standardized dissociation is performed only if spontaneous 
648 
exotropia is NOT observed during step 1 (control was not a 3, 4, or 5). Instead, control 
649 
will be a 0, 1, or 2; this is determined based on the worst score determined from 3 
650 
successive 10-second periods of dissociation: 
651 
• An occluder is placed over the right eye for 10 seconds and then removed; the 
652 
length of time it takes for the re-establishment of fusion is measured in seconds. 
653 
• The left eye is then occluded for a 10-second period (second assessment under 
654 
dissociation) and after uncovering the eye, the time for re-establishment of fusion 
655 
is similarly measured in seconds. 
656 
• A third assessment is performed, by covering the eye that required the longer time 
657 
to re-fuse on the first two 10-second dissociations. After uncovering the eye, the 
658 
length of time (in seconds) it takes for the reestablishment of fusion is measured 
659 
in seconds. 
660 
The worst level of control for the three 10-second periods of dissociation by occlusion 
661 
should be recorded.  
662 

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Since the control score is the slowest time of the three assessments, if a score of 2 (>5 
663 
seconds recovery) is noted on the first or second dissociation, then subsequent 
664 
dissociation(s) are not needed. 
665 
If the child has a micro-esotropia by the cover-uncover test but an exodeviation by 
666 
PACT, the control scale applies to the exodeviation. 
667 
8. Measurement of Divergence Amplitude: Testing must be performed by a pediatric 
668 
ophthalmologist, pediatric optometrist, or certified orthoptist. The examiner will be required 
669 
to be masked to treatment group. Testing time is approximately 2-4 minutes. 
670 
• Divergence amplitude to be measured at distance (6 meters) 
671 
• Using the PEDIG-approved IXT7 prism bar, record the break, and recovery points 
672 
according to the IXT7 Testing Procedures Manual. 
673 
• If manifest exotropia is present at the time of testing, amplitude testing will be 
674 
recorded as “unable.” 
675 
 
676 
9. Measurement of Convergence Amplitudes: Testing must be performed by a pediatric 
677 
ophthalmologist, pediatric optometrist, or certified orthoptist. The examiner will be required 
678 
to be masked to treatment group. Testing time is approximately 2-4 minutes. 
679 
• Convergence amplitude to be measured at distance (6 meters) 
680 
• Using the PEDIG-approved IXT7 prism bar, record the blur, break, and recovery 
681 
points according to the IXT7 Testing Procedures Manual. 
682 
• If manifest exotropia is present at the time of testing, amplitude testing will be 
683 
recorded as “unable.” 
684 
 
685 
The following information will be collected by interviewing the parent(s) or reviewing the 
686 
medical record: 
687 
 
688 
1) Date of birth, sex, race, ethnicity, spectacle correction, and prior treatment for IXT. 
689 
Assessment of Adverse Events: All adverse events including ocular adverse events, and 
690 
any events judged by the investigator to be related to patching treatment, occurring 
691 
between the time of initiating study eye treatment and the 12-month outcome exam will 
692 
be recorded.  
693 
 
694 
Each questionnaire is described briefly below. The procedures for administration are described in 
695 
the IXT7 Testing Procedures Manual. 
696 
 
697 
1. Pediatric Eye Questionnaire (PedEyeQ)61 
698 
The Pediatric Eye Questionnaire (PedEyeQ), is a pediatric eye-related quality of life and 
699 
functional vision instrument, validated for use in children with a variety of pediatric eye 
700 
conditions. The PedEyeQ is patient- and parent-derived and consists of age-appropriate Child 
701 
and Proxy components as well as a Parent component (to assess the effect on the parent 
702 
themselves).  
703 
i. 
The Child PedEyeQ, designed for children 5 to 17 years, has the following 4 
704 
domains: Functional Vision, Bothered by Eyes and Vision. Social, and Frustration / 
705 
Worry.  
706 

JAEB CENTER FOR HEALTH RESEARCH 
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ii. 
The Proxy PedEyeQ, designed for parents of children 0 to 17 years, has the following 
707 
5 domains: Functional Vision, Bothered by Eyes and Vision, Social, Frustration / 
708 
Worry, and Eye care. Both the Child and Proxy PedEyeQ assess the eye-related 
709 
quality of life and functional vision of the child.  
710 
iii. 
The Parent PedEyeQ addresses the effect of the child’s eye condition on the parent 
711 
and has the following 4 domains: Impact on Parent and Family, Worry about Child’s 
712 
Eye Condition. Worry about Self-perception and Interactions, and Worry about 
713 
Functional Vision.  
714 
 
