A Randomized Trial of Bilateral Lateral Rectus Recession Versus Unilateral Lateral Rectus Recession With Medial Rectus Resection for Intermittent Exotropia
Phase: NA
Conditions: Exotropia
Sponsor: Jaeb Center for Health Research

 
IXT1 Protocol v5.0 21Jun17 
 
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INTERMITTENT EXOTROPIA STUDY 1 
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(IXT1) 
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A Randomized Trial of Bilateral Lateral 
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Rectus Recession versus Unilateral Lateral 
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Rectus Recession with Medial Rectus 
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Resection for Intermittent Exotropia 
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PROTOCOL 
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Version 5.0 
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June 21, 2017 
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IXT1 Protocol v5.0 21Jun17 
INTERMITTENT EXOTROPIA STUDY 1 (IXT1) 
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A Randomized Trial of Bilateral Lateral Rectus Recession versus Unilateral Lateral Rectus 
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Recession with Medial Rectus Resection for Intermittent Exotropia 
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PROTOCOL AMENDMENT IV (6-21-17) 
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This amendment applies to subjects participating in the optional extension study from >3 years 
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to 8 years after randomization, which is described in Protocol Amendment II.  
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Protocol Change #1 
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Current Protocol (Protocol Amendment III 6-18-15) 
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Symptoms of diplopia are not assessed in the current version of the protocol.  
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Proposed Change 
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To assess symptoms of diplopia by asking subjects to complete the Diplopia Questionnaire at the 
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8-year visit.   
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Rationale for Change 
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Diplopia (double vision) is an important long-term outcome following surgery for strabismus and 
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may be an adverse effect of either or both the surgical approaches used in the study. We 
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proposed to collect standardized data to determine the frequency of this potential adverse effect 
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and whether it differs between treatment groups.  The Diplopia Questionnaire1 is a validated, 
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reliable 8-item self-administered questionnaire designed to assess the presence and frequency of 
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diplopia in specific gaze positions.   
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IXT1 Protocol v5.0 21Jun17 
INTERMITTENT EXOTROPIA STUDY 1 (IXT1) 
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A Randomized Trial of Bilateral Lateral Rectus Recession versus Unilateral Lateral Rectus 
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Recession with Medial Rectus Resection for Intermittent Exotropia 
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PROTOCOL AMENDMENT III (6-18-15) 
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This amendment applies to subjects participating in the optional extension study described in 
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Protocol Amendment II.  
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Protocol Change #1 
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Current Protocol (Protocol Amendment II 2-10-15) 
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 In the additional 5 years of follow up provided for by Protocol Amendment II (>3 years to 8 
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years after randomization), the study will cover the costs of each annual visit because they 
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include testing procedures that are not standard care in all practices.  Any other visits that are 
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part of routine care will be the subject’s (or his/her insurance companies) responsibility.   
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Proposed Change 
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In the additional 5 years of follow up provided for by Protocol Amendment II (>3 years to 8 
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years after randomization), the study will pay for visits specific to the research study, but will not 
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pay for usual care visits that would occur whether or not the child was in the study. The cost of 
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usual care visits will be the parent(s) or their insurance company’s responsibility.  
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Rationale for Change 
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Some visits will be needed as part of normal care; while some will be research related.  The 
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investigator will determine whether each annual visit is considered routine patient care or 
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specific to the research study.  
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IXT1 Protocol v5.0 21Jun17 
INTERMITTENT EXOTROPIA STUDY 1 (IXT1) 
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A Randomized Trial of Bilateral Lateral Rectus Recession versus Unilateral Lateral Rectus 
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Recession with Medial Rectus Resection for Intermittent Exotropia 
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PROTOCOL AMENDMENT II (2-10-15) 
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This optional amendment provides for study subjects to have an additional five years of follow 
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up after the 3-year primary outcome (>3 years to 8 years from randomization).  
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Objective 
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To compare long-term outcomes between subjects originally treated with bilateral lateral rectus 
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muscle recession versus unilateral lateral rectus recession with medial rectus resection for the 
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treatment of basic type and pseudo divergence excess type intermittent exotropia. 
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Protocol Specified Follow-up Visits  
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Visits will occur at 4, 5, 6, 7, and 8 years (±2 months) from randomization. Additional follow-up 
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visits are at investigator discretion.  
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Study Procedures and Data Collection 
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The following testing procedures will be performed in the following order:* 
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1. Health-Related Quality of Life Questionnaire (8-year visit only)  
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2. Diplopia Questionnaire (8-year visit only) 
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3. Visual acuity 
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 Testing will be performed using the electronic E-ETDRS testing protocol  
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 Testing must be performed in current refractive correction, if worn.    
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 If prism is currently prescribed, visual acuity testing should be performed with prism.   
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 If deliberate overminus** is currently prescribed, visual acuity testing should be 
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performed with the overminus correction.  
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 If visual acuity is 20/32 or worse (75 letters or less) in either eye, a manifest refraction 
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must be performed. If the examiner believes that the patient’s current correction is not 
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optimal, trial frames with new correction should be used for all testing at the visit.  This 
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includes testing visual acuity again, with the patient wearing trial frames.    
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4. Control of exodeviation assessment at distance and near #1:   
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 Testing must be performed in current refractive correction.   
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 If prism is currently prescribed, testing should be performed without prism.   
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 If deliberate overminus** is currently prescribed, testing should be performed in trial 
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frames without the overminus component of the prescription.   
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5. Preschool Randot stereoacuity testing at near (performed at 40 cm) 
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 Testing must be performed in current refractive correction.     
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 If prism is currently prescribed, stereoacuity testing should be performed with prism.   
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 If deliberate overminus** is currently prescribed, stereoacuity testing should be 
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performed with the overminus correction.   
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 Stereoacuity is tested immediately following the first assessment of control of the 
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exodeviation; no 10-minute break is needed.  
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6. Ocular alignment testing in prism or deliberate overminus (for patients currently prescribed 
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prism or deliberate overminus)   
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IXT1 Protocol v5.0 21Jun17 
 Measure ocular alignment at near only, in the primary position using cover/uncover, 
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SPCT and PACT  
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 This testing should be performed with prism or deliberate overminus (as applicable).   
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7. Control of exodeviation assessment at distance and near #2 (repeat) (see item #2) 
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 The second control testing is performed immediately after the previous testing—it does 
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not need to be performed before dissociative testing and no 10-minute break is needed.  
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 The same examiner should assess IXT control each of the three different times that 
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control is assessed during the annual study visit.   
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8. Ocular alignment in the primary position using cover/uncover, SPCT and PACT at distance 
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and near   
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 Testing must be performed in current refractive correction.   
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 If prism is currently prescribed, ocular alignment testing should be performed without 
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prism.   
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 If deliberate overminus** is currently prescribed, ocular alignment testing should be 
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performed in trial frames without the overminus component of the prescription.   
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9. Control of exodeviation assessment at distance and near #3 (repeat) (see item #2) 
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 The third control testing is to be performed immediately after the previous testing—it 
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does not need to be performed before dissociative testing and no 10-minute break is 
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needed.  
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 The same examiner should assess IXT control each of the three different times that 
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control is assessed during the annual study visit.   
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10. Cycloplegic refraction (7-year visit only)  
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 If the current correction at the 7-year visit is not optimal based on the cycloplegic 
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refraction, new spectacles should be prescribed.   
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*Testing procedures are performed as described in section 2.5 unless otherwise specified above.   
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**Deliberate overminus lenses = lenses that yield > 0.50 D more minus spherical equivalent (SE) 
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than the refraction SE.  
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All testing procedures are assessed unmasked.   
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At each annual visit, data on treatments used or prescribed, current refractive correction, and the 
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last refraction will be recorded.    
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Treatment  
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Treatment in the extension study is at investigator discretion, including non-surgical treatment 
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and reoperation.   
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Costs 
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The parent/guardian of each subject will be compensated $50 per visit for completion of each 
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annual protocol-specified follow-up visit (4-, 5-, 6-, 7-, and 8- year) for a maximum of $250.  If 
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there are extenuating circumstances, and the subject is unable to complete the annual study visits 
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without additional funds due to travel costs, additional funds may be provided. 
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In the additional 5 years of follow up provided for by Protocol Amendment II (>3 years to 8 
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years after randomization), the study will pay for visits specific to the research study, but will not 
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IXT1 Protocol v5.0 21Jun17 
pay for usual care visits that would occur whether or not the child was in the study. The cost of 
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usual care visits will be the parent(s) or their insurance company’s responsibility.  
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Treatment is at investigator discretion and is not part of this protocol.  Any costs associated with 
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treatment will not be paid for by the study.  The study will pay for a pair of spectacles (lenses 
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and frames) at the 7-year visit; spectacle changes / new spectacles prescribed at other times will 
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not be paid for by the study.   
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Risks 
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The procedures in this study are part of daily eye care practice in the United States and pose no 
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known risks.  
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Subject Contact During Follow Up  
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Between annual visits, subjects will be called by the Jaeb Center to promote retention; birthday 
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and holiday cards will be sent annually, and a subject newsletter may be sent.   
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Re-consenting of Subjects  
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An informed consent form for the extension study will be signed by parents who elect to 
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continue their child’s study participation. An assent for the extension study will be signed by the 
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participating subject, as applicable.  Re-consenting generally will occur at the 3-year visit but 
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could occur at other times either before or after participation in the 3-year study has ended.  A 
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subject (and respective parent) may withdraw from the study at any time.  
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Statistical Analysis 
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Statistical analyses will primarily be cross-sectional comparisons of outcomes including ocular 
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alignment, exotropia control, and stereoacuity between treatment groups at each annual visit.   
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The analysis of the primary basic IXT cohort  will be considered primary whereas the analyses in 
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the smaller primary pseudo divergence excess IXT cohort and the secondary cohort  will be 
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considered exploratory.  
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Statistical analyses may also be performed combining some or all of the cohorts.  
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A detailed statistical analysis plan will be written and finalized prior to the completion of the 
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study and may supersede the plan briefly described herein.  
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IXT1 Protocol v5.0 21Jun17 
INTERMITTENT EXOTROPIA STUDY 1 (IXT1) 
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A Randomized Trial of Bilateral Lateral Rectus Recession versus Unilateral Lateral Rectus 
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Recession with Medial Rectus Resection for Intermittent Exotropia 
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PROTOCOL AMENDMENT (4-30-10) 
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This amendment provides for the following protocol changes:  
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Protocol Change #1 
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Current Protocol 
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One of the eligibility criteria requires the largest exodeviation at either distance or near to be 
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between 15 and 50 PD (inclusive) by prism and alternate cover test (PACT). 
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Proposed Change 
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Change the eligibility criteria to require that the largest exodeviation at either distance, near, or 
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remote distance be between 15 and 50 PD (inclusive) by prism and alternate cover test (PACT) 
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(sections 1.3, 1.4, 2.2.1, and 6.1).  Add an additional eligibility criterion requiring that the 
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exodeviaton must be at least 15 PD at distance or near (sections 1.3, 1.4, and 2.2.1).   
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Rationale for Change 
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Surgical dose must be based on the largest angle uncovered by PACT at distance (6 meter), near, 
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or remote distance (at least 50 feet). The largest angle in the surgical dose tables in the protocol 
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is 50 PD because BLRrec is considered by many clinicians to be inadequate for correcting angles 
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larger than 50 PD.  Because randomization would not be appropriate for patients with angles 
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greater than 50 PD, the eligibility criteria is being tightened to exclude not only patients with 
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distance or near angles >50 PD, but also those patients with remote distance angles >50 PD.  
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Because one of the criteria for surgical success at 3 years requires a reduction of more than 10PD 
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in the largest of the distance and near angles at enrollment, the additional eligibility criteria 
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requiring that the angle be at least 15 PD at distance or near was needed to ensure that more than 
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10 PD improvement would be possible in at least the distance or the near angles.   
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Protocol Change #2 
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Current Protocol 
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There is no upper limit on the amount of hyperopia allowed for eligibility. Refractive correction is 
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required for patients with hyperopia >+5.00 D and the guidelines for prescribing refractive correction 
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specify that residual (uncorrected) hyperopia cannot exceed +5.00 D.    
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Proposed Change 
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Add an eligibility criterion which specifies ‘no hyperopia greater than +3.50 D spherical 
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equivalent (SE) in either eye’ (sections 1.3, 1.4, and 2.2.1). Omit from the enrollment chapter the 
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guideline requiring spectacle correction be prescribed for hyperopia >+5.00 D and the guideline 
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requiring that spectacle correction have no more than +5.00 D residual hyperopia (section 2.2.1).  
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For follow up, change to require refractive correction for patients with hyperopia >+3.50D 
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(section5.3.1) and change refractive correction guidelines to specify that residual (uncorrected) 
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hyperopia cannot exceed +3.50 D (section5.3.2).          
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IXT1 Protocol v5.0 21Jun17 
Rationale for Change 
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The proposed changes are to make refractive error eligibility and prescription guidelines 
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consistent with those in the IXT2 study.  The reasons for this change are as follows: 1) it was felt 
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that making these items parallel between the two studies will avoid confusion among study 
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investigators, 2) it is expected that the percentage of otherwise-eligible IXT patients with 
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hyperopia greater than +3.50 D SE is very low, and 3) that patients with very high hyperopia 
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might be more likely to have a neurologic condition and might be a different than the typical IXT 
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patient 
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Protocol Change #3 
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Current Protocol 
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All patients are randomized regardless of whether the magnitude of their exodeviation increased or 
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decreased out of study eligibility range (15 to 50 PD) before surgery has occurred.     
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Proposed Change 
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Patients in whom the magnitude of the largest of the most recent distance, near, and remote 
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distance angles has decreased to <15 PD or increased to >50 PD before surgery will be dropped 
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from the study if they have not yet been randomized. If such patients have already been 
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randomized, it is at investigator discretion whether to perform surgery and what type of surgical 
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method to perform (i.e. BLRrec, R&R, or any other type of procedure). Changes made to 
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sections 2.6 and 3.1.    
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Rationale for Change 
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The study is aiming to evaluate surgical outcomes in patients whose largest preoperative angle is 
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between 15 and 50 PD.  Given that the surgery window extends to 60 days after enrollment and 
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that surgery could potentially occur even later, it is possible that a patient’s exotropia could 
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increase or decrease out of the eligibility range of 15 to 50 PD before surgery. As discussed in 
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protocol change #1 above, randomization to BLRrec or R&R would not be appropriate in 
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patients whose angle was greater than 50 PD.  In addition, the largest preoperative angle is 
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required to be a minimum of 15 PD to ensure that a reasonable amount improvement would be 
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required to meet one of the study’s treatment success criteria--an exodeviation less than 10 PD 
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by PACT at distance and near and reduction of more than 10 PD from largest of distance and 
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near angles at enrollment. 
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Protocol Change #4 
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Current Protocol 
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Currently the surgical dose tables start with doses for 15 PD angles.   
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Proposed Change 
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In surgical dose tables 1 and 2 (section 3.3), removed 15 PD angles, added 16 PD angles using 
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the 15 PD doses, and added 18 PD angles using the 20 PD doses. 
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Rationale for Change 
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There was an inconsistency between the angles listed in the surgical dose tables and the prism 
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increments that the IXT1 Procedures Manual specifies should be used for measuring ocular 
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IXT1 Protocol v5.0 21Jun17 
alignment. Prisms in 2 PD increments should be used for angles between 10 and 20 PD, therefore 
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an angle between 15-20 PD could be measured as 16 PD or 18 PD, but not as 15 PD.   
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Protocol Change #5 
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Current Protocol 
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Control of exodeviation is measured at enrollment only.   
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Proposed Change 
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Control of exodeviation would be measured at masked exams as well as at enrollment (sections 
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1.3 and 4.5).  
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Rationale for Change 
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Although control of exodeviation will not be included in the definition of the primary outcome of 
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surgical failure, it is felt worthwhile to evaluate whether patients who received one type of 
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surgical procedure might have better control if their exodeviation persists or recurs, particularly 
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if the primary analysis does not find a difference in surgical failure rates between the two 
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procedures. 
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Protocol Change #6 
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Current Protocol 
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Currently the protocol is inconsistent with regard to whether treatment with overminus refractive 
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correction is allowed during postoperative follow up. The protocol on post-operative treatment 
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(section 4.1) indicates that any non-surgical treatment of any overcorrection, undercorrection, or 
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deviations associated with diplopia is at investigator discretion at any time during the study.  
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However, the guidelines for refractive correction during follow-up (section 5.3.2) indicate that 
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deliberate overminus using refractive correction with more than 0.50 D of overminus will not be 
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allowed.   
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Proposed Change 
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The prohibition of deliberate overminus with more than 0.50 D of overminus will be removed 
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from the refractive correction guidelines during follow up (section 5.3.2), although it will be 
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retained in the refractive correction guidelines for enrollment. 
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Rationale for Change 
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This change resolves a protocol inconsistency.   
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Protocol Change #7 
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Current Protocol 
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Mandatory treatment with prism is currently required for patients with a constant esotropia of 
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greater than 6 PD at distance and near at 8 weeks, however the level of constant esotropia at 
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distance and near which constitutes surgical failure at 6 months or later is at least 6 PD.  
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Proposed Change 
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Require mandatory treatment with prism at 8 weeks for patients with a constant esotropia of at 
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least 6 PD at distance and near (sections 1.4, 4.1, and 4.4.1).   
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IXT1 Protocol v5.0 21Jun17 
 
