Intermittent Exotropia Study 6: A Pilot Randomized Clinical Trial of Base-in Prism Spectacles for Intermittent Exotropia
Phase: NA
Conditions: Exotropia Intermittent
Sponsor: Jaeb Center for Health Research

 
IXT6 Pilot Study Protocol v1.0 29May2019 
 
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INTERMITTENT EXOTROPIA STUDY 6 
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(IXT6) 
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A Pilot Randomized Clinical Trial of Base-in 
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Prism Spectacles for Intermittent Exotropia 
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PROTOCOL 
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Version 1.0 
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May 29, 2019 
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IXT6 Pilot Study Protocol v1.0 29May2019 
 
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CONTACT INFORMATION  
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COORDINATING CENTER 
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Danielle L. Chandler MSPH (Coordinating Center Principal Investigator) 
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Jaeb Center for Health Research 
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15310 Amberly Drive, Suite 350 
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Tampa, FL 33647 
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Phone (888) 79PEDIG or (813) 975-8690 
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Fax (888) 69PEDIG or (813) 975-8761 
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PROTOCOL CHAIRS 
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David G. Morrison, M.D. 
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Department of Ophthalmology and Visual Sciences 
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Vanderbilt University Medical Center 
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1211 Medical Center Drive 
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Nashville, TN 37232 
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Phone 615-936-1035 
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Email: david.morrison.1@vanderbilt.edu 
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Allison I. Summers, O.D., M.C.R. 
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Casey Eye Institute 
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Oregon Health & Science University 
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3375 SW Terwilliger Blvd 
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Portland, OR 97239 
 
