A Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia
Phase: NA
Conditions: Intermittent Exotropia
Sponsor: Jaeb Center for Health Research

IXT5 Protocol v3.0 (11-22-19) 
 
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INTERMITTENT EXOTROPIA STUDY 5 
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(IXT5) 
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A Randomized Clinical Trial of Overminus 
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Spectacle Therapy for Intermittent Exotropia 
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PROTOCOL 
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Version 3.0 
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November 22, 2019 
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IXT5 Protocol v3.0 (11-22-19) 
PROTOCOL AMENDMENT II (11-22-19) 
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Note that changes to the original (18-month) protocol (protocol changes #1 through #5) are 
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incorporated throughout the protocol.  The 18 to 36 month extension study protocol (protocol 
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change #6) is detailed at the end of this protocol amendment II.      
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Protocol Change #1 – Discontinue weaning overminus lens treatment between 12-15 
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months  
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Original Protocol 
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A three-month period of weaning of overminus consisted of prescribing the overminus group 
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subjects -1.25D overminus (half of the -2.50D prescribed at randomization) at the 12-month visit 
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and wearing this correction until discontinuing the overminus completely at the 15-month visit.  
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The purpose of weaning overminus as opposed to discontinuing overminus abruptly was to 
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potentially help retain the effect of the overminus off treatment.   
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Changed Protocol  
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At the 12-month visit, subjects in the overminus treatment group will have overminus treatment 
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discontinued immediately, without weaning.  These subjects will be prescribed the non-
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overminus spectacles they would have been prescribed at 15 months in the original protocol 
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(section 2.6.1).   
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The flow chart in section 1.17 has been updated.  Section 4.3.2 on risks of overminus was also 
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updated.   
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Relevant additions to the analysis plan:   
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• Because weaning may increase the retention of the treatment effect once off treatment, 
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discontinuing the weaning may decrease the off-treatment effect observed at 18-months.  
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For this reason, the 18-month off-treatment analyses will be performed using 1) the full 
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cohort, and 2) a cohort limited to subjects who were prescribed weaning between 12 to 15 
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months (i.e., prior to weaning being discontinued per Protocol Amendment II) (see 
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modifications to section 5.2).  
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• In addition, 18-month distance control and change from baseline will be tabulated by 
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treatment group according to prescribed weaning status (i.e., full, partial, or no prescribed 
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weaning) (section 5.3.2.2).  
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Rationale  
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The Data Safety Monitoring Committee (DSMC) concluded on 10/25/19 that progression of 
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myopia is occurring more frequently in subjects treated with overminus spectacles compared to 
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non-overminus spectacles.  Between baseline and 12 months, the mean change in spherical 
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equivalent refractive error at 12 months was -0.42 D (diopter) in the overminus group and -0.05 
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D in the non-overminus group (difference = 0.39 D P = <.0001).  The proportion of subjects 
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whose spherical equivalent refractive error changed by more than 1.00D was 17% in the 
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overminus group (29 of 168); and 2% in the non-overminus group (3 of 146).  The DSMC 
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recommended that all subjects active in the full treatment* or weaning phases in both treatment 
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groups be asked to come in for a visit as soon as possible to be given the new information, 
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complete their pending follow-up visit, receive study-paid non-overminus glasses (regular 
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IXT5 Protocol v3.0 (11-22-19) 
glasses or no-correction glasses) to be worn through 18 months, and be invited to continue in the 
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study after 18 months to be treated at investigator discretion and to return for visits at 24 and 36 
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months.  
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*Note that the protocol does not require amending the 0 to 12-month on-treatment period in 
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order to discontinue full overminus treatment given that the 37 remaining 12-month visits (as of 
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11/5/19) were planned to occur by December 2019.  These 12-month visits will be completed 
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only slightly early (all subjects have ≥9 months of treatment).  As detailed above, non-overminus 
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glasses will be prescribed between 12 and 18 months.   
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Protocol Change #2 
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Original Protocol 
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A lens change was required at the 15-month visit in both treatment groups to allow for discontinuation 
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of half-strength (-1.25D) overminus spectacles in the overminus group.  The 15-month glasses 
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prescription is the same as the non-overminus group has received throughout the protocol.        
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Changed Protocol  
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The 15-month spectacle prescription is the same as in the original protocol (i.e., non-overminus for 
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both treatment groups), but whether a patient needs to receive a change in spectacles at 15 months to 
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achieve this prescription depends on whether their spectacles had been changed to non-overminus at 
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the 12-month visits occurring after Protocol Amendment II.   
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Section 2.6.1 on treatment in the overminus group has been revised as follows:    
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15-Month* 
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• If the 12-month spectacles for a subject were issued before Protocol Amendment II and 
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therefore contain partial-strength overminus (-1.25D), they should be changed to non-
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overminus lenses at the 15-month visit to discontinue the overminus treatment.     
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• If the 12-month spectacles for a subject were issued on/after Protocol Amendment II and 
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therefore are already non-overminus spectacles, the non-overminus spectacles should be 
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continued at the 15-month visit. 
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*Unless the subject has already met deterioration criteria confirmed by masked examiner as 
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described in section 3.7, in which case spectacles are prescribed at investigator discretion. 
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Section 2.6.2 on treatment in the non-overminus group has been revised as follows:    
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15-Month* 
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• If the 12-month spectacles for a subject were issued before Protocol Amendment II and, the 
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non-overminus lenses should be replaced with new non-overminus spectacles at the 15-
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month visit, to maintain masking of treatment groups.     
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• If the 12-month spectacles for a subject were issued on/after Protocol Amendment II and 
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therefore are already non-overminus spectacles, the non-overminus spectacles should be 
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continued at the 15-month visit.  There is no longer a reason to change the glasses to 
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maintain masking, given that both treatment groups would already be wearing non-
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overminus glasses in this situation.    
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*Unless the subject has already met deterioration criteria confirmed by masked examiner as 
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described in section 3.7 in which case spectacles are prescribed at investigator discretion. 
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IXT5 Protocol v3.0 (11-22-19) 
 
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Rationale for Change 
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Whether glasses need to be changed at 15-months depends on when each subject’s 12-month glasses 
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were issued, before or on/after Protocol Amendment II.  See details in changes to protocol (above).      
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Protocol Change #3 
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Original Protocol 
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Cycloplegic refraction and autorefraction were not performed at the 18-month visit.  
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Changed Protocol  
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Cycloplegic refraction will be performed at the 18-month visit, and autorefraction will be mandatory if 
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an autorefractor is available at the site (section 3.4).  Analysis of 18-month refractive error data was 
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added to section 5.4.1.       
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Rationale for Change 
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Given the increased myopia progression in the overminus lens group, the 18-month visit is the first 
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opportunity to assess whether the overminus group continues to have higher myopia than the non-
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overminus group or whether the two treatment groups start to become similar once treatment is 
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discontinued.   
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Protocol Change #4 
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Original Protocol 
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Cycloplegic axial length and additional biometry were not measured in the study.   
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Changed Protocol  
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Cycloplegic axial length, flat corneal radius, anterior chamber depth, and lens thickness (if 
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available) will be measured at 18-months (section 3.4).  Analyses for this data are described in 
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section 5.3.1.5 and 5.3.1.6      
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Rationale for Change 
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Given the increased myopia progression in the overminus lens group, the study is interested in whether 
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axial length also differs between treatment groups.   
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Protocol Change #5 
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Original Protocol 
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Study-paid spectacles (lenses and frame) were provided at the 12-month visit and a change of 
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lenses was provided at the 15-month visit.       
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Changed Protocol  
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Study-paid spectacles (frames and lenses) will be provided at 12 months, 15 months and 18 months 
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(section 4.7)      
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Rationale for Change 
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Paying for a full set of spectacles at the 15-month visit will enable the study to offer a full set of 
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spectacles to all patients coming in for early visits to have treatment discontinued. Study-paid 
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IXT5 Protocol v3.0 (11-22-19) 
spectacles will be provided at 18 months now that cycloplegic refraction is being performed to check 
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the spectacle prescription at that time.   
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Protocol Change #6 
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Original Protocol 
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The study ends with the 18-month visit.  
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Changed Protocol (also see next page) 
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This Protocol Amendment allows for an extended follow up period from the 18 to 36 months after 
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randomization. All patients enrolled in IXT5 will be invited to participate, regardless of whether they 
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are still active in the 18-month study. See specifications on next page.   
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Rationale for Change 
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Given the higher rate of myopia progression observed in overminus group vs. non-overminus group 
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between randomization and 12 months, the goal is to determine whether the overminus group 
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continues to have higher myopia than the non-overminus group or whether the two treatment groups 
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will have similar myopia progression over the long term.         
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IXT5 Protocol v3.0 (11-22-19) 
PROTOCOL AMENDMENT II (11-22-19) PROTOCOL CHANGE #6 (CONTINUED) 
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EXTENDED FOLLOW UP BETWEEN 18 TO 36 MONTHS 
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This protocol change allows for an extended follow up period 18 to 36 months after 
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randomization.   
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Objective 
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To compare long-term refractive error between subjects originally treated with either overminus 
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spectacles or non-overminus spectacles as part of the 18-month randomized trial.   
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Protocol Specified Follow-up Visits  
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Visits will occur at 24 months (±3 months) and 36 months (±3 months) from randomization. 
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Study Procedures/Data Collection 
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The following testing procedures will be performed in the following order: using similar 
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methods as the 18-month visit except where noted.   
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1. Treatments used since the last visit  
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2. Visual acuity 
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• Measured using the investigator’s usual testing procedure using an optotype method.        
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• Testing must be performed in current refractive correction.    
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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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3. Control of the Exodeviation #1 - masked  
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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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4. Stereoacuity Testing – - masked stereoacuity is tested only once, with no repeat testing on 
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the same day or a subsequent day.   
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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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5. Control of the Exodeviation #2 – masked see details under Control Testing #1 above 
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6. Cover Test and PACT Testing - masked 
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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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7. Control of the Exodeviation #3 – - masked see details under Control Testing #1 above 
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IXT5 Protocol v3.0 (11-22-19) 
8. Assessment of Deviation Throughout Exam- masked 
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9. Cycloplegic Refraction 
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11. Cycloplegic Autorefraction (mandatory if autorefractor is available at the site) as described in 
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section 3.4 
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12. Cycloplegic Axial Length Measurement and Additional Biometry (mandatory if biometer is 
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available at the site) as described in section 3.4 
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• 
Axial length 
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Flat corneal radius 
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• Anterior Chamber depth 
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• Lens thickness, if available 
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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.  Note that prescribing underplus or no plus is not considered deliberate 
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overminus.  
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Steps #3 through #8 must be performed in order by a masked examiner who is a pediatric 
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ophthalmologist, pediatric optometrist, or certified orthoptist. 
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Treatment  
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After 18 months, IXT treatment (surgical, non-surgical, management of refractive error) is at 
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investigator discretion.   
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Costs 
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The parent/guardian of each subject will be compensated $50 for completion of each of the 24-
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month and 36-month visits, up to a total of $100. If there are extenuating circumstances, and the 
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subject is unable to complete the annual study visits without additional funds due to travel costs, 
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additional funds may be provided. 
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The study will pay for visits specific to the research study, but will not pay for usual care visits 
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that would occur whether or not the subject was in the study.  The cost of usual care visits will be 
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the responsibility of the subject or his/her insurance company.  
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The study will pay for a pair of spectacles (lenses and frames) at the first extension study visit 
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(24 months or 36 months). Spectacle changes / new spectacles prescribed at other times will not 
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be paid for by the study.   
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Treatment after 18-months is at investigator discretion and is not part of this protocol.  Any costs 
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associated with treatment will 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 may be called periodically by the Jaeb Center to promote 
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retention.     
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IXT5 Protocol v3.0 (11-22-19) 
Re-consenting of Subjects  
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An addendum to the original informed consent form (and addendum to the assent form, if 
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required) for the extension study will be signed by parents who elect to continue their child’s 
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study participation.   Re-consenting will occur at the next 12, 15, or 18-month randomized trial 
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visit but could occur at other times either before or after participation in the 18-month trial has 
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ended. A subject (and respective parent) may withdraw from the study at any time. 
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Statistical Analyses 
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The following analyses will be completed separately at the 24-month and 36-month visits to 
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evaluate the effect of the overminus treatment approach followed by usual clinical care versus 
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the non-overminus treatment approach followed by usual clinical care: 
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• Spherical equivalent refractive error will be compared between treatment groups using an 
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ANCOVA model that adjusts for baseline spherical equivalent refractive error.  The 
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treatment group difference and a 95% confidence interval will be calculated.  
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• Mean distance control (average of 3 measurements) will be compared between treatment 
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groups using an analysis of covariance (ANCOVA) model, which adjusts for baseline 
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distance control, distance PACT, age, refractive error, and use of ADHD medication, to 
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address potential residual confounding.  
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• The proportion of subjects with no spontaneous tropia will be compared between treatment 
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groups as in section 5.1.2.1.  
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• Axial length, flat corneal radius, anterior chamber depth, and lens thickness (if available) will 
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be compared between treatment groups as in section 5.3.2.3 and   
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• Secondary outcomes of near control, angle magnitude, and near stereoacuity will also be 
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compared between treatment groups as in section 5.3.1.  
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• Treatments used since the last visit will be tabulated by treatment group.  
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IXT5 Protocol v3.0 (11-22-19) 
PROTOCOL AMENDMENT I (11-8-16) 
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This amendment provides for the following protocol changes:  
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Protocol Change #1 
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Original Protocol 
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At the time of enrollment and each follow-up visit at 6, 12, 15, and 18 months, parents are asked to 
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respond to a survey of symptoms potentially associated with spectacle treatment (headaches, eye 
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strain, and other problems with spectacle wear) based on their observations of their child in the past 2 
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weeks.   
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Changed Protocol  
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1. To add a 7-question survey of intermittent exotropia symptoms to be administered to the child.  
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2. To add a health-related quality of life questionnaire to evaluate whether either treatment impacts 
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the effect of intermittent exotropia on quality of life. 
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• Children ages 5 and older at the time of enrollment will complete an 11-item 
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questionnaire to assess how their eye condition affects their quality of life.  Children 4 
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years of age and younger at the time of enrollment will not complete the child 
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questionnaire.  
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• A 16-item parental questionnaire will assess how the child’s eye condition affects the 
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quality of life of the parent (for all subjects).   
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3. The surveys and questionnaires will be completed at the time of enrollment; and at 6-month, 12-
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month, and 18-month follow-up visits.   
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Rationale for Change 
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There is value in determining how overminus treatment may impact the child’s intermittent 
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exotropia symptoms and the child’s and parent’s quality of life.  Recently, a patient derived 7-
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question intermittent exotropia symptom survey has been developed for childhood IXT and, 
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previously, a patient and parent derived HRQOL instrument has been developed specifically for 
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IXT and used successfully in previous PEDIG IXT studies.     
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Protocol Change #2 
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Original Protocol 
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Both the 12-month on-treatment comparison of mean distance control and the 18-month off-
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treatment comparison of mean distance control are considered separate primary analyses, with 
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each allocated 0.05 alpha.    
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Changed Protocol 
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The 12-month on-treatment comparison will be the sole primary analysis and the 18-month off-
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treatment comparison changed to a planned secondary analysis upon which sample size 
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continues to be based.    
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Rationale for Change 
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The previous allocation of 0.05 alpha to both the 12-month on-treatment comparison and the 18-
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month off-treatment leads to an experiment-wise alpha of up to 0.10. Selecting one comparison 
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as the primary analysis limits the experiment-wise alpha to no more than 0.05. Whether 
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IXT5 Protocol v3.0 (11-22-19) 
overminus spectacles can improve control of exotropia after 12 months of treatment is the 
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primary study question.  The 18-month off-treatment analysis can be considered the secondary 
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question.  First, the overminus weaning schedule may require refinement before we can 
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definitively determine the effect of overminus after treatment is discontinued.  Second, an on-
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treatment effect would need to be seen at 12 months in order to potentially see an effect off-
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treatment at 18 months.  Finally, clinicians who use overminus to delay another form of 
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treatment, such as surgery, may be less interested in the off-treatment effect.  Whether a benefit 
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of overminus can be maintained off treatment, will still be addressed by the 18-month off-
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treatment comparison as a planned secondary analysis.    
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Protocol Change #3 
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Original Protocol 
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The primary analysis uses the observed 12-month visit data regardless of whether non-
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randomized treatment was prescribed.  Subjects who are lost to follow up before the 12-month 
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visit are excluded. The 18-month off treatment analysis was defined similarly.  
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Changed Protocol 
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The primary analysis (section 5.1) will be defined as follows:  
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• Subjects who are treatment crossovers (non-overminus group subjects who are prescribed 
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overminus therapy; overminus group subjects who have overminus spectacles formally 
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discontinued) will have their observed 12-month data analyzed provided they complete at 
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least one distance control testing at the 12-month outcome exam; otherwise their average 
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distance control score will be imputed using multiple imputation.  
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• Subjects who are prescribed IXT treatment other than overminus or non-overminus 
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refractive correction (e.g. surgery, vision therapy, patching) will have their average 
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distance control score imputed using multiple imputation, using data from all visits prior 
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to the initiation of the alternative therapy. Multiple imputation will be used for these 
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subjects regardless of whether any control testing is completed at the 12-month visit.   
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• Subjects who are lost to follow up before the 12-month visit will also have their outcome 
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imputed using multiple imputation.           
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The original primary analysis is now an alternative analysis in section 5.1.1.1, along with the 
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original alternative analysis.  A third alternative analysis has been added to explore the effect of 
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how treatment crossovers are handled in the primary analysis. 
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The secondary 18-month off-treatment analysis was changed in parallel (section 5.2).   
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Rationale for Change 
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For subjects who are prescribed treatment other than what they were randomized to (e.g. surgery, 
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overminus spectacles, vision therapy) the 12-month visit data would reflect the effect of the non-
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randomized treatment they receive.  If a higher proportion of subjects in the non-overminus 
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group are prescribed a non-randomized treatment that is more effective than the overminus 
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spectacles, the study might fail to detect an effect of overminus, if one exists.  It was felt 
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acceptable and conservative to analyze the observed 12-month data for treatment crossovers 
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given that these subjects are receiving study treatments; however, it was felt appropriate to 
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impute 12-month data using multiple imputation for subjects who are prescribed IXT treatment 
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other than overminus or non-overminus refractive correction (e.g. surgery, vision therapy, 
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IXT5 Protocol v3.0 (11-22-19) 
patching), an approach which would not be expected to bias the analysis either toward or against 
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a treatment effect of overminus (although any procedure for handling of this issue has some 
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potential for bias).  A similar rationale applies to the 18-month off-treatment analyses.    
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This amendment also provides for the following minor protocol corrections/clarifications:   
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• Section 2.6.2 was edited to clarify the spectacle prescription for the non-overminus 
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group.  
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• Section 2.6.1 was edited to clarify that the same is true for the overminus group at 15-
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months.   
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• Section 5.4.4 was edited to define the analyses with respect to the added intermittent 
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exotropia symptom survey and the HRQOL questionnaires.  
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• Section 3.6 was edited to specify what should be done if a masked exam cannot be 
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completed prior to a patient starting non-randomized treatment; and to specify that if the 
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investigator is starting non-randomized treatment, the subject does not return for a 
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stereoacuity retest if stereoacuity is decreased.    
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• Section 5.2 on the 18-month off-treatment analyses was edited to delete several sections 
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which were redundant with section 5.1 on the 12-month on-treatment analyses. A short 
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paragraph now states that these analyses are repeated at 18 months. 
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• Sections 5.1.2.1 and 5.3 were edited to indicate that the details of the secondary and 
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additional analyses will be part of a separate statistical analysis plan. 
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IXT5 Protocol v3.0 (11-22-19) 
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 CHAIRS 
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Angela M. Chen, O.D., M.S. 
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Marshall B. Ketchum University 
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Southern California College of Optometry 
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2575 Yorba Linda Blvd. 
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Fullerton, CA 92831 
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Phone (714) 463-7569-7432 
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Fax (714) 992-7846 
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Email: angelachen@ketchum.edu 
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S. Ayse Erzurum, M.D., F.A.C.S 
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Eye Care Associates, Inc. 
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10 Dutton Dr 
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Youngstown, OH 44502 
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Phone: (330) 746-7691 
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Fax: (330) 743-8322 
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Email: Erzurum2020@gmail.com 
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IXT5 Protocol v3.0 (11-22-19) 
TABLE OF CONTENTS 
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CHAPTER 1: BACKGROUND AND SUMMARY ....................................................................................................... 1-1 
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1.1 
Intermittent Exotropia............................................................................................................................. 1-1 
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1.2 
Overminus Lens Therapy ....................................................................................................................... 1-1 
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1.3 
Possible Mechanisms of Overminus Lens Therapy ................................................................................ 1-1 
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1.4 
Short-term and Long-term Rationale for Using Overminus Lens Therapy ............................................ 1-1 
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1.5 
Public Health Importance of Proposed Randomized Clinical Trial ........................................................ 1-2 
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1.6 
Previous Studies of Overminus Lens Therapy ....................................................................................... 1-2 
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1.7 
Methods of Prescribing Overminus ........................................................................................................ 1-4 
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1.8 
Customized Method of Prescribing Overminus ...................................................................................... 1-5 
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1.9 
Fixed Method of Prescribing Overminus ................................................................................................ 1-5 
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1.10 
Determining Dose of Overminus for Current Study ............................................................................... 1-5 
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1.11 
Results of the IXT3 Pilot RCT ............................................................................................................... 1-6 
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1.12 
Questions Related to Overminus Lens Therapy ..................................................................................... 1-7 
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1.13 
Definitions of Treatment Response ........................................................................................................ 1-7 
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1.14 
Timing of Outcome Intervention for Current Study ............................................................................... 1-8 
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1.15 
Study Objective ...................................................................................................................................... 1-8 
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1.16 
Synopsis of Study Design ....................................................................................................................... 1-8 
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1.17 
Study Flow Chart .................................................................................................................................. 1-10 
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CHAPTER 2: ENROLLMENT AND RANDOMIZATION ......................................................................................... 2-1 
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2.1 
Eligibility Assessment and Informed Consent ........................................................................................ 2-1 
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2.2 
Eligibility Criteria ................................................................................................................................... 2-1 
490 
2.3 
Historical Information ............................................................................................................................ 2-2 
491 
2.4 
Testing at the Enrollment Visit ............................................................................................................... 2-2 
492 
2.5 
Confirmation of Eligibility / Timing of Randomization ......................................................................... 2-6 
493 
2.6 
Randomization ........................................................................................................................................ 2-6 
494 
2.6.1 
Treatment for Overminus Group ....................................................................................................... 2-7 
495 
2.6.2 
Treatment for Non-Overminus Group ............................................................................................... 2-8 
496 
CHAPTER 3: FOLLOW-UP AND MANAGEMENT ................................................................................................... 3-1 
497 
3.1 
Follow-up Schedule ................................................................................................................................ 3-1 
498 
3.2 
Telephone Calls ...................................................................................................................................... 3-1 
499 
3.3 
Masking of Treatment Group ................................................................................................................. 3-1 
500 
3.3.1 
Masked Examiner Testing ................................................................................................................. 3-2 
501 
3.4 
Outcome Visit Testing Procedures ......................................................................................................... 3-2 
502 
3.5 
Repeat Stereoacuity Testing on a Subsequent Day ................................................................................. 3-5 
503 
3.6 
Additional Visits ..................................................................................................................................... 3-5 
504 
3.7 
Deterioration Criteria .............................................................................................................................. 3-6 
505 
3.8 
Initiating Non-Randomized Treatment for IXT ...................................................................................... 3-6 
506 
3.9 
Treatment of Amblyopia ........................................................................................................................ 3-7 
507 
3.10 
Management of Refractive Error ............................................................................................................ 3-7 
508 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS ............................................................................................ 4-1 
509 
4.1 
Contacts by the Jaeb Center for Health Research ................................................................................... 4-1 
510 
4.2 
Subject Withdrawals ............................................................................................................................... 4-1 
511 
4.3 
Risks ....................................................................................................................................................... 4-1 
512 
4.3.1 
Risks of Examination Procedures ...................................................................................................... 4-1 
513 
4.3.2 
Risk of Overminus Lens Therapy ...................................................................................................... 4-1 
514 
4.3.3 
Risk Assessment ................................................................................................................................ 4-1 
515 
4.4 
Reporting of Adverse Events .................................................................................................................. 4-1 
516 
4.5 
Discontinuation of Study ........................................................................................................................ 4-2 
517 
4.6 
Travel Reimbursement ........................................................................................................................... 4-2 
518 
4.7 
Study Costs ............................................................................................................................................. 4-2 
519 
4.8 
General Considerations........................................................................................................................... 4-2 
520 
CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .................................................... 5-1 
521 