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Rationale for Change 
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Although these concepts are different—i.e. what level of constant esotropia should receive 
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mandatory prism treatment for patient safety, and what level is appropriate for determining 
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surgical failure—it was felt it would be less confusing and easier for investigators to remember if 
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the cutoffs used were identical.       
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Protocol Change #8 
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Current Protocol 
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The current protocol does not specify whether patients wearing prism and/or overminus should 
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have clinical assessments performed with prism and/or overminus, or without.   
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Proposed Change 
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Clarified refractive correction to be used for testing during follow-up (section 4.3, 4.4, 4.5).  
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Ocular alignment testing (and control assessments at masked exams) should be performed in 
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current correction without any prism or deliberate overminus that has been prescribed.  
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Stereoacuity testing and visual acuity testing should be performed in current correction with any 
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prism or deliberate overminus that has been prescribed.  
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Rationale for Change 
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For ocular alignment, it was felt that the patient’s true deviation should be assessed and that this 
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would best be achieved by taking measurements in current correction but without prism and 
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without overminus 
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For stereoacuity and visual acuity testing, it was felt that we should measure the patient’s best 
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stereoacuity and visual acuity, which for patients prescribed prism and/or deliberate overminus 
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would likely be achieved with current correction including prism and/or deliberate overminus. 
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Protocol Change #9  
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Current Protocol 
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Protocol change #8 specifies that during follow up, stereoacuity testing should be performed with 
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any prism or deliberate overminus that has been prescribed.  
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Proposed Change 
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At the 3-year visit, patients who are currently prescribed prism and/or deliberate overminus will 
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have Preschool Randot Stereoacuity at near repeated without wearing prism or overminus 
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(sections 4.5.3 and 6.3.1). This additional Preschool Randot retest without prism and without 
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overminus should occur after all initial stereoacuity testing has been completed (ie. after the 
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Titmus Fly at near) and before the control of exodeviation assessment. This testing without prism 
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and overminus is for an exploratory analysis and is not considered in the determining whether 
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the patient meets surgical failure criteria.             
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Rationale:  
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Although patients wearing prism will have stereoacuity measured with prism, is of interest to 
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know whether a patient classified as a success would still be classified as a success if the patient 
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had been measured without prism.  Because ‘success’ only applies to the 3-year visit (whereas 
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failure can be called at any visit from 6 months onward), we propose to measure stereoacuity 
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IXT1 Protocol v5.0 21Jun17 
both with prism and without prism at the 3-year visit only. The with-prism measurement will 
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count toward the primary outcome, and the without-prism measurement will be used in an 
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exploratory analysis which would avoid calling a patient a success at 3-years on the basis of a 
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better stereo that is enhanced by prism. The same logic should apply to patients wearing 
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deliberate overminus—ie. stereoacuity should be measured with the overminus throughout the 
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study but that it should be repeated without the overminus at the 3-year exam with this latter test 
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used in the exploratory analysis.    
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This amendment also provides for the following minor protocol clarifications:   
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 Clarified guidelines for prescribing the spherical component of refractive correction (sections 
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2.2.1 and 5.3.2)  
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 Specified test distances for stereoacuity testing and for ocular alignment testing (sections 2.5, 
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4.3, 4.4, 4.5).    
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 Clarified refractive error eligibility criteria that treatment with prism or overminus lenses 
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must be discontinued at least one week prior to enrollment (section 2.2.1).  
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 Clarified eligibility criteria that visual acuity in the worse eye must be ‘0.3 logMAR or 
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better,’ to eliminate confusion about whether ‘at least 0.3 logMAR’ meant at least 0.3 
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logMAR numerically (meaning worse acuity) or qualitatively (meaning better acuity) 
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(sections 1.4 and 2.2.1).    
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 Clarified that hangback, hemi-hangback, and adjustable techniques will not be allowed for 
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this protocol, however, the surgeon may make epi-scleral tickbites at the intended insertion 
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site and then bring the sutures forward to take a standard scleral bite at the original insertion 
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site (section 3.3).  
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IXT1 Protocol v5.0 21Jun17 
 
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CONTACT INFORMATION 
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COORDINATING CENTER 
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Raymond T. Kraker, M.S.P.H. (Director) 
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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 CHAIR 
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Sean P. Donahue, M.D., Ph.D. 
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Professor of Ophthalmology and Visual Sciences, 
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Sam and Darthea Chair in Ophthalmology 
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Chief, Pediatric Ophthalmology Service, Vanderbilt Children’s Hospital 
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Vanderbilt University Medical Center 
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2311 Pierce Avenue 
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Nashville, TN 37232 
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Phone:  (615) 936-1035 (Assistant: Bethany) 
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Fax (615) 936-1540 
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Pager (615) 831-4449 
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Home phone: (615) 377-9469  
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Email address:  Sean.donahue@vanderbilt.edu 
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IXT1 Protocol v5.0 21Jun17 
TABLE OF CONTENTS 
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CHAPTER 1: BACKGROUND AND SUMMARY .......................................................................................... 1-1 
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1.1 
Background ............................................................................................................................... 1-1 
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1.2 
Study Objective ........................................................................................................................ 1-2 
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1.3 
Synopsis of Study Design ......................................................................................................... 1-2 
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1.4 
Study Flow Chart ...................................................................................................................... 1-4 
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CHAPTER 2: ENROLLMENT AND RANDOMIZATION .......................................................................... 2-2 
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2.1 
Eligibility Assessment and Informed Consent ......................................................................... 2-2 
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2.2 
Eligibility and Exclusion Criteria ............................................................................................. 2-2 
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2.2.1 
Eligibility.............................................................................................................................. 2-2 
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2.2.2 
Exclusion Criteria ................................................................................................................. 2-3 
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2.3 
Determination of IXT Type ...................................................................................................... 2-4 
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2.4 
Historical Information .............................................................................................................. 2-5 
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2.5 
Examination Procedures at the Enrollment Visit...................................................................... 2-5 
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2.6 
Randomization .......................................................................................................................... 2-8 
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2.7 
Repeat Enrollment Visit ........................................................................................................... 2-8 
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CHAPTER 3: SURGICAL TREATMENT ......................................................................................................... 3-1 
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3.1 
Surgery Timing ......................................................................................................................... 3-1 
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3.2 
Surgical Treatment ................................................................................................................... 3-1 
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3.3 
Surgical Dose ............................................................................................................................ 3-1 
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CHAPTER 4: FOLLOW-UP .................................................................................................................................... 4-1 
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4.1 
Treatment .................................................................................................................................. 4-1 
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4.2 
Follow-up Visit Schedule ......................................................................................................... 4-1 
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4.3 
1-Week Follow-up Exam.......................................................................................................... 4-1 
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4.4 
8-Week Follow-up Exam.......................................................................................................... 4-2 
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4.4.1 
Management of Esotropia and Diplopia at the 8-week Exam .............................................. 4-3 
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4.5 
Masked Exams at Six-month Intervals from Six Months to 3 Years ....................................... 4-3 
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4.5.1 
Surgical Failure Criteria ....................................................................................................... 4-5 
498 
4.5.2 
Masked Examiner Testing .................................................................................................... 4-5 
499 
4.5.3 
Patients Wearing Prism and/or Deliberate Overminus at 3-Years ....................................... 4-6 
500 
4.6 
Additional Visits ....................................................................................................................... 4-6 
501 
4.7 
Re-operation ............................................................................................................................. 4-6 
502 
4.8 
Treatment of Amblyopia .......................................................................................................... 4-6 
503 
CHAPTER 5: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ......................................... 5-1 
504 
5.1 
Contacts by the Jaeb Center for Health Research ..................................................................... 5-1 
505 
5.2 
Patient Withdrawals .................................................................................................................. 5-1 
506 
5.3 
Management of Refractive Error .............................................................................................. 5-1 
507 
5.3.1 
Refractive Error Requiring Correction ................................................................................. 5-1 
508 
5.3.2 
Refractive Correction Guidelines ......................................................................................... 5-1 
509 
5.4 
Risks ......................................................................................................................................... 5-2 
510 
5.4.1 
Risks of Examination Procedures ........................................................................................ 5-2 
511 
5.4.2 
Risks of Surgery ................................................................................................................... 5-2 
512 
5.4.3 
Risk Assessment ................................................................................................................... 5-2 
513 
5.5 
Reporting of Adverse Events .................................................................................................... 5-2 
514 
5.6 
Discontinuation of Study .......................................................................................................... 5-2 
515 
5.7 
Travel Reimbursement ............................................................................................................. 5-2 
516 
5.8 
Study Costs ............................................................................................................................... 5-3 
517 
CHAPTER 6: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS ............................... 6-1 
518 
6.1 
Primary Data Analysis .............................................................................................................. 6-1 
519 
6.1.1 
Classification of Outcome .................................................................................................... 6-1 
520 
6.2 
Secondary Data Analysis .......................................................................................................... 6-2 
521 

 
IXT1 Protocol v5.0 21Jun17 
6.2.1 
Subgroup Analyses ............................................................................................................... 6-2 
522 
6.2.2 
Surgical Failure Proportion at 3 Year Timepoint ................................................................. 6-2 
523 
6.2.3 
Success Proportion at 3 Year Timepoint .............................................................................. 6-3 
524 
6.2.4 
Analysis of Secondary Outcomes ........................................................................................ 6-3 
525 
6.3 
Exploratory Analyses ............................................................................................................... 6-3 
526 
6.3.1 
Exploratory Analyses in Primary Cohort ............................................................................. 6-3 
527 
6.3.2 
Exploratory Analyses in Patients with Baseline Angle > 40 to 50 PD ................................ 6-3 
528 
6.4 
Safety Analyses ........................................................................................................................ 6-4 
529 
6.5 
Additional Tabulations and Analyses ....................................................................................... 6-4 
530 
6.6 
Interim Analysis ....................................................................................................................... 6-4 
531 
6.7 
Sample Size Estimation ............................................................................................................ 6-4 
532 
CHAPTER 7: REFERENCES ................................................................................................................................. 7-1 
533 
 