715 
Each of the Child, Proxy, and Parent domains is independently scored using established 
716 
Rasch look-up tables and converted on a scale of 1 to 100 (each domain scored separately for 
717 
each instrument). Completion time is approximately 10 minutes for the child, 10-15 minutes 
718 
for the parent; child and parent questionnaires can be completed concurrently. The PedEyeQ 
719 
questionnaires administered at enrollment will be the versions repeated throughout the study.  
720 
 
721 
2. Intermittent Exotropia Symptom Survey62  
722 
The Intermittent Exotropia Symptom Survey is a patient- and parent-derived intermittent 
723 
exotropia-related symptom instrument designed to identify the presence and severity of 
724 
symptoms in children with IXT. This questionnaire consists of 22 items completed by 
725 
children aged 5 years or older.  
726 
 
727 
• All children will use the three-level response scale (not at all, sometimes, a 
728 
lot), administered by clinical staff either verbally or using a matching card.  
729 
• If possible, children should be positioned such that they are unable to view 
730 
their parents during testing and parents should be advised not to influence 
731 
their child’s responses.  
732 
 
733 
Children 4 years and younger at enrollment will not complete the full questionnaire, but will 
734 
answer the single question (#8) regarding diplopia. Time for completion of the full Symptom 
735 
Survey is 5-7 minutes.  
736 
 
737 
3. Assessment of Diplopia by Parent 
738 
An estimate of the frequency of diplopia (if any) will be determined by asking the parent 
739 
whether “your child has complained of double vision over the last week.” If yes, the parent is 
740 
asked how frequently the child has complained of double vision: “2 times or less per day,” 
741 
“or “more than 2 times per day.” Any study personnel may ask the parent to rate diplopia. 
742 
Testing time is approximately 1 minute. 
743 

 
IXT7PROTV1.0_19APR2022 
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Chapter 5: Unanticipated Problem and Adverse Event Reporting 
744 
5.1 Unanticipated Problems 
745 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
746 
problems meeting the criteria below. Sites must report Unanticipated Problems to the IRB within 
747 
seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
748 
experience, or outcome that meets all the following criteria: 
749 
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
750 
that are described in the protocol related documents, such as the IRB-approved research 
751 
protocol and informed consent document; and (b) the characteristics of the subject 
752 
population being studied 
753 
• Related or possibly related to participation in the research (possibly related means there is 
754 
a reasonable possibility that the incident, experience, or outcome may have been caused 
755 
by the procedures involved in the research) 
756 
• Suggests that the research places participants or others at a greater risk of harm than was 
757 
previously known or recognized (including physical, psychological, economic, or social 
758 
harm)  
759 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
760 
involving a specific site such as unanticipated problems that occur at the Coordinating Center or 
761 
at another participating entity such as a pharmacy or laboratory. These instances must be 
762 
reported to the JCHR IRB within seven (7) calendar days of recognition. The Director of the 
763 
Human Research Protection Program will report to the appropriate regulatory authorities if the 
764 
IRB determines that the event indeed meets the criteria of an Unanticipated Problem that requires 
765 
further reporting.  
766 
 
767 
5.2 Adverse Events 
768 
Although no adverse events are anticipated, any new reduction in VA of 3 or more lines (≥15 
769 
letters on ETDRS) or reduction in Randot Preschool Stereoacuity of 2 or more levels, will be 
770 
tabulated between treatment groups.  
771 
No surgical procedures are part of the protocol, and no treatments are being prescribed that are 
772 
not part of usual care. Investigators will abide by local IRB reporting requirements. 
773 
5.3 Safety Oversight 
774 
A Data and Safety Monitoring Committee (DSMC) will review compiled safety data at periodic 
775 
intervals, with a frequency of no less than twice a year. The DSMC can request modifications to 
776 
the study protocol or suspension or outright stoppage of the study if deemed necessary based on 
777 
the totality of safety data available. Details regarding DSMC review will be documented in a 
778 
separate DSMC charter.  
779 
The objective of the DSMC review is to decide whether the study (or study treatment for an 
780 
individual or study cohort) should continue per protocol, proceed with caution, be further 
781 
investigated, be discontinued, or be modified and then proceed. Suspension of enrollment (for a 
782 
particular group, a particular study site, or for the entire study) is a potential outcome of a DSMC 
783 
safety review. 
784 
 