IXT5 Protocol v3.0 (11-22-19) 
5.1 
Primary Objective:  Efficacy on Overminus Treatment (12 Months) ..................................................... 5-1 
522 
5.1.1 
Primary Analysis - Mean Distance Control at 12-Months (On-Treatment) ....................................... 5-1 
523 
5.1.1.1 
Alternatives to the Primary Analysis ............................................................................................ 5-2 
524 
5.1.2 
Secondary Distance Control Outcomes at 12 Months (On-Treatment) ............................................. 5-2 
525 
5.1.2.1 
No Spontaneous Tropia at 12 Months ........................................................................................... 5-2 
526 
5.1.2.2 
Change in Distance Control at 12 Months .................................................................................... 5-2 
527 
5.2 
Objective #2: Efficacy of Overminus After Treatment Discontinuation (18 Months) ........................... 5-3 
528 
5.3 
Additional Analyses ............................................................................................................................... 5-3 
529 
5.3.1 
Additional Secondary Outcomes ....................................................................................................... 5-3 
530 
5.3.1.1 
Deterioration ................................................................................................................................. 5-3 
531 
5.3.1.2 
Near Control .................................................................................................................................. 5-3 
532 
5.3.1.3 
Angle Magnitude .......................................................................................................................... 5-4 
533 
5.3.1.4 
Stereoacuity................................................................................................................................... 5-4 
534 
5.3.1.5 
Axial Length Measurement at 18 Months ..................................................................................... 5-4 
535 
5.3.1.6 
Additional Ocular Biometric Parameters at 18 Months ................................................................ 5-4 
536 
5.3.1.7 
Compliance with Spectacle Wear ................................................................................................. 5-4 
537 
5.3.2 
Exploratory Analyses ......................................................................................................................... 5-4 
538 
5.3.2.1 
Mean Distance Control in Baseline Subgroups ............................................................................. 5-4 
539 
5.3.2.2 
Mean Distance Control at 18 Months According to Prescribed Weaning Status .......................... 5-5 
540 
5.3.2.3 
Patients with Baseline Control 3 to <5 Points ............................................................................... 5-5 
541 
5.4 
Safety Analyses ...................................................................................................................................... 5-5 
542 
5.4.1 
Refractive Error at 12 and 18 Months ................................................................................................ 5-5 
543 
5.4.2 
Development of Esodeviation ............................................................................................................ 5-5 
544 
5.4.3 
Reduction of Distance Visual Acuity................................................................................................. 5-5 
545 
5.4.4 
Adverse Symptoms/Impact on Quality of Life .................................................................................. 5-5 
546 
5.5 
Protocol Adherence and Additional Tabulations .................................................................................... 5-5 
547 
5.6 
Interim Analysis ..................................................................................................................................... 5-6 
548 
5.7 
Sample Size ............................................................................................................................................ 5-6 
549 
5.7.1 
Sample Size for Objective #1: Efficacy on Overminus Treatment .................................................... 5-6 
550 
5.7.2 
Sample Size for Objective #2: Efficacy of Overminus After Treatment Discontinuation ................. 5-7 
551 
CHAPTER 6: REFERENCES ......................................................................................................................................... 6-1 
552 
 
553 
   
554 
 
555 
 
556 
 
 
557 
 
558 

IXT5 Protocol v3.0 (11-22-19) 
1-1 
CHAPTER 1: BACKGROUND AND SUMMARY 
559 
 
560 
This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and 
561 
funded through a cooperative agreement from the National Eye Institute.  It is one of a series of 
562 
randomized trials and observational studies that address management of intermittent exotropia 
563 
in children. 
564 
 
565 
1.1 
Intermittent Exotropia 
566 
Intermittent exotropia (IXT) is the most common form of childhood-onset exotropia with an 
567 
incidence of 32.1 per 100,000 in children under 19 years of age.1  The onset of IXT is thought 
568 
to often occur in the first year of life.2  Among children 1 to 2.5 years of age, IXT has been 
569 
estimated to occur in 245 children per 100,000.3  IXT is characterized by an exotropia that is 
570 
not constant and is mainly present in the distance but may also be present at near. 
571 
 
572 
Treatment for IXT may be either non-surgical or surgical.4  While surgery is often considered 
573 
for treatment of IXT, many cases of IXT are treated using non-surgical interventions,5,6 such as 
574 
overminus lenses or occlusion.7 
575 
 
576 
1.2 
Overminus Lens Therapy  
577 
Overminus lens therapy involves prescription of additional minus power in the spectacle lenses 
578 
and the spectacles are worn full-time. 
579 
 
580 
Overminus lens therapy for exodeviations was described as early as 1913 by Landolt.8  In a 
581 
survey of US and Canadian pediatric ophthalmologists,9 52% reported that they routinely used 
582 
some form of non-surgical therapy in the management of childhood IXT, with 34% of the 52% 
583 
using overminus lenses.  When the same survey was administered to members of the 
584 
International Strabismological Association, half of the respondents said they used overminus 
585 
lenses to treat childhood IXT.10  
586 
 
587 
1.3 
Possible Mechanisms of Overminus Lens Therapy 
588 
The mechanism of overminus lens therapy for IXT is uncertain.  It is thought to work by 
589 
stimulating accommodative convergence, therefore reducing the angle of exodeviation and 
590 
allowing fusion,11 or by clearing distance blur (caused by excess compensatory accommodative 
591 
convergence) and thus allowing fusion.5  An alternative hypothesis is that fusional convergence 
592 
often induces convergence accommodation that results in distance blur, but this induced blur is 
593 
mitigated by minus lenses allowing the better control of the IXT without blur.12  Regardless of 
594 
the mechanism, overminus lens therapy may reduce the angle of the exodeviation, or increase 
595 
the control of the exodeviation (reducing the amount of time the exodeviation is manifest), or 
596 
both. 
597 
 
598 
1.4 
Short-term and Long-term Rationale for Using Overminus Lens Therapy 
599 
There appear to be two main reasons for implementing overminus lens treatment in IXT:  
600 
• As a temporizing measure to reduce the angle of the exodeviation, or increase the 
601 
control of the exodeviation, or both, for example in a child considered too young for 
602 
surgery or vergence training exercises. 
603 
• As a long-term strategy, to treat the IXT by improving control of the exodeviation, with 
604 
eventual weaning of the overminus at a time when the child is well compensated in his 
605 
or her regular refractive correction.  
606 

IXT5 Protocol v3.0 (11-22-19) 
1-2 
 
607 
1.5 
Public Health Importance of Proposed Randomized Clinical Trial  
608 
Although overminus lens treatment for IXT is widely used in clinical care, there have been no 
609 
RCTs evaluating its long-term effectiveness.  Evaluating the effectiveness of overminus lens 
610 
treatment for IXT has important public health implications because successful treatment may 
611 
reduce the proportion of children needing to undergo surgery.  Conversely, evidence of poor 
612 
treatment effectiveness with overminus lens therapy would prevent children from undergoing 
613 
unnecessary treatment with overminus lenses. 
614 
 
615 
1.6 
Previous Studies of Overminus Lens Therapy 
616 
Previous studies of overminus lens therapy have been mainly limited to small case series, most 
617 
with poorly defined methods of prescribing overminus, variable amounts of overminus 
618 
prescribed, and poorly defined definitions of success (Table 1).  
619 
 