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Phone: 503-494-7830 
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Fax: 503-494-5372 
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Email: summersa@ohsu.edu 
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TABLE OF CONTENTS 
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CHAPTER 1 BACKGROUND AND SUMMARY......................................................................................................... 1-1 
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1.1 
Intermittent Exotropia............................................................................................................................. 1-1 
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1.2 
Prism Treatment for IXT ........................................................................................................................ 1-1 
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1.3 
Previous Studies of Prism Therapy for IXT ........................................................................................... 1-1 
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1.4 
Possible Mechanisms of Prism Therapy ................................................................................................. 1-2 
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1.5 
Methods of Prescribing Prism for IXT ................................................................................................... 1-2 
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1.6 
Potential Problems with Prescribing Corrective Prism ........................................................................... 1-3 
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1.7 
Potential Problems with Prescribing Customized Prism......................................................................... 1-3 
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1.8 
Prism Adaptation .................................................................................................................................... 1-3 
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1.9 
Determining the Dose of Prism for the Current Study ........................................................................... 1-4 
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1.10 
Public Health Importance of Proposed Randomized Clinical Trial ........................................................ 1-4 
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1.11 
Questions Related to Prism Therapy ...................................................................................................... 1-4 
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1.12 
Definitions of Treatment Response ........................................................................................................ 1-4 
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1.13 
Timing of Intervention, Outcome for Current Study .............................................................................. 1-5 
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1.14 
Study Objective ...................................................................................................................................... 1-5 
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1.15 
Synopsis of Study Design ....................................................................................................................... 1-5 
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1.16 
Study Flow Chart .................................................................................................................................... 1-8 
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CHAPTER 2 ENROLLMENT AND RANDOMIZATION ........................................................................................... 2-1 
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2.1 
Eligibility Assessment and Informed Consent/Assent ............................................................................ 2-1 
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2.2 
Eligibility Criteria for Enrollment .......................................................................................................... 2-1 
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2.3 
Historical Information ............................................................................................................................ 2-3 
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2.4 
Testing at the Enrollment Exam ............................................................................................................. 2-3 
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2.5 
Confirmation of Eligibility and Completion of Enrollment.................................................................... 2-6 
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2.6 
Prism Adaptation Test Screening ........................................................................................................... 2-6 
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2.6.1 
Prism Adaptation Test ....................................................................................................................... 2-6 
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2.7 
Eligiblity for Randomization .................................................................................................................. 2-6 
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2.8 
Randomization ........................................................................................................................................ 2-8 
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CHAPTER 3 TREATMENT AND FOLLOW-UP ......................................................................................................... 3-1 
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3.1 
Treatment for Prism Group ..................................................................................................................... 3-1 
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3.2 
Treatment for Non-prism Group ............................................................................................................. 3-1 
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3.3 
Post-Randomization Criteria for Refractive Error Correction ................................................................ 3-1 
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3.4 
Follow-up Visit Schedule ....................................................................................................................... 3-2 
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Telephone Call ........................................................................................................................................ 3-2 
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3.6 
Masked Examiner Testing ...................................................................................................................... 3-2 
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3.7 
Outcome Visit Testing Procedures ......................................................................................................... 3-2 
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3.8 
Additional Visits ..................................................................................................................................... 3-5 
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3.9 
Surgical or Non-Surgical Treatment ....................................................................................................... 3-5 
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3.10 
Treatment of Amblyopia ........................................................................................................................ 3-5 
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3.11 
Management of Refractive Error ............................................................................................................ 3-5 
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CHAPTER 4 MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ............................................................... 4-1 
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4.1 
Contacts by the Jaeb Center for Health Research and Sites ................................................................... 4-1 
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4.2 
Participant Withdrawals ......................................................................................................................... 4-1 
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4.3 
Risks ....................................................................................................................................................... 4-1 
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4.3.1 
Risks of Examination Procedures ...................................................................................................... 4-1 
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4.3.2 
Risk of Prism Therapy ....................................................................................................................... 4-1 
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4.3.3 
Risk Assessment ................................................................................................................................ 4-1 
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4.4 
Reporting Adverse Events ...................................................................................................................... 4-1 
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4.5 
Discontinuation of Study ........................................................................................................................ 4-2 
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4.6 
Travel Reimbursement ........................................................................................................................... 4-2 
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Study Costs ............................................................................................................................................. 4-2 
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4.8 
General Considerations  .......................................................................................................................... 4-2 
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CHAPTER 5 SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS ...................................................... 5-1 
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Sample Size ............................................................................................................................................ 5-1 
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Primary Analysis .................................................................................................................................... 5-1 
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5.2.1 
Decision Guideline for Determining Whether to Proceed to a Randomized Trial ............................. 5-1 
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5.3 
Secondary Analysis -- Distance Control ................................................................................................. 5-2 
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Secondary Analysis – No Spontaneous Tropia ....................................................................................... 5-2 
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Additional Analyses ............................................................................................................................... 5-2 
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5.5.1 
Change in Distance Control ............................................................................................................... 5-2 
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5.5.2 
Near Control ...................................................................................................................................... 5-2 
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5.5.3 
Ocular Alignment .............................................................................................................................. 5-3 
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5.5.4 
Near Stereoacuity ............................................................................................................................... 5-3 
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5.5.5 
Suppression ........................................................................................................................................ 5-3 
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5.5.6 
Fusional Convergence........................................................................................................................ 5-3 
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5.5.7 
Adverse Symptoms of Intermittent Exotropia and Prism Spectacle Wear......................................... 5-3 
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5.5.8 
Distance Visual Acuity ...................................................................................................................... 5-3 
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5.5.9 
Compliance of Spectacle Wear .......................................................................................................... 5-4 
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5.5.10 
Alternative Approach to Primary Analysis ........................................................................................ 5-4 
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5.5.11 
Mean Distance Control in Subgroups ................................................................................................ 5-4 
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5.5.12 
Masking Assessment.......................................................................................................................... 5-4 
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5.6 
Sample Size and Analysis for Prism Adaptation Testing Screening Study ............................................ 5-4 
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CHAPTER 6 REFERENCES ........................................................................................................................................... 6-1 
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CHAPTER 1 BACKGROUND AND SUMMARY 
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This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is 
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funded through a cooperative agreement from the National Eye Institute.  It is one of a series of 
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randomized trials and observational studies conducted by PEDIG that address management of 
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intermittent exotropia (IXT) in children. 
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1.1 
Intermittent Exotropia 
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The most common type of childhood-onset exotropia is IXT,1-4 with a reported incidence of 
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32.1/100,000,1 occurring more frequently in females5 and in Asian children.4, 6, 7 IXT is a term 
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used to describe several subgroups of intermittent exodeviations, namely basic, true divergence 
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excess, pseudo divergence excess, and convergence insufficiency IXT. Many cases of 
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exodeviations are characterized by an exotropia that occurs primarily for distance viewing, but 
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may also be present at near. Normal binocular single vision and normal stereoacuity are usually 
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present at near when the exotropia is controlled, although stereoacuity can be reduced in about 
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25% of cases.8, 9 
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The current management of IXT includes observation as well as surgical and non-surgical 
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interventions.8 Many practitioners treat IXT patients using non-surgical approaches such as part-
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time patching, over-minus lenses, vision therapy10, 11 or prism.12, 13  
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1.2 
Prism Treatment for IXT 
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One non-surgical treatment for IXT is base-in corrective or relieving prism,14, 15 which eliminates 
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or reduces the convergence demand, respectively. Corrective prism is a term used when the full 
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angle of deviation is corrected with prism while relieving prism provides prism correction less 
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than the full angle of deviation.  Although corrective base-in prism for IXT has been reported to 
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have a favorable treatment benefit in two small retrospective studies,12, 13 its clinical 
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effectiveness (either using corrective or relieving prism) has not yet been studied prospectively 
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in either randomized or non-randomized controlled trials. 
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1.3 
Previous Studies of Prism Therapy for IXT 
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While many studies have reported use of prism as part of a multi-faceted non-surgical treatment 
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approach and adjunct to surgical treatment of strabismus in general, we are aware of only two 
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small studies that have evaluated corrective prism alone as an intervention specifically for IXT:  
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Pratt-Johnson and Tillson 197912  
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Twenty-five children (aged 2-8 years) with small-angle (<20Δ) IXT were evaluated 
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retrospectively, 13 of whom had undergone previous surgery but had residual or recurrent IXT. 
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Spectacles were prescribed with base-in prism (typically Fresnel Press-On prism that was 
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generally split evenly between the eyes) that fully corrected the maximum angle of deviation. Six 
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of 25 never obtained their prism spectacles and 7 of 25 wore them < 50% of the time, and these 
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patients (total n=13) were used as a pseudo-control group. The other 12 patients wore their prism 
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spectacles >50% of awake hours for 12 months to 2.5 years (8 of 12 had undergone previous 
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surgery). Prism was discontinued for 1 month and outcomes were evaluated.  
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The outcome was “cure,”  defined by the authors as meeting all of the following criteria: 1) no 
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monocular eye closure in sunlight; 2) no manifest tropia at any distance; 3) 40 arc secs of 
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stereopsis on the Wirt test; 4) divergence amplitudes ≥ 5Δ on the synotophore (major 
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amblyoscope) using a foveal fusion target; 5) recognition of diplopia immediately when the 
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divergence amplitude was exceeded; 6) good convergence amplitude; and 7) total convergence 
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and divergence amplitudes > 20Δ in the synotophore (major amblyoscope) or in free space with 
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prisms.  
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Results: Eight of 12 patients (67%) in the prism group met criteria for cure (2 of 4 with 
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previously un-operated IXT and 6 of 8 with previously operated IXT). None of the 13 patients in 
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the pseudo control group met criteria for cure.  However, it is important to recognize that this 
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was not a true control group, and it is unknown if additional clinical factors were present that 
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limited patient compliance. 
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Véronneau-Troutman et al 197613 
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The authors retrospectively evaluated 14 patients (average age of 8.3 years; range 3 to 26 years) 
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with IXT (mean angle of deviation 26.4Δ, range 12-45Δ), treated with Fresnel prisms (fully 
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correcting the average of distance and near horizontal deviation plus any vertical). Average 
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duration of treatment was 3.7 months and outcomes were assessed out of prism (time out of 
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prism not provided).  
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Results: Control of the IXT was reported to be improved (some changed from constant XT to 
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either IXT or exophoria, some changed from IXT to exophoria), the angle of deviation decreased 
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on average by 4.6∆, and mean convergence amplitudes improved by 6.2∆ at distance and 9.3∆ at 
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near.  
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While the prism amounts prescribed in the aforementioned studies were fully “corrective” (prism 
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power equaled the exodeviation angle), it was stated that the prism amount was often a mean of 
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near and distance deviations.   
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In contrast to fully corrective prism, Vérnonneau-Troutman subsequently suggested in her 
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textbook on prisms that “the minimum power necessary to achieve control of the exodeviation at 
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distance” should be prescribed.16  Others also recommend that the minimum “relieving” prism 
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that provides improved sensorimotor fusion (e.g., control, suppression, stereopsis) be 
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prescribed.14, 15   
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1.4 
Possible Mechanisms of Prism Therapy  
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Whether relieving or correcting prism is used, the mechanism for improvement of IXT with 
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prism therapy is largely unknown. In the short term, prism may improve the ability of the child 
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to control the exodeviation by reducing or eliminating the fusional convergence demand 
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necessary to align the eyes (less convergence is required for bifoveal stimulation with the prism 
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than without). In the longer term, prism therapy for IXT may benefit the individual by increasing 
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the time of fusion and perhaps weakening suppression, leading to an improvement in the ability 
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to control the exodeviation.12 The majority of patients with IXT typically have normal sensory 
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fusion and reduced compensating fusional convergence ability,14-16 and therefore the adage that 
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“sensory fusion is the best orthoptics” forms the basis for this treatment; the anticipation is that 
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better sensory fusion will encourage the development of better motor control.17  
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1.5 
Methods of Prescribing Prism for IXT 
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There is currently no universally accepted formula or method for determining the optimal prism 
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treatment for patients with IXT.  The amount of prism prescribed to treat IXT in previous studies 
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and in clinical practice varies and is based on 3 philosophical approaches:  
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1.  Corrective prism is prescribed for the full angle of deviation. 
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2. Customized prism: the minimum prism required to comfortably improve fusion (e.g., 
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better control, change of diplopia or suppression response to a fusion response on testing, 
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decrease in the frequency of the IXT based on cover-uncover testing).  This approach 
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could result in corrective or relieving prism being prescribed, albeit for IXT, the 
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customized approach usually results in relieving prism and rarely in corrective prism. 
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3. A fixed amount of relieving prism (e.g., always prescribe 5∆ or 10∆) or a prism 
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magnitude that is a percentage of the maximum exodeviation: The percentage of the 
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deviation to correct is typically 33% to 50% of the maximum deviation18 and is usually 
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divided equally between the two eyes.14, 18  
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Regardless of which method is used to determine the amount, prism can be prescribed by adding 
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Fresnel Press-On prism to spectacles or grinding prism into the lenses, Although Fresnel prism is 
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a treatment option, most patients prefer ground-in prism because of better cosmetic appearance 
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and improved clarity of vision.  
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1.6 
Potential Problems with Prescribing Corrective Prism 
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Corrective prism is typically prescribed by dividing the total prism deviation and placing half as 
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base-in prism in front of each eye to encourage bifoveal fusion.  Despite these attempts to induce 
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bifoveal stimulation, one can argue that this situation may not be ideal for patients who continue 
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to suppress when fully aligned.  In such cases, it is possible that the prisms either would have no 
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benefit to the long term improvement of control of the IXT or prism adaptation could occur.18 
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Additionally, the use of corrective prism is less practical in larger deviations as more optical 
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aberrations may occur with larger prism magnitudes, in addition to the spectacle lenses being 
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larger and heavier.  
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1.7 
Potential Problems with Prescribing Customized Prism 
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Another approach to prescribing prism for treatment of IXT is a customized approach, where the 
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amount of base-in prism to prescribe is the minimum amount of prism that is required to 
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comfortably improve some aspect of sensorimotor fusion (e.g., better control, change of diplopia 
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or suppression response to a fusion response on testing, decrease the frequency of the IXT based 
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on cover-uncover testing, increase in stereoacuity) as determined by testing in the office.  
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Because of the variable nature of IXT, the amount of prism magnitude needed for an individual 
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patient might vary from one moment to another. In addition, this approach is quite dependent on 
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the subjective interpretation of the examiner. Finally, prism adaptation could occur for relieving 
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prism as well, thus increasing the magnitude of the deviation.  For these reasons, a customized 
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method of prescribing prism for IXT is not conducive to a standardized study protocol. 
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1.8 
Prism Adaptation 
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Prism adaptation is a term that describes sensorimotor adaptation to prism treatment and can be 
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part of the normal vergence system.19  However, when prisms are placed to correct the angle of 
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deviation in some patients, especially with acquired esotropia, the patient “adapts” to the prism 
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in place, thus effectively making the deviation larger.  The Prism Adaptation Study demonstrated 
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greater surgical success in patients with acquired esotropia when the larger, prism-adapted, angle 
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was targeted for surgery.20 
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This same phenomenon has been observed clinically in other types of strabismus as well.  It is 
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possible that patients with IXT could prism adapt to a larger angle when base-in prism is used as 
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treatment for IXT.  Because the proposed benefit of prism therapy for IXT is increased time of 
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bifoveal fusion, patients who fully prism-adapt to the prescribed base-in prism (no improvement 
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in the angle with the prism in place), would not be expected to have any treatment benefit, and so 
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will be excluded in this study. Whereas patients who do not prism-adapt, or only partially prism-
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adapt (a smaller residual angle in prism, compared with before prism), are hypothesized to 
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improve. 
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1.9 
Determining the Dose of Prism for the Current Study 
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The consensus of the Planning Committee was to prescribe relieving prism.  This decision was 
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based primarily on the clinical experience of the Planning Committee.  Consensus was reached 
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to prescribe a base-in prism magnitude that was 40% of the largest exodeviation at distance or 
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near for a maximum eligible exodeviation of 35∆ at both distance and near. This amount of 
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relieving prism was determined based on Caloroso’s residual vergence demand guidelines,14 
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prism guidelines from Roper-Hall,18 and expert opinion. Given the maximum deviation of 35∆, 
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the largest magnitude of prism to be prescribed will be 14∆ (7∆ for each eye). This magnitude of 
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ground-in prism was agreed to be feasible in terms of appearance, weight, and optical 
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aberrations.  The minimum prism dose would be 6∆ (3∆ for each eye) based on the study-defined 
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exodeviation of at least 16∆ at distance. 
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1.10 
Public Health Importance of Proposed Randomized Clinical Trial  
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Although prism treatment for IXT is used in clinical practice by some eye care providers, there 
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have been no randomized clinical trials evaluating its effectiveness.  If prism treatment can 
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successfully restore binocular alignment and facilitate improved control of the IXT without the 
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need for surgery or office visits for other treatments, there potentially would be a significant cost 
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savings. On the other hand, evidence that prism treatment for IXT is not effective would reduce 
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the utilization of this treatment, allowing children to receive more effective treatments with less 
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delay and avoiding the cost of unnecessary glasses.  
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1.11 
Questions Related to Prism Therapy 
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There have been no rigorous studies that address the following important questions related to 
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prism therapy: 
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1. Does prism therapy have an initial short-term therapeutic effect on IXT while wearing 
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prism (over a number of weeks)? 
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2. Does prism therapy continue to have a long-term therapeutic benefit for IXT while 
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wearing prism spectacles (over many months or years)? 
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3. Does prism therapy have a long-term therapeutic effect for IXT when prism spectacles 
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are tapered and discontinued? 
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In the initial planning stages of the study we considered a full-scale RCT to address these 
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questions, likely comparing prism therapy to non-prism spectacles. On further discussion, it 
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became apparent that the lack of published data using relieving prism therapy lends itself to the 
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need for a pilot study to answer question 1 prior to moving forward with questions 2-3.  As a first 
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step, we determined that a pilot study was needed to evaluate whether there is a short-term 
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therapeutic treatment effect while wearing base-in relieving prism over a period of weeks, noting 
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that if there is not a treatment effect in the short-term, then a long-term benefit would not be 
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expected. 
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1.12 
Definitions of Treatment Response 
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Previous PEDIG studies have used a “control score” (the proportion of time that the deviation is 
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manifest) to judge improvement or worsening of IXT or response to treatment.21-24 A single 
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control score has been found to be highly variable.25 26 Due to this variability, a more adequate 
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representation of control during the day can better be achieved by measuring the “triple control 
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score,”26 which is a mean of 3 control measures obtained at various times during an examination.   
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Because the purpose of the treatment of IXT with prism spectacles is to better align the eyes for a 
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greater proportion of time, and single binocular vision with high grade stereoacuity is associated 
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with good ocular alignment, it is reasonable to primarily focus on “control” of the distance 
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deviation as the first step in evaluating the effectiveness of prism treatment as in prior overminus 
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studies (IXT3, IXT5).23   
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1.13 
Timing of Intervention, Outcome for Current Study  
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To evaluate the initial response to prism spectacles, this 8-week pilot randomized clinical trial 
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(RCT) is proposed.  If a reasonable initial response without significant adverse effects is found, a 
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subsequent full-scale RCT would evaluate the long-term effectiveness of prism (e.g., over 1 
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year) and then evaluate the subsequent effectiveness of maintaining control after the prism 
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treatment has been discontinued (e.g., 6 months after discontinuation of prism). This approach 
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was successfully used previously to explore overminus spectacles as a treatment for IXT through 
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an 8-week pilot RCT (IXT3), followed by a full-scale longer RCT to evaluate the long-term 
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effectiveness on treatment and after discontinuation of treatment (IXT5).  
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1.14 
Study Objective 
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The objective of this short-term, pilot randomized trial comparing spectacles with relieving 
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prism to spectacles without prism is to determine whether to proceed to a full-scale, longer-term 
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randomized trial. This decision will be based primarily on assessing the initial (8-week) 
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response to prism by comparing treatment groups on the following outcomes: 
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 Mean distance IXT control score (the mean of 3 control scores) (primary outcome) 
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 The proportion of participants demonstrating a “treatment response,” defined as ≥1 point 
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improvement in the mean distance IXT control score without spontaneous exotropia during 
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control testing (secondary outcome) 
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 The proportion of participants reporting adverse effects and good/excellent spectacle wear 
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compliance 
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1.15 
Synopsis of Study Design 
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Major Eligibility Criteria for Enrollment (see section 2.2 for a complete listing) 
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 Age 3 to < 13 years  
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 Intermittent exotropia meeting all of the following criteria: 
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o Mean distance control score of ≥2.00 points with at least 1 measure of 3, 4, or 5 
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points (i.e, spontaneous tropia) from the 3 assessments during the exam 
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o A near control score ≤4 on at least 1 of 3 assessments (cannot have score of 5, 5, 5) 
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o Distance exodeviation between 16∆ and 35∆ (inclusive) by PACT 
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o Near exodeviation between 10∆ and 35∆ (inclusive) by PACT 
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o Near deviation does not exceed distance deviation by more than 10∆ by PACT (i.e., 
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convergence insufficiency-type IXT excluded) 
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 No dissociated vertical deviation (DVD) 
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 No vertical deviation >3∆ in primary gaze at distance or near  
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 No patterns (such as an “A” or “V” pattern) with a downgaze measurement of >10∆ 
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difference from straight ahead by PACT, measured per investigator’s routine method 
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 No treatment for IXT or amblyopia (other than refractive correction) within the past 4 
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weeks, including vision therapy, orthoptics, patching, atropine, or other penalization 
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 No substantial overminus spectacles (spectacles overminused by more than 1.00D SE than 
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the most recent cycloplegic refraction and ALSO results in minus SE power in the 
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spectacles; underplussing is allowed) within the past 4 weeks   
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 No prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
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 No previous use of prism spectacles 
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 Refractive error between -6.00D spherical equivalent (SE) and +2.50D SE (inclusive)  
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(based on a cycloplegic refraction performed within 7 months but prior to the day of  
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enrollment)  
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 Refractive correction (must be worn for at least 1 week if refractive error meets any of the 
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following (based on a cycloplegic refraction performed within 7 months but prior to the day 
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of enrollment):  
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o SE anisometropia ≥1.00D 
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o Astigmatism ≥1.00D in either eye 
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o SE myopia ≥-0.50D in either eye 
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 If spectacles have been prescribed and are worn, they must meet the following pre-
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enrollment criteria: 
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o SE anisometropia corrected to within 1.00D of full SE anisometropic difference 
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o Astigmatism corrected to within 1.00D of full magnitude; axis within 10 degrees if 
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astigmatism ≤1.00D and axis within 5 degrees if astigmatism >1.00D 
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Additional Eligibility Criteria for Randomization Based on Prism Adaptation Testing  
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 Exodeviation by PACT while wearing “trial” relieving prism for 30 minutes is smaller at 
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distance or near than measured during initial testing (e.g. not fully adapting to prism at both 
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distances) 
404 
 No new esotropia on cover test at near while wearing “trial” relieving prism for 30 minutes, 
405 
compared with enrollment measurement taken without prism   
406 
 No esodeviation >6∆ on PACT at near while wearing “trial” relieving prism for 30 minutes 
407 
 