785 

 
IXT7PROTV1.0_19APR2022 
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5.4 Stopping Criteria 
786 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
787 
Monitoring Committee) prior to the preplanned completion of follow-up for all study 
788 
participants. There are no pre-specified formal guidelines for stopping the study for futility or 
789 
efficacy. 
790 
 
791 
5.5 Participant Discontinuation of Study Treatment 
792 
Rules for discontinuing study treatment use are described below.  
793 
• The investigator believes it is unsafe for the participant to continue to receive the 
794 
treatment.  
795 
• The participant or parent requests that the treatment be stopped. 
796 
Even if the study treatment is discontinued, the participant will be encouraged to remain in the 
797 
study through the 3-month visit. 
798 
 
 
799 

 
IXT7PROTV1.0_19APR2022 
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Chapter 6: Miscellaneous Considerations 
800 
6.1 Contacts by the Jaeb Center for Health Research and Sites 
801 
The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided 
802 
with the parent’s contact information. The Jaeb Center may contact the parents of the 
803 
participants. Permission for such contacts will be included in the Informed Consent Form. The 
804 
principal purpose of the contacts will be to develop and maintain rapport with the participant and 
805 
family and to help coordinate scheduling of the outcome examinations.  
806 
 
807 
6.2 Participant Compensation 
808 
Participant compensation will be specified in the informed consent form. 
809 
6.3 Participant Withdrawal 
810 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
811 
participants who withdraw, their data will be used up until the time of withdrawal. 
812 
6.4 Confidentiality 
813 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
814 
used instead of their name. Protected health information gathered for this study will be shared 
815 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
816 
participant information may also be provided to research sites involved in the study.
817 

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PAGE 36 OF 50 
Chapter 7: Statistical Considerations 
818 
7.1 Statistical and Analytical Plans 
819 
The approach to sample size and statistical analyses are summarized below. 
820 
 
821 
7.2 Primary Objective and Hypothesis 
822 
The study has one primary objective:  
823 
1) To determine if participants with IXT undergoing full-time patching have more 
824 
improvement in mean distance control between baseline and 3 months than participants 
825 
being observed without treatment. 
826 
 
827 
The primary outcome is a comparison of the change in the mean distance control scores (average 
828 
of 3 measurements) at 3 months between the full-time patching group and the observation group. 
829 
The study is designed as a superiority study to evaluate two 2-sided primary null hypotheses that 
830 
the changes in the mean control scores in the two groups at 3 months are the same versus the 
831 
alternative hypothesis that they are different. 
832 
Hypothesis Test for Objective # 1 – FT vs OBS at 3 Months:  
833 
 
834 
Hnull 
 
FT mean change in distance control over 3 months = OBS mean change in distance control over 3 months 
835 
Halternative  
FT mean change in distance control over 3 months ≠ OBS mean change in distance control over 3 months 
836 
 
837 
 
838 
7.3 Sample Size 
839 
Sample size estimation is based on data from our previous IXT2 randomized trial comparing 
840 
observation versus part-time patching for intermittent exotropia, limited to 278 participants with 
841 
similar baseline age (3 to <9 years) and baseline control score at distance (2 or higher).22 Data 
842 
are summarized in Table 1 below.  
843 
 
 
844 

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Table 1 – Previous IXT2 Randomized Trial Data in 3- to <9-Year-Olds with IXT* 
845 
Distance Control Scores** 
Cohort 
IXT2  
Glasses Alone 
 
(Observation) 
IXT2  
Part-time Patching 
 
(3 hours/Day) 
Baseline 
 
 
n 
147 
131 
Mean (SD) 
2.88 (1.01) 
2.93 (1.00) 
3-Month Score 
 
 
n 
131 
116 
Mean Score (SD) 
2.59 (1.35) 
2.15 (1.23) 
95% CI for Mean Score 
2.35 to 2.82 
1.92 to 2.37 
95% CI for SD Score 
1.21 to 1.54 
1.09 to 1.41 
3-Month Change from Baseline 
 
 
n 
131 
116 
Mean Change (SD) 
0.30 (1.23) 
0.78 (1.38) 
95% CI for Mean Change 
0.09 to 0.51 
0.53 to 1.04 
95% CI for SD Change 
1.09 to 1.40 
1.22 to 1.59 
*Participants aged 3 to <9 years old with baseline distance control score of 2 or higher (worse). 
846 
** A single measure of control was obtained at each visit in the IXT2 study.  
847 
 