620 
Table 1.  Previous studies of overminus lens treatment for IXT 
621 
Author, 
year 
Subject 
population 
Method of over-minus 
determination 
Results 
Comment 
Kennedy 
195413 
N=103 
successfully 
treated 
subjects 
(failures 
excluded) 
Multiple tests of 
accommodation performed 
(described in detail by 
author). “Final lens selected 
is arrived at in light of all 
the data yielded by the 
various tests outlined, and is 
usually the lowest powered 
concave lens which 
produces objective 
orthophoria.” 
Power may subsequently be 
changed.  
Report only 
included 
successful 
subjects 
Success defined as 
presence of one of the 
following: 
“cosmetically 
straight,” “some 
fusion,” or “constant 
fusion.” 
Treatment duration 
not reported 
Caltrider 
198314 
N=35 
N=10/35 seen 
1 year after 
discontinuing 
overminus 
Prescribed between 2.00D 
and 4.00D overminus.  No 
other details provided. 
46% 
qualitative 
improvement 
in overminus; 
7/10 
maintained 
improvement 
out of 
overminus 
Qualitative 
improvement defined 
as neither parents nor 
physician noticing 
manifest exodeviation 
when wearing 
overminus. 
Treatment duration 
from 2 to 156 months 
 
 
622 

IXT5 Protocol v3.0 (11-22-19) 
1-3 
Author, 
year 
Subject 
population 
Method of over-minus 
determination 
Results 
Comment 
Goodacre 
198515 
N=34 aged 1 
to 6 years 
All prescribed 3.00D 
overminus initially. Amount 
of minus increased at follow-
up if necessary to further 
improve control (up to a max 
of 5.00D overminus).  
No other details provided. 
62% “cured” 
Cure defined as 
exophoria near, 
distance, and far 
distance when wearing 
overminus lenses. 
Treatment duration at 
least 12 months 
Rutstein 
198916 
N=40 aged 1 
to 15 years 
Amount of overminus 
prescribed ranged from 0.50D 
to 3.75D. No other details 
provided. 
Outcomes not 
described in 
terms of 
overminus 
success 
Main outcome measure 
was change in 
refractive error (after 
wearing overminus). 
No treatment outcomes 
reported 
Donaldson 
199117 
N=18 aged 2 
to 17 years 
"Children of normal 
retinoscopy were generally 
ordered 2.00D, 2.50D or 
3.00D overminus depending 
on the ophthalmologist’s 
assessment of expected 
tolerance." 
72% success 
Success defined as 
binocular single vision 
for all distances & 
symptoms relieved 
when wearing 
overminus lenses. 
Treatment duration at 
least 6 months. 
Reynolds 
199411 
N=74 aged 14 
months to 13 
years 
Prescribed 1.00D to 2.50D 
overminus: the initial amount 
was “varied according to 
baseline refractive error and 
age of subject.” No other 
details provided. 
62% success 
Success defined as 
conversion to 
orthophoria, pure 
exophoria, or IXT 
<10pd. 
Treatment duration at 
least 3 to 6 months 
Kushner 
199918 
N=74 mean 
age 4 years 
Prescribed overminus 
spectacles “if seem beneficial 
in controlling deviation”. 
For myopic refractions: 
additional 1.00D to 2.00D 
overminus. 
For hyperopic refractions: 
additional minus until final SE 
between -1.00D and -2.00D. 
In addition 4 to 6 prism 
diopters base in also 
incorporated in some cases. 
If satisfactory control not seen 
at first follow-up exam, added 
patching for anti-suppression 
19% 
“improved 
control” 
without 
overminus 
correction 
 
46% still in 
overminus 5 
years later 
Outcomes regarding 
effectiveness of 
overminus not clearly 
reported (study 
primarily on whether 
overminus causes 
myopia). 
Treatment duration 
from 6 to 156 months. 
 
 
623 

IXT5 Protocol v3.0 (11-22-19) 
1-4 
Author, 
year 
Subject 
population 
Method of over-minus 
determination 
Results 
Comment 
Watts 
200519 
N=24 aged 2-
17 years 
Prescribed "maximum 
tolerated minus": minimum 
2.00D to maximum 4.00D 
depending on ability to read 
20/20 and N5 with 
overminus in place.  
Hyperopic subjects - Rx 
reduced by minimum of 
2.00D, max 4.00D. 
71% 
Success defined as 
improved control 
(reduction in 
Newcastle control 
score) when 
wearing overminus.  
Treatment duration 
3 months. 
Rowe 
200920 
N=21 aged 1-9 
years, 
Newcastle 
control score 
of 3 or worse 
Prescribed minimum minus 
to reduce angle and achieve 
control of the manifest 
deviation at near & dist. 
Started with 1.00D and 
increased by 0.50D 
increments until control was 
achieved. Actual over-
minus initially prescribed: 
median 2.00D; range 1.00D 
to 3.00D. 
24% 
success 
(out of 
overminus) 
 
Success defined as 
exophoria at near, 
distance, and far 
distance, with 
binocular control at 
all distances OUT 
of overminus 
spectacles at 5 
years follow-up. 
Treatment duration 
from 6 to 62 
months in 
overminus and 
from 6 to 39 
months out of 
overminus. 
PEDIG 
2015 
N=58 aged 3-
<7 years (n=27 
overminus, 
n=31 non-
overminus, 
Office control 
score 2 or 
worse (mean of 
3 measures) 
RCT: Reduce sphere by 
2.50D in overminus group, 
non-overminus spectacles or 
no spectacles in non-
overminus group 
Mean 
control 2.0 
vs 2.8 
points 
favoring 
overminus. 
59% 
success vs 
39% 
success  
Improvement in 
mean control score 
from baseline to 8 
weeks while on 
treatment. Success 
defined as 
improvement of 
mean control score 
1 point or more at 8 
weeks while on 
treatment. 
 
624 
1.7 
Methods of Prescribing Overminus  
625 
As illustrated in Table 1 above, the amount of overminus prescribed in previous studies varied 
626 
from 0.50D to 4.00D, and also differed by the preference for one of 4 philosophical approaches 
627 
for prescribing overminus:  
628 
1. a fixed amount of overminus, regardless of cycloplegic refractive error 
629 
2. a fixed amount of overminus over and above cycloplegic refractive error, to achieve a 
630 
specific amount of accommodative demand 
631 
3. a customized approach, tailoring the amount of overminus to a response during a single 
632 
office examination, either in improved control or improved angle of distance exotropia 
633 

IXT5 Protocol v3.0 (11-22-19) 
1-5 
4. a customized approach, tailoring the amount of overminus to a response over 
634 
successive office visits in improved control or improved angle of distance exotropia  
635 
 
636 
1.8 
Customized Method of Prescribing Overminus 
637 
Although a customized approach to prescribing overminus is sometimes used in clinical 
638 
practice, there are significant obstacles to incorporating such approach into a rigorous clinical 
639 
study.  The measures used to assess response to overminus are intrinsically variable.  Most 
640 
practitioners use “control” (the proportion of time that the deviation is manifest) to judge 
641 
response, but although control can be quantified more rigorously in the office using an office 
642 
control score,21 a single control score has been found to be highly variable.22 Adequate 
643 
representation of control can better be achieved by measuring control at least three times 
644 
during an office exam and calculating a mean value.23 
645 
 
646 
Prior to embarking on the IXT3 pilot study, members of the IXT3 Planning Committee piloted 
647 
the assessment of control through several steps of increasing or decreasing the overminus lens 
648 
power to determine a power that better controls the IXT, in a single office examination.  We 
649 
found this method far too time consuming and unworkable for the proposed RCT even when 
650 
assessing response to each level of overminus with a single measure of control.   
651 
 
652 
In summary, it would be very challenging to develop a protocol that would allow for 
653 
customized prescribing of overminus using established methods for assessing control. 
654 
 
655 
1.9 
Fixed Method of Prescribing Overminus 
656 
Whereas some clinicians prescribe a fixed overminus spectacle correction regardless of the 
657 
cycloplegic refraction (e.g., -1.50D spectacles for a patient with plano and for a patient with 
658 
+0.50D hyperopia), others prescribe a predetermined amount of overminus by adding the 
659 
minus power to the cycloplegic refraction e.g., adding -1.50D overminus for all subjects, they 
660 
would prescribe -1.50D spectacles for plano and -1.00D spectacles for +0.50D hyperopia. 
661 
 
662 
Polling the PEDIG Investigator group at an Investigator meeting (Feb. 7, 2014) revealed that 
663 
the vast majority (>95%) would prefer a prescribing approach that standardized the amount of 
664 
induced accommodation achieved by adding a fixed amount of overminus to the cycloplegic 
665 
refraction.  This method reflects the commonly held belief that the treatment mechanism of 
666 
overminus is related to induced accommodation. 
667 
 
668 
A fixed amount of overminus (-2.50D) was implemented successfully in the recently 
669 
completed PEDIG IXT3 randomized pilot study and results were encouraging that this dose of 
670 
overminus appeared effective. 
671 
 
672 
1.10 
Determining Dose of Overminus for Current Study 
673 
In the IXT2 study (patching versus observation) we found that a large proportion of 3- to <11-
674 
year-old children (the target age range for this overminus study) presented with low levels of 
675 
hyperopia.  Nearly all such children were not wearing spectacles because they were able to 
676 
accommodate well and did not need the hyperopic correction for excellent visual acuity.  If we 
677 
are to include children with hyperopia in a study of overminus lenses, we can only include 
678 
those with low levels of hyperopia if we want to limit the amount of overminus.  Otherwise, we 
679 
would create untenable situations, such as including a subject with +2.50D hyperopia, 
680 
prescribing 2.50D overminus, writing a spectacle prescription for 0.00D sphere, and calling 
681 
this prescription “overminus” treatment. 
682 
 
683 

IXT5 Protocol v3.0 (11-22-19) 
1-6 
The consensus of the IXT3 Planning Committee, affirmed by the Investigator Group at the 
684 
February 2014 Study Group meeting, was that a final spectacle prescription of -1.50D SE 
685 
should be the lowest level of overminus spectacles prescribed and still be considered 
686 
“overminus” for a RCT.  Doses of overminus greater than 2.50D were of concern to many 
687 
PEDIG Investigators.  For example, overminus of 4.00D was felt to be unreasonable, requiring 
688 
accommodation of 4.00D at distance fixation and 7.00D for near activities and reading.  
689 
 
690 
A reasonable dose of overminus for the IXT3 pilot study was therefore felt to be -2.50D over 
691 
the cycloplegic refraction.  The dose of -2.50D was successfully implemented in the study, was 
692 
tolerated well, and appeared to be effective.  In an effort to offer a consistent level of 
693 
overminus treatment for all subjects in IXT3, the study was limited to children with up to 
694 
+1.00D SE hyperopia, and a standard overminus of 2.50D was prescribed to all subjects.  This 
695 
ensured that the final spectacle prescription of -1.50D SE was the lowest level of overminus 
696 
spectacles prescribed while maintaining a constant accommodative demand.  Given the 
697 
acceptability and promising results in IXT3 pilot RCT, a dose of -2.50D over the cycloplegic 
698 
refraction will also be used in the present full RCT.  For the analogous reasons described 
699 
above, hyperopic refractive error in the present full RCT will also be limited to ≤1.00D SE 
700 
hyperopia. 
701 
 
702 
1.11 
Results of the IXT3 Pilot RCT 
703 
The IXT3 pilot RCT was designed to evaluate the short-term effectiveness of overminus 
704 
spectacles in improving control of IXT.  58 children ages 3 to < 7 years old with IXT were 
705 
randomized to receive either overminus spectacles (-2.50D over cycloplegic refraction) or 
706 
observation (non-overminus spectacles if needed, or no spectacles) and control was assessed by 
707 
a masked examiner after 8 weeks of treatment. At 8 weeks, mean distance control was better in 
708 
the 27 children treated with overminus spectacles than in the 31 children who were observed 
709 
without overminus treatment (2.0 vs 2.8 points, difference = -0.80 points (95% CI = -1.49 to -
710 
0.11 points), P = 0.01 for one-sided test).  When defining a treatment response as an 
711 
improvement in mean distance control score of 1 point or more, 59% of subjects in the 
712 
overminus group versus 39% of subjects in the observation group were classified as responders 
713 
(Difference 21%; 95% CI -6% to 45%; P=0.07 for one-sided test).  No significant differences 
714 
were observed between groups when comparing mean near control score or the proportion of 
715 
subjects with near control improving 1 point or more.  Side effect profiles regarding headaches, 
716 
eyestrain, avoidance of near activities, and blur appeared similar between treatment groups.  
717 
 
718 
Prior to the start of IXT3, criteria were determined for making the decision whether to proceed 
719 
to a long-term RCT of overminus treatment for IXT.  Based on the mean difference in distance 
720 
control, if the difference in mean favored overminus and P≤0.05, the decision would be to 
721 
proceed. If the difference in mean favored overminus but P>0.05, the decision to proceed was 
722 
classified as uncertain.  If the difference in mean did not favor overminus, the decision would 
723 
be to not proceed.  Regarding the proportion of subjects with distance control improving 1 
724 
point or more, if the response rate in overminus subjects was 20% or more than the response 
725 
rate in the observation group, the decision would be to proceed with a larger RCT.  If that same 
726 
difference in proportions was 10-19% higher in the over minus group, the decision would be 
727 
uncertain, and if the response rate was <10% higher in the overminus group, the decision 
728 
would be to not proceed.  Based on the findings of the IXT3 pilot RCT, with a difference in 
729 
mean distance control of -0.80 points with P=0.01 (favoring overminus) and a difference in 
730 
response rate of 21%, the decision whether to proceed to a larger scale RCT was to proceed 
731 
using each set of criteria.  We therefore concluded that we should conduct a larger and longer 
732 

IXT5 Protocol v3.0 (11-22-19) 
1-7 
trial to assess the effectiveness of overminus treatment on the ability to control IXT, both while 
733 
on treatment and after discontinuing treatment. 
734 
 
735 
1.12 
Questions Related to Overminus Lens Therapy 
736 
The recently completed IXT3 pilot study addressed the question of whether overminus lens 
737 
therapy has an initial short-term therapeutic effect for IXT while wearing overminus 
738 
spectacles.  There have been no rigorous studies that address the following important questions 
739 
related to overminus lens therapy: 
740 
• Does overminus lens therapy have a long-term therapeutic effect for IXT while 
741 
wearing overminus spectacles (over many months or years)? 
742 
• Does overminus lens therapy have a long-term therapeutic effect for IXT after 
743 
overminus spectacles are discontinued?  
744 
 
745 
1.13 
Definitions of Treatment Response  
746 
Previous studies have differed in their definitions of treatment response, including reduction of 
747 
the magnitude of exodeviation,11,14,24 improved control,20,25 or both combined with good 
748 
stereoacuity and good cosmesis assessed by parental impression.24  Some studies report 
749 
outcomes while the subject is still in overminus lens treatment,19,25 some post-treatment,14,20 
750 
and for others, treatment status at outcome is unclear.11,13,24 
751 
 
752 
Because the initial purpose of the treatment of IXT with overminus spectacles is to better align 
753 
the eyes for a greater proportion of the time, and single binocular vision with high grade 
754 
stereoacuity is only associated with good ocular alignment, it would seem reasonable to 
755 
primarily focus on improved “control” of the distance deviation as the first step in evaluating 
756 
effectiveness of overminus lens treatment.  Due to the variability of single measures of control, 
757 
we used the recently described “triple control score,”23 a mean of 3 measures obtained at 
758 
standardized times during a 20- to 40-minute office examination in the IXT3 pilot RCT, which 
759 
was easily implementable.  Therefore, we will use the “triple control score” as the primary 
760 
outcome measure in the proposed full RCT.  
761 
 
762 
Treatment effect will be assessed in our study by comparing the treatment group mean control 
763 
scores at the outcome examination (primary analysis) and by comparing the proportion of 
764 
subjects with “treatment response” (secondary analysis).  
765 
 
766 
Data simulations were used to estimate the amount of change in control expected from test-
767 
retest variability (including short term variability of the condition) and to evaluate the risk of 
768 
misclassification using various thresholds for defining treatment response.  A set of 10,000 
769 
stable subjects each with a mean control score (average of 3 measurements) of 2 or worse was 
770 
simulated using 1) the distribution of baseline distance control scores from subjects 3 to <11 
771 
years of age in the IXT2 study who would be eligible for the present study to estimate initial 
772 
control scores, and 2) actual test-retest data collected on 336 test-retest pairs from 158 IXT 
773 
subjects at the Mayo Clinic to estimate the probability that a subsequent score would be a 
774 
certain value (e.g., probability that a control score of five would subsequently test a three).  
775 
Based on the simulated data, the mean difference in control expected from test-retest 
776 
variability was estimated at -0.058 points with a standard deviation of 0.926 points.  The 
777 
simulations-estimated 95% limits of agreement of 1.82 points indicated that for a given subject, 
778 
a 2-point change in the mean control score would be required to have reasonable certainty of 
779 
exceeding test–retest variability.  Using a 2-point threshold, the simulations yielded a 
780 
misclassification rate for improvement of 2% assuming no real change has occurred.  
781 