534 

 
 
CHAPTER 1: BACKGROUND AND SUMMARY 
535 
 
536 
This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and 
537 
funded through a cooperative agreement from the National Eye Institute.  It is one of a series of 
538 
randomized trials and observational studies underway or planned that address management of 
539 
intermittent exotropia. 
540 
 
541 
1.1 
Background 
542 
Intermittent exotropia (IXT) is the most common form of childhood onset exotropia with an 
543 
incidence of 32.1 per 100,000 in children under 19 years of age.2  Intermittent exotropia is 
544 
characterized by an exotropia that is not constant and is mainly present when viewing at distance, 
545 
but may also be present at near.  Normal binocular single vision (BSV) is typically present at 
546 
near when the exotropia is controlled, with evidence of normal (occasionally sub-normal) 
547 
stereoacuity.  Although the natural history of the condition is largely unknown, many children 
548 
with IXT are treated using either surgical or non-surgical interventions.  The rationale for 
549 
intervention in childhood IXT is that extended periods of misalignment may lead to entrenched 
550 
suppression, resulting in loss of BSV.  Intervention may also aim to address the social effects 
551 
caused by the appearance of misaligned eyes.  Many children treated for IXT are currently 
552 
treated surgically.3-5 
553 
 
554 
There is poor agreement as to which type of surgery is most effective for the correction of IXT 
555 
and the debate has long been related to differentiation between IXT sub-types.  Based on 
556 
distance-near angle disparity, IXT sub-types are classified as: 1) basic (similar magnitude of 
557 
misalignment at distance and near); 2) true divergence excess (larger at distance); 3) pseudo 
558 
divergence excess (initially larger at distance, but near angle increases following occlusion or 
559 
with addition of plus lenses at near); 4) convergence insufficiency (larger at near).  Basic and 
560 
pseudo divergence excess appear to be the most common of the sub-types,6 and are also the types 
561 
for which there is most disagreement regarding the optimum surgical approach.  The two most 
562 
common procedures are bilateral lateral rectus recession (BLRrec) and unilateral lateral rectus 
563 
recession combined with a medial rectus resection in the same eye (R&R).  Traditionally, 
564 
BLRrec has been advocated where there is a larger distance angle, and R&R where there is a 
565 
similar angle at distance and near.7,8  A survey of American strabismus surgeons published in 
566 
19909 found that the majority performed BLRrec for both basic and divergence excess types.  
567 
Similarly, we found by polling our investigator group that the majority still perform a BLRrec 
568 
for basic type IXT.  Nevertheless, controversy still exists as to which of these surgical 
569 
approaches is superior.10  Advocates of the BLRrec procedure tend to hold that surgery should be 
570 
based purely on the distance angle of deviation.5,11  Proponents of R&R surgery suggest 
571 
resection of the medial rectus best addresses the exodeviation at near.7,12   
572 
 
573 
The proposed advantage of the R&R procedure is that resecting the medial rectus, with a 
574 
possible longer term initial overcorrection, is necessary for a stable and superior long-term 
575 
outcome.  Nevertheless, those who favor the BLRrec procedure suggest that the more profound 
576 
and prolonged initial overcorrection occurring with R&R is not only unnecessary, but may in 
577 
fact be harmful.  A persistent overcorrection may be associated with the development of 
578 
diplopia, amblyopia, and loss of stereoacuity.  On the other hand, critics of the BLRrec 
579 
procedure suggest that long-term recurrence rates are higher.  Poor motor outcomes are likely to 
580 
require reoperation and therefore the long-term success rates of these surgeries have public 
581 
health importance in terms of cost to society.  
582 
 
583 

 
 
Evaluating initial and long-term surgical outcomes in the proposed RCT will answer questions 
584 
regarding the failure rates of these surgeries and also provide needed data on the potential harm 
585 
of each procedure.   
586 
 
587 
Only one prospective randomized clinical trial addresses success rates of BLRrec versus R&R 
588 
for IXT.12  After between 12-15 months of follow up, 82% of 17 patients undergoing an R&R 
589 
had a satisfactory outcome compared to 52% of 19 patients undergoing a BLRrec.  Nevertheless, 
590 
there are some important limitations of this previous study.  The sample size was very small.  
591 
The study population was a sub-group of patients with basic type IXT, excluding patients with 
592 
basic IXT whose angle of deviation increased at far distance or following occlusion, thus 
593 
limiting the generalizability of the results.  In addition, outcomes were assessed unmasked, 
594 
potentially biasing the results.  One observational study13 of 103 patients (90% of whom had 
595 
basic type IXT) found 1-year success rates of 56% for BLRrec and 60% for R&R.  A 
596 
retrospective study14 of 115 patients with basic type IXT reported success rates of 69% for 
597 
BLRrec and 77% for R&R after an average of 15 months of follow up.  Other studies comparing 
598 
surgery types are limited not only by retrospective study design but also by inclusion of other 
599 
types of exotropia, making it difficult to interpret results.  In addition, many different criteria for 
600 
success are used, precluding meaningful comparison of success rates between studies.  This lack 
601 
of evidence makes it very difficult to counsel parents of children with IXT regarding the likely 
602 
success and complication rate of either procedure, limiting our ability to make informed 
603 
management decisions.  Establishing the respective failure rates through the proposed study will 
604 
allow physicians to offer patients the type of surgery with the highest chance of long-term 
605 
success, minimizing suboptimal results and repeat surgeries.  
606 
 
607 
The present study is being conducted to compare the effectiveness of BLRrec with R&R for the 
608 
surgical treatment of basic type and pseudo divergence excess type IXT. 
609 
 
610 
1.2 
Study Objective 
611 
To evaluate the effectiveness of bilateral lateral rectus muscle recession versus unilateral lateral 
612 
rectus recession with medial rectus resection procedures for the treatment of basic type and 
613 
pseudo divergence excess type intermittent exotropia 
614 
 
615 
1.3 
Synopsis of Study Design 
616 
Major Eligibility Criteria (see sections 2.2 and 2.3 for a complete listing and definition of type of 
617 
IXT) 
618 
 Age 3 to < 11 years  
619 
 Intermittent exotropia (manifest deviation) meeting all of the following:  
620 
o Intermittent exotropia at distance OR constant exotropia at distance and either 
621 
intermittent exotropia or exophoria at near  
622 
o Exodeviation at least 10 PD at distance AND near by prism and alternate cover test 
623 
(PACT) 
624 
o Exodeviation at least 15 PD at distance OR near by PACT 
625 
o Largest exodeviation at either distance, near, or remote distance between 15 and 50 
626 
PD (inclusive)  
627 
o Basic type or pseudo divergence excess type (as defined in section 2.3) 
628 
 Stereoacuity of 400 arcsec or better at near by Preschool Randot stereotest (better of 2 
629 
measures) 
630 

 
 
 Visual acuity in the worse eye 0.3 logMAR or better (20/40 on ATS HOTV or 70 letters on 
631 
E-ETDRS)  
632 
 No interocular difference of visual acuity  more than 0.2 logMAR (2 lines on ATS HOTV or 
633 
10 letters on E-ETDRS testing) 
634 
 No hyperopia greater than +3.50 D spherical equivalent in either eye 
635 
 Absence of high AC/A ratio (exclude > 6:1) 
636 
 No previous intraocular surgery, strabismus surgery, or botulinum toxin treatment 
637 
 Investigator planning to perform surgery for correction of IXT 
638 
 
639 
Sample Size 
640 
189 patients with basic type IXT with largest exodeviation between 15 and 40 PD by PACT at 
641 
remote distance, distance, or near, and 189 patients with pseudo divergence excess type IXT with 
642 
largest exodeviation between 15 and 40 PD by PACT at remote distance, distance,  or near (total 
643 
of 378 patients).  Additional patients with exotropia > 40 PD to 50 PD will be enrolled during 
644 
recruitment of the above sample size. 
645 
 
646 
Treatment  
647 
Randomization (1:1) to surgical correction of IXT with a bilateral lateral rectus recession 
648 
(BLRrec) or a unilateral lateral rectus recession with medial rectus resection (R&R) 
649 
 
650 
Visit Schedule   
651 
 Enrollment  
652 
 Randomization (the day of surgery or the working day before surgery) 
653 
 Surgery 
654 
 1 week  3 days from surgery 
655 
 8 weeks  2 weeks from surgery 
656 
 6 months  1 month from randomization (masked) 
657 
 12 months ± 2 months from randomization (masked) 
658 
 18 months  2 months from randomization (masked) 
659 
 24 months ± 2 months from randomization (masked) 
660 
 30 months  2 months from randomization (masked) 
661 
 3-Year Primary Outcome Exam: 3 years  2 months from randomization (masked) 
662 
 
663 
Ocular alignment and visual acuity will be tested at each visit.  Control of the exodeviation will 
664 
be assessed at enrollment and at all masked exams. Stereoacuity will be tested at all visits except 
665 
the 1-week visit.  Health-related quality of life will be assessed at baseline, at 6 months, and at 3 
666 
years after randomization. 
667 
 
668 
Primary Analysis 
669 
As defined in the analysis plan, the primary analysis will consist of a treatment group 
670 
comparison of the proportion of patients who meet criteria for failure at the 3-year outcome 
671 
exam (section 4.5.1) among patients with largest baseline preoperative exodeviation between 15 
672 
and 40 PD by PACT at remote distance, distance, or near.  
673 
 
674 
Separate analyses will be conducted within groups defined by IXT type:   
675 
 Basic type IXT 
676 
 Pseudo divergence excess type IXT 
677 
678 

 
 
1.4 
Study Flow Chart 
679 
1.5 
680 
YES 
Bilateral lateral rectus recession (BLRrec) 
Unilateral recession-resection (R&R) 
Major Eligibility Criteria  
 Age 3 to < 11years 
 Intermittent exotropia (manifest deviation) meeting all of the following:  
o Intermittent exotropia at distance OR constant exotropia at distance and either intermittent exotropia or 
exophoria at near  
o Exodeviation at least 10 PD at distance AND near by PACT 
o Exodeviation at least 15 PD at distance OR near by PACT 
o Largest exodeviation at either distance, near, OR remote distance  between 15 and 50 PD (inclusive) by PACT 
o Basic type or pseudo divergence excess type (as defined in section 2.3) 
 Stereoacuity of 400 arcsec or better at near by Preschool Randot Stereotest 
 Visual acuity in the worse eye 0.3 logMAR or better (20/40 by ATS HOTV for patients < 7 years or 70 letters on 
E-ETDRS for patients ≥ 7 years old) 
 No interocular difference of visual acuity more than  0.2 logMAR (2 lines by ATS HOTV for patients < 7 years 
old or 10 letters by E-ETDRS for patients >=7 years old)   
 No hyperopia greater than +3.50 D spherical equivalent in either eye 
 Wearing appropriate spectacles or contact lenses for at least one week if refractive error meets refractive 
correction criteria 
 Absence of high AC/A ratio (exclude >6:1) 
 No previous strabismus surgery or botulinum toxin treatment 
 No previous intraocular eye surgery or refractive surgery 
 No ocular disorders which would reduce visual acuity (other than refractive error) 
 No coexisting vertical deviation, oblique muscle dysfunction, and A or V pattern,  if condition warrants vertical 
transposition of horizontal rectus muscles, oblique surgery, or vertical rectus muscle surgery 
 No limitation of ocular rotations due to restrictive or paretic strabismus 
 No significant neurological impairment such as cerebral palsy   
 Investigator wishes to perform surgery for correction of IXT 
 
Enrollment Testing Procedures 
 Health-related quality of life questionnaire 
 Stereoacuity testing with current correction  
o 
Preschool Randot at near - if stereoacuity is worse than 40 arcsec, retest and use better of 2 measurements 
for eligibility  
o 
Distance Randot 
o 
Titmus Fly/Circles at near  
 IXT control at distance and near 
 Ocular alignment with current correction tested using cover/uncover, SPCT, and PACT, at distance, remote 
distance (PACT only), and near  
 Visual acuity with current correction and using ATS HOTV (patients < 7 years old) or E-ETDRS (patients ≥ 7 
years old)  
 Ocular exam (if not done in last 6 months) 
 Cycloplegic refraction (if not done in last 6 months) 
Randomize (the day of surgery or working day before) 
1 week ± 3 days after surgery 
 Ocular alignment in primary at distance and near (cover/uncover, SPCT and PACT) in current refractive 
correction without any prescribed prism or overminus 
 Visual acuity testing using ATS HOTV or E-ETDRS (use same method as at enrollment) in current refractive 
correction with any prescribed prism or overminus 
Surgery 
NO 

 
IXT1 Protocol v5.0 21Jun17 
  
1-1 
 
 
 
681 
 
 
682 
If 30-month visit 
If 30-month visit 
Are any of the surgical failure criteria met? (see above) 
No – End of study 
Yes – Surgical failure 
End of study 
No – continue follow-up 
Yes – Surgical failure 
 Investigator may re-operate 
 Continue follow-up 
Primary Outcome Exam (Masked) 3 years ± 3 months after surgery 
 