848 
 
849 
In IXT2, after 3 months of observation versus treatment with 3 hours per day patching, the 
850 
observation group had a mean change based upon a single measure of distance control of 0.30 
851 
points (95% CI, 0.09 to 0.51 points) with a standard deviation of 1.23 points (95% CI, 1.09 to 
852 
1.40 points); and the 3 hours per day patching group had a mean change based upon a single 
853 
measure of distance control of 0.78 points (95% CI, 0.53 to 1.04 points) with a standard 
854 
deviation of 1.38 points (95% CI, 1.22 to 1.59 points); group difference patching – observation = 
855 
0.49 (95% CI 0.16 to 0.81). The correlation between distance control score at baseline and 
856 
change from baseline after 3 months was R=0.39 (95% CI, 0.27 to 0.48).  
857 
We are aware of no previous data on distance control score among children with IXT treated 
858 
with full-time patching. In our IXT5 study, after 6 months of treatment with overminus 
859 
spectacles, the mean change in distance control was 1.40 points (95% CI, 1.18 to 1.63 points) 
860 
with a standard deviation of 1.48 points (95% CI, 1.34 to 1.66 points). There was no 3-month 
861 
outcome in the IXT5 study; however, in the IXT3 pilot study, those treated with overminus 
862 
spectacles improved on average 1.2 points (95% CI, 0.5 to 1.9 points) with a standard deviation 
863 
of 1.8 points (95% CI, 1.4 to 2.5 points) after 8 weeks. Therefore, we estimate that a mean 
864 
change of 1.45 points after 3 months of full-time patching in the current study is reasonable for 
865 
an active treatment. 
866 
Sample Size Estimation: 
867 
The study will be powered for the primary objective.  
868 
Assuming a mean change in distance control score after 3 months of 0.30 points in the 
869 
observation group and 1.45 points in the full-time patching group; we estimate that the true 
870 
difference is 1.15 points between full-time patching and observation at 3 months.  
871 
 
872 

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Hypothesis Test for Objective – FT vs OBS at 3 Months:  
873 
Assuming a pooled standard deviation of 1.5 points for change in distance control score after 3 
874 
months, and a correlation of 0.30 between distance control score at baseline and change from 
875 
baseline after 3 months, a total sample size of 68 participants (34 per group) completing the 3-
876 
month outcome has 90% power with a type I error rate of 5% to evaluate whether there is a 
877 
treatment group difference between FT patching and OBS if the true difference is 1.15 points, 
878 
Table 2. Accounting for 5% loss to follow-up after 3 months, a total of 72 participants (36 per 
879 
treatment group) will need to be enrolled. The overall number of participants with an interocular 
880 
difference in distance VA of 2 logMAR lines (10 letters on E-ETDRS for patients ≥7 years old) will be 
881 
limited to 14. 
882 
Table 2: Total Sample Size for Difference in Mean Distance Control Score  
883 
Standard Deviation  
of Change in Distance  
Control (points) 
Treatment Group Difference for Outcome of Mean Change in 
Distance Control (points) 
0.85 
1.00 
1.15 
1.4 
106 
78 
60 
1.5 
122 
90 
68 
1.6 
138 
100 
78 
Cells indicate N for the overall study (two treatment groups combined with a ratio of 1:1), using a 2-sided test with 
884 
alpha 0.05, from an analysis of covariance model evaluating a difference between treatment groups for mean change 
885 
from baseline in distance control, controlling for baseline distance control.  
886 
 