IXT5 Protocol v3.0 (11-22-19) 
1-8 
Nevertheless, defining response as a 2-point change was ultimately not felt to be feasible given 
782 
that the target population in which overminus lenses are often used includes subjects with 
783 
control scores as low as 2 points (no exotropia unless dissociated, recovers in > 5 seconds) and 
784 
that it was felt very unlikely that a large proportion of such subjects could improve to a score 
785 
of 0 (pure phoria).  Consequently, the IXT3 Planning Committee consensus was that a 
786 
clinically meaningful “response” would be defined as an improvement of at least 1 point on the 
787 
mean control score.  For a 1-point threshold (the secondary outcome measure in IXT3), the 
788 
simulations yielded a misclassification rate for improved versus not improved of 18% 
789 
assuming no real change has occurred.  Therefore, in IXT3, the control group response rate 
790 
was estimated to be 18% (rounded to 20%) assuming no real change occurs.  As a result, it is 
791 
acknowledged that the response rate was overestimated in both treatment groups. The same 
792 
issues exist for the analogous secondary analyses in the current full RCT; hence, the proportion 
793 
of subjects with both a 1-point and 2-point change are secondary outcomes, and the primary 
794 
analysis will be based on a group comparison of the continuous measure of control. 
795 
 
796 
1.14 
Timing of Outcome Intervention for Current Study  
797 
The results of IXT3 suggest that a short-term (8 weeks) treatment with overminus spectacles is 
798 
effective in improving control while wearing overminus spectacles without inducing 
799 
significant adverse events. It is therefore reasonable to conduct a larger and longer full-scale 
800 
RCT to evaluate the long-term on-treatment effectiveness of overminus lenses (e.g., 12 
801 
months) and then evaluate the subsequent effectiveness of maintaining control during a 
802 
weaning period (e.g., 3 months) and after the overminus lens treatment has been discontinued 
803 
(e.g., 3 months after return to non-overminus spectacles). 
804 
 
805 
1.15 
Study Objective 
806 
The objectives of this randomized trial comparing overminus lens treatment to non-overminus 
807 
(spectacles without overminus or spectacles with plano lenses) are to determine: 
808 
• The long-term on-treatment effect of overminus treatment on distance IXT control 
809 
score (primary objective). 
810 
• The off-treatment effect of overminus treatment on distance IXT control score, 
811 
following weaning* and 3 months off treatment (secondary objective). 
812 
 
813 
*Note that weaning was changed to immediate discontinuation of overminus in Protocol 
814 
Amendment II). 
815 
 
816 
1.16 
Synopsis of Study Design 
817 
Major Eligibility Criteria (see section 2.2 for a complete listing) 
818 
• 
Ages 3 to < 11 years 
819 
• 
IXT (manifest deviation) meeting all of the following criteria: 
820 
o At distance: IXT or constant XT (mean distance control score of 2 points or more on 
821 
scale of 1 to 5) 
822 
o At near: IXT, exophoria, or orthophoria (mean near control <4 points on scale of 1 to 5) 
823 
o Exodeviation ≥ 15∆ at distance by PACT 
824 
o Near deviation does not exceed distance by more than 10∆ by PACT 
825 
• 
No treatment for IXT or amblyopia (other than refractive correction) within the past 4 
826 
weeks, including vision therapy, patching, atropine, or other penalization.  
827 
• 
No substantial overminus treatment (spectacles overminused by more than 1.00D SE than 
828 
the most recent cycloplegic refraction) within the past 6 months 
829 
• 
No prior strabismus, intraocular, or refractive surgery (including Botox injection) 
830 

IXT5 Protocol v3.0 (11-22-19) 
1-9 
• 
Refractive error between -6.00D SE and +1.00D SE (inclusive) in the most myopic / least 
831 
hyperopic eye (based on a cycloplegic refraction performed within 2 months or at the end 
832 
of the enrollment exam) 
833 
 
834 
Sample size and Treatment Groups 
835 
Sample size has been estimated to be 384 subjects, randomly assigned (1:1) to the following 
836 
groups:  
837 
• Overminus Group (-2.50D over the cycloplegic refraction) 
838 
• Non-overminus Group (non-overminus glasses of full cycloplegic refraction. Except 
839 
hyperopes (SE) will have full correction of astigmatism with the sphere component 
840 
adjusted symmetrically so that the SE is plano in the least hyperopic eye; if no astigmatism 
841 
is present, hyperopes will wear a plano lens in the least hyperopic eye with the sphere of 
842 
the fellow eye adjusted symmetrically from the cycloplegic refraction.) 
843 
 
844 
Visit / Contact Schedule  
845 
All visits/contacts are timed from randomization unless otherwise specified   
846 
• Enrollment Visit 
847 
• Repeat Enrollment Visit (within 1 month of initial Enrollment, if needed) 
848 
• 1-Month Phone call: 3 weeks (3-4 weeks)  
849 
• 3-Month Phone call: 3 months (3-4 months)  
850 
• 6-Month Office Visit: 6 months ± 1 month 
851 
• 9-Month Phone call: 9 months (9-10 months)  
852 
• 12-Month On-Treatment Primary Outcome Visit: 12 months ± 1 month   
853 
• 13-Month Phone call: 3-4 weeks following 12-month visit 
854 
• 15-Month Partial-Treatment* Visit: 15 months ± 1 month  
855 
• 16-Month Phone call: 3-4 weeks following 15-month visit  
856 
• 18-Month Off-Treatment Primary Outcome Visit: 18 months ± 1 month  
857 
*Or Off Treatment Interim Visit for subjects who formally discontinued treatment before the 
858 
15-month visit, after Protocol Amendment II. 
859 
 
860 
Testing Procedures  
861 
Distance and near control of IXT (3 measurements), cover test, distance and near PACT, and 
862 
near stereoacuity will be measured by a study-qualified examiner at enrollment, and by a 
863 
Masked Examiner at all follow-up visits.  Distance visual acuity will be measured by a study-
864 
qualified examiner at all visits.  Health-related quality of life, symptoms of intermittent 
865 
exotropia, and symptoms that may be associated with overminus spectacle wear will be 
866 
assessed at enrollment and the 6-month, 12-month and 18-month outcome visits.  Cycloplegic 
867 
refraction will be performed at the end of the enrollment visit (if not performed within prior 2 
868 
months) and at the 12-month and 18-month visits. 
869 
 
870 
Primary Analysis 
871 
• Treatment group comparison of mean distance control scores (mean of 3 assessments 
872 
during the exam) at 12 months (on-treatment comparison) 
873 
 
874 
Secondary Analysis 
875 
• Treatment group comparison of mean distance control scores (mean of 3 assessments 
876 
during the exam) at 18 months (off-treatment comparison) 
 
877 

IXT5 Protocol v3.0 (11-22-19) 
1-10 
1.17 
Study Flow Chart 
878 
 
879 
Randomization 
Non-Overminus Group  
Non-overminus spectacles or spectacles with 
plano lenses (see below)  
Overminus Group 
Overminus spectacles  
(see below)  
Prescribe New Spectacles: Overminus Group 
  
 Fully correct astigmatism in both eyes 
 Add -2.50D to the sphere component of both eyes 
Prescribe New Spectacles: Non-Overminus Group 
 Fully correct astigmatism in both eyes 
 Prescribe sphere: 
 If least hyperopic eye has SE myopia: 
 Prescribe full sphere in both eyes 
 If least hyperopic eye has SE hyperopia or emmetropia: 
 Prescribe sphere so that spectacles will have plano 
SE in the least hyperopic eye 
 Match any reduction of sphere made to the least 
hyperopic eye in the fellow eye 
Subject DOES NOT meet all 
other eligibility criteria 
Do not proceed- not eligible 
Spectacles OK or  
Not wearing spectacles and not required 
Spectacles NOT OK or  
Not wearing spectacles but required 
Subject DOES NOT meet all 
other eligibility criteria 
Do not proceed- not eligible 
Subject meets  
all other eligibility criteria 
 
Subject meets all 
eligibility criteria 
Based on cycloplegic refraction performed within 2 months of enrollment or at end of enrollment exam… 
Major Eligibility Criteria 
 
Ages 3 to < 11 years 
 
IXT (manifest deviation) meeting all of the following criteria: 
o 
IXT or constant XT at distance (mean distance control score of 2 points or more) 
o 
IXT, exophoria, or orthophoria at near (mean near control better than 5 points) 
o 
Exodeviation ≥ 15∆ at distance by PACT 
o 
Near deviation does not exceed distance by more than 10∆ by PACT 
 
Refractive error between -6.00D SE and +1.00D SE (inclusive) in the most myopic / least hyperopic eye based on 
cycloplegic refraction within prior 2 months or at the end of the enrollment exam 
 
Pre-study correction (if worn) must meet eligibility criteria (section 2.2) based on cycloplegic refraction within prior 2 
months or at the end of the enrollment exam 
 
No treatment for IXT or amblyopia (other than refractive correction) within the past 4 weeks, including vision therapy, 
patching, atropine, or other penalization.  
 
No previous substantial overminus treatment within the past 6 months (spectacles overminused by more than 1.00D SE) 
 
No prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
 
Enrollment Exam Testing Procedures  
 
Lensometry 
 
Health-related quality of life questionnaire and symptom surveys 
 
IXT control assessment #1 (distance and near) 
 
Randot Preschool stereoacuity at near 
 
IXT control assessment #2 (distance and near) 
 
Cover test then Prism and Alternate Cover Test (distance and near, distance with -2.00D lens for AC/A) 
 
IXT control assessment #3 (distance and near) 
 
Assessment of control throughout exam 
 
Distance visual acuity 
 
Cycloplegic autorefraction (if available at site) 
 
Cycloplegic refraction (if not performed within prior 2 months) 
Prescribe new glasses meeting criteria 
Bring back within 1month to reassess 
eligibility at a Repeat Enrollment Visit  

IXT5 Protocol v3.0 (11-22-19) 
1-11 
880 
3-Month Phone Call (3 to 4 months from Randomization) 
 
Engage family and encourage compliance  
9-Month Phone Call (9 to 10 months from Randomization) 
Engage family and encourage compliance  
6-Month Office Visit (± 1 month) 
 
Lensometry 
 
Health-related quality of life questionnaire and symptom surveys 
 
IXT control assessment #1(distance and near) 
 
Randot Preschool stereoacuity at near 
 
IXT control assessment #2 (distance and near) 
 
Cover test 
 
Prism and Alternate Cover Test (distance and near) 
 
IXT control assessment #3 (distance and near) 
 
Assessment of control throughout exam 
 
Distance visual acuity (same method as enrollment) 
12-Month On-Treatment Primary Outcome Visit (± 1 month)  
 
Lensometry 
 
Health-related quality of life questionnaire and symptom surveys 
 
IXT control assessment #1(distance and near) 
 
Randot Preschool stereoacuity at near  
 
IXT control assessment #2 (distance and near) 
 
Cover test 
 
Prism and Alternate Cover Test (distance and near) 
 
IXT control assessment #3 (distance and near) 
 
Assessment of control throughout exam 
 
Distance visual acuity (same method as enrollment) 
 
Cycloplegic autorefraction (mandatory if available at site) 
 
Cycloplegic refraction 
 
ADHD medication use data collection 
1-Month Phone Call: 3 to 4 weeks after Randomization 
 
Assess whether subject has received spectacles  
Both Treatment Groups 
Overminus: Discontinue Overminus / Prescribe Non-overminus  
Non-overminus: Continue Non-Overminus 
Based on cycloplegic refraction at 12 months: 
 Fully correct astigmatism in both eyes 
 Prescribe sphere: 
 If least hyperopic eye has SE myopia: 
 Prescribe full sphere in both eyes 
 If least hyperopic eye has SE hyperopia or emmetropia: 
 Prescribe sphere so that spectacles will have plano SE in the least hyperopic eye 
 Match any reduction of sphere made to the least hyperopic eye in the fellow eye 

IXT5 Protocol v3.0 (11-22-19) 
1-12 
881 
15-Month Partial-Treatment Outcome Visit (± 1 month) 
 
Lensometry 
 
IXT control assessment #1(distance and near) 
 
Randot Preschool stereoacuity at near 
 
IXT control assessment #2 (distance and near) 
 
Cover test 
 
Prism and Alternate Cover Test (distance and near) 
 
IXT control assessment #3 (distance and near) 
 
Assessment of control throughout exam 
 
Distance visual acuity (same method as enrollment) 
16-Month Phone Call (3 to 4 weeks after 15-month Visit) 
Maintain rapport, assess whether subject has received new spectacles (if new 
were prescribed) 
18-Month Off-Treatment Secondary Outcome Visit (± 1 month) 
 
Lensometry 
 
Health-related quality of life questionnaire and symptom surveys 
 
IXT control assessment #1(distance and near) 
 
Randot Preschool stereoacuity at near 
 
IXT control assessment #2 (distance and near) 
 
Cover test 
 
Prism and Alternate Cover Test (distance and near, distance with -2.00D lens for AC/A) 
 
IXT control assessment #3 (distance and near) 
 
Assessment of control throughout exam 
 
Distance visual acuity (same method as enrollment) 
 
Cycloplegic refraction  
 
Cycloplegic autorefraction (mandatory if available at site) 
 
Cycloplegic axial length measurement and additional biometry (mandatory if available at site) 
13-Month Phone Call (3 to 4 weeks after 12-month Visit) 
Assess whether subject has received new spectacles  
 
If 12-month spectacles were prescribed before Protocol Amendment II, 
prescribe non-overminus spectacles at 15 months in both treatment groups 
 
If 12-month spectacles were prescribed on/after Protocol Amendment II,  
continue the same non-overminus spectacles at 15 months  
 

IXT5 Protocol v3.0 (11-22-19) 
2-1 
CHAPTER 2: ENROLLMENT AND RANDOMIZATION 
882 
 
883 
2.1 
Eligibility Assessment and Informed Consent 
884 
The randomized trial will include approximately 384 subjects aged 3 to < 11 years with IXT. 
885 
As the randomization goal approaches, sites will be notified of the end date for recruitment.  
886 
Subjects whose parents have signed an informed consent form may be entered into the 
887 
randomized trial up until the end date, which means the expected number for the randomized 
888 
trial might be exceeded.  The maximum number of randomly assigned subjects will be 450. 
889 
 
890 
A child is considered for the study after undergoing a routine eye examination (by a study 
891 
investigator as part of standard care) that identifies IXT that appears to meet the eligibility 
892 
criteria.  The study will be discussed with the child’s parent(s) or guardian(s) (referred to 
893 
subsequently as parent(s)).  Parent(s) who express an interest in the study will be given a copy 
894 
of the informed consent form to read.  Written informed consent must be obtained from the 
895 
parent prior to performing any study-specific procedures that are not part of routine care. 
896 
 
897 
2.2 
Eligibility Criteria 
898 
The following criteria must be met for the child to be enrolled in the study: 
899 
 