408 
Sample size 
409 
Up to 100 participants will be enrolled for same-day prism adaptation testing until up to 64 
410 
participants meeting the randomization eligibility criteria based on the prism adaptation test are 
411 
randomized (32 per treatment group). 
412 
 
413 
Treatment Groups 
414 
Randomization (1:1) to the following groups:  
415 
 Prism Group: Spectacles with refractive correction AND base-in relieving prism (40% of the 
416 
greater of the exodeviation by PACT at distance or near) equally divided between the 2 
417 
lenses 
418 

 
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1-7 
 Non-prism Group: Spectacles with refractive correction (or plano spectacles if no significant 
419 
refractive error) and no prism 
420 
 
421 
Visit Schedule  
422 
 Enrollment Visit 
423 
 If eligible, Randomization (same day as enrollment visit or within 7 days)  
424 
 3-week phone call (21 to 28 days) after randomization  
425 
 Outcome Exam: 8 weeks (± 2 weeks) after randomization  
426 
 
427 
 
428 
Testing Procedures  
429 
Distance and near control of IXT (3 measurements), near stereoacuity, distance and near cover 
430 
test, and distance and near PACT will be measured by a study-qualified examiner at enrollment, 
431 
and by a Masked Examiner at 8 weeks.  The prism adaptation test will be assessed by a study-
432 
qualified examiner at enrollment. Distance visual acuity, fusional convergence amplitude, and 
433 
suppression will be assessed by a study-qualified examiner at both visits.  In addition, symptoms 
434 
of headache, eye strain, dizziness, nausea, and problems with spectacle wear will be assessed at 
435 
both visits. 
436 
 
437 
Primary Analysis 
438 
 A comparison of mean distance control scores (mean of 3 assessments over the exam) 
439 
between the prism group and the non-prism group at 8 weeks. 
440 
 
441 
Secondary Analyses 
442 
 A comparison of the proportion of participants showing a “treatment response,” defined as an 
443 
improvement of ≥1 point in distance control (mean of the 3 assessments over the exam) 
444 
between enrollment and 8 weeks. 
445 
 A comparison of the proportion of participants showing no spontaneous tropia during control 
446 
testing at the outcome exam. 
447 
  
448 
Ancillary Screening Study/Analysis 
449 
 As part of screening for participants who are eligible for the randomized trial, an ancillary 
450 
study of prism adaptation testing will evaluate the initial response to relieving prism in the 
451 
amount which would be prescribed if the participant were randomized to the prism group.  
452 
The objective is to define the proportion of participants who fully prism adapt after 30 
453 
minutes of wearing “trial” relieving prism, defined as no reduction in magnitude of deviation 
454 
by PACT when measured in relieving prism at both distance and near compared with the 
455 
original deviation measured without relieving prism. 
456 
 
 
457 

 
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1-8 
1.16 
Study Flow Chart
458 
 
459 
Participant does NOT meet all 
eligibility criteria or does not complete 
all required testing 
 
Do not proceed – participant not eligible 
Participant meets all eligibility criteria 
AND completes all required testing 
 
Complete Enrollment and  
continue to Prism Adaptation Test 
Major Eligibility 

Ages 3 to < 13 years 

IXT (manifest deviation) meeting all of the following criteria: 
o
IXT or constant XT at distance (mean distance control score of 2.0 or more) and with at 
least 1 measure of 3, 4 or 5) 
o
IXT or exophoria at near (no control score of 5 on all 3 near assessments) 
o
Distance deviation between 16∆ and 35∆ by PACT 
o
Near deviation between 10∆ and 35∆ by PACT 
o
Near deviation does not exceed distance by more than 10∆ by PACT 

No dissociated vertical deviation  (DVD) 

No vertical >3∆ in primary gaze at distance, or near  

No pattern (such as “A” or “V”) with a downgaze measurement of >10∆ difference from 
straight ahead (by PACT using investigator’s routine method) 

No previous non-surgical treatment for IXT within the past 4 weeks (other than refractive 
correction), including vision therapy, patching, atropine, or substantial overminus spectacles, 
defined as spectacles overminused by more than 1.00D SE than the cycloplegic refractive error 
and ALSO results in minus SE power in the spectacles (i.e. underplussing is allowed)   

No prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 

No prior use of prism spectacles 

Cycloplegic refraction within 7 months of enrollment (but prior to the day of enrollment)  

Refractive error between -6.00D SE and +2.50D SE (inclusive) (based on a cycloplegic 
refraction performed within 7 months, but prior to the day of enrollment)  

Distance visual acuity (any optotype) in both eyes according to age normal values as follows:   
o
20/50 or better for 3- to <4-year olds  
o
20/40 or better for 4- to <5-year olds 
o
20/32 or better for 5- to <7-year olds 
o
20/25 or better for ≥7-year olds 

Interocular difference of distance visual acuity 2 lines 

Must be wearing refractive correction (pre-study spectacles) for at least 1 week if refractive 
error (based on cycloplegic refraction performed within 7 months) meets any of the following:  
o
SE anisometropia ≥1.00D 
o
Astigmatism ≥1.00D in either eye 
o
SE myopia ≥-0.50D in either eye 

If spectacles are worn, they must meet the following pre-enrollment criteria: 
o
SE anisometropia corrected within 1.00D of full SE anisometropic difference 
o
Astigmatism corrected within 1.00D of full magnitude; axis within 10 degrees if 
≤1.00D and within 5 degrees if >1.00D 
o
No overminus (i.e., no more than 1.00D more minus SE than full SE if also resultant 
minus SE) 
o
No overplus (i.e., no more than 1.00D more plus SE than the full SE) 
  
Enrollment Exam Testing Procedures  

Lensometry 

Symptom survey and spectacle surveys 

IXT control assessment #1(distance and near) 

Randot Preschool stereoacuity at near 

IXT control assessment #2 (distance and near) 

Cover Test (distance and near) 

Prism and Alternate Cover Test (distance and near, distance with -2.00D lens for AC/A) 

IXT control assessment #3 (distance and near) 

Fusional convergence amplitude testing (distance) 

Suppression assessment 

Distance visual acuity (any optotype)  

 
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00
460 
461 
Participant does NOT meet 
randomization criteria 
 
Do not randomize  
Participant follow-up ends 
Are all of the following criteria met while wearing “trial” relieving prism?  
 

Exodeviation by PACT is smaller at distance or near than measured during initial testing 

No NEW esotropia by cover test at near 

No esodeviation >6∆ on PACT at near 
Non-Prism Group 
Non-prism spectacles 
Prism Group 
Spectacles with base-in prism 
3-Week Phone Call 
Assess whether participant has received spectacles 
Randomization 
 YES 
 
Prism Adaptation Test  

30 min wearing relieving prism and refractive correction in trial frames 

While wearing prism in trial frames, retest  
o
Cover Test at near 
o
Prism and Alternate Cover Test (PACT) at distance and near  
8-Week  ( ± 2 weeks) Outcome Exam 
The following procedures are performed by someone other than the masked examiner: 

Lensometry 

Compliance assessment 

Symptom and spectacles surveys  
 
The following procedures must be performed by the Masked Examiner where indicated: 

IXT control assessment #1(Masked) (distance and near)  

Randot Preschool stereoacuity (Masked) 

IXT control assessment #2 (Masked) (distance and near)  

Cover Test (Masked) (distance and near) 

Prism and Alternate Cover Test (Masked) (distance and near) 

IXT control assessment #3 (Masked) (distance and near) 

Fusional convergence amplitude (distance)  

Suppression  

Distance visual acuity by same method used at enrollment   
 NO 

 
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CHAPTER 2 ENROLLMENT AND RANDOMIZATION 
462 
 
463 
2.1 
Eligibility Assessment and Informed Consent/Assent 
464 
A child is considered for the study after undergoing a routine eye examination (by a study 
465 
investigator as part of standard care) where an IXT is identified and the child appears to meet 
466 
the eligibility criteria for enrollment.  The study will be discussed with the child’s parent(s) or 
467 
guardian(s) (referred to subsequently as parent(s)).  Parent(s) who express an interest in the 
468 
study will be given a copy of the informed consent form to read.  Written informed consent 
469 
must be obtained from the parent prior to performing any study-specific procedures that are not 
470 
part of routine care. 
471 
 