887 
If the true effect with FT patching is as small as 0.99, the study would still have 80% power to 
888 
reject the null in favor of a difference (and 1.05 with 85%).  
889 
7.4 Interim Monitoring 
890 
Given the short duration of the primary outcome at 3 months, there will be no formal interim 
891 
analysis for stopping the study early for efficacy or futility.  
892 
7.5 Analysis Datasets  
893 
The primary efficacy analysis will follow an intent-to-treat (ITT) principle. Therefore, the 
894 
primary analysis dataset will include all randomized participants with imputation for those 
895 
missing the 3-month outcome and will analyze them according to the group they were originally 
896 
assigned. Sensitivity analyses of the primary outcome will follow a modified ITT principle and 
897 
use observed data with no imputation for missing outcomes.  
898 
7.6 Analysis of the Primary Efficacy Endpoints 
899 
The mean of three individual distance control scores will be tabulated by treatment group at 3 
900 
months. The change from baseline in mean control score (mean of three assessments) will be 
901 
compared between the FT patching group and the OBS group at 3 months using an analysis of 
902 
covariance (ANCOVA) model that adjusts for the mean distance control score at baseline and 
903 
distance angle by PACT at baseline. An estimate of difference between the groups will be 
904 
reported along with a 95% confidence interval and p-value.  
905 

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When the protocol-specified three measures of control are not performed at the outcome exam, 
906 
the mean of two tests will be used for analysis if only 2 distance control tests are completed; the 
907 
single distance control score will be used for analysis if only 1 testing is completed. 
908 
Participants who miss the 3-month visit or who do not complete any control testing at the 3-
909 
month visit will have an average distance control score imputed using multiple imputation. 
910 
The multiple imputation will be performed using Monte Carlo Markov Chain (MCMC) modeling 
911 
that includes the mean distance controls at the outcome visit and the following baseline factors: 
912 
mean distance control, and distance PACT.  
913 
 Sensitivity Analyses 
914 
The following analyses will be performed as sensitivity analyses to the primary analysis:  
915 
Sensitivity Analysis #1 (Complete Case Analysis Including Visits within Analysis Window):  
916 
• All participants who complete 1 or more distance control tests at the 3-month visit within the 
917 
analysis window (± 1 month) will have their observed 3-month data analyzed  
918 
• Participants who miss the 3-month visit entirely or who do not complete any control testing 
919 
at the 3-month visit within the analysis window will be excluded from the analysis 
920 
Sensitivity Analysis #2 (Complete Case Analysis Including Visits within Protocol Window):  
921 
• Repeat the above sensitivity analysis using observed data from participants who completed 
922 
the 3-month visit within the protocol window (± 2 weeks).  
923 
 
924 
Sensitivity Analysis #3 (ITT minus participants with IOD 2 logMAR lines at enrollment): 
925 
• The overall number of participants with an interocular difference in distance VA of 2 
926 
logMAR lines (10 letters on E-ETDRS for patients ≥7 years old) will be limited to 14. 
927 
• The ITT analyses as described in 7.5 will be repeated excluding these participants.  
928 
 
929 
7.7 Analysis of the Secondary Endpoints 
930 
All secondary analyses described below will use observed data only. Treatment group 
931 
comparisons specified in the sections below will be controlled using false discovery rate (FDR) 
932 
at the 5% probability level to account for the multiple outcomes. For all secondary analyses, an 
933 
estimate of difference between the groups will be reported at each timepoint along with an FDR-
934 
adjusted confidence interval and p-value unless otherwise specified. Further details about the 
935 
secondary analyses below will be part of a separate statistical analysis plan (SAP). 
936 
 Near Control 
937 
At 3 months, near control will be evaluated similarly to the distance control primary analysis 
938 
(section 7.6) using ANCOVA models that adjust for the mean near control score at baseline and 
939 
the near angle by PACT at baseline. 
940 
Additionally, the proportion of participants with 2 or more points improvement in control from 
941 
baseline will be compared between the treatment groups at 3 months using a two-sided Barnard’s 
942 
test with calculation of a two-sided FDR-adjusted confidence interval on the difference in 
943 
proportions. This will be done separately for control at distance and near. 
944 