900 
Inclusion Criteria 
901 
• Age 3 years to < 11 years  
902 
• Intermittent exotropia (manifest deviation) meeting all of the following criteria: 
903 
• At distance: intermittent exotropia or constant exotropia  
904 
o Mean distance control score of 2 points or more (mean of 3 assessments over 
905 
the exam) 
906 
• At near: intermittent exotropia, exophoria, or orthophoria  
907 
o Subject cannot have a score of 5 points on all 3 near assessments of control 
908 
• Exodeviation at least 15∆ at distance measured by PACT 
909 
• Near deviation does not exceed distance deviation by more than 10∆ by PACT 
910 
(convergence insufficiency type IXT excluded) 
911 
• Distance visual acuity (any optotype method) in each eye of 0.4 logMAR (20/50) or better 
912 
if age 3 years and 0.3 logMAR (20/40) or better if 4 years or older. 
913 
• Interocular difference of distance visual acuity ≤0.2 logMAR (2 lines on a logMAR chart) 
914 
• Refractive error between -6.00D SE and +1.00D SE (inclusive) in the most myopic / least 
915 
hyperopic eye based on a cycloplegic refraction performed within the past 2 months or at 
916 
the end of the enrollment exam. 
917 
• If refractive error (based on cycloplegic refraction performed within past 2 months or at 
918 
the end of the enrollment exam) meets any of the following criteria, then pre-study 
919 
spectacles are required and must have been worn for at least 1 week prior to enrollment:  
920 
• SE anisometropia ≥1.00D 
921 
• Astigmatism ≥1.50D in either eye 
922 
• SE myopia ≥-1.00D in either eye 
923 
Pre-study refractive correction, if worn, must meet the following criteria relative to the 
924 
cycloplegic refraction performed within past 2 months or at the end of the enrollment 
925 
exam: 
926 
• SE anisometropia must be corrected within <1.00D of the SE anisometropic 
927 
difference  
928 

IXT5 Protocol v3.0 (11-22-19) 
2-2 
• Astigmatism must be corrected within <1.00D of full magnitude; axis must be 
929 
within 10 degrees. 
930 
• The SE of the spectacles must not meet the definition of substantial overminus (see 
931 
exclusion criteria below) 
932 
• Gestational age ≥ 32 weeks 
933 
• Birth weight > 1500 grams 
934 
• Parent understands the protocol and is willing to accept randomization to overminus 
935 
spectacles or non-overminus spectacles 
936 
• Parent has home phone (or access to phone) and is willing to be contacted by Jaeb Center 
937 
staff and Investigator’s site staff 
938 
• Relocation outside of area of an active PEDIG site within next 18 months is not anticipated 
939 
 
940 
Exclusion Criteria 
941 
• Treatment for IXT or amblyopia (other than refractive correction) within the past 4 weeks, 
942 
including vision therapy, patching, atropine, or other penalization. 
943 
• Current contact lens wear 
944 
• Substantial deliberate overminus treatment within the past 6 months, defined as spectacles 
945 
overminused by more than 1.00D SE than the cycloplegic refractive error (assessed within 
946 
2 months or at the end of the enrollment exam)  
947 
• Prior strabismus, intraocular, or refractive surgery (including BOTOX injection) 
948 
• Abnormality of the cornea, lens, or central retina 
949 
• Down syndrome or cerebral palsy 
950 
• Severe developmental delay which would interfere with treatment or evaluation (in the 
951 
opinion of the investigator).  Subjects with mild speech delays or reading and/or learning 
952 
disabilities are not excluded. 
953 
• Any disease known to affect accommodation, vergence, and ocular motility such as 
954 
multiple sclerosis, Graves orbitopathy, dysautonomia, myasthenia gravis, or current use of 
955 
atropine for amblyopia 
956 
• Anti-seizure medications [e.g., carbamazepine (Tegretol, Carbatrol, Epitol, or Equetro), 
957 
diazepam (Valium or Diastat), clobazam (Frisium or Onfri), clonazepam (Klonopin), 
958 
lorazepam (Ativan), ethosuximide (Zarontin), felbamate (Felbatol), lacosamide (VIMPAT), 
959 
gabapentin (Neurontin), oxcarbazepine (Oxtellar XR or Trileptal), phenobarbital, phenytoin 
960 
(Dilantin or Phenytek), pregabalin (Lyrica), tiagabine (Gabitril), topiramate (Topamax), 
961 
valproate (Depakote), or zonisamide (Zonegran), vigabatrin (Sabril)] 
962 
 
963 
2.3 
Historical Information 
964 
Historical information elicited will include the following: date of birth, sex, race, ethnicity, 
965 
cycloplegic refraction, cycloplegic autorefraction (performed within 2 months or at 
966 
enrollment), prior treatment for IXT, spectacle correction, and use of ADHD and anti-seizure 
967 
medications. 
968 
 
969 
2.4 
Testing at the Enrollment Visit 
970 
Initial testing at the enrollment visit should be performed without cycloplegia and with the 
971 
subject’s habitual correction (with spectacles if currently wearing, or without spectacles if not 
972 

IXT5 Protocol v3.0 (11-22-19) 
2-3 
currently wearing).* Trial frames should NOT be used for testing at the enrollment visit for 
973 
any reason.  
974 
 
975 
* The exception is a subject wearing spectacles not required by pre-randomization criteria 
976 
(see section 2.2).  This subject can be tested with or without these spectacles, provided 
977 
visual acuity criteria are still met under the condition in which they are evaluated (see 
978 
section 2.2). 
979 
 
980 
There is no specified “waiting” time that needs to occur between measurements, although 
981 
testing must be performed in the following specified order at the enrollment visit, an exception 
982 
being that distance visual acuity can be tested either at the start of the visit or at the end of the 
983 
visit: 
984 
 
985 
1. Spectacle Prescription Verification (Lensometry): Prior to performing the enrollment 
986 
examination, the subject’s pre-randomization spectacle correction (if worn) is to be verified 
987 
using a lensometer. 
988 
2. Health-Related Quality of Life Questionnaire and Symptom Surveys:  
989 
• A brief survey of symptoms that may be associated with overminus such as 
990 
headaches, eye strain, and problems with spectacle wear will be administered to 
991 
the parents of the subjects.  Parents are asked to respond to the survey questions 
992 
based on their observations of their child in the past 2 weeks.    
993 
• A brief survey of intermittent exotropia symptoms will be administered to the 
994 
child. 
995 
• Health-related quality of life (HRQOL) will be assessed using the following two 
996 
components of the Intermittent Exotropia Questionnaire (IXTQ).26,27    
997 
1. Child IXTQ: A child questionnaire for children ages 5 years or older to 
998 
assess how the child feels about his/her eye condition. Children 4 years 
999 
and younger at the time of enrollment will not complete the child 
1000 
questionnaire. 
1001 
2. Parent IXTQ: A parental questionnaire to assess how the child’s eye 
1002 
condition affects the parent (in all children).   
1003 
 
1004 
STEPS 3 through 9 must be performed in the specified order by the same study-certified 
1005 
examiner (pediatric ophthalmologist, pediatric optometrist, or certified orthoptist) on the 
1006 
same day.  
1007 
 
1008 
3. Control of the Exodeviation #1:  
1009 
Control of exodeviation will be assessed in the habitual correction at distance and near 
1010 
using a standardized IXT control scale (see below).21  
1011 
o Distance (6 meters) – fixing on an accommodative target such as a video or reading 
1012 
optotype letters 
1013 
o Near (1/3 meter) – fixing on Lang near-viewing stick or similar accommodative target 
1014 
 
1015 
The scale below applies to both distance and near separately.  
1016 
 
1017 
Intermittent Exotropia Control Scale 
1018 
5 = Constant Exotropia 
1019 

IXT5 Protocol v3.0 (11-22-19) 
2-4 
4 = Exotropia > 50% of the 30-second period before dissociation 
1020 
3 = Exotropia < 50% of the 30-second period before dissociation 
1021 
2 = No exotropia unless dissociated, recovers in >5 seconds 
1022 
1 = No exotropia unless dissociated, recovers in 1-5 seconds 
1023 
0 = No exotropia unless dissociated, recovers in <1 second (phoria) 
1024 
Not applicable = No exodeviation present  
1025 
 
1026 
 
1027 
Directions:  
1028 
 
1029 
Step1: Assessment before any dissociation: Levels 5 to 3 are assessed during a 30-second 
1030 
period of observation; first at distance fixation and then at near fixation for another 
1031 
30-second period.  Both distance and near are assessed before any dissociation (i.e., 
1032 
before step 2, when assessing control scores of 0, 1 and 2).  If the subject is 
1033 
spontaneously tropic (score 3, 4 or 5) at a specified test distance, then step 2 
1034 
(assessment after standard dissociation) is skipped at that specific test distance. 
1035 
 
1036 
Step 2: Assessment with standardized dissociation: If no exotropia is observed during step 
1037 
1 (i.e., the 30-second period of observation at the specified test distance), levels 2 to 
1038 
0 are then assessed as the worst of 3 rapidly successive trials of dissociation: 
1039 
1. An occluder is placed over the right eye for 10 seconds and then removed, 
1040 
measuring the length of time it takes for fusion to become re-established. 
1041 
2. The left eye is then occluded for a 10-second period (second assessment under 
1042 
dissociation) and the time to re-establish fusion is similarly measured. 
1043 
3. A third assessment under dissociation is performed, covering the eye (for a 10-
1044 
second period) that required the longest time to re-fuse. 
1045 
The worst level of control observed following the three 10-second periods of occlusion 
1046 
should be recorded. Since the level under dissociation is recorded as the worst of the 
1047 
three assessments, if a score of 2 (>5 seconds recovery) is noted on the first or second 
1048 
dissociation, then subsequent dissociation(s) are not needed. 
1049 
 
1050 
If the patient has a micro-esotropia by cover test but an exodeviation by PACT, the scale 
1051 
applies to the exodeviation. 
1052 
4. Stereoacuity Testing: Stereoacuity will be assessed with habitual correction (if any) using 
1053 
the Randot Preschool stereotest at near (performed at 40 cm).  A specific level of 
1054 
stereoacuity is not required for eligibility. 
1055 
5. Control of the Exodeviation #2 (repeat) (see item #3). 
1056 
6. Cover Test 
1057 
• Assessed in primary position at distance (6 meters) and near (1/3 meters) using 
1058 
procedures outlined in the IXT Testing Procedures Manual  
1059 
7. PACT Testing & AC/A Determination:   
1060 
• PACT will be assessed in primary gaze and without cycloplegia as follows and using 
1061 
procedures outlined in the IXT Testing Procedures Manual. 
1062 
• At distance (6 meters) and near (1/3 meter) in habitual correction 
1063 
• AC/A assessment at distance (6 meters) measuring the PACT with the subject wearing 
1064 
-2.00D lenses over his/her habitual correction. The AC/A ratio is calculated by taking 
1065 
the difference between the distance PACT measurements with and without -2.00D 
1066 
lenses and dividing the difference by 2.  
1067 
8. Control of the Exodeviation #3 (repeat) (see item #3) 
1068 

IXT5 Protocol v3.0 (11-22-19) 
2-5 
9. Assessment of Deviation Throughout Exam 
1069 
• The nature of the exodeviation will be classified at distance and near as either constant, 
1070 
intermittent, phoric, or no deviation based on observations of the examiner assessing 
1071 
control during the entire examination period from the first assessment of control 
1072 
through the last assessment of control. The nature of the deviation will be recorded as: 
1073 
• Constant if a manifest tropia is present 100% of the time during the 
1074 
examination, including during all 3 control tests (score of 5 for each test)  
1075 
• Intermittent if a manifest tropia is present (including after dissociation) but 
1076 
not 100% of the time during the entire exam.   
1077 
• Phoric if a tropia is not observed at any time but a phoria is present.  
1078 
• No deviation if no deviation is present at any time.   
1079 
• If the child appears to have a constant tropia but shows excellent stereoacuity that may 
1080 
be inconsistent with the diagnosis of constant tropia, the examiner should look over the 
1081 
child's polarized glasses to determine whether the child is indeed constantly tropic (by 
1082 
direct observation with a cover test). 
1083 
10. Distance Visual Acuity Testing: Monocular distance visual acuity testing with the habitual 
1084 
correction and without cycloplegia will be measured using the investigators usual testing 
1085 
procedure. 
1086 
• 
Visual acuity testing method must use optotypes. 
1087 
• 
Visual acuity must be tested using the same testing procedure throughout the entire 
1088 
study. 
1089 
• 
Visual acuity will be recorded as Snellen equivalents in logMAR increments. 
1090 
• 
Visual acuity may be tested at the start of the exam or at the end of the exam (not 
1091 
between steps #3 and #9). 
1092 
11. Cycloplegic Autorefraction (if available at site):  
1093 
• If an autorefractor is available at the site, refractive error must be measured with the 
1094 
autorefractor following cycloplegia with 1% cyclopentolate (see cycloplegic refraction 
1095 
below).  These measures will be used to determine myopic progression in both groups, 
1096 
but will not be used to assess eligibility or to prescribe spectacle correction during the 
1097 
study.  Recorded values will be based on a single measurement by the instrument 
1098 
(which may be a mean of several individual measures, depending on system). The 
1099 
autorefraction should be done on the same day as the cycloplegic refraction, which may 
1100 
be done within 2 months of enrollment.   
1101 
12. Cycloplegic Refraction:  
1102 
• A cycloplegic refraction will be performed at the end of the enrollment visit if not done 
1103 
within 2 months of enrollment.  
1104 
• The cycloplegic refraction used to assess eligibility must be/have been performed 30 to 
1105 
45 minutes following at least one application of cyclopentolate 1% per investigator’s 
1106 
usual dosage and timing routine. 
1107 
o The cycloplegic refraction is based on cycloplegic retinoscopy, which may be 
1108 
done with glasses off or as an over-refraction in front of the current spectacles.  
1109 
Subjective refraction is allowed. 
1110 
o When an over-refraction of current eye glasses is performed, the reported 
1111 
cycloplegic refraction will be the sum of the current spectacle power and the 
1112 
over-refraction. 
1113 
13. Additional Clinical Testing:  
1114 

IXT5 Protocol v3.0 (11-22-19) 
2-6 
• Ocular examination as per investigator’s clinical routine to rule out ocular abnormality 
1115 
or lens opacity (if not performed within 7 months)  
1116 
 
1117 
All testing must be performed within 7 days before randomization except where otherwise 
1118 
noted above.   
1119 
 
1120 
2.5 
Confirmation of Eligibility / Timing of Randomization 
1121 
All testing to assess eligibility for randomization must be performed without cycloplegia and 
1122 
with the subject’s current correction (with spectacles if currently wearing or without spectacles 
1123 
if not currently wearing).   
1124 
 
1125 
Eligibility criteria relating to refractive error and spectacle correction are based upon the 
1126 
cycloplegic refraction done within 2 months of enrollment or at the end of the enrollment exam 
1127 
(for subjects without a prior cycloplegic refraction performed within 2 months of enrollment). 
1128 
• If all eligibility criteria are met (including appropriate pre-study refractive correction, if 
1129 
required—see section 2.2), the subject should be randomized on the day of enrollment 
1130 
testing (or up to 7 days later).  
1131 
• If all eligibility criteria are met other than the subject needing to be prescribed new pre-
1132 
study refractive correction or needing a change in pre-study refractive correction 
1133 
(section 2.2):  
1134 
• Prescribe new spectacles paid for by the study 
1135 
• Have the subject return for a repeat enrollment exam (paid for by the study) 
1136 
within 1 month and after wearing the new pre-study spectacles for at least 1 
1137 
week.  All enrollment testing except cycloplegic refraction must be repeated. 
1138 
o If the subject meets all eligibility criteria at the repeat enrollment exam, 
1139 
he/she will be eligible for randomization at that time (or up to 7 days 
1140 
later). 
1141 
o If the subject fails any eligibility criteria at the repeat enrollment exam, 
1142 
the patient is not eligible for randomization and will end study 
1143 
participation.  
1144 
 
1145 
2.6 
Randomization  
1146 
Randomization will occur within 7 days after confirming that the subject meets the eligibility 
1147 
criteria.   
1148 
 
1149 
Subjects entering the study will be randomly assigned with equal probability to one of the 
1150 
following groups: 
1151 
• Overminus Group  
1152 
• Non-overminus Group  
1153 
 
1154 
The Jaeb Center will construct a separate Master Randomization List using a permuted block 
1155 
design stratified by site and baseline distance control.  A subject is officially enrolled in the 
1156 
randomized trial when the website randomization process is completed. 
1157 
 
1158 
Subjects and parents will be masked to the treatment group assignment. 
1159 
 
1160 

IXT5 Protocol v3.0 (11-22-19) 
2-7 
2.6.1 
Treatment for Overminus Group  
1161 
NOTE: Details of spectacles to be prescribed will be automatically calculated by the study 
1162 
website.  
1163 
 
1164 
No IXT treatment other than the study spectacles specified below can be prescribed at 
1165 
any time during the study unless the subject meets deterioration criteria described in 
1166 
section 3.7.   
1167 
 