472 
Participants aged 3 to <13 years with IXT who meet all eligibility criteria will be enrolled in 
473 
the study and will undergo same-day prism adaptation testing.  Depending on the results of the 
474 
prism adaptation test, participants will either enter the randomized trial or will end study 
475 
participation. Up to 100 participants will be enrolled in the study until at least 64 have been 
476 
randomized. As the randomization goal approaches, sites will be notified of the end date for 
477 
enrollment.  Participants whose parents have signed an informed consent form can be enrolled 
478 
and potentially randomized up until the end date, which means the randomization goal might 
479 
be exceeded.  The maximum number of participants who will be randomized is 80. 
480 
 
481 
2.2 
Eligibility Criteria for Enrollment 
482 
The following criteria must be met for the child to be enrolled in the study: 
483 
 
484 
Inclusion Criteria 
485 
 Age 3 to < 13 years  
486 
 Intermittent exotropia meeting all of the following criteria: 
487 
o Intermittent exotropia or constant exotropia at distance 
488 
 Mean distance control score of ≥2.0 points (mean of 3 assessments over the 
489 
exam) and with at least one measure of 3, 4, or 5, (spontaneous tropia) during 
490 
control testing 
491 
o Intermittent exotropia or exophoria at near 
492 
 Child cannot have a score of 5 points on all 3 near assessments of control 
493 
o Distance exodeviation at least 16∆ measured by PACT and no larger than 35∆ 
494 
o Near exodeviation at least 10∆ measured by PACT and no larger than 35∆ 
495 
o Near deviation does not exceed the distance deviation by more than 10∆ by PACT 
496 
(convergence insufficiency-type IXT excluded) 
497 
 Distance visual acuity (by any optotype method) in both eyes according to age normal 
498 
values27, 28 as follows:   
499 
o 20/50 or better for 3- to <4-year olds  
500 
o 20/40 or better for 4- to <5-year olds 
501 
o 20/32 or better for 5- to <7-year olds 
502 
o 20/25 or better for ≥7-year olds  
503 
 Interocular difference of distance visual acuity ≤ 2 lines (0.2 logMAR) 
504 
 Refractive error between -6.00D SE and +2.50D SE (inclusive) (based on a cycloplegic 
505 
refraction performed within 7 months but prior to the day of enrollment) 
506 
 Refractive correction (pre-study spectacles) worn for at least 1 week if refractive error 
507 
(based on cycloplegic refraction performed within 7 months) meets any of the following:  
508 
o SE anisometropia ≥1.00D 
509 

 
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o Astigmatism ≥1.00D in either eye 
510 
o SE myopia ≥-0.50D in either eye 
511 
 If spectacles are worn, they must meet the following pre-enrollment criteria: 
512 
o SE anisometropia corrected within <1.00D of full SE anisometropic difference 
513 
o Astigmatism corrected within <1.00D of full magnitude; axis within 10 degrees if 
514 
1.00D of astigmatism and within 5 degrees if >1.00D of astigmatism 
515 
 Gestational age ≥ 32 weeks 
516 
 Birth weight >1500 grams 
517 
 Parent understands the protocol and is willing to accept randomization to prism spectacles 
518 
or non-prism spectacles 
519 
 Parent has home phone (or access to phone) and is willing to be contacted by Jaeb Center 
520 
staff and Investigator’s site staff 
521 
 Relocation outside of area of an active PEDIG site within next 8 weeks is not anticipated 
522 
 
523 
Exclusion Criteria 
524 
 Dissociated vertical deviation (DVD) 
525 
 Vertical deviation >3∆ in primary gaze at distance or near  
526 
 Pattern (such as an “A” or “V” pattern) with a downgaze measurement of >10∆ difference 
527 
from straight ahead by PACT, measured by investigator’s routine method 
528 
 Treatment for IXT or amblyopia (other than refractive correction) within the past 4 weeks, 
529 
including vision therapy, orthoptics, patching, atropine, or other penalization 
530 
 Substantial overminus spectacles (spectacles overminused by more than 1.00D SE than 
531 
the most recent cycloplegic refraction and ALSO results in minus SE power in the 
532 
spectacles; i.e. underplussing is allowed) within the past 4 weeks   
533 
 Prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
534 
 Prior use of prism spectacles 
535 
 Current contact lens wear 
536 
 Abnormality of the cornea, lens, or central retina 
537 
 Down syndrome or cerebral palsy 
538 
 Developmental delay which would, in the opinion of the investigator, interfere with 
539 
treatment or evaluation. Mild speech delays, reading disability, and learning disabilities are 
540 
not excluded. 
541 
 Any condition that would, in the investigator’s opinion, result in poor spectacle compliance  
542 
 Disease known to affect accommodation, vergence, or ocular motility such as multiple 
543 
sclerosis, Graves orbitopathy, myasthenia gravis, diabetes mellitus, or Parkinson disease 
544 
 Current use of any ocular or systemic medication known to affect accommodation or 
545 
vergence, such as anti-anxiety agents (e.g., Librium or Valium), anti-arrhythmic agents 
546 
(e.g., Cifenline, Cibenzoline), anti-cholinergics (e.g., motion sickness patch 
547 
(scopolamine)), bladder spasmolytic drugs (e.g., Propiverine), hydroxychloroquine, 
548 
chloroquine, phenothiazines (e.g., Compazine, Mellaril, Thorazine), tricyclic 
549 
antidepressants (e.g., Elavil, Nortriptyline, Tofranil) 
550 
 
551 
 
 
552 

 
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2-3 
Additional Eligibility Criteria for Randomization Based on Prism Adaptation Testing  
553 
 Exodeviation by PACT while wearing “trial” relieving prism is smaller at distance or near 
554 
than measured during intial PACT testing (e.g. not fully adapting to prism at both 
555 
distances) 
556 
 No NEW esotropia by cover test at near while wearing “trial” relieving prism 
557 
o An esotropia at near also present on enrollment measurement is allowed because 
558 
monofixational intermittent exotropia may be associated with a small angle 
559 
esotropia 
560 
 No esodeviation >6∆ on PACT at near while wearing relieving prism 
561 
 
562 
2.3 
Historical Information 
563 
Historical information elicited will include the following: date of birth, sex, race, ethnicity, 
564 
cycloplegic refraction, prior treatment for IXT, spectacle correction, and medical history.   
565 
 
566 
2.4 
Testing at the Enrollment Exam 
567 
All testing must be performed with the participant wearing “habitual correction” (with 
568 
spectacles if child currently wears spectacles or without spectacles if child is not wearing 
569 
spectacles).*  
570 
 
571 
* The exception is for a participant who does not require spectacles per IXT6 protocol 
572 
but is wearing a pair of spectacles that do not meet pre-enrollment spectacle tolerances 
573 
(see section 2.2). This participant can have enrollment testing performed with or 
574 
without these spectacles, provided the visual acuity eligibility criteria are met (see 
575 
section 2.2).  If visual acuity criteria are not met, the child is not eligible at that visit.  
576 
 
577 
There is no specified “waiting” time that needs to occur between enrollment measurements, 
578 
although testing must be performed without cycloplegia and in the following specified order at 
579 
the enrollment visit: 
580 
 
581 
1. Spectacle Prescription Verification (Lensometry):  
582 
 Prior to performing the enrollment examination, the participant’s habitual spectacle 
583 
correction (if worn) is to be verified using a lensometer and compared with study 
584 
spectacle requirements using procedures outlined in the IXT6 Testing Procedures 
585 
Manual. 
586 
2. Symptom and Spectacle Surveys:  
587 
 A brief survey of IXT symptoms will be administered to the child. Response options 
588 
are based on frequency of observations: never, sometimes, and all the time. 
589 
 A brief survey of symptoms that may be associated with prism spectacle wear such as 
590 
headaches, eye strain, and problems with spectacle wear will be administered to the 
591 
parent of the participant.  Parents are asked to respond to the survey questions based on 
592 
their observations of their child in the past 2 weeks.  Response options are based on 
593 
frequency of observations: never, rarely, sometimes, often, always, and not applicable. 
594 
STEPS 3 through 8 must be performed in the specified order by the same study-certified 
595 
examiner (pediatric ophthalmologist, pediatric optometrist, or certified orthoptist) on the 
596 
same day and without cycloplegia.  
597 

 
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3. Control of the Exodeviation #1: Control of the exodeviation will be assessed in the habitual 
598 
correction*(see above) in primary position at distance and near using the PEDIG IXT 
599 
control scale (see below)29 and as outlined the IXT6 Testing Procedures Manual. 
600 
 Distance (6 meters) – fixing on an accommodative target such as a video or small 
601 
letters 
602 
 Near 1/3m (33cm)–  fixing on Gulden near fixation target or similar accommodative 
603 
target) 
604 
 The scale below applies to both distance and near separately.  
605 
 
606 
Intermittent Exotropia Control Scale 
607 
5 = Constant Exotropia 
608 
4 = Exotropia > 50% of the 30-second period before dissociation 
609 
3 = Exotropia < 50% of the 30-second period before dissociation 
610 
2 = No exotropia unless dissociated, recovers in >5 seconds 
611 
1 = No exotropia unless dissociated, recovers in 1-5 seconds 
612 
0 = No exotropia unless dissociated, recovers in <1 second (phoria) 
613 
Not applicable =  No exodeviation present  
614 
 
615 
Directions:  
616 
 
617 
Step1: Assessment before any dissociation: Eye alignment is observed for a 30-second 
618 
period with distance fixation.  The time in seconds that a spontaneous IXT is observed 
619 
is counted, and the appropriate control score (3, 4, or 5) is assigned for distance 
620 
fixation. This is then repeated for near fixation for another 30-second period; if an 
621 
exotropia is observed, then the time in seconds that an eye is observed to be exotropic is 
622 
counted and the appropriate score of 3, 4, or 5 is assigned. If a score of ≥3 is present, 
623 
then Step 2 (dissociation) is not required for that test distance. First distance and then 
624 
near fixation are assessed before any dissociation (i.e., before step 2). 
625 
 
626 
Step 2: Assessment with standardized dissociation is performed only if spontaneous 
627 
exotropia is NOT observed during step 1 (control was not a 3, 4, or 5).  Instead, control 
628 
will be a 0, 1, or 2; this is determined based on the worst score determined from 3 
629 
successive 10-second periods of dissociation: 
630 
 An occluder is placed over the right eye for 10 seconds and then removed; the 
631 
length of time it takes for the re-establishment of fusion is measured in seconds. 
632 
 The left eye is then occluded for a 10-second period (second assessment under 
633 
dissociation) and after uncovering the eye, the time for re-establishment of fusion is 
634 
similarly measured in seconds. 
635 
 A third assessment is performed, by covering the eye that required the longer time 
636 
to re-fuse on the first two 10-second dissociations.  After uncovering the eye, the 
637 
length of time it takes for the re-establishement of fusion is measured in seconds. 
638 
 
639 
The worst level of control for the three 10-second periods of dissociation by occlusion 
640 
should be recorded.  
641 
Since the control score is the slowest time of the three assessments, if a score of 2 (>5 
642 
seconds recovery) is noted on the first or second dissociation, then subsequent 
643 
dissociation(s) are not needed. 
644 
If the child has a micro-esotropia by the cover test but an exodeviation by PACT, the 
645 
control scale applies to the exodeviation. 
646 