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 Angle of Deviation 
945 
At 3 months, a two-sided comparison of magnitude of the angle of deviation by PACT will be 
946 
performed between treatment groups using an ANCOVA model, which adjusts for baseline 
947 
PACT. The treatment group difference and an FDR-adjusted confidence interval will be 
948 
calculated. The analysis will be completed separately at distance and at near.  
949 
Additionally, the proportion of participants with improvement of distance and near angle greater 
950 
than the test/retest variability63 will be compared between the treatment groups at 3 months using 
951 
a two-sided Barnard’s test with calculation of a two-sided FDR-adjusted confidence interval on 
952 
the difference in proportions. 
953 
 Level of Suppression 
954 
The proportion with each level of suppression (negligible, mild, moderate, or dense) will be 
955 
compared between treatment groups at 3 months using an exact Wilcoxon rank sum test. 
956 
 Proportion with Anomalous Retinal Correspondence 
957 
For those able to perform the test, the proportions of normal versus anomalous retinal 
958 
correspondence will be compared between treatment groups at 3 months using a two-sided 
959 
Barnard’s test for the difference in proportions. 
960 
 Convergence and Divergence Fusional Amplitudes 
961 
The distribution of fusional convergence amplitude (blur point, break point, and recovery) and 
962 
fusional divergence amplitude (break point and recovery point) will be described and compared 
963 
between treatment groups at 3 months using an exact Wilcoxon rank sum test. When no blur is 
964 
reported for fusion convergence, the break point will be used for analysis. 
965 
 IXT Symptom Survey Score 
966 
The IXT Symptom Survey will be completed by children at the enrollment and 3-month exams. 
967 
The distribution for each individual item (‘Never’, ‘Sometimes’, ‘All the Time) will be tabulated 
968 
for each treatment group within subgroups defined by age 5 to 9 years (all items) and age <5 
969 
years for the single diplopia question. 
970 
 PedEyeQ Score 
971 
The PedEyeQ consists of 3 components: child, proxy, and parent. After applying existing Rasch 
972 
scoring,61 the average score for each of the domains within the three components will be 
973 
compared between treatment groups at 3 months using an ANCOVA model, which adjusts for 
974 
baseline PedEyeQ score. The treatment group difference and an FDR-adjusted confidence 
975 
interval will be calculated. 
976 
 Binocular Diplopia by Parental Report 
977 
The proportion of binocular diplopia at 3 months with a frequency of “more than 2 times per 
978 
day” over the last week at distance or near, by parental report will be compared treatment groups 
979 
at 3 months using a two-sided Barnard’s test. 
980 
 
981 

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7.8 Exploratory Analyses 
982 
Exploratory analyses described below will use observed data only. Point estimates and 95% CIs 
983 
will be reported for each outcome with no adjustment for multiplicity.  
984 
 Actual Patch Wear Time 
985 
The distribution of actual patch wear time will be tabulated overall and by treatment groups. The 
986 
potential correlation between actual patch wear time in the FT patching group and the change 
987 
from baseline in the following outcomes will be evaluated at 3 months (when collected): 
988 
1. Distance control score  
989 
2. Near control score 
990 
3. Distance angle of deviation 
991 
4. Near angle of deviation 
992 
5. Level of suppression 
993 
6. Convergence fusional amplitudes 
994 
7. Divergence fusional amplitudes 
995 
8. Symptom survey score 
996 
9. Diplopia assessment by Parent 
997 
10. PedEyeQ score (each domain) 
998 
A Spearman correlation coefficient and 95% confidence interval will be calculated for each 
999 
outcome.  
1000 
 Outcome of Retinal Correspondence Testing 
1001 
The relationship of retinal correspondence response with respect to the following outcomes 
1002 
within each treatment group will be evaluated at 3 months: 
1003 
1. Distance control score  
1004 
2. Near control score 
1005 
3. Distance angle of deviation 
1006 
4. Near angle of deviation 
1007 
5. Level of suppression 
1008 
6. Convergence fusional amplitudes 
1009 
7. Divergence fusional amplitudes 
1010 
8. Symptom survey score 
1011 
9. Diplopia assessment by Parent 
1012 
10. PedEyeQ score 
1013 
For continuous outcome variables, the difference in means between participants with normal 
1014 
versus anomalous retinal correspondence will be calculated along with a 95% confidence 
1015 
interval. For categorical outcome variables, the difference in proportions between participants 
1016 
with normal versus anomalous retinal correspondence will be calculated along with a 95% 
1017 
confidence interval.  
1018 

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 Subgroup Analysis of Distance Control 
1019 
The treatment group comparison of distance control will be assessed at 3 months in subgroups 
1020 
based on gender and race/ethnicity in accordance with NIH guidelines; however, no effect 
1021 
modification is expected for these factors. 
1022 
 