1168 
Enrollment Visit 
1169 
• 
Subjects randomly assigned to the overminus group will be prescribed spectacles 
1170 
based on a cycloplegic refraction as follows: 
1171 
o Fully correct the astigmatism in both eyes (if present) 
1172 
o Add -2.50D to the sphere component of the cycloplegic refraction for both 
1173 
eyes 
1174 
• 
Overminus spectacles are prescribed to be worn all waking hours through the 12-
1175 
month outcome visit. 
1176 
 
1177 
12-Month Visit* 
1178 
• 
At the 12-month outcome visit, overminus treatment will be discontinued and new non-
1179 
overminus spectacles will be prescribed based on the 12-month cycloplegic refraction 
1180 
as follows*: 
1181 
• If the cycloplegic refraction is spherical and plano or any amount of hyperopia in 
1182 
both eyes (with no astigmatism and no anisometropia), subjects will wear spectacles 
1183 
with plano lenses in both eyes to maintain masking. 
1184 
• Otherwise, fully correct astigmatism in both eyes and prescribe sphere as follows: 
1185 
• If least hyperopic eye has SE myopia: 
1186 
• Prescribe the full sphere in both eyes   
1187 
• If least hyperopic eye has SE hyperopia or emmetropia: 
1188 
• Prescribe sphere so that spectacles will have plano SE in the least 
1189 
hyperopic eye 
1190 
• Match any reduction of sphere made to the least hyperopic eye in the 
1191 
fellow eye 
1192 
• 
Subjects will wear the new prescription all waking hours until the 18-month visit. 
1193 
 
1194 
* Unless the subject has already met deterioration criteria confirmed by masked examiner 
1195 
as described in section 3.7 in which case spectacles are prescribed at investigator 
1196 
discretion. 
1197 
 
1198 
15-Month Visit* 
1199 
• If the 12-month spectacles for a subject were issued before Protocol Amendment II and 
1200 
therefore contain partial-strength overminus (-1.25D), the spectacles should be changed 
1201 
to non-overminus spectacles at the 15-month to discontinue the overminus (see 12-
1202 
month prescribing above).     
1203 
• If the 12-month spectacles for a subject were issued on/after Protocol Amendment II 
1204 
and therefore are already non-overminus spectacles, the non-overminus spectacles 
1205 
should be continued at the 15-month visit. 
1206 
 
1207 

IXT5 Protocol v3.0 (11-22-19) 
2-8 
* Unless the subject has already met deterioration criteria confirmed by masked examiner 
1208 
as described in section 3.7. in which case spectacles are prescribed at investigator 
1209 
discretion. 
1210 
 
1211 
2.6.2 
Treatment for Non-Overminus Group  
1212 
NOTE: Details of spectacles to be prescribed will be automatically calculated by the study 
1213 
website.   
1214 
 
1215 
No IXT treatment other than the study spectacles specified below can be prescribed at 
1216 
any time during the study unless the subject meets deterioration criteria described in 
1217 
section 3.7. 
1218 
 
1219 
Enrollment Visit 
1220 
• Subjects in the non-overminus group will be prescribed spectacles based on the 
1221 
cycloplegic refraction as follows:  
1222 
• If the cycloplegic refraction is spherical and between plano sphere and +1.00D 
1223 
sphere in both eyes (with no astigmatism and no anisometropia), subjects will 
1224 
wear spectacles with plano lenses in both eyes to maintain masking. 
1225 
• Otherwise, fully correct the astigmatism and prescribe sphere as follows:  
1226 
• If least hyperopic eye has SE myopia: 
1227 
• Prescribe the full sphere in both eyes   
1228 
• If least hyperopic eye has SE hyperopia or emmetropia: 
1229 
• Prescribe sphere so that spectacles will have plano SE in the least 
1230 
hyperopic eye 
1231 
• Match any reduction of sphere made to the least hyperopic eye in 
1232 
the fellow eye 
1233 
• Subjects will wear the new prescription all waking hours until the 12-month visit. 
1234 
 
1235 
12-Month Visit* 
1236 
• Spectacles will be updated at the 12- -month visit using the same prescribing 
1237 
guidelines at enrollment (see above) but using the 12-month cycloplegic refraction, 
1238 
unless the subject has already met deterioration criteria confirmed by masked 
1239 
examiner as described in section 3.7 in which case spectacles are prescribed at 
1240 
investigator discretion.   
1241 
• To maintain masking, lenses will be replaced even if there is no change in the 
1242 
cycloplegic refraction. 
1243 
 
1244 
* Unless the subject has already met deterioration criteria confirmed by masked examiner as 
1245 
described in section 3.7 in which case spectacles are prescribed at investigator discretion. 
1246 
 
1247 
15-Month Visit* 
1248 
• If the 12-month spectacles for a subject were issued before Protocol Amendment II, the 
1249 
non-overminus lenses should be replaced at the 15-month visit to maintain masking of 
1250 
treatment groups (see 12-month prescribing above).      
1251 
• If the 12-month spectacles for a subject were issued on/after Protocol Amendment II 
1252 
and therefore are already non-overminus spectacles, the non-overminus spectacles 
1253 
should be continued at the 15-month visit.)  There is no longer a reason to change the 
1254 

IXT5 Protocol v3.0 (11-22-19) 
2-9 
glasses to maintain masking, because both treatment groups are already wearing non-
1255 
overminus glasses.   
1256 
*Unless the subject has already met deterioration criteria confirmed by masked examiner as 
1257 
described in section 3.7 in which case spectacles are prescribed at investigator discretion. 
1258 

IXT5 Protocol v3.0 (11-22-19) 
3-1 
CHAPTER 3: FOLLOW-UP AND MANAGEMENT 
1259 
 
1260 
3.1 
Follow-up Schedule 
1261 
The follow-up schedule is timed from randomization as follows:  
1262 
• 1-Month Phone call: 3 weeks (3-4 weeks)  
1263 
• 3-Month Phone call: 3 months (3-4 months)  
1264 
• 6-Month Office Visit: 6 months ± 1 month 
1265 
• 9-Month Phone call: 9 months (9-10 months)  
1266 
• 12-Month On-Treatment Primary Outcome Visit: 12 months ± 1 month  
1267 
• 13-Month Phone call: 3-4 weeks following 12-month visit) 
1268 
• 15-Month Off-Treatment Interim Visit: 15 months ± 1 month  
1269 
• 16-Month Phone call: 3-4 weeks following 15-month visit)  
1270 
• 18-Month Off-Treatment Primary Outcome Visit: 18 months ± 1 month  
1271 
 
1272 
Additional visits may be scheduled at investigator discretion. 
1273 
 
1274 
Subjects with a drop (worsening) of 2 or more octaves from baseline in near stereoacuity 
1275 
during follow-up (see section 3.7), confirmed by a retest on the same day, will need to return 
1276 
for an additional retest on a subsequent day. 
1277 
 
1278 
3.2 
Telephone Calls  
1279 
At each time during the study when subjects in both groups receive new study spectacles, the 
1280 
site will contact parents to determine whether the study spectacles (overminus spectacles/non-
1281 
overminus spectacles/plano spectacles) have been dispensed/received.  These calls will occur 3 
1282 
weeks following the enrollment, 12-month, and 15-month visits as defined above.  
1283 
 
1284 
The site will record the date that the new spectacles were received or document that they have 
1285 
not been received as of the call date.  Parents will be reminded to have their children wear the 
1286 
spectacles all waking hours.  
1287 
 
1288 
Additional protocol-specified calls to engage the subject and encourage spectacle compliance 
1289 
will be made from the investigator’s site at 3 months and 9 months following randomization as 
1290 
defined above.   
1291 
 
1292 
Additional calls may be made as needed as outlined in section 4.1.   
1293 
 
1294 
3.3 
Masking of Treatment Group 
1295 
Subjects will be masked to treatment group throughout the study. Subjects who do not have 
1296 
refractive error that requires correction (see sections 2.6.1 and 2.6.2) will be prescribed plano 
1297 
lenses if randomized to the non-overminus group.     
1298 
 
1299 
Key outcome testing at each follow-up visit (see section 3.3.1) will be performed by an 
1300 
examiner masked to treatment group. Although the examiner will see the subject’s spectacles 
1301 
during test, the presumption is that treatment group is unlikely to be discerned because 1) all 
1302 
subjects will be wearing spectacles and 2) because both treatment groups will have a range of 
1303 
prescriptions depending on subjects’ underlying refractive error in addition to whether an 
1304 
overminus component is included. The Masked Examiner must be a pediatric ophthalmologist, 
1305 

IXT5 Protocol v3.0 (11-22-19) 
3-2 
pediatric optometrist, or certified orthoptist. The Masked Examiner should preferably be 
1306 
someone other than the investigator.  
1307 
 
1308 
If necessary at rare sites, the Masked Examiner may be the investigator if the investigator 
1309 
remains masked to the randomized treatment. At such sites, for prescription of spectacles 
1310 
throughout the study, the investigator should sign two prescriptions (one overminus 
1311 
prescription and one non-overminus prescription), after which an unmasked coordinator would 
1312 
provide the parent with the appropriate prescription according to the subject’s treatment group.     
1313 
 
1314 
The investigator will be unmasked to treatment group except at rare sites in which he/she must 
1315 
serve as the masked examiner. The investigator should not discuss a subject’s treatment group 
1316 
with the subject or his/her parents.   
1317 
 
1318 
3.3.1 
Masked Examiner Testing   
1319 
A masked examiner will assess the following at the 6-month, 12-month, 15-month, and 18-
1320 
month visits regardless of whether or not the subject has already met deterioration criteria 
1321 
confirmed by masked examiner as described in section 3.7 at a previous visit: 
1322 
• 
Control assessment #1 
1323 
• 
Stereoacuity 
1324 
• 
Control assessment #2 
1325 
• 
Cover test 
1326 
• 
PACT 
1327 
• 
Control assessment #3 
1328 
• 
Assessment of deviation throughout the exam 
1329 
 
1330 
The Masked Examiner must not verify the spectacles using lensometry, discuss compliance of 
1331 
spectacle wear with the subject or parents, or administer the symptom survey.  The Masked 
1332 
Examiner should not review the subject’s medical record prior to the exam.  
1333 
 
1334 
3.4 
Outcome Visit Testing Procedures 
1335 
If deterioration has NOT been confirmed by masked exam at a previous visit, subjects should 
1336 
be tested in study specific spectacles (i.e., overminus spectacles or non-overminus spectacles 
1337 
including plano spectacles).  If deterioration has been confirmed by masked exam at a previous 
1338 
visit, subjects will be tested in their current refractive correction.  
1339 
 
1340 
Someone other than the Masked Examiner will ensure that the subject is wearing the 
1341 
appropriate spectacles (as described above) prior to the masked exam. 
1342 
 
1343 
Subjects not bringing their spectacles to the outcome visit (or who have had their spectacles 
1344 
discontinued for any reason) will be tested in trial frames.  Subjects who have had their 
1345 
spectacles discontinued (not likely to occur) should be tested in plano trial frames. To avoid 
1346 
potential unmasking, the trial lenses must have wire frames (not red or black indicating minus 
1347 
or plus power).  Care should be taken to cover any power-indicating markings with tape to 
1348 
ensure that masking is maintained. 
1349 
 
1350 
The following procedures should be performed by the appropriate examiner (see below) and in 
1351 
order where specified: 
1352 
 
1353 

IXT5 Protocol v3.0 (11-22-19) 
3-3 
The following procedures are tested first by someone other than the Masked Examiner:  
1354 
1. Spectacle Prescription Verification (Lensometry):  Prior to performing the outcome 
1355 
examination, the subject’s spectacle correction will be verified using a lensometer 
1356 
(including plano lenses). 
1357 
• Spectacles should meet the following tolerances:  
1358 
➢ Sphere within 0.50D of prescribed 
1359 
➢ Cylinder within 0.50D of prescribed 
1360 
➢ Axis within 10 degrees of prescribed  
1361 
• If spectacles do not meet these tolerances, the subject should be tested with trial 
1362 
frames with the intended prescription in place. 
1363 
2. Compliance Assessment: Compliance with spectacle wear since receiving the spectacles 
1364 
will be assessed based on discussion with the parents and using the following scale: 
1365 
o Excellent (76% to 100%) 
1366 
o Good (51% to 75%) 
1367 
o Fair (26% to 50%) 
1368 
o Poor (≤ 25%) 
1369 
3. Health-Related Quality of Life Questionnaire and Symptom Surveys (6-month, 12-month, 
1370 
and 18-month visits only):  The parent and child will complete the same questionnaire and 
1371 
symptom surveys as described at the time of enrollment.   
1372 
After the above assessments, the following procedures must be performed in the specified 
1373 
order by the Masked Examiner.  All procedures should be performed with the subject 
1374 
wearing his/her current study spectacles (or trial frames if study spectacles were not 
1375 
brought to the visit) and without cycloplegia:  
1376 
Although tests #4 through #10 must be performed in the specified order, there is no specified 
1377 
‘waiting’ time that needs to occur between measurements.  
1378 
4. Control of the Exodeviation #1 (Masked): A Masked Examiner will assess control of 
1379 
exodeviation at distance and near fixation using the intermittent exotropia control scale.28-30   
1380 
5. Stereoacuity Testing (Masked): Stereoacuity will be assessed using the Randot Preschool 
1381 
stereotest at 40 cm.  If the subject has no measurable stereo, this finding will be recorded as 
1382 
“nil”.  
1383 
 
1384 
 
If stereoacuity has decreased by 2 octaves or more (see Table 2 below) from baseline:  
1385 
• Stereoacuity must be retested on the same day by the masked examiner. 
1386 
Retesting can be performed any time after the final assessment of control (Step 
1387 
10) but prior to any cycloplegia.   
1388 
o If the stereoacuity is still reduced 2 octaves or more from baseline on the 
1389 
same-day retest, the subject must be brought back for a retest of 
1390 
stereoacuity on a different day (see section 3.5).     
1391 
 
 
1392 

IXT5 Protocol v3.0 (11-22-19) 
3-4 
Table 2: Preschool Randot Stereotest 
1393 
Baseline stereoacuity, 
in arcsec 
Level needed at follow-up visit 
to require retest, in arcsec 
40” 
200”, 400”, 800”, nil 
60” 
400”, 800”, nil 
100” 
400”, 800”, nil 
200” 
800”, nil 
400” 
Nil 
800” 
Nil 
Nil 
Not applicable 
 
1394 
6. Control of the Exodeviation #2 (repeat) (see item #4) (Masked) 
1395 
7. Cover Test (Masked):  Assessed in primary position at distance (6 meters) and near (1/3 
1396 
meter) as outlined in the IXT Testing Procedures Manual. 
1397 
8. PACT Testing (Masked):  A Masked Examiner will assess: 
1398 
• PACT in primary position at distance (6 meters) and near (1/3 meter) as outlined in 
1399 
the IXT Testing Procedures Manual.  
1400 
• AC/A ratio (18-month visit only) at distance (6 meters) measuring the PACT with 
1401 
the subject wearing -2.00D lenses over his/her habitual correction. The AC/A ratio 
1402 
is calculated by taking the difference between the distance PACT measurements 
1403 
with and without -2.00D lenses and dividing the difference by 2.  
1404 
9. Control of the Exodeviation #3 (repeat) (see item #4) (Masked) 
1405 
10. Assessment of Deviation Throughout Exam (Masked) 
1406 
 
1407 
The following procedures should be performed by either the Masked Examiner or 
1408 
another study-certified examiner: 
1409 
 
1410 
11. 
Distance Visual Acuity Testing: Monocular distance visual acuity testing with the 
1411 
habitual correction and without cycloplegia will be measured using the same testing 
1412 
procedure as used for enrollment. Visual acuity may be tested at the start of the exam or 
1413 
before the cycloplegic refraction. 
1414 
12. 
Cycloplegic Autorefraction (12-month and 18-month visits only, mandatory if 
1415 
autorefractor is available at the site) 
1416 
• Refractive error must be measured with the same autorefractor used at enrollment 
1417 
following cycloplegia with 1% cyclopentolate (see cycloplegic refraction below). 
1418 
• If cycloplegic autorefraction was completed at enrollment, then it must be measured 
1419 
with the same autorefractor used at enrollment.  
1420 
• Regardless of whether cycloplegic autorefraction was completed at enrollment, it is 
1421 
mandatory to measure cycloplegic autorefraction if an autorefractor is available at 
1422 
the site.   
1423 
• Recorded values will be based on a single measurement by the instrument (which 
1424 
may be a mean of several individual measures depending on system) 
1425 
13. 
Cycloplegic Axial Length Measurement and Additional Biometry (18-month visit only) 
1426 
(see manual of procedures). 
1427 