 
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4. Stereoacuity Testing:  
647 
 Stereoacuity will be assessed with habitual correction using the Randot Preschool 
648 
stereotest at near (performed at 40 cm).  A specific level of stereoacuity is not required 
649 
for eligibility (i.e., a score of “nil” is allowed, but a child who, in the opinion of the 
650 
investigator, does not understand the test would not be eligible.)  
651 
5. Control of the Exodeviation #2 (repeat) (see item #3): 
652 
 The same examiner should assess IXT control for all three assessments of control 
653 
during the enrollment visit.   
654 
6. Cover Test:  
655 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
656 
certified orthoptist. 
657 
 Cover Test will be assessed in primary position at distance (6 meters) and near (1/3 m), 
658 
using procedures outlined in the IXT6 Testing Procedures Manual. 
659 
 If the child has a micro-esotropia by the cover test but an exodeviation by PACT, the 
660 
esodeviation will be recorded for the cover test. 
661 
7.  PACT Testing & AC/A Determination:   
662 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
663 
certified orthoptist. 
664 
 PACT will be assessed in primary gaze using the IXT6-approved prism set and without 
665 
cycloplegia at distance (6 meters) and near (1/3 m) in habitual correction. The 
666 
procedure will include bracketing to find and record the high neutral endpoint as 
667 
outlined in the IXT6 Testing Procedures Manual. 
668 
 AC/A assessment is performed by measuring the PACT at distance (6 meters) with 
669 
the participant wearing -2.00D lenses over the habitual correction. The AC/A ratio is 
670 
calculated automatically by the website by taking the difference between the distance 
671 
PACT measurements with and without the -2.00D lenses and dividing the difference 
672 
by 2.  
673 
8. Control of the Exodeviation #3 (repeat) (see item #3): 
674 
 The same examiner should assess control for all three assessments of control during 
675 
the enrollment visit.   
676 
9. Fusional Convergence Amplitude Testing: 
677 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
678 
certified orthoptist using procedures outlined in the IXT6 Testing Procedures 
679 
Manual. 
680 
 Fusional convergence amplitude to be measured at distance 
681 
 Using the PEDIG-approved IXT6 prism bar, record the blur, break, and recovery 
682 
points according to the IXT6 Testing Procedures Manual. 
683 
10. Suppression:  
684 
 Assessment of suppression at distance using the Suppression Scale using procedures 
685 
outlined in the IXT6 Testing Procedures Manual.   
686 
11. Distance Visual Acuity Testing:  
687 
 Monocular distance visual acuity testing with the habitual correction and without 
688 
cycloplegia will be measured using the investigator’s usual method (recognition 
689 
acuity using any optotype).  
690 
12. Additional Clinical Testing:  
691 
 Ocular examination as per the investigator’s clinical routine to rule out ocular 
692 
abnormality or lens opacity (if not performed within 7 months)  
693 

 
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694 
2.5 
Confirmation of Eligibility and Completion of Enrollment 
695 
Completion of enrollment will occur at the conclusion of the Enrollment Exam after 
696 
confirming that all eligibility criteria are met. Participants not meeting all eligiblity criteria or 
697 
who are unable to complete enrollment testing other than fusional convergence amplitude and 
698 
suppression testing are not eligible for the study.   
699 
 
700 
Eligibility criteria relating to refractive error and spectacle correction are based upon the 
701 
cycloplegic refraction done within 7 months of enrollment.  
702 
 If all eligibility criteria are met the participant is enrolled and included in the Prism 
703 
Adaptation Test Screening.  
704 
 If all eligibility criteria are not met, the participant is not enrolled or included in the 
705 
Prism Adaptation Test Screening.  
706 
 
707 
2.6 
Prism Adaptation Test Screening 
708 
Participants who meet all enrollment criteria at the enrollment exam will undergo same-day 
709 
prism adaptation testing. The results of the prism adaptation test will be used to determine 
710 
eligibility for randomization. 
711 
 
712 
2.6.1 Prism Adaptation Test 
713 
The prism adaptation test procedure is documented in the IXT6 Testing Procedures Manual. 
714 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
715 
certified orthoptist. 
716 
 Testing must be done without cycloplegia.  
717 
 The purpose of testing is to assess a child’s initial response to the amount of relieving 
718 
prism that would be prescribed if randomly assigned to the prism spectacles group (see 
719 
table 1, section 3.1).  
720 
 The examiner will place BOTH of the following in the IXT6 approved trial frame and 
721 
have the child wear it continuously for at least 30 minutes:  
722 
o Trial lenses equal to the amount of refractive correction in the habitual spectacles, 
723 
or no correction if habitual lenses are not worn. 
724 
o Trial prism lenses from the IXT6 trial prism set with protocol-determined amount 
725 
of relieving prism (see table 1, section 3.1), with the following caveat: 
726 
 To avoid the need for trial prisms of 3.5∆ for cases in which the total prism 
727 
magnitude of 7∆, a 4∆ prism will be placed in front of the eye that normally 
728 
deviates, and 3∆ prism will be placed in front of the other eye.    
729 
 After 30 minutes of wearing the prism in trial frames, perform the following in primary 
730 
position while the participant continues to wear the prism trial frames:  
731 
o Cover test at near  
732 
o PACT testing at distance and at near  
733 
 
734 
2.7 
Eligiblity for Randomization 
735 
The results of the prism adaptation test determine whether the participant is eligible for 
736 
randomization or whether study participation will end.  
737 
 
738 
Participants ARE eligible to be randomized if ALL of the following criteria are met:  
739 
 The participant has not fully adapted to prism at distance AND near 
740 

 
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2-7 
o The participant’s PACT measurement at distance while wearing "trial” relieving 
741 
prism is smaller than the originally measured deviation at distance OR near when 
742 
not wearing prism (i.e., at least some reduction in deviation with prism) 
743 
 The participant has no NEW near esotropia by cover test while wearing the“trial” 
744 
relieving prism (e.g., a microesotropia previously noted on near cover test during initial 
745 
testing and also noted at this time is allowed) 
746 
 The participant has no esodeviation >6∆ on PACT at near while wearing “trial” 
747 
relieving prism 
748 
 
749 
Participants who fail to meet any of the above criteria will not be randomized and will 
750 
discontinue study participation.  
751 
 
752 
Examples:  
753 
Consider the following participants, each with a 30∆ exodeviation measured by PACT at 
754 
both distance and near. These participants are now all wearing 40% relieving prism (12∆, 
755 
with 6∆ base-in in each lens) in a trial frame with habitual refractive correction. After 30 
756 
minutes of wearing prism, the participants have their deviation measured by the PACT in 
757 
primary position while wearing the trial frame including relieving prism. Post- prism 
758 
adaptation PACT measures are given in the following examples: 
759 
 
760 
Patient is eligible based upon prism adaption and CAN be randomized. 
761 
 
762 
1. Example 1 - No Prism Adaptation:   
763 
Wearing prism, the participant now measures 18∆ exodeviation at distance by 
764 
PACT and 18∆ exodeviation at near by PACT, and no esotropia by cover test at 
765 
near.  The angle has decreased by the amount of prism given, so there is no prism 
766 
adaptation. 
767 
2. Example 2 - Partial Prism Adaptation:   
768 
Wearing prism, the participant now measures 30∆ exodeviation at distance by 
769 
PACT and 25∆ exodeviation at near by PACT, and no esotropia by cover test at 
770 
near.  The distance angle has not decreased while wearing prism but the near angle 
771 
has decreased while wearing prism. 
772 
3. Example 3 – Pre-Existing Micro-Esotropia at Near: 
773 
Wearing prism, the participant measures 18∆ exodeviation at distance by PACT and 
774 
18∆ exodeviation at near by PACT, but is esotropic at near by cover test (reflecting 
775 
pre-existing monofixation; where, in this case, the tropia and phoria are in the 
776 
opposite direction). The esotropia was present prior to prism adaptation. 
777 
The PACT angle has decreased by the amount of prism given, so there is no prism 
778 
adaptation.  
779 
 
780 
Patient is NOT eligible based upon prism adaption and CANNOT be randomized. 
781 
 
782 
1. Example 1 - Full Prism Adaptation:    
783 
Wearing prism, the participant now measures 30∆ exodeviation by PACT at 
784 
distance and near with the prism in place.  The patient has completely adapted to 
785 
the prism and is NOT eligible due to complete prism adaptation. 
786 
 
787 
 
788 

 
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2-8 
2. Example 2 – New Esotropia at Near:   
789 
Wearing prism, the participant now measures 18∆ exodeviation at distance by 
790 
PACT and 4∆ esodeviation at near by PACT and has an esotropia by cover test at 
791 
near. The participant did not previously have an underlying esotropia. This 
792 
participant is NOT eligible due to the new esotropia at near. 
793 
3. Example 3 – Esodeviation at Near now >6Δ by PACT: 
794 
Wearing prism, the participant measures 18∆ exodeviation at distance by PACT and 
795 
8∆ esodeviation at near by PACT, although the participant is not esotropic at near 
796 
by cover test.  This participant is NOT eligible due to an esodeviation >6∆ at near 
797 
by PACT while wearing prism. 
798 
 
799 
2.8 
Randomization  
800 
Randomization will occur within 7 days after the participant has met all eligibility criteria 
801 
(Section 2.2), completes prism adaptation testing (Section 2.6), and meets the randomization 
802 
criteria (Section 2.7).  
803 
 
804 
Participants eligible for randomization will be randomly assigned with equal probability to one 
805 
of the following groups: 
806 
 Prism group: spectacles with refractive correction (if required) and relieving prism as 
807 
outlined in table 1 (see section 3.1) 
808 
 Non-prism group: spectacles with refractive correction (if required) and no prism 
809 
The Jaeb Center will construct a separate Master Randomization List using a permuted block 
810 
design stratified by mean distance control score (2 to <3, 3 to <4, 4 to 5).  A participant is 
811 
officially randomized when the website randomization process is completed.  
812 
 
 
813 

 
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3-1 
CHAPTER 3 TREATMENT AND FOLLOW-UP 
814 
 
815 
3.1 
Treatment for Prism Group  
816 
Participants assigned to the prism group will be prescribed spectacles with base-in prism 
817 
ground into each lens.  Total prism prescribed will be equal to 40% of the largest deviation at 
818 
distance or near measured by PACT, with the total prism divided equally between the two 
819 
lenses (Table 1).  The prism spectacles must be worn all waking hours.  No IXT treatment 
820 
other than the prism spectacles can be prescribed for the duration of the study. Refractive 
821 
correction will be prescribed according to criteria in section 3.3. 
822 
 
823 
Table 1: Prescribed Prism According to Maximum Exodeviation   
824 
Maximum exodeviation by 
PACT  (Larger Value of 
Distance or Near) 
 
Total Base-in 
Prism Magnitude* 
Base-in Prism 
Magnitude 
for Each Eye 
16∆ 
6∆ 
3∆ 
18∆ 
7∆ 
3.5∆ 
20∆ 
8∆ 
4∆ 
25∆ 
10∆ 
5∆ 
30∆ 
12∆ 
6∆ 
35∆ 
14∆ 
7∆ 
*Total prism is 40% of the larger exodeviation comparing the distance and near PACT.    
825 
 