1023 
7.9 Safety Analyses 
1024 
 
1025 
 Deterioration 
1026 
The number and proportion of participants with deterioration, as defined below, will be tabulated 
1027 
for each treatment group at 3 months as a safety outcome. 
1028 
Deterioration is defined as meeting one of the following criteria at the 3 months follow-up visit: 
1029 
 
1030 
1. Constant exotropia at least 10Δ at distance AND near by SPCT: 
1031 
o Constant is defined as an exotropia present throughout the examination and 
1032 
confirmed by cover/uncover testing performed at least 3 different times over the 
1033 
course of the exam (including during assessment of IXT control). 
1034 
2. Decrease in near stereoacuity of at least 2 levels from baseline, or to nil, measured using 
1035 
the Randot Preschool Stereotest. 
1036 
 Reduction of Distance Visual Acuity 
1037 
Any cases of 1) interocular difference ≥0.3 logMAR and 2) reduced visual acuity in best 
1038 
refractive correction (≥0.3 logMAR) in either eye will be tabulated by treatment group at 3 
1039 
months. 
1040 
 Diplopia 
1041 
After 3 months, any new cases of diplopia ‘Sometimes’ or ‘All the Time’, based on response to 
1042 
item 8 from the IXT symptom survey (asked as a single question for children ages 3 and 4 years 
1043 
of age) will be tabulated for each treatment group. In addition, diplopia occurring ‘Never’, 
1044 
‘Sometimes’, or ‘All the Time’ will also be tabulated for each treatment group.  
1045 
 
1046 
7.10 Patching Adherence 
1047 
Patching adherence (as reported by the parent) will be tabulated at the 3-month visit for the FT 
1048 
patching treatment group, as will reasons for any major deviations. 
1049 
7.11 Additional Tabulations and Analyses 
1050 
The following tabulations and analyses will be performed: 
1051 
• A flow chart accounting for all participants according to treatment group  
1052 
• Visit completion rates according to treatment group 
1053 
• Baseline demographics and clinical characteristics overall and by treatment group at 
1054 
randomization 
1055 
• Protocol deviations according to treatment group 
 
1056 

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Chapter 8: Data Collection and Monitoring 
1057 
8.1 Case Report Forms and Other Data Collection 
1058 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1059 
collected in electronic case report forms, this will be considered the source data. For any data 
1060 
points for which the eCRF is not considered source (e.g., lab results that are transcribed from a 
1061 
printed report into the eCRF), the original source documentation must be maintained in the 
1062 
participant’s study chart or medical record. This source must be readily verifiable against the 
1063 
values entered into eCRF. Even where all study data are directly entered into the eCRFs at office 
1064 
visits, evidence of interaction with a live participant must be recorded (e.g., office note, visit 
1065 
record, etc.). 
1066 
Electronic device data files are obtained from the study software and individual hardware 
1067 
components. These electronic device files are considered the primary source documentation. 
1068 
Each participating site will maintain appropriate medical and research records for this trial, in 
1069 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1070 
confidentiality of participants. 
1071 
 
1072 
8.2 Study Records Retention 
1073 
Study documents should be retained for a minimum of 3 years after completion of the final grant 
1074 
reporting. These documents should be retained for a longer period, however, if required by local 
1075 
regulations. No records will be destroyed without the written consent of the sponsor, if 
1076 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
1077 
no longer need to be retained. 
1078 
 
1079 
8.3 Quality Assurance and Monitoring 
1080 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1081 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1082 
conducted and data are generated, documented and reported in compliance with the protocol 
1083 
adhering to Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as 
1084 
to ensure that the rights and wellbeing of trial participants are protected and that the reported trial 
1085 
data are accurate, complete, and verifiable. Adverse events will be prioritized for monitoring. 
1086 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1087 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1088 
Investigations — A Risk-Based Approach to Monitoring” (August 2013). This plan describes in 
1089 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1090 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1091 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1092 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1093 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1094 
verity and completeness of the key site data.  
1095 
 
 
1096 

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Elements of the RBM may include: 
1097 
• Qualification assessment, training, and certification for sites and site personnel 
1098 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1099 
procedures 
1100 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1101 
review of entered data and edits, statistical monitoring, study closeout 
1102 
• On-site monitoring (site visits): source data verification, site visit report 
1103 
• Agent/Device accountability 
1104 
• Communications with site staff 
1105 
• Patient retention and visit completion 
1106 
• Quality control reports 
1107 
• Management of noncompliance 
1108 
• Documenting monitoring activities 
1109 
• Adverse event reporting and monitoring 
1110 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1111 
order to maintain current and personal knowledge of the study through review of the records, 
1112 
comparison with source documents, observation and discussion of the conduct and progress of 
1113 
the study. The investigational site will provide direct access to all trial related sites, source 
1114 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1115 
inspection by local and regulatory authorities. 
1116 
 