IXT5 Protocol v3.0 (11-22-19) 
3-5 
• Axial length 
1428 
• Flat corneal radius 
1429 
• Anterior Chamber depth 
1430 
• Lens thickness, if available 
1431 
14. 
Cycloplegic Refraction (12-month and 18-month visits) 
1432 
• A cycloplegic refraction will be performed at the 12-month and 18-month visits. 
1433 
The cycloplegic refraction will be performed regardless of whether a cycloplegic 
1434 
autorefraction is performed. 
1435 
• Cycloplegic refraction is performed 30 to 45 minutes following at least one 
1436 
application of cyclopentolate 1% per investigator’s usual dosage and timing routine. 
1437 
• The cycloplegic refraction is based on cycloplegic retinoscopy, which may be done 
1438 
with glasses off or as an over-refraction in front of the current spectacles.  
1439 
Subjective refraction is allowed. 
1440 
• When an over-refraction of current eye glasses is performed, the reported 
1441 
cycloplegic refraction will be the sum of the current spectacle power and the over-
1442 
refraction. 
1443 
15. 
ADHD and Seizure Medication Use Data Collection (12-month visit only) 
1444 
• At the 12-month visit, data regarding any ADHD and seizure medication use in the 
1445 
past 12 months will be collected. 
1446 
 
1447 
3.5 
Repeat Stereoacuity Testing on a Subsequent Day 
1448 
At any follow-up visit (including the 18-month outcome visit), subjects whose near 
1449 
stereoacuity by the Randot Preschool Stereoacuity test is worse by 2 octaves or more from 
1450 
baseline on both the initial test and the same-day retest by a Masked Examiner must return for 
1451 
a retest of stereoacuity by a masked examiner on a subsequent day. This return visit must be 
1452 
within 1 month of the follow-up visit (including the 18-month outcome visit).  
1453 
• This return visit must also be after the child has received his/her new glasses prescribed 
1454 
at the follow-up visit (applies only to the 12-month and 15-month visits). 
1455 
• A Masked Examiner must test the stereoacuity at this repeat visit.  If stereoacuity is still 
1456 
reduced 2 octaves or more from baseline, stereoacuity is retested after a short rest 
1457 
period.  
1458 
o If the stereoacuity has worsened by 2 octaves or more from baseline (confirmed 
1459 
by a retest), the investigator may initiate non-randomized treatment for IXT at 
1460 
his/her discretion (see section 3.8) 
1461 
o If stereoacuity has not worsened by 2 octaves or more from baseline, the subject 
1462 
will continue the randomized treatment unless the subject has already met 
1463 
deterioration criteria at a previous visit confirmed by masked examiner as 
1464 
described in section 3.7 in which case spectacles are prescribed at investigator 
1465 
discretion.  
1466 
• No testing other than stereoacuity testing is required.    
1467 
 
1468 
3.6 
Additional Visits 
1469 
Investigators may schedule additional visits at their own discretion.  
1470 
 
1471 
If the investigator plans to initiate non-randomized treatment for IXT at an additional visit, a 
1472 
masked examination (following all testing procedures in section 3.4 except for the cycloplegic 
1473 

IXT5 Protocol v3.0 (11-22-19) 
3-6 
refraction / autorefraction) must be performed prior to initiating the new treatment.  If a 
1474 
masked examiner is unavailable, data from an unmasked exam should be entered on the 
1475 
website, noting that the examiner was unmasked.  If the investigator is starting non-randomized 
1476 
treatment, the subject does not return for a stereoacuity retest if stereoacuity is decreased 
1477 
(section 3.7).      
1478 
 
1479 
3.7 
Deterioration Criteria 
1480 
Subjects who meet either of the following at any visit will be considered to have met 
1481 
deterioration criteria.   
1482 
• Motor deterioration:  Control of the exodeviation measures 5 (constant exotropia) on all 
1483 
three assessments at distance and near.  The exodeviation does not need to be constant 
1484 
throughout the entire exam provided that it is constant during all three control testings. 
1485 
• Stereoacuity deterioration:  Drop in near stereoacuity of at least 2 octaves (as defined in 
1486 
section 3.4) (at least 0.6 log arcsec) from enrollment stereoacuity, or to nil, confirmed 
1487 
by a retest by a Masked Examiner on a subsequent day (section 3.5).  Note: subjects 
1488 
with nil stereoacuity at enrollment will not be able to deteriorate with respect to a drop 
1489 
in near stereoacuity. 
1490 
 
1491 
Subjects who meet deterioration criteria may have non-randomized treatment for IXT started at 
1492 
investigator discretion.  Whether or not a subject starts non-randomized treatment for IXT 
1493 
during the study, all subjects will still be followed at regular study visit intervals through the 
1494 
end of the study. 
1495 
 
1496 
3.8 
Initiating Non-Randomized Treatment for IXT 
1497 
Non-randomized treatment for IXT is not permitted during the study unless the subject has met 
1498 
deterioration criteria (see section 3.7). If neither deterioration criterion is met but the subject is 
1499 
experiencing overwhelming social concerns or significant symptoms associated specifically 
1500 
with the exodeviation, the investigator must call the protocol chair to discuss the case and 
1501 
obtain approval for an exception prior to initiating non-randomized treatment for IXT. 
1502 
 
1503 
Non-randomized treatment for IXT refers to any treatment other than that which the subject 
1504 
was randomized to. It includes but is not limited to:   
1505 
• Surgery 
1506 
• Occlusion 
1507 
• Vergence exercises 
1508 
• Overminus spectacles (in non-overminus group) 
1509 
• Cycloplegia 
1510 
• Formal discontinuation of overminus spectacles (in overminus group) – note that 
1511 
subject non-compliance with overminus spectacles is not considered formal 
1512 
discontinuation. 
1513 
 
1514 
If the investigator plans to initiate non-randomized treatment for IXT at an additional visit 
1515 
rather than a protocol-specified visit, a masked examination must be performed prior to 
1516 
initiating the new treatment (section 3.6).   
1517 
 
1518 
Subjects who have started non-randomized treatment for IXT during the study will still be 
1519 
followed at regular study visit intervals through the end of the study. 
1520 
 
1521 

IXT5 Protocol v3.0 (11-22-19) 
3-7 
3.9 
Treatment of Amblyopia 
1522 
Given the exclusion of subjects with amblyopia, the rate of developing amblyopia during the 
1523 
study is expected to be low.  Nevertheless, if amblyopia develops during the study, the 
1524 
investigator may initiate amblyopia treatment, however initiating atropine, other cycloplegic 
1525 
drops, or levodopa is not allowed. 
1526 
 
1527 
3.10 
Management of Refractive Error 
1528 
Management of refractive error will follow study guidelines (see sections 2.6.1 and 2.6.2) for 
1529 
the duration of the study.  A cycloplegic refraction will be performed for all subjects at the 12-
1530 
month visit and the 18-month visit. These data are used to adjust the glasses at 12-,15- and 18-
1531 
month visits. 
1532 
 
1533 

IXT5 Protocol v3.0 (11-22-19) 
4-1 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS 
1534 
 
1535 
4.1 
Contacts by the Jaeb Center for Health Research  
1536 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided 
1537 
with the parent’s contact information.  The Jaeb Center will contact the parents of the subjects 
1538 
only when necessary.  Permission for such contacts will be included in the Informed Consent 
1539 
Form.  The principal purpose of the contacts will be to develop and maintain rapport with the 
1540 
subject and/or family and to help coordinate scheduling of the outcome examinations.   
1541 
 
1542 
4.2 
Subject Withdrawals 
1543 
Parents may withdraw their child from the study at any time.  This is expected to be a very 
1544 
infrequent occurrence in view of the study design’s similarity to routine clinical practice.  If the 
1545 
parents indicate that they want to withdraw their child from the study, the investigator personally 
1546 
should attempt to speak with them to determine the reason.  If their interest is in transferring the 
1547 
child’s care to another eye care provider, every effort should be made to comply with this and at 
1548 
the same time try to keep the subject in the study under the new provider’s care. 
1549 
 
1550 
4.3 
Risks 
1551 
There are no risks involved in this study that would not be part of usual care when treating with 
1552 
either overminus or non-overminus lenses.   
1553 
 
1554 
4.3.1 
Risks of Examination Procedures 
1555 
The procedures in this study are part of daily eye care practice in the United States and Canada 
1556 
and pose no known risks. 
1557 
 
1558 
4.3.2 
Risk of Overminus Lens Therapy 
1559 
The risks involved in the study are identical to those for a child treated with overminus lens 
1560 
therapy who is not participating in the study.   
1561 
 
1562 
Some subjects treated with overminus lenses may experience eye strain when wearing the 
1563 
spectacles; the eye strain typically dissipates with removal of the spectacles.  
1564 
 
1565 
Among previous retrospective reports, some have indicated that there may be an increased rate 
1566 
of myopia development when accommodation is stimulated,11,18,31 whereas others have reported 
1567 
no increase in myopia following overminus lens therapy.  However, unpublished data from the 
1568 
current ongoing randomized trial suggests that myopic progression over one year is greater in 
1569 
subjects treated with overminus lenses vs. those treated with non-overminus lenses, and that 
1570 
myopic progression was most often observed in overminus group subjects who had spherical 
1571 
equivalent myopia of -0.50 D or greater at baseline (PEDIG unpublished, 2019).   
1572 
 
1573 
4.3.3 
Risk Assessment  
1574 
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.404, which is 
1575 
research not involving greater than minimal risk.   
1576 
 
1577 
4.4 
Reporting of Adverse Events 
1578 
Although no adverse events are anticipated as a result of overminus therapy or non-overminus 
1579 
spectacle wear, any new cases of amblyopia, constant esotropia, or constant exotropia at distance 
1580 
and near will be reported.  No surgical procedures are part of the protocol and no treatments are 
1581 

IXT5 Protocol v3.0 (11-22-19) 
4-2 
being prescribed that are not part of usual care.  Investigators will abide by local IRB reporting 
1582 
requirements. 
1583 
 
1584 
4.5 
Discontinuation of Study 
1585 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1586 
Monitoring Committee) prior to the pre-planned completion of enrollment and follow-up for all 
1587 
subjects. 
1588 
 
1589 
4.6 
Travel Reimbursement 
1590 
The parent of each subject will be compensated $50 for completion of each of the following 
1591 
visits: the enrollment, repeated enrollment (if required), 6-, 12-, 15-, and 18-month visits, and 
1592 
any additional visits (i.e. if required prior to starting alternative treatment or required to retest 
1593 
stereoacuity).  If there are extenuating circumstances, and the subject is unable to complete a 
1594 
study visit without additional funds due to travel costs, additional funds may be provided.  
1595 
 
1596 
4.7 
Study Costs 
1597 
The study will pay for visits specific to the research study, but will not pay for usual care visits 
1598 
that would occur whether or not the subject was in the study.  The cost of usual care visits will be 
1599 
the responsibility of the subject or his/her insurance company.  
1600 
  
1601 
Study spectacles (frames and lenses) will be provided by the study at enrollment (if necessary, as 
1602 
described in section 2.5), at randomization, 12-, 15-, and 18-month visits, at no cost to the 
1603 
subject.   
1604 
 
1605 
The study will not pay for bifocal lenses or photochromic lenses. 
1606 
 
1607 
4.8 
General Considerations 
1608 
The study is being conducted in compliance with the policies described in the study policies 
1609 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
1610 
the protocol described herein, and with the standards of Good Clinical Practice. 
1611 
 
1612 
Data will be directly collected in electronic CRFs, which will be considered the source data. 
1613 
 
1614 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
1615 
recruitment goal. 
1616 
 
1617 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
1618 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
1619 
2013). 
1620 

IXT5 Protocol v3.0 (11-22-19) 
5-1 
 
1621 
CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
1622 
 
1623 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1624 
analysis plan will be written and finalized without knowledge of study data.  The analysis plan 
1625 
synopsis in this chapter contains the framework of the anticipated final analysis plan, which will 
1626 
supersede these sections when it is finalized. 
1627 
 
1628 
5.1 
Primary Objective:  Efficacy on Overminus Treatment (12 Months) 
1629 
The primary objective is to determine the efficacy of overminus lenses after 12 months of 
1630 
treatment.    
1631 
 
1632 
5.1.1 
Primary Analysis - Mean Distance Control at 12-Months (On-Treatment)  
1633 
The primary analysis will be a two-sided comparison of mean 12-month control of the distance 
1634 
exodeviation (average of 3 measurements) between treatment groups using an analysis of 
1635 
covariance (ANCOVA) model, which adjusts for baseline distance control, distance PACT, age, 
1636 
refractive error, and use of ADHD medication, to address potential residual confounding.  
1637 
 
1638 
The treatment group difference (overminus – non-overminus) and a 95% confidence interval will 
1639 
be calculated.   
1640 
   
1641 
The 12-month distance control score for analysis for each subject is the mean of the 3 control 
1642 
assessments completed at the visit.  When the protocol-specified three measures of control are 
1643 
not performed at the outcome exam, the mean of two tests will be used for analysis if only 2 
1644 
distance control tests are completed; the single distance control score will be used for analysis if 
1645 
only 1 testing is completed.   
1646 
 
1647 
The primary analysis will follow a modified intention-to-treat principle, with all subjects 
1648 
analyzed according to their randomized treatment group and with the following stipulations:  
1649 
• Subjects who are treatment crossovers (non-overminus group subjects who are prescribed 
1650 
overminus; overminus group subjects who have overminus spectacles formally 
1651 
discontinued) will have their observed 12-month data analyzed provided they complete at 
1652 
least one distance control testing at the 12-month outcome exam; otherwise their average 
1653 
distance control score will be imputed using multiple imputation.   
1654 
• Subjects who are prescribed IXT treatment other than overminus or non-overminus 
1655 
refractive correction (e.g. surgery, vision therapy, patching) will have their average 
1656 
distance control score imputed using multiple imputation, regardless of whether any 
1657 
control testing is completed at the 12-month visit.   
1658 
• Subjects who miss the 12-month visit or who do not complete any control testing at the 
1659 
12-month visit will also have their average distance control score imputed using multiple 
1660 
imputation.32     
1661 
 
1662 
The multiple imputation will be performed using Monte Carlo Markov Chain (MCMC) modeling 
1663 
that includes data from baseline and follow up visits (for subjects who are prescribed IXT 
1664 
treatment other than overminus or non-overminus refractive correction, only data from visits up 
1665 
to and including the visit at which treatment was prescribed will be used). 
1666 
 
1667 

IXT5 Protocol v3.0 (11-22-19) 
5-2 
The primary analysis will include subjects who enter the randomized trial but are later found to 
1668 
be ineligible. 
1669 
 
1670 
5.1.1.1 Alternatives to the Primary Analysis  
1671 
The following analyses will be performed as alternatives to the primary analysis:   
1672 
 
1673 
Alternative Analysis #1:   
1674 
• All subjects who complete 1 or more distance control testing at the 12-month visit, including 
1675 
treatment crossovers and subjects who are prescribed IXT treatment other than overminus or 
1676 
non-overminus refractive correction, will have their observed 12-month data analyzed.  
1677 
• Subjects who miss the 12-month visit entirely or who do not complete any control testing at 
1678 
the 12-month visit will be excluded from the analysis. 
1679 
 
1680 
Alternative Analysis #2:   
1681 
• Subjects who are prescribed IXT treatment other than overminus or non-overminus refractive 
1682 
correction for any reason at any time before the 12-month visit will have the average distance 
1683 
control score (single) imputed using the average distance control score from the last visit 
1684 
prior to starting non-randomized treatment for IXT.  
1685 
• All other subjects, including treatment crossovers, will be analyzed as in the primary 
1686 
analysis.  
1687 
 