Health-related quality of life questionnaire 
 
Same testing as visits occurring between 6 months and 30 months 
 
For patients wearing prism or deliberate overminus, after the initial stereoacuity testing, the Preschool Randot        
at near should be repeated in current refractive correction without prism or deliberate overminus.    
Are any of the surgical failure criteria met? 
 Exotropia at distance OR near at any time during the exam with a magnitude of at least 
10 PD by SPCT, confirmed by a retest 
 Constant esotropia at least 6 PD by SPCT at distance OR near, confirmed by a retest 
 Decrease in Preschool Randot near stereoacuity at least 2 octaves from enrollment, or 
to nil, confirmed by a retest 
8 weeks ± 2 weeks after surgery 
 Stereoacuity testing (Preschool Randot at near, Distance Randot, and Titmus Fly & Circles at near) in current 
refractive correction with any prescribed prism or overminus 
 Ocular alignment with in primary at distance and near (cover/uncover, SPCT and PACT) in current refractive 
correction without any prescribed prism or overminus 
 Visual acuity testing using ATS HOTV or E-ETDRS (use same method as at enrollment) in current refractive 
correction with any prescribed prism or overminus 
Constant ET at least 6 PD by SPCT at distance AND near? 
Masked exams every 6 months between 6 and 30 months after surgery 
 Health-related quality of life questionnaire (6-month exam only) 
 Stereoacuity testing (Preschool Randot at near, Distance Randot, Titmus Fly & Circles at near) in current 
refractive correction with any prescribed prism or overminus – Masked  
 IXT control at distance and near in current refractive correction without any prescribed prism or overminus - 
Masked 
 Ocular alignment, in primary at distance and near (cover/uncover, SPCT and PACT) in current refractive 
correction without any prescribed prism or overminus - Masked 
 Retesting of stereoacuity and/or ocular alignment to confirm surgical failure Masked (if required—see section 
4.5.1)   
 Visual acuity testing using ATS HOTV or E-ETDRS (use same method as at enrollment) in current refractive 
correction with any prescribed prism or overminus 
 Cycloplegic refraction (if not performed within the last 12 months) 
Manage with prism 
Manage at investigator discretion 
 

 
IXT1 Protocol v5.0 21Jun17 
  
2-2 
 
 
CHAPTER 2: ENROLLMENT AND RANDOMIZATION 
683 
 
684 
2.1 
Eligibility Assessment and Informed Consent 
685 
A minimum of 378 subjects (189 with basic type IXT and 189 with pseudo divergence excess 
686 
type IXT) are expected to be enrolled for the primary cohort (section 6.1), with a goal to enroll 
687 
an appropriate representation of minorities.  An additional 76 patients are expected to be enrolled 
688 
for the secondary cohort (section 6.3) during recruitment for the primary cohort.  As the 
689 
enrollment goal approaches, sites will be notified of the end date for recruitment.  Subjects who 
690 
have signed an informed consent form can be randomized up until the end date, which means the 
691 
expected recruitment might be exceeded.  The maximum number of randomized subjects will be 
692 
474. 
693 
 
694 
For patients who appear eligible for the study following a “standard-care” or preliminary 
695 
examination, the study will be discussed with the child’s parent(s) or guardian(s) (referred to 
696 
subsequently as parent(s)).  Parent(s) who express an interest in the study will be given a copy of 
697 
the informed consent form to read.  Written informed consent must be obtained from the parent 
698 
prior to performing any study-specific procedures that are not part of the patient’s routine care. 
699 
 
700 
2.2 
Eligibility and Exclusion Criteria 
701 
2.2.1 
Eligibility 
702 
The following criteria must be met for the patient to be enrolled in the study: 
703 
1. Age 3 to < 11 years  
704 
2. Intermittent exotropia (manifest deviation) meeting all of the following:  
705 
 Intermittent exotropia at distance OR constant exotropia at distance and either 
706 
intermittent exotropia or exophoria at near  
707 
 Exodeviation at least 10 PD at distance AND near by PACT 
708 
 Exodeviation at least 15 PD at distance OR near by PACT 
709 
 Largest exodeviation at distance, near OR remote distance between 15 and 50 PD 
710 
(inclusive) by PACT 
711 
 Basic type or pseudo divergence excess type (as defined in section 2.3) 
712 
3. Stereoacuity of 400 arcsec or better at near by Preschool Randot stereotest (better of 2 
713 
measures if initial test shows worse than 40 arcsec) 
714 
4. Visual acuity in the worse eye 0.3 logMAR or better (20/40 by ATS HOTV for patients < 7 
715 
years old or 70 letters E-ETDRS testing for patients ≥ 7 years old) 
716 
5. No hyperopia greater than +3.50 D spherical equivalent in either eye 
717 
6. Patients must be wearing spectacles or contact lenses for at least one week if refractive error 
718 
(based on cycloplegic refraction performed within 6 months prior to enrollment) meets any 
719 
of the following: 
720 
 Myopia > -0.50 D spherical equivalent in either eye 
721 
 Anisometropia > 1.00 D spherical equivalent 
722 
 Astigmatism > 2.00 D in either eye if ≤ 5 years old and > 1.50 D if > 5 years old   
723 
Refractive correction for patients meeting the above refractive error criteria must meet the 
724 
following guidelines:  
725 
 Anisometropia spherical equivalent must be within 0.25 D of full correction. 
726 

 
IXT1 Protocol v5.0 21Jun17 
  
2-3 
 
 
 Astigmatism cylinder must be within 0.25 D of full correction and axis must be 
727 
within 5 degrees of full correction.   
728 
 For hyperopia, the spherical component can be reduced at investigator discretion 
729 
provided the reduction is symmetrical.  Prescribing any refractive correction to yield 
730 
lenses that are more myopic than -0.50 D spherical equivalent (SE) is considered 
731 
deliberate overminus and is not allowed at enrollment. However, prescribing no 
732 
correction or prescribing less than the full cycloplegic hyperopic correction (i.e., 
733 
prescribing reduced plus) is not considered the same as overminusing for this protocol 
734 
and is allowed because most patients without intermittent exotropia and hyperopic SE 
735 
refractions in this range would not typically be prescribed a refractive correction.   
736 
 
For myopia, the intent is to fully correct, but the spherical component can be 
737 
undercorrected by investigator discretion provided the reduction is symmetrical and 
738 
results in no more than -0.50 D SE residual (i.e., uncorrected) myopia. Prescribing a 
739 
correction that yields more than 0.50 D more minus SE than the cycloplegic refraction 
740 
SE is considered deliberate overminus and is not allowed at enrollment. 
741 
Patients who have undergone treatment with prism or deliberate overminus refractive 
742 
correction (as defined above) must have discontinued prism and/or any deliberate 
743 
overminus for at least one week prior to enrollment.   
744 
Note that the refractive correction guidelines and the requirement to wear refractive 
745 
correction for at least one week apply not only to patients who require refractive correction 
746 
under the above criteria but also to any other patient who is wearing refractive correction.  
747 
7. No atropine use within the last week 
748 
8. Gestational age > 34 weeks 
749 
9. Birth weight > 1500 grams 
750 
10. Investigator plans to perform surgery, is willing to perform either surgical procedure, and is 
751 
not planning to use adjustable sutures.  
752 
11. Parent understands protocol, has agreed to surgery, and is willing to accept randomization to 
753 
one-eye surgery or two-eye surgery 
754 
12. Parent has home phone (or access to phone) and is willing to be contacted by Jaeb Center 
755 
staff 
756 
13. Relocation outside of area of an active PEDIG site within next 3 years is not anticipated 
757 
 
758 
2.2.2 
Exclusion Criteria 
759 
1. Coexisting vertical deviation, oblique muscle dysfunction, DVD, or A or V pattern, any of 
760 
which the investigator plans to address with vertical transposition of horizontal rectus 
761 
muscles, oblique surgery, or vertical rectus muscle surgery, i.e., only small vertical 
762 
deviations, oblique muscle dysfunction, DVD, and A or V patterns not requiring surgery are 
763 
allowed 
764 
2. Limitation of ocular rotations due to restrictive or paretic strabismus 
765 
3. Craniofacial malformations affecting the orbits 
766 
4. Interocular visual acuity difference of more than 0.2 logMAR (2 lines on ATS HOTV 
767 
for patients 3 to < 7 years old or 10 letters on E-ETDRS for patients ≥ 7 years old) 
768 
and/or investigator plans to initiate amblyopia treatment at this time.   
769 

 
IXT1 Protocol v5.0 21Jun17 
  
2-4 
 
 
5. High AC/A ratio (exclude > 6:1 by gradient method) 
770 
6. Prior strabismus surgery or botulinum toxin injection 
771 
7. Ocular disorders that would reduce visual acuity (except refractive error) 
772 
8. Prior intraocular or refractive surgery 
773 
9. Significant neurological impairment such as cerebral palsy.  Patients with mild speech and/or 
774 
learning disabilities are eligible.  
775 
10. Investigator planning to change refractive correction at this time (if the patient is otherwise 
776 
eligible, the investigator should consider prescribing refractive correction and bringing the 
777 
patient back at a later time for enrollment). 
778 
 
779 
2.3 
Determination of IXT Type  
780 
IXT will be classified (see classification below) at enrollment prior to randomization as: 
781 
 Basic Type 
782 
 Pseudo Divergence Excess Type 
783 
 
784 
The following types of IXT are not eligible: 
785 
 True Divergence Excess Type 
786 
 Convergence Insufficiency Type 
787 
 High AC/A Type 
788 
 
789 
Classification of IXT type will be done as follows (also see flowchart on next page):   
790 
 
791 
Using the PACT at distance and near:  
792 
 If the measured deviation at near is > 10 PD larger than at distance, the IXT is classified as 
793 
convergence insufficiency type.  
794 
 If the distance and near deviations are within 10 PD of one another, the IXT is classified as 
795 
basic type.   
796 
 If the measured deviation at distance is > 10 PD larger than at near, +3.00 D lenses should be 
797 
placed over the current correction (using trial frames or Halberg clips) and the deviation at 
798 
near should be re-measured by the PACT. 
799 
o If the angles equalize (distance and near within 10 PD) OR near exceeds distance by > 10 
800 
PD, the +3.00 D lenses at near should be removed and -2.00 D lenses should be placed 
801 
over the current correction (using trial frames or Halberg clips) and the deviation at 
802 
distance should be re-measured.  
803 
 If the distance angle with the -2.00 D lenses decreases by > 12 PD (compared to 
804 
the distance measure without the -2.00 D lenses), the IXT type is classified as 
805 
high AC/A type; otherwise the IXT type is classified as pseudo divergence 
806 
excess type. 
807 
o If the distance angle exceeds near by > 10 PD measured with the +3.00 D lenses at near, 
808 
the patient should be occluded for 45 minutes, after which the distance and near 
809 
deviations should be measured again in the current refractive correction, while 
810 
maintaining the dissociation.  If the near and distance deviations equalize (within 10 PD) 
811 
or if near exceeds distance, the type of IXT is classified as pseudo divergence excess 
812 
type.  Otherwise, the type IXT is classified as true divergence excess type. 
813 
 
814 

 
IXT1 Protocol v5.0 21Jun17 
  
2-5 
 
 
 
815 
2.4 
Historical Information 
816 
Historical information elicited will include the following: date of birth, gender, race, ethnicity, 
817 
prior treatment, and spectacle correction.  In addition, investigators will be asked to provide the 
818 
reason(s) for performing surgery. 
819 
 
820 
2.5 
Examination Procedures at the Enrollment Visit  
821 
1. Health-Related Quality of Life Questionnaire: Health-related quality of life (HRQOL) will be 
822 
assessed using the Intermittent Exotropia Questionnaire (IXTQ).15  This questionnaire 
823 
consists of 3 components:  
824 
1. Child questionnaire (for children ages 5 years or older) – consists of 12 items which 
825 
assess how the child feels about his/her eye condition.  
826 
o The version for children aged 5 to < 8 years has a three-level response scale (not at 
827 
all, sometimes, a lot) and is administered by clinical staff either verbally or using a 
828 
matching card.   
829 
o The version for children aged 8 years and older has a five-level response scale 
830 
(never, almost never, sometimes, often, almost always) and is self-administered.  
831 
However, it may be administered verbally by clinical staff if the child cannot read 
832 
the questionnaire by him- or herself. 
833 
Assess deviation at distance and near by PACT 
Distance = Near 
(within 10 PD) 
Distance > Near 
(>10 PD) 
Near > Distance 
(>10 PD) 
Basic type 
(eligible) 
Convergence 
insufficiency type 
(not eligible) 
+3.00 D near test 
Distance = Near (within 10 PD) 
OR Near > Distance (>10 PD)  
Distance > Near 
(>10 PD) 
Distance > Near 
(>10 PD) 
45 minutes occlusion 
Pseudo divergence 
excess type 
(eligible) 
True divergence 
excess type 
(not eligible) 
No decrease in distance 
angle of > 12 PD 
Decrease in distance 
angle of > 12 PD 
High AC/A type  
(not eligible) 
Distance = Near (within 10 PD)  
OR Near > Distance (>10 PD) 
-2.00 D distance test 