826 
3.2 
Treatment for Non-prism Group  
827 
Participants in the non-prism group will be prescribed non-prism spectacles according to 
828 
refractive error correction criteria in section 3.3. No IXT treatment other than non-prism 
829 
refractive correction can be prescribed for the duration of the study.   
830 
 
831 
3.3 
Post-Randomization Criteria for Refractive Error Correction  
832 
All participants in the study will be wearing spectacles following randomization and all those 
833 
who habitually wore spectacles pre-study will be provided new spectacles for masking 
834 
purposes (paid for by the study). All participants in both groups will be prescribed spectacles to 
835 
correct their refractive error (or plano as appropriate) and those in the prism group will also 
836 
have prism incorporated.   
837 
 
838 
Refractive error correction for new spectacles for both groups will be calculated automatically 
839 
by the study website and will meet all of the following criteria: 
840 
 Fully correct astigmatism (if present) 
841 
 If less hyperopic eye has SE myopia: 
842 
o Prescribe the full sphere in both eyes   
843 
 If less hyperopic eye has SE hyperopia or emmetropia: 
844 
o After correction of astigmatism, prescribe sphere so that spectacles will have plano 
845 
SE in the less hyperopic eye  
846 
o Match any reduction of sphere made to the less hyperopic eye in the fellow eye 
847 
 Prism (if in prism group) will be split equally between eyes (see section 3.1) 
848 
 
849 
Participants in both groups must wear their refractive correction all waking hours. 
850 
 
851 

 
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NOTE: Because the study is providing spectacles to all randomized participants, those with 
852 
any degree of refractive error (astigmatism, myopia, or anisometropia) will be prescribed 
853 
spectacles with some refractive correction. Only participants who have no refractive error or 
854 
have pure spherical hyperopia that is equal between both eyes will be prescribed plano lenses. 
855 
 
856 
3.4 
Follow-up Visit Schedule 
857 
The follow-up visit schedule is timed from randomization as follows:  
858 
 Telephone call: 3 weeks (21 to 28 days) after randomization to check that the 
859 
spectacles have been dispensed/received and that the participant is wearing the new 
860 
spectacles 
861 
 Outcome Visit: 8 weeks (±2 weeks) after randomization 
862 
 
863 
Additional visits may be scheduled at investigator discretion although no data will be entered 
864 
on the website. 
865 
 
866 
3.5 
Telephone Call  
867 
At 3 weeks following randomization, the site will contact the parents to determine whether the 
868 
study-prescribed spectacles have been received and that the child is wearing them.  The site 
869 
will record the date that the new spectacles were received or document that they have not been 
870 
received as of the call date. If spectacles have not been received, the site will record comments 
871 
about factors involved in the delay. Sites will encourage full-time wear of the study spectacles. 
872 
 
873 
3.6 
Masked Examiner Testing   
874 
At the 8-week outcome visit, a Masked Examiner, who is a pediatric ophthalmologist, pediatric 
875 
optometrist, or certified orthoptist, will assess the control of the exodeviation and perform 
876 
PACT testing (see section 2.6.1).   
877 
 
878 
The Masked Examiner must be someone other than the investigator.  
879 
 
880 
The Masked Examiner must not verify the spectacles using lensometry, discuss compliance of 
881 
spectacle wear with the participant or parents, administer the symptom or spectacle survey, 
882 
access the medical history, or enter data on the study website.   
883 
 
884 
Given that the study spectacles will not be concealed in any way, instructions for the masked 
885 
examiner will include the importance of maintaining masking if possible; examiners should try 
886 
not to inspect the participants’ spectacles during testing.  After completion of the masked exam 
887 
testing, the masked examiner will indicate whether or not the participant appears to be wearing 
888 
prism correction.  
889 
 
890 
3.7 
Outcome Visit Testing Procedures 
891 
All outcome assessments should be completed with the participant wearing study spectacles 
892 
(i.e., prism spectacles or non-prism spectacles).   
893 
 
894 
Participants will be tested in trial frames in the following cases:  
895 
 Participant did not bring study spectacles to the outcome exam  
896 
 Participant’s study spectacles are outside refractive error and/or prism tolerances  
897 
 Participant lost study spectacles  
898 
 Partcipant never received study spectacles  
899 

 
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3-3 
Someone other than the Masked Examiner will ensure that the participant is wearing the study-
900 
prescribed spectacles (including plano spectacles if prescribed) before the masked exam. 
901 
The following procedures should be performed by the appropriate examiner (see below) and in 
902 
the order specified: 
903 
 
904 
The following procedures are tested first by someone other than the Masked Examiner:  
905 
1. Spectacle Prescription Verification (Lensometry):  Prior to performing the outcome 
906 
examination, the participant’s spectacle correction will be verified using a lensometer 
907 
(including plano lenses).  (See IXT6 Testing Procedures Manual) 
908 
 Lenses will be measured through the viewing position by marking the pupil position on 
909 
the lenses and performing lensometry at this position 
910 
 If spectacles do not meet the tolerances listed below, the participant should be tested 
911 
with trial frames with the intended prescription in place. 
912 
 
913 
Prism Group  
914 
 Spectacle sphere, cylinder, and axis should meet the following tolerances:  
915 
o Sphere within 0.50D of prescribed 
916 
o Astigmatism within 0.50D of prescribed 
917 
o Axis within 10 degrees of prescribed astigmatism if ≤1.00D and within 5 
918 
degrees of prescribed astigmatism if >1.00D 
919 
 Spectacle prism should meet the following tolerances:  
920 
o The net horizontal prism is <3∆ from the prescribed prism based on Table 1 
921 
(section 3.1) 
922 
o The net vertical prism is <2∆   
923 
 
       
924 
Examples of Prism Spectacle Manufacture Tolerance 
925 
 Examples within tolerance:  
926 
o 1∆ base-down both lenses (in addition to correct horizontal amount 
927 
prescribed) 
928 
o 3∆ base-in right lens, 5∆ base-in left lens when 4∆ base-in for both lenses 
929 
was prescribed 
930 
 Examples NOT within tolerance: 
931 
o 1∆ base-down right lens, 1∆ base-up left lens (in addition to correct 
932 
horizontal amount prescribed) 
933 
o 6∆ base-in right lens, 5∆ base-in left lens when 4∆ base-in for both lenses 
934 
was prescribed 
935 
 
936 
Non-Prism Group 
937 
 Spectacle sphere, cylinder, and axis should meet the following tolerances:  
938 
o Sphere within 0.50D of prescribed 
939 
o Astigmatism within 0.50D of prescribed 
940 
o Axis within 10 degrees of prescribed astigmatism if ≤1.00D and within 5 
941 
degrees of prescribed astigmatism if >1.00D 
942 
 Because unintended prism can occur due to decentration, spectacle prism should meet 
943 
the following tolerances:  
944 
o The net horizontal prism is 1∆  
945 
o The net vertical prism is 1∆  
946 
 
947 

 
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Examples of Non-Prism Spectacle Manufacture Tolerance 
948 
 Examples within tolerance:  
949 
o 2∆  base down both lenses 
950 
o 1∆  base in right lens, 1 base out left lens 
951 
o No prism right lens, 1∆ base in left lens 
952 
 Examples NOT within tolerance: 
953 
o 2∆ base-in right lens, 2∆ base-in left lens  
954 
o 1∆  base up right lens, 1∆  base down left lens 
955 
2. Compliance Assessment: Compliance with spectacle wear since receiving the spectacles 
956 
will be assessed based on review of the compliance calendars and discussion with the 
957 
parents and child using the following scale: 
958 
 Excellent (76% to 100%) 
959 
 Good (51% to 75%) 
960 
 Fair (26% to 50%) 
961 
 Poor (≤ 25%) 
962 
3. Symptom and Spectacle Surveys:  
963 
 A brief survey of IXT symptoms will be administered to the child.  
964 
 A brief survey of symptoms that may be associated with prism spectacle wear 
965 
will be administered to the parents of the participant.  Parents are asked to 
966 
respond to the survey questions based on their observations of their child in the 
967 
past 2 weeks. 
968 
 
969 
Once the assessments listed above are completed, the following procedures must be 
970 
performed in the specified order. Procedures indicated as “masked” must be tested by 
971 
the Masked Examiner. Procedures not indicated as “masked” may be tested by the 
972 
Masked Examiner or another study-qualified examiner although it is preferred that they 
973 
be completed by the Masked Examiner. All procedures should be performed with the 
974 
participant wearing the study spectacles (or trial frames if required) and without 
975 
cycloplegia:  
976 
Although testing must be performed in the specified order; there is no specified “waiting” time 
977 
that needs to occur between different tests.  
978 
4. Control of the Exodeviation #1 (Masked): A Masked Examiner will assess control of 
979 
exodeviation at distance and near fixation using the Intermittent Exotropia Control Scale.29   
980 
5. Stereoacuity Testing (Masked): Stereoacuity will be assessed using the Randot Preschool 
981 
stereotest at 40 cm.   
982 
6. Control of the Exodeviation #2  (Masked, see item #4) 
983 
 The same masked examiner who assessed IXT Control #1 does this second measure of 
984 
control.   
985 
7. Cover Test (Masked): 
986 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
987 
certified orthoptist. 
988 
 Cover Test will be assessed in primary position at distance (6 meters) and near (1/3 m) 
989 
using procedures outlined in the IXT6 Testing Procedures Manual. 
990 
8. PACT Testing (Masked):  A Masked Examiner will assess the PACT in primary position 
991 

 
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3-5 
at distance (6 meters) and near (1/3 m) as outlined in the IXT6 Testing Procedures Manual. 
992 
9. Control of the Exodeviation #3  (Masked, see item #4) 
993 
 The same masked examiner who assessed IXT Control #1 & 2 does this third measure 
994 
of control.   
995 
10. Fusional Convergence Amplitude Testing 
996 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
997 
certified orthoptist. 
998 
 Convergence amplitudes will be measured at distance 
999 
 Using the PEDIG-approved IXT6 prism bar, record the blur, break, and recovery points 
1000 
according to the IXT6 Testing Procedures Manual. 
1001 
11. Suppression:  
1002 
 Testing must be performed by a pediatric ophthalmologist, pediatric optometrist, or 
1003 
certified orthoptist. 
1004 
 Assessment of suppression at distance using the Suppression Scale and procedures 
1005 
outlined in the IXT6 Testing Procedures Manual. 
1006 
12. Distance Visual Acuity Testing:  
1007 
 Monocular distance visual acuity testing without cycloplegia will be measured using 
1008 
the same method used at enrollment.   
1009 
 
1010 
3.8 
Additional Visits 
1011 
Investigators may schedule additional visits at their discretion, although no data will be entered 
1012 
on the website.   
1013 
 
1014 
3.9 
Surgical or Non-Surgical Treatment 
1015 
Strabismus surgery and non-surgical treatments for IXT, other than the study-prescribed 
1016 
spectacles, are not allowed during the study.  If the investigator feels that additional treatment 
1017 
is needed outside of study guidelines, please contact a study chair for further clarification. 
1018 
 
1019 
3.10 
Treatment of Amblyopia 
1020 
Given the exclusion of participants with amblyopia and the short duration of the trial, no 
1021 
treatment for amblyopia is allowed during the study. 
1022 
 