1117 
8.4 Protocol Deviations 
1118 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1119 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
1120 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
1121 
and implemented promptly. 
1122 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
1123 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1124 

 
IXT7PROTV1.0_19APR2022 
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Chapter 9:  Ethics/Protection of Human Participants 
1125 
9.1 Ethical Standard 
1126 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1127 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1128 
21 CFR Part 56, and/or the ICH E6. 
1129 
 
1130 
9.2 Institutional Review Boards 
1131 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1132 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1133 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1134 
require review and approval by the IRB before the changes are implemented to the study. All 
1135 
changes to the consent form will be IRB approved; a determination will be made regarding 
1136 
whether previously consented participants need to be re-consented. 
1137 
 
1138 
9.3 Informed Consent Process 
1139 
 Consent Procedures and Documentation 
1140 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1141 
the study and continues throughout the individual’s study participation. Extensive discussion of 
1142 
risks and possible benefits of participation will be provided to the participants and their families. 
1143 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1144 
document. The investigator will explain the research study to the participant and answer any 
1145 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1146 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1147 
research participants. Participants will have the opportunity to carefully review the written 
1148 
consent form and ask questions prior to signing. 
1149 
The participants should have the opportunity to discuss the study with their surrogates or think 
1150 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1151 
prior to any procedures being done specifically for the study. The participants may withdraw 
1152 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1153 
will be given to the participants for their records. The rights and welfare of the participants will 
1154 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1155 
affected if they decline to participate in this study. 
1156 
 Participant and Data Confidentiality 
1157 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1158 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1159 
samples and genetic tests in addition to the clinical information relating to participants. 
1160 
Therefore, the study protocol, documentation, data, and all other information generated will be 
1161 
held in strict confidence. No information concerning the study or the data will be released to any 
1162 
unauthorized third party without prior written approval of the sponsor. 
1163 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1164 
regulatory agencies or company supplying study product may inspect all documents and records 
1165 
required to be maintained by the investigator, including but not limited to, medical records 
1166 

 
IXT7PROTV1.0_19APR2022 
PAGE 46 OF 50 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
1167 
study site will permit access to such records. 
1168 
The study participant’s contact information will be securely stored at each clinical site for 
1169 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1170 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1171 
sponsor requirements. 
1172 
Study participant research data, which is for purposes of statistical analysis and scientific 
1173 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research. This will not 
1174 
include the participant’s contact or identifying information. Rather, individual participants and 
1175 
their research data will be identified by a unique study identification number. The study data 
1176 
entry and study management systems used by clinical sites and by Jaeb Center for Health 
1177 
Research staff will be secured and password protected.  
1178 
At the end of the study, all study databases will be de-identified and archived at the Jaeb Center 
1179 
for Health Research. 
1180 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1181 
obtained from the NIH. This certificate protects identifiable research information from forced 
1182 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1183 
disclose identifying information on research participation in any civil, criminal, administrative, 
1184 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1185 
researchers and institutions from being compelled to disclose information that would identify 
1186 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1187 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1188 
 Future Use of Data 
1189 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research. 
1190 
After the study is completed, the de-identified, archived data will be made available to the 
1191 
public. 
1192 

 
IXT7PROTV1.0_19APR2022 
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Chapter 10: References 
1193 
1. 
Govindan M, Mohney BG, Diehl NN, Burke JP. Incidence and types of childhood 
1194 
exotropia: A population-based study. Ophthalmology. 2005;112(1):104-108. 
1195 
2. 
Friedman DS, Repka MX, Katz J, et al. Prevalence of amblyopia and strabismus in white 
1196 
and African American children aged 6 through 71 months. The Baltimore Pediatric Eye 
1197 
Disease Study. Ophthalmology. 2009;116(11):2128-2134. 
1198 
3. 
Nusz KJ, Mohney BG, Diehl NN. Female predominance in intermittent exotropia. Am J 
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