 
IXT1 Protocol v5.0 21Jun17 
  
2-6 
 
 
o If possible, children should be positioned such that they are unable to view their 
834 
parents during testing and parents should be advised not to influence their child’s 
835 
responses.  
836 
o Children 4 years and younger will not complete a child questionnaire. 
837 
2. Parent proxy questionnaire – consists of 12 items which assess how the parent feels the 
838 
child’s eye condition affects the child. 
839 
o The questionnaire has a five-level response scale (never, almost never, sometimes, 
840 
often, almost always) and is self-administered.   
841 
3. Parental questionnaire – consists of 17 items which assess how the child’s eye condition 
842 
affects the parent.  
843 
o The questionnaire has a five-level response scale (never, almost never, sometimes, 
844 
often, almost always) and is self-administered.   
845 
2. Stereoacuity Testing: stereoacuity will be assessed in current refractive correction using the 
846 
following:  
847 
 Preschool Randot stereotest at near (performed at 40 cm): If stereoacuity is worse than 40 
848 
arcsec, it must be retested and the better of the 2 measurements will be used for 
849 
eligibility. 
850 
 Distance Randot stereotest (performed at 3 meters) 
851 
 Titmus Fly & Circles stereotest at near (performed at 40 cm) (note: Animals are not 
852 
tested) 
853 
Stereoacuity should be tested before any other clinical testing.  If stereoacuity is not tested 
854 
first, the patient must take a 10 minute break following any dissociative testing (e.g., visual 
855 
acuity or ocular alignment) prior to testing stereoacuity.   
856 
3. Control of exodeviation: Control of exodeviation will be measured in current refractive 
857 
correction at distance and near using the Office Control Score.16  
858 
 Distance (6 meters)  - fixating on an accommodative target such as a video for younger 
859 
children or reading optotype letters for older children 
860 
 Near (1/3 meter – fixating on Lang-near viewing stick or similar accommodative target) 
861 
 
862 
The scale below applies to both distance and near.  
863 
Intermittent Exotropia Control Scale16 
864 
5 = Constant Exotropia 
865 
4 = Exotropia > 50% of the 30-second period before dissociation 
866 
3 = Exotropia < 50% of the 30-second period before dissociation 
867 
2 = No exotropia unless dissociated, recovers in > 5 seconds 
868 
1 = No exotropia unless dissociated, recovers in 1-5 seconds 
869 
0 = No exotropia unless dissociated, recovers in < 1 second (phoria) 
870 
 
871 
 Levels 5 to 3 are assessed during a 30-second period of observation first at distance 
872 
fixation and then assessed at near fixation for another 30-second period. 
873 
 If no exotropia is observed during the 30-second period of observation, levels 2 to 0 are 
874 
then graded as the worst of three rapidly successive trials: 
875 
1. An occluder is placed over the right eye for 10 seconds and then removed, 
876 
measuring the length of time it takes for fusion to become re-established. 
877 
2. The left eye is then occluded for a 10-second period and the time to re-establish 
878 
fusion is similarly measured. 
879 

 
IXT1 Protocol v5.0 21Jun17 
  
2-7 
 
 
3. A third trial of 10-second occlusion is performed, covering the eye that required the 
880 
longest time to re-fuse. 
881 
 The worse level of control observed following the three 10-second periods of occlusion 
882 
should be recorded.  If the patient has a micro-esotropia by SPCT but an exodeviation by 
883 
PACT, the scale applies to the exodeviation. 
884 
 Testing of control must be performed by a pediatric ophthalmologist, pediatric 
885 
optometrist, or a certified orthoptist. 
886 
 Testing must be done prior to dissociative testing or at least 10 minutes after such testing. 
887 
4. Ocular alignment testing:  
888 
 Strabismic deviations will be assessed in current refractive correction (either spectacles, 
889 
contact lenses, or a trial frame) by the cover/uncover test and then measured with the 
890 
Simultaneous Prism and Cover Test (SPCT) (if tropia is of sufficient duration to 
891 
measure) and Prism and Alternate Cover Test (PACT) in primary position at near (1/3 
892 
meter), distance (6 meters) and remote distance (at least 50 feet, e.g., out the window or 
893 
down a long hallway) (PACT only) as outlined in the IXT Testing Procedures Manual. 
894 
 The deviation will be recorded as constant if a manifest tropia is present 100% of the time 
895 
during the examination, determined by at least 3 cover/uncover tests (one must be before 
896 
any dissociation), or as intermittent if a manifest tropia is present (including after 
897 
dissociation) but not 100% of the time  during the entire exam.  The magnitude of the 
898 
deviation may change (vary) independently of the frequency of the deviation; frequency 
899 
of tropia (constant vs. intermittent) is determined solely by whether the manifest tropia is 
900 
present all or some of the time, including after dissociation.  If a tropia is not observed at 
901 
any time but a phoria is present, then the deviation will be recorded as not tropic (phoric 
902 
only).  If no deviation is present at any time, ‘no deviation’ will be recorded.   
903 
o If the child appears to have a constant tropia but shows excellent stereoacuity that 
904 
may be inconsistent with the diagnosis of constant tropia, the examiner should look 
905 
over the child’s polarized glasses to determine whether the child is indeed 
906 
constantly tropic (by direct observation by cover/uncover test). 
907 
 The deviating eye will be recorded as "right", "left", or "alternates." 
908 
 Testing will be performed following control of exodeviation testing and prior to any 
909 
cycloplegia. 
910 
 Ocular motility will be assessed including: ductions, oblique muscle dysfunctions, 
911 
dissociated vertical deviations, and nystagmus. 
912 
 Ocular alignment testing must be performed by a pediatric ophthalmologist, pediatric 
913 
optometrist, or certified orthoptist. 
914 
5. Visual Acuity Testing: Visual acuity testing will be done with current refractive correction 
915 
without cycloplegia by a certified examiner with the Electronic Visual Acuity tester (EVA) 
916 
using the ATS single surround HOTV protocol for patients < 7 years old and using the E-
917 
ETDRS for patients ≥ 7 years old.  The protocol for conducting the visual acuity testing is 
918 
described in the ATS Testing Procedures Manual.  For each patient, the same visual acuity 
919 
testing protocol used at enrollment will be used throughout the study.   
920 
6. Ocular Examination as per investigator’s clinical routine (if not performed within 6 months) 
921 
7. Cycloplegic Refraction (if not performed within 6 months) 
922 
 If refractive error as measured by cycloplegic refraction meets any of the following, then 
923 
the patient must be wearing spectacles or contact lenses for at least a week: 
924 
o Myopia > -0.50 D spherical equivalent in either eye 
925 

 
IXT1 Protocol v5.0 21Jun17 
  
2-8 
 
 
o Anisometropia > 1.00 D spherical equivalent 
926 
o Astigmatism > 2.00 D astigmatism in either eye if ≤ 5 years old and > 1.50 D if > 5 
927 
years old   
928 
 
929 
2.6 
Randomization 
930 
Randomization will be done on the day of surgery or the working day before surgery, to 
931 
minimize potential treatment-group-related patient withdrawals between randomization and 
932 
surgery.  
933 
 
934 
Patients enrolled in the study will be randomized (1:1) to receive surgical correction of their IXT 
935 
by one of the 2 following surgical procedures: 
936 
1. Bilateral lateral rectus recessions (BLRrec) 
937 
2. Unilateral lateral rectus recession with medial rectus resection (R&R) - a unilateral lateral 
938 
rectus recession combined with a medial rectus resection in the same eye.  Choice of eye at 
939 
investigator discretion based on any interocular difference, position under anesthesia, fixation 
940 
preference, or forced duction testing.  Reason for choice of eye will be recorded. 
941 
 
942 
The Jaeb Center will construct a separate Master Randomization List using a permuted block 
943 
design stratified by site and cohort type (patients with basic type IXT with baseline angle size 
944 
15-40 PD, patients with pseudo divergence excess type IXT with baseline angle size 15-40 PD, 
945 
all other patients) which will specify the order of treatment group assignments.  A patient is 
946 
officially enrolled when the website randomization process is completed. 
947 
 
948 
Patients in whom the magnitude of the largest of the most recent distance, near, and remote 
949 
distance angles has decreased to <15 PD or increased to >50 PD before surgery will be dropped 
950 
from the study if they have not yet been randomized. If such patients have already been 
951 
randomized, it is at investigator discretion whether to perform surgery and what type of surgical 
952 
method to perform (i.e. BLRrec, R&R, or any other type of procedure).    
953 
 
954 
Patients not randomized within 12 months of enrollment will be dropped from the study.   
955 
 
956 
2.7 
Repeat Enrollment Visit 
957 
If surgery is delayed for any reason to a date more than 60 days from the enrollment visit, the 
958 
visit must be repeated.  All examination procedures listed in section 2.5 must be repeated at this 
959 
visit.  For surgeries occurring within 60 days of enrollment, the investigator has the option of 
960 
repeating the alignment measurements prior to surgery—if repeated, the measurement used to 
961 
determine surgical dose will be recorded on the Randomization Form. 
962 
 
963 

 
IXT1 Protocol v5.0 21Jun17 
  
3-1 
 
 
CHAPTER 3: SURGICAL TREATMENT 
964 
 
965 
3.1 
Surgery Timing 
966 
Once randomized, the investigator is required to perform the assigned surgery type the same day 
967 
or the next working day.   
968 
 
969 
In the rare case that surgery is cancelled after randomization, surgery should be rescheduled 
970 
within 60 days.  For surgeries occurring within 60 days of enrollment, the investigator has the 
971 
option of repeating the alignment measurements prior to surgery.  If surgery is not performed 
972 
within 60 days, the enrollment exam must be repeated (section 2.7).  
973 
 
974 
If a patient has been randomized but the magnitude of the largest of the most recent distance, 
975 
near, and remote distance angles has decreased to <15 PD or increased to >50 PD before surgery, 
976 
it is at investigator discretion whether to perform surgery and what type of surgical method to 
977 
perform (i.e., BLRrec, R&R, or any other type of procedure).    
978 
 
979 
If a patient has been randomized, even if surgery is not performed, the patient will remain in the 
980 
study and will complete all follow-up visits between 6 months and 3 years from randomization. 
981 
 
982 
3.2 
Surgical Treatment  
983 
Each patient is randomly assigned to one of the two surgical procedures. 
984 
1. Bilateral lateral rectus recessions (BLRrec) 
985 
2. Unilateral lateral rectus recession with medial rectus resection (R&R) – a unilateral 
986 
lateral rectus recession combined with a medial rectus resection in the same eye.  Choice 
987 
of eye is at investigator discretion based on any interocular difference, position under 
988 
anesthesia, fixation preference, or forced duction testing.  Reason for choice of eye will 
989 
be recorded. 
990 
 
991 
3.3 
Surgical Dose 
992 
The magnitude of deviation for which to perform surgery will be the largest preoperative 
993 
deviation recorded at near, distance, or remote distance fixation by PACT.  Data on this 
994 
deviation will be entered on the Randomization Form. The recommended surgical doses are 
995 
listed in Table 1 and Table 2, and will be generated as part of the randomization report.  For 
996 
recessions, the measurement of surgical dose should be made from the insertion of the muscle 
997 
after muscle disinsertion.  For resections, the measurement of surgical dose should be made from 
998 
the insertion of the muscle prior to muscle disinsertion.  Surgeons may adjust the surgical dose 
999 
within 1.0 mm for each muscle at their discretion to account for individual patient variables, such 
1000 
as lateral incomitance and age.   
1001 
 
1002 
Hangback, hemi-hangback, and adjustable techniques will not be allowed for this protocol, 
1003 
however, the surgeon may make epi-scleral tickbites at the intended insertion site and then bring 
1004 
the sutures forward to take a standard scleral bite at the original insertion site.  
1005 
 
1006 
The target deviation, actual surgical dose, and any reasons for departure from the recommended 
1007 
dose tables will be recorded on the Surgery Form.  Any complications during surgery will be 
1008 
recorded.  
1009 
 
1010 

 
IXT1 Protocol v5.0 21Jun17 
  
3-2 
 
 
 
1011 
 
1012 
Table 1: Bilateral lateral rectus recession (BLRrec): 
1013 
Angle of largest deviation 
Amount to recess each LR 
16 PD 
4.0 mm 
18 PD 
5.0 mm 
20 PD 
5.0 mm 
25 PD 
6.0 mm 
30 PD 
7.0 mm 
35 PD 
7.5 mm 
40 PD 
8.0 mm 
45 PD 
8.5 mm 
50 PD 
9.0 mm 
LR = lateral rectus 
1014 
 
1015 
Table 2: Unilateral lateral rectus recession with medial rectus resection (R&R): 
1016 
Angle of largest deviation 
Amount to recess LR 
Amount to resect MR 
16 PD 
4.0 mm 
3.0 mm 
18 PD 
5.0 mm 
4.0 mm 
20 PD 
5.0 mm 
4.0 mm 
25 PD 
6.0 mm 
5.0 mm 
30 PD 
7.0 mm 
5.5 mm 
35 PD 
7.5 mm 
6.0 mm 
40 PD 
8.0 mm 
6.5 mm 
45 PD 
8.5 mm 
6.5 mm 
50 PD 
9.0 mm 
7.0 mm 
LR = lateral rectus MR = medial rectus 
1017 
 
1018 

 
IXT1 Protocol v5.0 21Jun17 
  
4-1 
 
 
CHAPTER 4: FOLLOW-UP 
1019 
 
1020 
4.1 
Treatment 
1021 
Initial treatment consists of the randomly-assigned surgery as described in chapter 3.  
1022 
 
1023 
Following the surgery, nonsurgical treatment of any overcorrection, undercorrection, or 
1024 
deviations associated with diplopia is at investigator discretion at any time during the study, with 
1025 
the following stipulation:  
1026 
 If at the 8 week visit a constant esotropia at least 6 PD by SPCT at distance and near is 
1027 
present, the condition must be managed with prism (section 4.4.1).  
1028 
 
1029 
Reoperation or treatment with botulinum toxin is not permitted during the first 6 months 
1030 
following surgery.  After the 6-month exam, a patient may undergo reoperation or treatment with 
1031 
botulinum toxin only after criteria for surgical failure are met (section 4.5.1). 
1032 
 