1023 
3.11 
Management of Refractive Error 
1024 
Because of the short duration of the study, the spectacles prescribed at randomization may not 
1025 
be changed or discontinued without contacting a protocol chair.   
1026 
 
1027 
In the event that spectacles are lost or damaged after randomization but before the outcome 
1028 
visit, the spectacles may only be replaced with the same spectacle prescription that was 
1029 
prescribed at randomization. 
1030 
 
1031 

 
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4-1 
CHAPTER 4 MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1032 
 
1033 
4.1 
Contacts by the Jaeb Center for Health Research and Sites 
1034 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided 
1035 
with the parent’s contact information.  The Jaeb Center will contact the parents of the 
1036 
participants only when necessary.  Permission for such contacts will be included in the Informed 
1037 
Consent Form.  The principal purpose of the contacts will be to develop and maintain rapport 
1038 
with the participant and/or family and to help coordinate scheduling of the outcome examination.   
1039 
 
1040 
The site investigator or coordinator will directly contact the parents of each participant 3 weeks 
1041 
after randomization to determine if the spectacles have been received, if the child is wearing the 
1042 
spectacles, and whether there are any concerns.  Full-time wear of the spectacles will be 
1043 
encouraged. 
1044 
 
1045 
4.2 
Participant Withdrawals 
1046 
Parents may withdraw their child from the study at any time.  This is expected to be a very 
1047 
infrequent occurrence in view of the study design’s similarity to routine clinical practice and the 
1048 
short duration of the study.  If the parents indicate that they want to withdraw their child from the 
1049 
study, the investigator personally should attempt to speak with them to determine the reason.  If 
1050 
their interest is in transferring the child’s care to another eye care provider, every effort should 
1051 
be made to comply with this and at the same time try to keep the child in the study under the new 
1052 
provider’s care. 
1053 
 
1054 
4.3 
Risks 
1055 
There are no risks that would exceed standard of care treatment involved in this study when 
1056 
treating with either prism or non-prism spectacles.   
1057 
 
1058 
4.3.1 Risks of Examination Procedures 
1059 
The procedures in this study are part of daily eye care practice in the United States and pose no 
1060 
known risks. 
1061 
 
1062 
4.3.2 Risk of Prism Therapy 
1063 
The risks involved in the study are identical to those for a child treated with prism therapy who is 
1064 
not participating in the study.   
1065 
 
1066 
Some participants treated with prism may experience eye strain or notice distortion when 
1067 
wearing the spectacles; these typically dissipate over time and also with removal of the 
1068 
spectacles.  
1069 
 
1070 
4.3.3 Risk Assessment  
1071 
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.404, which is 
1072 
research not involving greater than minimal risk.   
1073 
 
1074 
4.4 
Reporting Adverse Events 
1075 
Although no adverse events are anticipated as a result of prism therapy or non-prism spectacle 
1076 
wear, any new cases of amblyopia or new cases of constant esotropia will be reported.  No 
1077 

 
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4-2 
surgical procedures are part of the protocol and no treatments are being prescribed that are not 
1078 
part of usual care.  Investigators will abide by local IRB reporting requirements. 
1079 
4.5 
Discontinuation of Study 
1080 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1081 
Monitoring Committee) prior to the pre-planned completion of enrollment and follow-up of all 
1082 
participants. 
1083 
 
1084 
4.6 
Travel Reimbursement 
1085 
The parent of each participant enrolled in the study (i.e., undergoing prism adaptation testing)  
1086 
will be compensated $50 (by gift card or check) for completing the Enrollment Exam, regardless 
1087 
of whether the participant is randomized.  The parent of each randomized participant will also 
1088 
receive an additional $50 (by gift card or check) for completing the 8-week outcome visit. If 
1089 
there are extenuating circumstances, and the participant is unable to complete the 8-week 
1090 
outcome visit without additional funds due to travel costs, additional funds may be provided. 
1091 
 
1092 
4.7 
Study Costs 
1093 
The study will pay for visits that are done just for the research study. The participant or their 
1094 
insurance company will not be responsible for the cost of visits done just for the research study.  
1095 
The study will not pay for usual care visits.  Usual care visits are those that would occur whether 
1096 
or not the subject is in the study.  The cost of usual care visits will the responsibility of the 
1097 
participant or their insurance company.  
1098 
 
1099 
 The study will pay for the 8-week study visit, as it is done just for the research study.  
1100 
Neither the participant or their insurance company will be responsible for the cost of the 
1101 
8-week study visit.  
1102 
 The study will pay for the participant’s study glasses.   
1103 
 
1104 
The study will not pay for contact lenses, tinted lenses, or antireflective coating.   
1105 
 
1106 
 
1107 
4.8 
General Considerations  
1108 
The study is being conducted in compliance with the policies described in the study policies 
1109 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
1110 
the protocol described herein, and with the standards of Good Clinical Practice. 
1111 
 
1112 
Data will be directly collected in electronic CRFs, which will be considered the source data. 
1113 
 
1114 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
1115 
recruitment goal. 
1116 
 
1117 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
1118 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
1119 
2013). 
1120 

 
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5-1 
CHAPTER 5 SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
1121 
 
1122 
The sample size and statistical analyses are summarized below.   
1123 
 
1124 
The data collected in this short-term, pilot randomized trial will primarily be used to obtain 
1125 
preliminary estimates of treatment effect in both the prism and non-prism group to determine 
1126 
whether to proceed to a full-scale, longer-term randomized trial of prism vs. non-prism.  
1127 
 
1128 
5.1 
Sample Size 
1129 
Because this study is a pilot study, sample size has not been statistically calculated.  The sample 
1130 
size of 64 participants (32 participants per group) who pass the prism adaptation test (i.e., do not 
1131 
fully prism adapt) is a convenience sample that is expected to provide at least 60 participants (30 
1132 
participants per group) for analysis after adjusting for up to 5% loss to follow-up.  
1133 
 
1134 
The primary analysis section (section 5.2)  indicates the level of statistical power/precision that 
1135 
the sample size of 30 participants per group (60 total) provides.    
1136 
 
1137 
5.2 
Primary Analysis  
1138 
The primary analysis will be an intent-to-treat comparison of mean 8-week control of the 
1139 
distance exodeviation (average of 3 measurements) between treatment groups using an analysis 
1140 
of covariance (ANCOVA) model, which adjusts for baseline distance control.   
1141 
 
1142 
5.2.1 Decision Guideline for Determining Whether to Proceed to a Randomized Trial   
1143 
The data collected in this short-term, pilot randomized trial will primarily be used to determine 
1144 
whether to proceed to a full-scale, longer-term randomized trial of prism vs. non-prism. A 
1145 
decision guideline has been developed to aid in this decision (see below).  The side effect 
1146 
profiles in each treatment group will also be considered when deciding whether to proceed with a 
1147 
full-scale trial. 
1148 
 
1149 
The decision guideline for determining whether to proceed to a full-scale randomized trial will 
1150 
be based on the primary analysis estimate of the treatment group difference in mean distance 
1151 
control scores at 8 weeks.  The standard deviation of 8-week distance control in IXT3 was 1.5 
1152 
points (95% CI = 1.2 to 1.8 points). The convenience sample of 64 participants yields relatively 
1153 
low statistical power (61%) for detecting a difference if the true difference = -0.75 assuming an 
1154 
SD in the current study of 1.5 points and accounting for up to 5% loss to follow up.  As the 
1155 
statistical power is poor, the decision guideline was based solely on the size of the observed 
1156 
difference in mean control scores (prism – non-prism).  The decision is: 
1157 
 Proceed if the observed difference ≤ -0.75 points 
1158 
 Uncertain if the observed difference favors the prism group by less than 0.75 points (diff <0 
1159 
and >-0.75)  
1160 
 Do not proceed if the observed difference is zero or favors the non-prism group (diff ≥0) 
1161 
 
1162 
 
1163 
*Note that differences (prism – non-prism) favoring prism will be negative given that lower 
1164 
control scores indicate better control.   
1165 
 
1166 
 
1167 

 
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Table 1: Probabilities of Proceed, Uncertain, and Do Not Proceed Decisions Given the True 
1168 
Treatment Group Difference in Means* 
1169 
 
 
Decision Guideline #1: Whether to Proceed to 
Full-Scale Randomized Trial Based on 
OBSERVED Difference in Means in Pilot Study 
TRUE Treatment Group Difference  
(Prism – Non-prism)   
(in points) 
 
-0.25 
 
-0.50 
 
-0.75 
 
-1.0  
 
-1.25 
 
Proceed** if observed difference is ≤-≤0.75 
 
11% 
 
27% 
 
50% 
 
73% 
 
89% 
 
Uncertain if observed difference is <0 and > -0.75 
 
62% 
 
62% 
 
46% 
 
26% 
 
11% 
 
Do not proceed if observed difference is ≥0 
 
27% 
 
11% 
 
4% 
 
1% 
 
0% 
* Table cells show the probability of making the given decision if the true difference is the 
1170 
given amount. Estimates were calculated using a 1-sided t-test, a standard deviation of 1.5 
1171 
and 30 participants per treatment group.  
1172 
** The ‘proceed’ row is the  chance of observing a difference of 0.75 points or larger favoring 
1173 
prism given varying assumptions for the true treatment difference. 
1174 
 
1175 
As seen in Table 1, the probability of making a ‘proceed’ decision when the true mean difference 
1176 
is -0.75 points or larger is 50%, the probability of an ‘uncertain’ decision is 46% , and the 
1177 
probability of a ‘do not proceed’ decision is 4%.  Even if the true mean difference is as small as  
1178 
-0.50 points, the probablility of a “do not proceed” decision is still low at 11%. 
1179 
 
1180 
5.3 
Secondary Analysis -- Distance Control 
1181 
The secondary analysis will calculate the proportion (and two-sided 95% confidence interval) of 
1182 
participants with a “treatment response,” defined as ≥1 point improvement in control of their 
1183 
distance exodeviation (average of 3 measurements) between baseline and the 8-week outcome 
1184 
exam. 
1185 
 
1186 
5.4 
Secondary Analysis – No Spontaneous Tropia  
1187 
The proportion of participants with no spontaneous tropia at 8 weeks will be compared between 
1188 
treatment groups using a two-sided Barnard’s test with alpha of 0.05, with calculation of a two-
1189 
sided 95% confidence interval on the difference in proportions.   
1190 
 
1191 
No spontaneous tropia at the 8-week primary outcome exam is defined as a score of ≤2 (0, 1, or 
1192 
2) on all three assessments of control at distance and at near.   
1193 
 
1194 
5.5 
Additional Analyses   
1195 
 
1196 
5.5.1 Change in Distance Control 
1197 
In addition to the primary analysis comparing mean change in distance control between 
1198 
treatment groups (see section 5.2), the distribution of change in distance control will also be 
1199 
compared between treatment groups using the Wilcoxon rank sum test. 
1200 
 