1033 
4.2 
Follow-up Visit Schedule 
1034 
Follow-up visits will be conducted at the following times:  
1035 
 1 week  3 days after surgery 
1036 
 8 weeks  2 weeks after surgery 
1037 
 6 months  1 month after randomization (masked) 
1038 
 12 months ± 2 months after randomization (masked) 
1039 
 18 months  2 months after randomization (masked) 
1040 
 24 months ± 2 months after randomization (masked) 
1041 
 30 months  2 months after randomization (masked) 
1042 
 3-Year Primary Outcome Exam: 3 years  2 months (masked) 
1043 
 
1044 
4.3 
1-Week Follow-up Exam 
1045 
The 1-week follow-up exam will be 1 week  3 days following surgery.   
1046 
 
1047 
At this visit, the following will occur:  
1048 
 Ocular alignment in the primary position using cover/uncover, SPCT (if tropia is of sufficient 
1049 
duration to measure), and PACT, both at distance (6 meters) and near (1/3 meter) fixations 
1050 
(section 2.5) 
1051 
o Testing must be performed in current refractive correction.   
1052 
o If prism is currently prescribed, ocular alignment testing should be performed 
1053 
without prism.   
1054 
o If deliberate overminus is currently prescribed, ocular alignment testing should be 
1055 
performed in trial frames without the overminus component of the prescription 
1056 
but which correct the remaining refractive error to within study guidelines.   
1057 
o Testing must be performed without cycloplegia. 
1058 
 Visual acuity by the same testing method used at enrollment 
1059 
 Testing must be performed in current refractive correction.   
1060 
 If prism is currently prescribed, visual acuity testing should be performed with prism.   
1061 
 If deliberate overminus is currently prescribed, visual acuity testing should be 
1062 
performed with the overminus correction. 
1063 

 
IXT1 Protocol v5.0 21Jun17 
  
4-2 
 
 
 If visual acuity is found to be reduced by 0.2 logMAR or more (2 lines or 10 letters) from 
1064 
the previous visit and the patient is wearing a Fresnel prism, visual acuity should be 
1065 
retested in trial frames.  
1066 
 Recording of any surgical or post-surgical complications. 
1067 
 
1068 
4.4 
8-Week Follow-up Exam 
1069 
The 8-week follow-up exam will be 8 weeks  2 weeks following surgery.  Prior to the patient’s 
1070 
examination, spectacle correction will be verified using a lensometer.  For patients wearing 
1071 
contact lenses, a dry over-refraction (i.e., non-cycloplegic retinoscopy) should be performed.   
1072 
 
1073 
At this visit, the following procedures will occur in the specified order: 
1074 
1. Stereoacuity - stereoacuity will be assessed using the following as in section 2.5:  
1075 
 Preschool Randot stereotest at near (performed at 40 cm)  
1076 
 Distance Randot stereotest (performed at 3 meters) 
1077 
 Titmus Fly & Circles stereotest at near (performed at 40 cm) (note: Animals are not 
1078 
tested) 
1079 
Testing must be performed in current refractive correction.   
1080 
 If prism is currently prescribed, stereoacuity testing should be performed with prism.   
1081 
 If deliberate overminus is currently prescribed, stereoacuity testing should be 
1082 
performed with the overminus correction.  
1083 
In the case of a protocol testing order violation, stereoacuity should be performed 10 
1084 
minutes after any dissociation. 
1085 
2. Ocular alignment in the primary position using cover/uncover, SPCT (if tropia is of sufficient 
1086 
duration to measure), and PACT, at both distance (6 meters) and near (1/3 meters) fixations 
1087 
(section 2.5). 
1088 
 Testing must be performed in current refractive correction.   
1089 
 If prism is currently prescribed, ocular alignment testing should be performed 
1090 
without prism.   
1091 
 If deliberate overminus is currently prescribed, ocular alignment testing should be 
1092 
performed in trial frames without the overminus component of the prescription 
1093 
but which correct the remaining refractive error to within study guidelines.   
1094 
 Testing must be performed without cycloplegia. 
1095 
3. Visual acuity by the same testing method used at enrollment 
1096 
 Testing must be performed in current refractive correction.   
1097 
 If prism is currently prescribed, visual acuity testing should be performed with 
1098 
prism.   
1099 
 If deliberate overminus is currently prescribed, visual acuity testing should be 
1100 
performed with the overminus correction.  
1101 
  If visual acuity is found to be reduced by 0.2 logMAR or more (2 lines or 10 letters) 
1102 
from the previous visit, and the patient is wearing a Fresnel prism, visual acuity 
1103 
should be retested in trial frames.  
1104 
 If visual acuity is found to be reduced by 0.2 logMAR or more (2 lines or 10 letters) 
1105 
from the previous visit (after removal of Fresnel prism if applicable), a cycloplegic 
1106 
refraction must be performed and visual acuity retested in current refractive 
1107 
correction based on the cycloplegic refraction 
1108 
 
1109 

 
IXT1 Protocol v5.0 21Jun17 
  
4-3 
 
 
Any additional post-surgical complications which have been recognized since the 1-week visit 
1110 
will be recorded.   
1111 
 
1112 
4.4.1 
Management of Esotropia and Diplopia at the 8-week Exam 
1113 
At the 8-week exam:  
1114 
 Constant esotropia at least 6 PD by SPCT at distance AND near must be managed with prism 
1115 
(either ground-in or Fresnel Press-On Optics; however, the study will only provide temporary 
1116 
press-on prisms).  The amount of prism prescribed should be the minimum amount of prism 
1117 
needed to neutralize the angle.  At each subsequent visit, an attempt should be made to 
1118 
reduce or discontinue prism.  Despite initiation of treatment with prism, patients will not be 
1119 
considered a surgical failure at the 8-week exam. 
1120 
o Treatment of any esotropia greater than 6 PD that cannot be managed with prism 
1121 
should be discussed with the protocol chair.  If a second surgical treatment is 
1122 
considered, this should be discussed with the protocol chair. 
1123 
 Any other esotropia, exotropia, or diplopia can be managed with nonsurgical treatment at 
1124 
investigator’s discretion (section 4.1).   
1125 
 
1126 
4.5 
Masked Exams at Six-month Intervals from Six Months to 3 Years 
1127 
The six masked exams are timed every 6 months from randomization as follows:  
1128 
 6 months ± 1 month after randomization  
1129 
 12 months ± 2 months after randomization   
1130 
 18 months ± 2 months after randomization   
1131 
 24 months ± 2 months after randomization   
1132 
 30 months ± 2 months after randomization   
1133 
 3 years ± 2 months after randomization (primary outcome exam)  
1134 
 
1135 
Prior to the patient’s examination, spectacle correction will be verified using a lensometer.  For 
1136 
patients wearing contact lenses, a dry over-refraction (i.e., noncycloplegic retinoscopy) should be 
1137 
performed. 
1138 
 
1139 
At these visits, the following testing procedures will occur in the specified order:  
1140 
1. Health-related quality of life questionnaires (6-month and 3-year visits only)  
1141 
2. Stereoacuity (masked) - stereoacuity will be assessed in current refractive correction, with 
1142 
prism if applicable, using the following as in section 2.5 and 4.5.2:  
 
1143 
o Preschool Randot stereotest at near (performed at 40 cm) 
1144 
o Distance Randot stereotest (performed at 3 meters) 
1145 
o Titmus Fly & Circles stereotest at near (performed at 40 cm) (note: Animals are not 
1146 
tested) 
1147 
Testing must be performed in current refractive correction.   
1148 
 If prism is currently prescribed, stereoacuity testing should be performed with prism.   
1149 
 If deliberate overminus is currently prescribed, stereoacuity testing should be 
1150 
performed with the overminus correction.  
1151 
In the case of a protocol testing order violation, stereoacuity should be performed 10 
1152 
minutes after any dissociation. 
1153 
3. Control of exodeviation: Control of exodeviation will be measured at distance (6 meters) and 
1154 
near (1/3 meter) using the Office Control Score16 as described in section 2.5. 
1155 

 
IXT1 Protocol v5.0 21Jun17 
  
4-4 
 
 
 Testing must be performed in current refractive correction.   
1156 
 If prism is currently prescribed, testing should be performed without prism.   
1157 
 If deliberate overminus is currently prescribed, testing should be performed in trial 
1158 
frames without the overminus component of the prescription but which correct the 
1159 
remaining refractive error to within study guidelines.   
1160 
4. Ocular alignment (masked) in the primary position using cover/uncover, SPCT (if tropia is of 
1161 
sufficient duration to measure), and PACT, at both distance (6 meters) and near (1/3 meter) 
1162 
fixations (sections 2.5 and 4.5.2). 
1163 
 Testing must be performed in current refractive correction.   
1164 
 If prism is currently prescribed, ocular alignment testing should be performed without 
1165 
prism.   
1166 
 If deliberate overminus is currently prescribed, ocular alignment testing should be 
1167 
performed in trial frames without the overminus component of the prescription but 
1168 
which correct the remaining refractive error to within study guidelines.   
1169 
 Testing must be performed without cycloplegia. 
1170 
5. Retesting of stereoacuity and/or ocular alignment to confirm surgical failure (masked) (if 
1171 
required)   
1172 
o If any of the surgical failure criteria appear to be met (section 4.5.1) based on initial 
1173 
testing, the criterion met will be retested by a masked examiner (section 4.5.2).   
1174 
o All retesting should be performed at least 10 minutes after the initial ocular 
1175 
alignment testing.   
1176 
6. Visual acuity in current refractive correction (without prism if worn) by the same testing 
1177 
method used at enrollment 
1178 
 Testing must be performed in current refractive correction.   
1179 
 If prism is currently prescribed, visual acuity testing should be performed with 
1180 
prism.   
1181 
 If deliberate overminus is currently prescribed, visual acuity testing should be 
1182 
performed with the overminus correction.  
1183 
 If visual acuity is found to be reduced by 0.2 logMAR from the previous visit and the 
1184 
patient is wearing a Fresnel  prism, visual acuity should be retested in trial frames.  
1185 
 If visual acuity is found to be reduced by 0.2 logMAR or more (2 lines or 10 letters) 
1186 
from the previous visit (after removal of Fresnel prism if applicable), a cycloplegic 
1187 
refraction must be performed and visual acuity retested in current refractive 
1188 
correction based on the cycloplegic refraction. 
1189 
7. Cycloplegic refraction if not performed within the last 12 months  
1190 
o Management of refractive error is subject to the guidelines in section 5.3. 
1191 
 
1192 
In addition, the following will be recorded:  
1193 
 Any nonsurgical treatment of exotropia, esotropia or symptomatic diplopia (e.g., prism) 
1194 
 Any treatment of amblyopia [interocular visual acuity difference of more than 0.2 
1195 
logMAR (2 lines on ATS HOTV or 10 letters on E-ETDRS) and worse eye acuity of 
1196 
worse than 0.3 logMAR (20/40 on ATS HOTV or 70 letters on E-ETDRS] 
1197 
 Any change in refractive correction 
1198 
 
1199 
Treatment can be prescribed as follows:  
1200 

 
IXT1 Protocol v5.0 21Jun17 
  
4-5 
 
 
 Nonsurgical treatment of any overcorrection, undercorrection, or deviations associated 
1201 
with diplopia is at investigator discretion.   
1202 
 If any of the surgical failure criteria are met (section 4.5.1), the investigator may elect to 
1203 
reoperate (section 4.7).  If none of the surgical failure criteria are met, the investigator 
1204 
should not reoperate. 
1205 
 
1206 
All patients should continue in follow up through 3-years, regardless of whether they undergo 
1207 
reoperation.   
1208 
 
1209 
4.5.1 
Surgical Failure Criteria 
1210 
Patients will be considered a surgical failure if at any visit occurring 6 months or later any of the 
1211 
following failure criteria are present by masked examiner testing (section 4.5.2)*:  
1212 
1. Exotropia at distance OR near at any time during the exam (i.e., can be constant or 
1213 
intermittent; determined by a cover/uncover test) with a magnitude of at least 10 PD by 
1214 
SPCT, confirmed by a retest   
1215 
2. Constant esotropia at distance OR near (determined by at least 3 cover/uncover tests—one 
1216 
must be before any dissociation) with a magnitude of at least 6 PD by SPCT, confirmed by a 
1217 
retest 
1218 
3. Decrease in Preschool Randot near stereoacuity at least 2 octaves (at least 0.6 log arcsec) (see 
1219 
Table 3) from the enrollment measurement, or to nil, confirmed by a retest 
1220 
 
1221 
Table 3: Preschool Randot Stereotest 
1222 
 
Baseline Stereoacuity, in arcsec 
Level needed at follow up visit to meet 
surgical failure criteria, in arcsec 
40” 
200” or worse 
60” 
400” or worse 
100” 
400” or worse 
200” 
800” or worse 
400” 
Nil 
 
1223 
*Note that both the initial testing and the retest must be performed by a masked examiner 
1224 
(section 4.5.2).  If a patient appears to have met one or more of the above surgical failure criteria 
1225 
but the retest(s) do not confirm that at least one criterion is met, the patient is not considered to 
1226 
be a surgical failure. 
1227 
 
1228 
Patients will also be considered a surgical failure if they undergo a second surgery or treatment 
1229 
with botulinum toxin at any time during the study.   
1230 
 
1231 
All patients will continue to return for all protocol-specified follow-up exams regardless of 
1232 
whether surgical failure criteria are met. 
1233 
 
1234 
4.5.2 
Masked Examiner Testing   
1235 
Stereoacuity and ocular alignment testing at the visit must be performed by a masked examiner.  
1236 
 
1237 
If retesting is needed, retesting should be performed at least 10 minutes after the initial ocular 
1238 
alignment testing.   
1239 

 
IXT1 Protocol v5.0 21Jun17 
  
4-6 
 
 
 First, if the surgical failure criterion related to a drop in Preschool Randot stereoacuity at 
1240 
near appears to be met (section 4.5.1); the masked examiner will retest Preschool Randot 
1241 
stereoacuity at near. 
1242 
 Second, if either of the surgical failure criteria related to presence of a tropia appear to be 
1243 
met (section 4.5.1), the masked examiner will retest cover/uncover testing and SPCT at 
1244 
distance and near (if tropia is of sufficient duration to measure). 
1245 
 
1246 
Because this examiner must be masked to the patient’s treatment group, the masked examiner 
1247 
must be someone other than the investigator/surgeon. 
1248 
 
1249 
4.5.3 Patients Wearing Prism and/or Deliberate Overminus at 3-Years  
1250 
In addition to the assessments listed in section 4.5, at the 3-year masked exam only, patients who 
1251 
are currently prescribed prism and/or deliberate overminus will have Preschool Randot 
1252 
Stereoacuity at near repeated in current refractive correction but without prism or overminus. 
1253 
This additional Preschool Randot retest without prism and without overminus should occur after 
1254 
all initial stereoacuity testing has been completed (ie. after the Titmus Fly at near) and before the 
1255 
control of exodeviation assessment. This testing without prism and overminus is for an 
1256 
exploratory analysis only (section 6.3.1) and is not considered in determining whether the patient 
1257 
meets surgical failure criteria for the primary analysis.        
1258 
 
1259 
4.6 
Additional Visits 
1260 
Investigators may schedule additional visits at their own discretion.  If the investigator feels the 
1261 
patient has met surgical failure criteria, then he/she must arrange a masked examiner testing 
1262 
(section 4.5.2) to confirm surgical failure criteria before performing additional surgery.  If the 
1263 
masked exam does not confirm that the surgical failure criteria have been met, additional surgery 
1264 
should not be performed.   
1265 
 
1266 
The patient will continue to follow the regular follow-up exam schedule following this additional 
1267 
visit. 
1268 
 
1269 
4.7 
Re-operation 
1270 
Re-operations of IXT and treatment with botulinum toxin for IXT are allowed during the study 
1271 
after completion of the first 6-month follow-up exam, if the patient meets the surgical failure 
1272 
criteria at any follow-up exam 6 months or later (see section 4.5.1).  The exception is patients 
1273 
with non-manageable esotropia following the 8-week exam who may require a second surgery 
1274 
before the 6-month exam.  Any reoperation or botulinum toxin treatment prior to the 6-month 
1275 
exam must be discussed with the protocol chair.  All patients undergoing either surgery a second 
1276 
time or treatment with botulinum toxin will be considered a surgical failure for the primary 
1277 
analysis.  The reason for the re-operation or botulinum toxin treatment must be recorded and the 
1278 
patient will continue to return for all protocol-specified follow-up exams. 
1279 
 
1280 
4.8 
Treatment of Amblyopia  
1281 
Treatment of amblyopia is allowed at investigator discretion at any time during follow up if a 
1282 
patient has an interocular difference of visual acuity more than 0.2 logMAR (2 lines on ATS 
1283 
HOTV or 10 letters on E-ETDRS) with a worse eye visual acuity of worse than 0.3 logMAR 
1284 
(20/40 on HOTV or  70 letters on E-ETDRS).  The method of treatment is at investigator 
1285 

 
IXT1 Protocol v5.0 21Jun17 
  
4-2 
 
 
discretion but cannot include atropine or overplus spectacle lenses.  Any amblyopia treatment 
1286 
will be recorded. 
1287 

 
IXT1 Protocol v5.0 21Jun17 
  
5-1 
 
 
CHAPTER 5: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1288 
 
1289 
5.1 
Contacts by the Jaeb Center for Health Research 
1290 
The Jaeb Center will maintain direct contact with the parents of each patient at least 2 times per 
1291 
year.  Permission for such contacts will be included in the Informed Consent Form.  The 
1292 
principal purpose of the contacts will be to develop and maintain rapport with the patient and/or 
1293 
family and to help coordinate scheduling of the outcome examinations.  Additional contacts will 
1294 
be made if necessary for the scheduling of follow-up visits. 
1295 
 
1296 
5.2 
Patient Withdrawals 
1297 
A patient (and respective parent) may withdraw from the study at any time.  This is expected to 
1298 
be a very infrequent occurrence in view of the study design’s similarity to routine clinical 
1299 
practice.  If the patient or parent indicates that they want to withdraw from the study, the 
1300 
investigator personally should attempt to speak with them to determine the reason.  If their 
1301 
interest is in transferring their care to another eye care provider, every effort should be made to 
1302 
comply with this and at the same time try to keep the patient in the study under the new 
1303 
provider’s care. 
1304 
 
1305 
5.3 
Management of Refractive Error 
1306 
A cycloplegic refraction should be performed every 12 months.  In addition, a refraction should 
1307 
be performed whenever the investigator suspects that refractive error may not be optimally 
1308 
corrected. 
1309 
 
1310 
For patients whose refractive error meets criteria for requiring a refractive correction (section 
1311 
5.3.1), the correction prescribed should meet the refractive correction guidelines (section 5.3.2).  
1312 
 
1313 
For patients whose refractive error does not meet the criteria for a required correction (section 
1314 
5.3.1), it is at investigator discretion whether to prescribe correction; however, if refractive 
1315 
correction is prescribed, it should meet the refractive correction guidelines (section 5.3.2). 
1316 
 
1317 
5.3.1 
Refractive Error Requiring Correction   
1318 
The following are the criteria for requiring refractive error correction: 
1319 
 Myopia > -0.50 D spherical equivalent in either eye 
1320 
 Hyperopia > +3.50 D spherical equivalent in either eye 
1321 
 Anisometropia > 1.00 D spherical equivalent 
1322 
 Astigmatism in either eye > 2.00 D if ≤ 5 years old and > 1.50 D if > 5 years old 
1323 
 
1324 
5.3.2 
Refractive Correction Guidelines 
1325 
The following are the guidelines for refractive correction which apply to patients meeting criteria 
1326 
for requiring refractive error correction (section 5.3.1) and to any other patient wearing refractive 
1327 
correction.   
1328 
 Anisometropia spherical equivalent must be within 0.25 D of full correction.  
1329 
 Astigmatism cylinder must be within 0.25 D of full correction and axis must be within 5 
1330 
degrees of full correction.   
1331 

 
IXT1 Protocol v5.0 21Jun17 
  
5-2 
 
 
 The spherical component can be reduced by investigator discretion provided the reduction is 
1332 
symmetrical and results in residual (i.e., uncorrected) spherical equivalent refractive error 
1333 
that does not exceed +3.50D hyperopia or -0.50 D myopia. 
1334 
 
1335 
The study will not pay for spectacles required at enrollment, but will pay for lens changes and/or 
1336 
new spectacles which are needed during follow up to keep the correction within the study 
1337 
guidelines (section 5.3).  All other new spectacles and/or lens changes will not be paid for by the 
1338 
study, as they are part of normal care.  The study will not pay for contact lenses. 
1339 
 
1340 
5.4 
Risks 
1341 
There are no risks involved in this study that would not be part of usual care.   
1342 
 
1343 
5.4.1 
Risks of Examination Procedures 
1344 
The procedures in this study are part of routine eye care practice in the United States and as part 
1345 
of this study they pose no additional known risks. 
1346 
 
1347 
5.4.2 
Risks of Surgery 
1348 
All surgical procedures are standard care.  The risks of surgery in this study are no different than 
1349 
surgery performed outside of the study. 
1350 
 
1351 
There is a very rare risk of death (less than 1 in 100,000), there is a very rare risk of loss of 
1352 
vision, and there is a risk of overcorrection or undercorrection which could require subsequent 
1353 
surgeries. 
1354 
 
1355 
5.4.3 
Risk Assessment  
1356 
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.404 which is 
1357 
research not involving greater than minimal risk.   
1358 
 
1359 
5.5 
Reporting of Adverse Events 
1360 
Each site is responsible for informing its IRB of serious treatment-related adverse events and for 
1361 
abiding by any other reporting requirements specific to his or her IRB.  Data on the 
1362 
complications of the study treatments will be tabulated regularly by the Coordinating Center for 
1363 
review by the Steering Committee.  Serious complications will be reported expeditiously to the 
1364 
Data and Safety Monitoring Committee, which will receive a full adverse event report semi-
1365 
annually.  Following each DSMC data review, a summary will be provided to IRBs. 
1366 
 
1367 
5.6 
Discontinuation of Study 
1368 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1369 
Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 
1370 
patients. 
1371 
 
1372 
5.7 
Travel Reimbursement 
1373 
The parent/guardian of each patient will be compensated $30 per visit for completion of each 
1374 
protocol-specified follow-up visit, for a maximum of $240.  If there are extenuating 
1375 
circumstances, and the patient is unable to complete study visits without additional funds due to 
1376 
travel costs, additional funds may be provided. 
1377 
 
1378 

 
IXT1 Protocol v5.0 21Jun17 
  
5-3 
 
 
5.8 
Study Costs  
1379 
The subject or his/her insurance will be responsible for the costs that are considered standard 
1380 
care.  This includes the initial examination, all follow up visits, all surgical procedures, and all 
1381 
costs involved in managing surgical complications. 
1382 
  
1383 
The study will not pay for spectacles required at enrollment, but will pay for lens changes and/or 
1384 
new spectacles which are needed during follow up to keep the correction within the study 
1385 
guidelines (section 5.3).  All other new spectacles and/or lens changes will not be paid for by the 
1386 
study, as they are part of normal care.  The study will not pay for contact lenses. 
1387 
 
1388 
The study will provide temporary press-on prisms and spectacles to mount the prism (if needed 
1389 
and the patient isn’t wearing glasses). 
1390 
 
1391 

 
IXT1 Protocol v5.0 21Jun17 
  
6-1 
 
 
CHAPTER 6: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
1392 
 
1393 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1394 
analysis plan will be written and finalized prior to the completion of the study.  The analysis plan 
1395 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1396 
 
1397 
6.1 
Primary Data Analysis  
1398 
The primary analysis cohort consists of patients whose largest exodeviation by PACT at 
1399 
distance, near, or remote distance at the enrollment exam is between 15 and 40 PD inclusive.  
1400 
 
1401 
The primary analysis will be a treatment group comparison of the proportion of patients with 
1402 
surgical failure by 3 years (section 6.1.1.).The primary analysis is stratified by IXT type (basic 
1403 
type and pseudo divergence excess type). 
1404 
 
1405 
The cumulative proportion of patients meeting criteria for failure by 3 years will be obtained 
1406 
using the Kaplan-Meier method and compared between treatment groups using the Z test.  This 
1407 
will allow patients who drop out prior to 3 years to contribute to the estimation of the proportion 
1408 
of surgical failure at 3 years.  In this analysis, all patients who meet surgical failure criteria prior 
1409 
to 3 years will be counted as failures at the first visit at which surgical failure criteria are met.  
1410 
The primary analysis will follow the intent-to-treat principle.  
1411 
 
1412 
6.1.1 
Classification of Outcome  
1413 
At the 3-year visit, each patient’s condition will be classified as either surgical failure, success, 
1414 
or indeterminate as follows: 
1415 
 
1416 
Failure = ANY of the following criteria are met at a visit 6 months or later:   
1417 
1. Exotropia at distance OR near at any time during the exam (i.e., can be constant or 
1418 
intermittent; determined by a cover/uncover test) with a magnitude of at least 10 PD by 
1419 
SPCT, confirmed by a retest   
1420 
2. Constant esotropia at distance OR near (determined by at least 3 cover/uncover tests—
1421 
one must be before any dissociation) with a magnitude of at least 6 PD by SPCT, 
1422 
confirmed by a retest 
1423 
3. Decrease in Preschool Randot near stereoacuity at least 2 octaves (at least 0.6 log arcsec) 
1424 
(see Table 3) from the enrollment measurement, or to nil, confirmed by a retest  
1425 
4. Reoperation or treatment with botulinum toxin 
1426 
 
1427 
Success = ALL of the following criteria are met at the 3-year visit: 
1428 
1. Exodeviation less than 10 PD (tropia or phoria) by PACT at distance and near and 
1429 
reduction of more than 10 PD from largest of distance and near angles at enrollment 
1430 
2. Esotropia less than 6 PD at distance and near by SPCT 
1431 
3. No decrease in Preschool Randot stereoacuity of 2 or more octaves from the enrollment 
1432 
stereoacuity and no drop to nil 
1433 
4. No reoperation or treatment with botulinum toxin  
1434 
5. No non-surgical treatment for IXT during the study 
1435 
 
1436 
Indeterminate = ALL of the following criteria are met at the 3-year visit: 
1437 
1. Patient meets one or more of the following:  
1438 

 
IXT1 Protocol v5.0 21Jun17 
  
6-2 
 
 
 Exophoria >=10PD by PACT at distance or near   
1439 
 Exodeviation less than 10PD by PACT at distance and near but no reduction of more 
1440 
than 10 PD from largest of distance and near angles at enrollment  
1441 
 Intermittent esotropia or esophoria >=6PD at distance and/or near  
1442 
2. No decrease in Preschool Randot stereoacuity of 2 or more octaves from the enrollment 
1443 
stereoacuity or a drop to nil 
1444 
3. No reoperation or treatment with botulinum toxin  
1445 
 
1446 
6.2 
Secondary Data Analysis 
1447 
All secondary analyses will be conducted on the primary cohort and stratified by IXT type. 
1448 
 