1201 

 
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5.5.2 Near Control  
1202 
Near control will be evaluated similarly to the distance control in the primary analysis (section 
1203 
5.2), secondary analyses (section 5.3, 5.4), and one of the additional analyses (section 5.5.1). 
1204 
5.5.3 Ocular Alignment  
1205 
The distribution of measures of ocular alignment at distance and near fixation by PACT will be 
1206 
described for the enrollment exam and the outcome exam for each treatment group.  Because 
1207 
participants in the prism group will have PACT measured at 8-weeks while wearing study-
1208 
prescribed relieving prism, we will account for this in analysis by adding the magnitude of the 
1209 
prescribed prism to the deviation by PACT while wearing prism for analysis of the total 
1210 
underlying deviation.  We acknowledge this has limitations as measurement through ground in 
1211 
prism is not equivalent to measurement without ground in prism. The distribution of change in 
1212 
ocular alignment will also be described for each treatment group. 
1213 
 
1214 
5.5.4 Near Stereoacuity  
1215 
The distribution of near stereoacuity will be described for the enrollment exam and the outcome 
1216 
exam for each treatment group. The distribution of change in near stereoacuity will also be 
1217 
described for each treatment group. 
1218 
 
1219 
5.5.5 Suppression  
1220 
As an exploratory analysis, the distribution of suppression level (none, mild, moderate, severe) 
1221 
will be described for the enrollment exam and the outcome exam for each treatment group.   
1222 
 
1223 
5.5.6 Fusional Convergence  
1224 
As an exploratory analysis, the distribution of fusional convergence amplitude (break point, blur 
1225 
point, and recovery) will be described, and compared between treatment groups for the 
1226 
enrollment exam and the outcome exam for each treatment group. 
1227 
 
1228 
5.5.7 Adverse Symptoms of Intermittent Exotropia and Prism Spectacle Wear 
1229 
Adverse symptoms of IXT will be assessed at enrollment and at the 8-week outcome exam using 
1230 
a symptom survey that is administered to the child (see section 2.4).  Response options are based 
1231 
on frequency of observations: never, sometimes, and always.  
1232 
 
1233 
Similarly, adverse symptoms that may be associated with prism spectacle wear will be assessed 
1234 
at enrollment and at the 8-week outcome exam using a spectacle survey that is administered to 
1235 
the parent.  Response options are based on frequency of observations: never, rarely, sometimes, 
1236 
often, always, and not applicable. 
1237 
 
1238 
For each survey separately, the distribution of scores on each survey item will be described for 
1239 
the enrollment exam and the outcome exam for each treatment group.   
1240 
 
1241 
5.5.8 Distance Visual Acuity  
1242 
Distance visual acuity will be assessed at enrollment and at the 8-week outcome exam. Any 
1243 
optotype method can be used for testing; however, the same method must be used at both the 
1244 
enrollment and 8-week outcome exam.   
1245 
 
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The distribution of distance visual acuity measures will be described for the enrollment exam and 
1247 
the outcome exam for each treatment group.  The distribution of change in visual acuity will also 
1248 
be described for each treatment group.   
1249 
 
1250 
5.5.9 Compliance of Spectacle Wear 
1251 
Parents will be asked to complete a compliance calendar by recording the percentage of time 
1252 
their child has worn the study-prescribed spectacle correction each day. Proportion of time worn 
1253 
each day will be described as excellent (76% to 100%), good (51% to 75%), fair (26% to 50%), 
1254 
poor (1 to  25%), or none (0%).  Based on review of the calendars and discussion with parents at 
1255 
the 8-week outcome exam, the investigator will record the total proportion of time worn as 
1256 
excellent (76% to 100%), good (51% to 75%), fair (26% to 50%), poor (1 to 25%), or none (0%: 
1257 
did not fill prescription or never picked up spectacles). 
1258 
 
1259 
The distribution of compliance will be assessed for each treatment group at the outcome exam. 
1260 
 
1261 
5.5.10  Alternative Approach to Primary Analysis 
1262 
A planned secondary analysis will be to repeat the primary analysis (see section 5.2) but limit it 
1263 
to participants who received their study spectacles in sufficient time to allow for the opportunity 
1264 
to have worn the spectacles for at least 4 weeks.   
1265 
 
1266 
5.5.11   Mean Distance Control in Subgroups  
1267 
As an exploratory analysis, the mean distance control score in subgroups based on baseline 
1268 
distance control severity will be estimated. The hypothesis for a subgroup effect based on 
1269 
distance control severity (2 to <3, 3 to <4, 4 to 5) is that poorer control is associated with larger 
1270 
treatment effect as suggested in a pilot study of overminus spectacles,23 another form of non-
1271 
surgical IXT treatment.  Although the greater magnitude of response with poorer baseline control 
1272 
may have been at least partly attributable to regression to the mean and having more room for 
1273 
improvement, the same magnitude of response was not seen in the observation group, suggesting 
1274 
that the larger treatment effect with poorer baseline control observed when treating with 
1275 
overminus spectacles could be real.23   
1276 
 
1277 
These planned subgroup analyses will repeat the primary analysis, adding the baseline factor and 
1278 
the baseline factor by treatment interaction. It is acknowledged that these analyses have very low 
1279 
power and only very strong interactions will be able to be detected. Any observed subgroup 
1280 
effects will require confirmation in a full-scale trial to be considered true effects. 
1281 
 
1282 
5.5.12 Masking Assessment  
1283 
At the 8-week visit, the proportion of masked examiners who responded that the patient appears 
1284 
to be wearing prism glasses will be compared between treatment groups using a two-sided 
1285 
Barnard’s test with alpha of 0.05, with calculation of a two-sided 95% confidence interval on the 
1286 
difference in proportions.   
1287 
 
1288 
5.6 
Sample Size and Analysis for Prism Adaptation Testing Screening Study  
1289 
In addition to the randomized trial, a separate analysis will include participants undergoing prism 
1290 
adaptation testing as part of screening for the randomized trial. The participants to be included 
1291 
will have met all randomized trial eligibility criteria other than that relating to the outcome of the 
1292 
prism adaptation test.   
1293 

 
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5-5 
 
1294 
No formal sample size has been calculated.  The convenience sample size will range between 64 
1295 
to 100 participants, depending on the number of participants screened with prism adaptation test 
1296 
in order to enroll 64 participants in the randomized trial.      
1297 
 
1298 
The analysis will be to estimate the proportion (and 95% confidence interval) of prism adaptation 
1299 
test-screened participants who fully prism adapt, defined as PACT after wearing relieving prism 
1300 
for 30 minutes (measured through the prism) ≥ original PACT (measured without prism) at both 
1301 
distance and near.  The prism adaptation tests from the initial enrollment visit will be included 
1302 
for analysis; repeat enrollment prism adaptation tests will be excluded.     
1303 

 
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6-1 
CHAPTER 6 REFERENCES 
1304 
 
1305 
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1306 
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1307 
2. Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of amblyopia and strabismus in 
1308 
African American and Hispanic children ages 6 to 72 months. The Multi-ethnic Pediatric Eye 
1309 
Disease Study. Ophthalmology 2008;115:1229-1236 e1221. 
1310 
3. Friedman DS, Repka MX, Katz J, et al. Prevalence of amblyopia and strabismus in white and 
1311 
African American children aged 6 through 71 months. The Baltimore Pediatric Eye Disease 
1312 
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1313 
4. Chia A, Dirani M, Chan YH, et al. Prevalence of amblyopia and strabismus in young 
1314 
singaporean chinese children. Invest Ophthalmol Vis Sci 2010;51:3411-3417. 
1315 
5. Nusz KJ, Mohney BG, Diehl NN. Female predominance in intermittent exotropia. Am J 
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Ophthalmol 2005;140:546-547. 
1317 
6. Chia A, Roy L, Seenyen L. Comitant horizontal strabismus: an Asian perspective. Br J 
1318 
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1319 
7. McKean-Cowdin R, Cotter SA, Tarczy-Hornoch K, et al. Prevalence of amblyopia or 
1320 
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8. Hatt SR, Gnanaraj L. Interventions for intermittent exotropia. Cochrane Database Syst Rev 
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9. Hatt SR, Leske DA, Mohney BG, Brodsky MC, Holmes JM. Classification and 
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10. Coffey B, Wick B, Cotter S, Scharre J, Horner D. Treatment options in intermittent 
1328 
exotropia: a critical appraisal. Optom Vis Sci 1992;69:386-404. 
1329 
11. Cooper J, Medow N. Intermittent exotropia, basic and divergence excess type. Binocul Vis 
1330 
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1331 
12. Pratt-Johnson JA, Tillson G. Prismotherapy in intermittent exotropia. A preliminary report. 
1332 
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1333 
13. Veronneau-Troutman S, Shippman S, Clahane AC. Prisms as an orthoptic tool in the 
1334 
management of primary exotropia. In: S. M, Mein J, Stockbridge L (eds), Orthoptics Past 
1335 
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1337 
14. Caloroso E, Cotter SA. Prescribing prisms for strabismus. In: Cotter SA (ed), Clincal uses of 
1338 
prism: a spectrum of applications. St. Louis: Mosby; 1995:193-234. 
1339 
15. Cotter SA, Franz KA. Therapeutic uses of prism for binocular vision disorders. In: Tasman 
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W, Jaeger EA (eds), Duane's ophthalmlogy. Philadelphia: Lippincott Williams & Wilkins; 
1341 
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1342 
16. Veronneau-Troutman A. Prismotherapy. Prisms in the medical and surgical management of 
1343 
strabismus. St. Louis: Mosby; 1994:107-143. 
1344 
17. London R. Passive treatments for early onset strabismus. In: Scheiman MM, London R (eds), 
1345 
Problems in optometry : Pediatric optometry. Philadelphia: JB Lippincott; 1990:480. 
1346 
18. Roper-Hall G. Optical management in strabismus: simple, advanced, and unconventional 
1347 
techniques. Am Orthopt J 2005;55:144-157. 
1348 
19. Helmholtz HV. Hanbuch der physiologischen optik. English. Helmholt's treatise on 
1349 
physiological optics, Translated from the 3rd German edition. New York: Dover 
1350 
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20. Repka MX, Connett JE, Scott WE, Prism Adaptation Study Research Group. The one-year 
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surgical outcome after prism adaptation for the management of acquired esotropia. 
1353 
Ophthalmology 1996;103:922-928. 
1354 
21. Pediatric Eye Disease Investigator Group. A randomized trial comparing part-time patching 
1355 
with observation for children 3 to 10 years of age with intermittent exotropia. Ophthalmology 
1356 
2014;121:2299-2310. 
1357 
22. Pediatric Eye Disease Investigator Group. A randomized trial comparing part-time patching 
1358 
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1359 
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1360 
23. Chen AM, Holmes  JM, Chandler DL, et al. A randomized trial evaluating short-term 
1361 
effectiveness of overminus lens therapy in children 3 to 6 years of age with intermittent 
1362 
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24. Pediatric Eye Disease Investigator Group. A randomized trial comparing bilateral lateral 
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1365 
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25. Hatt SR, Mohney BG, Leske DA, Holmes JM. Variability of control in intermittent 
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26. Hatt SR, Liebermann L, Leske DA, Mohney BG, Holmes JM. Improved assessment of 
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27. Pan Y, Tarczy-Hornoch K, Cotter SA, et al. Visual acuity norms in pre-school children: the 
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28. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual 
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1375 
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1376 
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1377 
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