1449 
6.2.1 
Subgroup Analyses  
1450 
A secondary analysis will assess whether the treatment group difference in the proportion of 
1451 
patients with surgical failure by 3 years varies in subgroups based on baseline factors.  
1452 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
1453 
significant treatment group difference.  Subgroup analyses will be interpreted with caution, 
1454 
particularly in the absence of an overall treatment group difference. 
1455 
 
1456 
The primary subgroups of interest are baseline monofixation status as determined using Titmus 
1457 
stereoacuity data, baseline monofixation status determined as using Preschool Randot 
1458 
stereoacuity data, and age.  Other baseline factors which will be assessed in exploratory 
1459 
subgroup analysis are prior treatment, near stereoacuity, distance stereoacuity, control of IXT, 
1460 
whether a constant exotropia was present at distance, and quality of life.  In accordance with NIH 
1461 
guidelines, a subgroup analysis of treatment efficacy according to gender, as well as 
1462 
race/ethnicity, will also be conducted.   
1463 
 
1464 
The general approach for subgroup analyses will be to determine the proportion of patients with 
1465 
surgical failure for each treatment group within each subgroup, using the same method as for the 
1466 
primary analysis.  Factors showing evidence of interaction with treatment effect will be formally 
1467 
assessed by including an interaction term in a Cox proportional hazards model that includes the 
1468 
factor.  In general, power will be low for formally detecting interactions unless the interaction is 
1469 
very large.  
1470 
 
1471 
6.2.2 
Surgical Failure Proportion at 3 Year Timepoint  
1472 
The binomial proportion of patients who meet surgical failure criteria at the 3 year visit (as 
1473 
opposed to by the 3 year visit) will be estimated for each treatment group and compared using 
1474 
Fisher’s exact test.   
1475 
 
1476 
Patients who do not return for the 3 year visit will not be included in the analysis, including 
1477 
patients who met surgical failure criteria at an intermediate visit.  Patients who complete the visit 
1478 
will be classified based on their status at 3 years, regardless of whether they met surgical failure 
1479 
criteria at an earlier timepoint, unless they have been re-operated (or treated with botulinum 
1480 
toxin), in which case they will be classified as a surgical failure. 
1481 
 
1482 
The potential for bias in the treatment group comparison is recognized.  Once a patient has met 
1483 
the clinical criteria for surgical failure criteria at an interim follow up visit, the decision to 
1484 
reoperate—and thus permanently classify the patient as a surgical failure for the analysis at 3 
1485 

 
IXT1 Protocol v5.0 21Jun17 
  
6-3 
 
 
years—is at the discretion of an unmasked investigator and therefore could be related to 
1486 
treatment group.  To assist in assessing for potential bias, the extent to which treatment group is 
1487 
related to the decision to reoperate will be evaluated.   
1488 
 
1489 
6.2.3 
Success Proportion at 3 Year Timepoint  
1490 
The estimated proportion of patients who meet criteria for ‘success’ at the 3-year outcome exam 
1491 
(section 6.1.1) will be calculated and compared between treatment groups using a Fisher’s exact 
1492 
test.  A 95% confidence interval on the difference of proportions between the two groups also 
1493 
will be calculated.   
1494 
 
1495 
The potential for bias in this treatment group comparison is recognized.  Once a patient has met 
1496 
the clinical criteria for surgical failure criteria at an interim follow up visit, the decision to 
1497 
reoperate—and thus prevent the patient from being classified as a success for the 3 year 
1498 
analysis—is at the discretion of an unmasked investigator and therefore could be related to 
1499 
treatment group.  To assist in assessing for potential bias, the extent to which treatment group is 
1500 
related to the decision to reoperate will be evaluated.   
1501 
 
1502 
6.2.4 
Analysis of Secondary Outcomes 
1503 
Additional secondary analyses will be performed to assess whether treatment group differences 
1504 
exist for secondary outcomes: near stereoacuity, distance stereoacuity, monofixation status as 
1505 
determined using Titmus stereoacuity data, monofixation status determined as using Preschool 
1506 
Randot stereoacuity data, development of amblyopia, and quality of life. 
1507 
 
1508 
6.3 
Exploratory Analyses  
1509 
6.3.1              Exploratory Analyses in Primary Cohort 
1510 
Exploratory analyses will be stratified by IXT type and conducted in the primary cohort (i.e. 
1511 
patients whose largest angle by PACT at enrollment is between 15 and 40 PD inclusive).   
1512 
 
1513 
As exploratory analyses, the primary analysis comparing failure proportions by 3 years (section 
1514 
6.1), the comparison of failure proportions at 3 years (6.2.2) the comparison of success 
1515 
proportions at 3 years (6.2.3) will be repeated using the same outcome classification of surgical 
1516 
failure, success, or indeterminate as described section 6.1.1., with the following exception: 
1517 
 At the 3-year visit, for patients who are currently prescribed prism and/or deliberate 
1518 
overminus: the Preschool Randot at near score to be used for the outcome classification will 
1519 
be the one tested without wearing prism or overminus.  If this measurement shows a decrease 
1520 
of at least 2 octaves (at least 0.6 log arcsec) from the enrollment measurement, or to nil, to 
1521 
avoid adding to testing burden and to the complexity of visits, a confirmatory retest is not 
1522 
needed to be considered a surgical failure for this analysis.   
1523 
 
1524 
 
1525 
6.3.2 Exploratory Analyses in Patients with Baseline Angle > 40 to 50 PD  
1526 
Additional exploratory analyses will be stratified by IXT type and conducted in a secondary 
1527 
cohort of patients whose largest angle by PACT at enrollment is > 40 to 50 PD.   
1528 
 
1529 
The proportion of patients with surgical failure by 3 years will be calculated and will be 
1530 
compared between treatment groups using the same method as for the primary analysis. 
1531 
 
1532 

 
IXT1 Protocol v5.0 21Jun17 
  
6-4 
 
 
6.4 
Safety Analyses 
1533 
Postoperative complications will be tabulated according to treatment group.   
1534 
 
1535 
6.5 
Additional Tabulations and Analyses 
1536 
The following will be tabulated according to treatment group: 
1537 
1. Baseline demographic and clinical characteristics  
1538 
2. Baseline data for study completers vs. non-completers  
1539 
3. Protocol deviations  
1540 
 
1541 
A flow chart will be constructed that accounts for all subjects.  Visit completion rates will be 
1542 
tabulated according to treatment group for each visit.  The percentage of subjects with visits 
1543 
completed in window, out of window, and missed for each visit will be tabulated.  
1544 
 
1545 
6.6 
Interim Analysis 
1546 
There are no plans to formally assess surgical failure at a timepoint earlier than 3 years because it 
1547 
is the long-term outcome that is of clinical interest and because the treatment groups are 
1548 
expected to differ in the timing of surgical failure and in the criteria met for surgical failure.  
1549 
Patients receiving unilateral lateral rectus recession with medial rectus resection (R&R) are 
1550 
expected to fail earlier, due primarily to consecutive esotropia (i.e., overcorrection) which cannot 
1551 
be managed with prism, whereas patients receiving bilateral lateral rectus recessions (BLRrec) 
1552 
are expected to have better short-term motor outcomes but fail later, due primarily to recurrence 
1553 
of the intermittent exotropia over the long term.  A treatment group comparison of failure 
1554 
proportions at a timepoint before 3 years would therefore be expected to be biased against R&R.  
1555 
 
1556 
An interim analysis of partial 3-year data is not planned because by the time 50% of the cohort 
1557 
has 3-year data, recruitment will have ended and all patients will have had surgery. 
1558 
 
1559 
6.7 
Sample Size Estimation 
1560 
The study is powered for an appropriate number of patients of each IXT type in the primary 
1561 
cohort.  
1562 
 
1563 
Table 4 shows the estimated number of patients needed per group to detect specific differences 
1564 
in the proportion of patients meeting surgical failure criteria by 3 years (section 6.1.1) with 
1565 
power of 0.90 and type I error rate of 0.05 using the Fisher’s exact test:  
1566 
 
1567 
Table 4: Sample size needed per group to detect the tabled difference in proportion of 
1568 
failure with type I error=5% and power=90% 
1569 
 
Proportion of failure for 
bilateral lateral recessions  
Proportion of failure for unilateral lateral rectus 
recessions with medial rectus resections  
0.35 
0.30 
0.25 
0.20 
0.15 
0.50 
240 
135 
85 
58 
41 
0.45 
523 
231 
128 
80 
53 
0.40 
2008 
496 
216 
118 
72 
0.35 
-- 
1182 
459 
197 
105 
0.30 
1882 
-- 
1713 
411 
173 
 
1570 

 
IXT1 Protocol v5.0 21Jun17 
  
6-5 
 
 
Based upon estimates in the literature for basic type IXT, the difference in failure proportion 
1571 
between bilateral lateral recessions (BLRrec) and unilateral lateral rectus recessions with medial 
1572 
rectus resections (R&R) for the treatment of IXT ranges from as little as 4% (failure rates of 44% 
1573 
vs. 40% respectively)13 to as much as 30% (failure rates of 48% vs. 18%  respectively).12  It was 
1574 
felt clinically meaningful to power the study to detect a difference between treatment groups 
1575 
only if the true difference was at least 25%, assuming a failure rate of 25% in the BLRrec group 
1576 
and 50% in the R&R group, respectively).  In the absence of literature comparing surgical 
1577 
outcomes in patients with pseudo divergence excess type IXT, the analysis for these patients will 
1578 
be powered similarly to the analysis for basic type IXT patients.  
1579 
 
1580 
Given estimated failure proportions of 50% with BLRrec and 25% with R&R, and accounting 
1581 
for 10% loss to follow-up prior to repeat operation, 378 patients will need to be enrolled in the 
1582 
primary cohort (189 with basic type IXT and 189 with pseudo divergence excess type IXT), half 
1583 
of whom will be randomized to each treatment group.   
1584 
 
1585 
An additional 76 patients whose largest exodeviation by PACT at enrollment is > 40 to 50 PD 
1586 
(38 with basic type IXT and 38 with pseudo divergence excess type IXT) are expected to be 
1587 
enrolled as a secondary cohort during recruitment for the primary cohort.  Recruitment for the 
1588 
secondary cohort will be monitored during recruitment of the primary cohort.  If a secondary 
1589 
cohort is enrolling fewer patients than expected, recruitment for the secondary cohort could be 
1590 
terminated before recruitment for the primary cohort has ended.   
1591 
 
1592 
As the enrollment goal approaches, sites will be notified of the end date for recruitment.  
1593 
Subjects who have signed an informed consent form can be randomized up until the end date, 
1594 
which means the expected recruitment might be exceeded.  The maximum number of 
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randomized subjects will be 474. 
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IXT1 Protocol v5.0 21Jun17 
  
7-1 
 
 
CHAPTER 7: REFERENCES 
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1. 
Holmes JM, Liebermann L, Hatt SR, Smith SJ, Leske DA. Quantifying diplopia with a 
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questionnaire. Ophthalmology 2013;120:1492-6. 
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2. 
Govindan M, Mohney BG, Diehl NN, Burke JP. Incidence and types of childhood 
1602 
exotropia: A population-based study. Ophthalmology 2005;112:104-8. 
1603 
3. 
von Noorden GK, Campos EC. Binocular vision and ocular motility: Theory and 
1604 
management of strabismus. 6th ed. St Louis, Mo: Mosby; 2002. 
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4. 
Wright K. Exotropia. In: Wright K, ed. Pediatric ophthalmology and strabsimus. St 
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Louis: Mosby Year Book; 1995:195-202. 
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5. 
Mitchell PR, Parks MM. Concomitant exodeviations. In: Tasman WS, ed. Duane's 
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clinical ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:1-17. 
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6. 
Kushner BJ, Morton GV. Distance/near differences in intermittent exotropia. Arch 
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Ophthalmol 1998;116:478-86. 
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7. 
Burian HM, Spivey BE. The surgical management of exodeviations. Am J Ophthalmol 
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1965;59:603-20. 
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8. 
Hardesty HH, Boynton JR, Keenan JP. Treatment of intermittent exotropia. Arch 
1614 
Ophthalmol 1978;96:268-74. 
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9. 
Romano PE, Wilson MF. Survey of current management of intermittent exotropia in the 
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USA and canada. In: Campos EC, ed. Strabismus and ocular motility disorders. London: 
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The Macmillan Press; 1990:391-6. 
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10. 
Cooper J, Medow N. Intermittent exotropia, basic and divergence excess type. Binocul 
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Vis Strabismus Q 1993;8:187-216. 
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11. 
Stoller SH, Simon JW, Lininger LL. Bilateral lateral rectus recession for exotropia: A 
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survival analysis. J Pediatr Ophthalmol Strabismus 1994;31:89-92. 
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12. 
Kushner BJ. Selective surgery for intermittent exotropia based on distance/near 
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differences. Arch Ophthalmol 1998;116:324-8. 
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13. 
Lee S, Lee YC. Relationship between motor alignment at postoperative day 1 and at year 
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1 after symmetric and asymmetric surgery in intermittent exotropia. Jpn J Ophthalmol 
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2001;45:167-71. 
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Fiorelli VM, Goldchmit M, Uesugui CF, Souza-Dias C. Intermittent exotropia: 
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Comparative surgical results of lateral recti-recession and monocular recess-resect. Arq 
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Bras Oftalmol 2007;70:429-32. 
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Hatt SR, Leske DA, Yamada T, Bradley EA, Cole SR, Holmes JM. Development and 
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initial validation of quality of life questionnaires for intermittent exotropia. 
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Ophthalmology IN PRESS. 
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Mohney BG, Holmes JM. An office-based scale for assessing control in intermittent 
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exotropia. Strabismus 2006;14:147-50. 
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