1688 
Additional sensitivity analyses may be conducted to explore the effect of the methods for 
1689 
handling subjects with missing data and subjects who received non-randomized treatment for 
1690 
IXT before 12 months.  
1691 
 
1692 
5.1.2 
Secondary Distance Control Outcomes at 12 Months (On-Treatment)  
1693 
Additional details of the secondary analyses in section 5.1.2.1 and 5.1.2.2 below will be part of a 
1694 
separate statistical analysis plan.   
1695 
 
1696 
5.1.2.1 No Spontaneous Tropia at 12 Months 
1697 
The proportion of subjects with no spontaneous tropia at 12 months will be compared between 
1698 
treatment groups using a two-sided Barnard’s test with alpha of 0.05, with calculation of a two-
1699 
sided 95% confidence interval on the difference in proportions.   
1700 
 
1701 
No spontaneous tropia at the 12-month primary outcome exam means both of the following must 
1702 
have been true during the examination:  
1703 
• 
Score of ≤2 (2 or better) on all three assessments of control at distance and at near 
1704 
• 
No spontaneous tropia at any time during the exam at distance or near 
1705 
 
1706 
An additional secondary analysis will assess this outcome according to whether these criteria 
1707 
were met at baseline, and according to subgroups based on severity of baseline distance control.   
1708 
 
1709 
5.1.2.2 Change in Distance Control at 12 Months   
1710 
Distance control will be reported as the distributions of baseline control, 12-month control, and 
1711 
change in control from baseline to 12 months, including % with ≥1 point change in control, ≥2 
1712 
points change, etc. 
1713 
 
1714 

IXT5 Protocol v3.0 (11-22-19) 
5-3 
The proportion of subjects with ≥1 point improvement in distance control between baseline and 
1715 
12 months will be compared between treatment groups using a two-sided Barnard’s test with 
1716 
alpha of 0.05, with calculation of a two-sided 95% confidence interval on the difference in 
1717 
proportions.  The proportion of subjects with ≥2 points improvement in distance control between 
1718 
baseline and 12 months will be compared similarly. 
1719 
 
1720 
5.2 
Objective #2: Efficacy of Overminus After Treatment Discontinuation (18 Months) 
1721 
The secondary objective is to assess the efficacy of overminus lenses after a period of weaning 
1722 
and discontinuation. 
1723 
 
1724 
Treatment group comparisons of mean distance control, the proportion of subjects with no 
1725 
spontaneous tropia, and change in distance control from baseline (section 5.1) will be repeated 
1726 
using the 18-month (off-treatment) data.   
1727 
 
1728 
These analyses will be performed on the full cohort which includes subjects who were and those 
1729 
who were not prescribed weaning of overminus between 12 to 15 months.  In addition, these 
1730 
analyses will be repeated limiting to subjects who were prescribed weaning (i.e. prior to weaning 
1731 
being discontinued per Protocol Amendment II). If retention of an on-treatment effect is stronger 
1732 
in subjects who have full weaning vs. less than full weaning, the 18-month treatment effect could 
1733 
be diluted in the full cohort analysis vs. the limited cohort.  The full cohort analysis will be 
1734 
considered the primary analysis for objective #2.   
1735 
 
1736 
5.3 
Additional Analyses 
1737 
Each additional analysis in this section will be conducted for both the 12-month on-treatment and 
1738 
18-month off-treatment time points. The details of the additional analyses will be part of a 
1739 
separate statistical analysis plan.  
1740 
  
1741 
5.3.1 
Additional Secondary Outcomes 
1742 
Analysis of near control, angle magnitude, stereoacuity, and treatment compliance will be 
1743 
performed as described below.   
1744 
 
1745 
5.3.1.1 Deterioration  
1746 
At both the 12-month and 18-month time points, the cumulative proportion of subjects who meet 
1747 
either of the deterioration criteria (section 3.7) by the time point will be estimated for each 
1748 
treatment group using the proportional hazards model to enable adjustment for potential residual 
1749 
confounding. The adjusted cumulative probability estimate will then be compared between 
1750 
treatment groups using the Z-test. The cumulative proportion of patients who meet stereoacuity 
1751 
deterioration criteria by the time point and the cumulative proportion of patients who have 
1752 
constant exotropia by the time point will also be estimated and compared between treatment 
1753 
groups using similar methods. Analytic methods which account for possible informative 
1754 
censoring will be explored for handling subjects who start non-randomized treatment for IXT. 
1755 
Such methods will also be explored for the stereoacuity deterioration and motor deterioration 
1756 
outcomes.    
1757 
 
1758 
5.3.1.2 Near Control 
1759 
At both the 12-month and 18-month time points, near control will be evaluated similarly to the 
1760 
distance control primary analysis (section 5.1.1) and secondary analysis (section 5.1.2).  
1761 
 
1762 

IXT5 Protocol v3.0 (11-22-19) 
5-4 
5.3.1.3 Angle Magnitude 
1763 
At both the 12-month and 18-month time points, a two-sided comparison of magnitude of the 
1764 
deviation by Prism Alternate Cover Test (PACT) will be compared between treatment groups 
1765 
using an ANCOVA model, which adjusts for baseline PACT. The treatment group difference 
1766 
and a 95% confidence interval will be calculated.  The analysis will be completed separately at 
1767 
distance and at near.  
1768 
  
1769 
5.3.1.4 Stereoacuity 
1770 
At both the 12-month and 18-month time points, a two-sided comparison of near stereoacuity by 
1771 
Preschool Randot Test will be compared between treatment groups using an ANCOVA model 
1772 
which adjusts for baseline stereoacuity. The treatment group difference and a 95% confidence 
1773 
interval will be calculated. 
1774 
 
1775 
5.3.1.5 Axial Length Measurement at 18 Months 
1776 
Mean 18-month axial length measurement will be compared between treatment groups using an 
1777 
ANOVA model.  The treatment group difference and a 95% confidence interval will be 
1778 
calculated. Adjustment for baseline is not possible given that these measurements were added 
1779 
late in the study (with Protocol Amendment II), long after recruitment had ended.  
1780 
  
1781 
5.3.1.6 Additional Ocular Biometric Parameters at 18 Months  
1782 
Mean 18-months flat corneal radius, anterior chamber depth, and lens thickness will each be 
1783 
compared between treatment groups using an ANOVA model.  The treatment group difference 
1784 
and a 95% confidence interval will be calculated.  Adjustment for baseline is not possible given 
1785 
that these measurements were added late in the study (with Protocol Amendment II), long after 
1786 
recruitment had ended.  
1787 
 
1788 
5.3.1.7 Compliance with Spectacle Wear  
1789 
Compliance with spectacle wear will be assessed at the 6-month and 12-month outcome exam.  
1790 
Parents will give an estimate of the proportion of the time their children wore their spectacles.  
1791 
Proportion of time worn will be described as excellent (76% to 100%), good (51% to 75%), fair 
1792 
(26% to 50%), or poor (≤ 25%).  The distribution of compliance will be assessed for each 
1793 
treatment group at the outcome exam. 
1794 
 
1795 
5.3.2 
Exploratory Analyses  
1796 
Exploratory analyses will be performed as specified below.   
1797 
 
1798 
5.3.2.1 Mean Distance Control in Baseline Subgroups   
1799 
The treatment group comparisons of 12-month and 18-month distance control will be assessed in  
1800 
subgroups based on baseline factors. The specific subgroups of interest include baseline distance 
1801 
control by severity, baseline age group (3 to <7 vs. 7 to <11), use of ADHD medications at any 
1802 
time between baseline and the 12-month visit (yes/no), and refractive error level.  In accordance 
1803 
with NIH guidelines, subgroup analyses of treatment efficacy according to sex, as well as 
1804 
race/ethnicity, will also be conducted.   
1805 
 
1806 
These planned subgroup analyses will repeat the primary analysis, including the baseline factor 
1807 
and the baseline factor by treatment interaction.  In general, statistical power will be low for 
1808 
detection of interactions unless the interaction is very large.  
1809 

IXT5 Protocol v3.0 (11-22-19) 
5-5 
 
1810 
Subgroup analyses will be interpreted with caution, particularly if the corresponding overall 
1811 
analysis does not demonstrate a significant treatment group difference.   
1812 
 
1813 
5.3.2.2 Mean Distance Control at 18 Months According to Prescribed Weaning Status 
1814 
Of the 355 expected 18-month visits (as of 11/5/19), approximately 283 subjects (80%) will have 
1815 
completed a full 3-months of prescribed weaning before discontinuing overminus (or non-
1816 
overminus); approximately 35 to 54 (20% to 25%) subjects will have completed partial weaning, 
1817 
and approximately 18 to 37 subjects (5% to 10%) are expected to have no weaning at all,  The 
1818 
summary statistics for and distribution of 18-month distance control will be tabulated according 
1819 
to treatment group and full, partial, or no prescribed weaning.  
1820 
 
1821 
5.3.2.3 Patients with Baseline Control 3 to <5 Points 
1822 
Exploratory analyses will be conducted limited to the cohort of subjects with baseline distance 
1823 
control 3-<5 points, a subset with better likelihood of improving ≥2 points and whose mean 
1824 
distance control at baseline is indicative of spontaneous tropia. It is noted that the remaining 
1825 
subjects (i.e., those with mean distance control scores at baseline <3 points) could potentially 
1826 
have shown a spontaneous tropia on one or two tests and still have a mean score <3 points.   
1827 
 
1828 
At both the 12-month and 18-month time points, the distance control primary analysis (section 
1829 
5.1.1) and secondary analysis (section 5.1.2) will be repeated using this cohort. 
1830 
 
1831 
5.4 
Safety Analyses  
1832 
 
1833 
5.4.1 
Refractive Error at 12 and 18 Months  
1834 
Mean 12-month spherical equivalent refractive error will be compared between treatment groups 
1835 
using an ANCOVA model which adjusts for baseline spherical equivalent refractive error.  The 
1836 
treatment group difference and a 95% confidence interval will be calculated.  
1837 
 
1838 
5.4.2 
Development of Esodeviation  
1839 
Development of any esodeviation will be tabulated by treatment group, indicating the magnitude 
1840 
of the esodeviation (by PACT) and whether it was a constant tropia, intermittent tropia, or a 
1841 
phoria.   
1842 
 
1843 
5.4.3 
Reduction of Distance Visual Acuity 
1844 
Any cases of reduced visual acuity in best refractive correction (≥2 logMAR lines) in either eye 
1845 
will be tabulated by treatment group.   
1846 
 
1847 
5.4.4 
Adverse Symptoms/Impact on Quality of Life 
1848 
The distribution of scores on each quality of life questionnaire item and each symptom survey 
1849 
item will be described for the enrollment exam and the 6-month, 12-month and 18-month 
1850 
outcome exams for each treatment group.  The distribution of change in scores will also be 
1851 
described for each treatment group.   
1852 
 
1853 
5.5 
Protocol Adherence and Additional Tabulations   
1854 
 
1855 
The following tabulations and analyses will be performed: 
1856 
• A flow chart accounting for all subjects according to treatment group for all visits.   
1857 

IXT5 Protocol v3.0 (11-22-19) 
5-6 
• Visit completion rates for each follow-up visit according to treatment group. 
1858 
• Protocol deviations according to treatment group. 
1859 
• Baseline demographic and clinical characteristics according to treatment group 
1860 
• Number of and reasons for unscheduled visits and phone calls 
1861 
• Number of and reasons for non-randomized treatment according to randomized treatment 
1862 
group 
1863 
 
1864 
Statistical tests will be performed as appropriate.  
1865 
 
1866 
5.6 
Interim Analysis  
1867 
This study will include a separate interim monitoring plan that may incorporate monitoring for 
1868 
futility and/or efficacy for the 12-month on-treatment outcome (objective #1).  The details of the 
1869 
formal interim monitoring plan will be developed in conjunction with the DSMC and 
1870 
incorporated into the statistical analysis plan prior to any tabulation or analysis of primary or 
1871 
secondary outcome data. 
1872 
 
1873 
5.7 
Sample Size 
1874 
Sample size has been calculated for both the primary12-month on-treatment objective and the 
1875 
secondary 18-month off-treatment objective.   
1876 
 
1877 
5.7.1 
Sample Size for Objective #1: Efficacy on Overminus Treatment 
1878 
Sample size has been calculated for both primary and secondary outcomes for the determining 
1879 
the efficacy of overminus lenses after 12 months of treatment.    
1880 
 
1881 
Primary Outcome – Comparison of Mean Distance Control at 12 months  
1882 
Sample size calculations have incorporated data from the IXT3 pilot RCT comparing observation 
1883 
vs. overminus.  In the pilot study, 8-week mean distance control was 2.0 points in the 27 children 
1884 
treated with overminus spectacles vs. 2.8 points in the 31 children who were observed without 
1885 
treatment (adjusted difference = -0.75 (-1.42 to -0.07) point; P = 0.01 for one-sided test).  
1886 
Standard deviation of 8-week distance control in IXT3 was 1.5 points (95% CI = 1.2 to 1.8 
1887 
points) and the correlation between baseline and 8-week distance control was 0.25 (95% CI = -
1888 
0.02 to 0.47).  
1889 
 
1890 
Reducing this -0.75 point 8-week on-treatment effect in the IXT3 pilot study to -0.65 points (to 
1891 
account for potential regression to the mean in the treatment effect observed in the pilot study) is 
1892 
thought to be a reasonable estimate of the 12-month on-treatment effect of overminus, given that 
1893 
many clinicians suspect the on-treatment effect to be reasonably constant over time. Assuming a 
1894 
conservative standard deviation of 1.8 points and using a 2-sided t-test with alpha = 0.05 and 
1895 
90% power, a sample size of 326 subjects (163 per treatment group) is needed to detect a mean 
1896 
difference in distance control scores (overminus – non-overminus), at 12 months, if the 
1897 
magnitude of true mean difference is -0.65 points or larger (Table 3).  An adjustment of the 
1898 
sample size by a factor of (1-Pearson’s r2) to account for the variance reduction expected from 
1899 
including baseline distance control scores in the ANCOVA analysis was considered but 
1900 
ultimately rejected given that the correlation between baseline and 12-month distance control 
1901 
might be expected to be less than the 0.25 correlation observed between baseline and the much-
1902 
shorter 8-week outcomes in the IXT3 pilot study (also, it reduces sample size by fewer than 20 
1903 
patients overall).  Accounting for up to 10% loss to follow-up over 12 months, the sample size 
1904 
for this objective would be 364 subjects overall (182 per group)   
1905 

IXT5 Protocol v3.0 (11-22-19) 
5-7 
  
1906 
Table 3:  Total Sample Size for Difference in Mean Distance Control Score at 12-Months  
1907 
Standard 
Deviation  
of Outcome 
Distance 
Control 
(points) 
 
 
Treatment Effect for 12-Month On-Treatment Outcome Distance Control 
(Overminus – Observation) (points) 
 
-0.40 
 
-0.45 
 
-0.50 
 
-0.55 
 
-0.60 
 
-0.65 
 
-0.70 
 
-0.75 
 
-0.80 
 
-0.90 
 
-1.0 
 
-1.25 
1.2 
382 
302 
246 
204 
172 
146 
126 
110 
98 
78 
64 
42 
1.3 
466 
354 
288 
238 
200 
172 
148 
130 
114 
90 
74 
48 
1.4  
518 
410 
332 
276 
232 
198 
172 
150 
132 
104 
86 
56 
1.6  
676 
534 
434 
358 
302 
258 
222 
194 
172 
136 
110 
72 
1.8 
854 
676 
548 
454 
382 
326 
280 
246 
216 
172 
140 
90 
1.9 
952 
752 
610 
504 
424 
362 
312 
272 
240 
190 
154 
100 
2.0 
1054 
834 
676 
558 
470 
400 
346 
302 
266 
210 
172 
110 
Cells indicate N for the overall study (both treatment groups combined), using a 2-sided test and 
1908 
alpha = 0.05. 
1909 
 
1910 
Secondary Outcome – No Spontaneous Tropia at 12 Months  
1911 
The proportion of subjects with a control score of 2 or better on all three 8-week distance control 
1912 
assessments in IXT3 was 67% in the overminus group vs. 42% in the observation group 
1913 
(difference = 25%; 95% CI = -2% to 49%); therefore, a conservative estimate of the true 
1914 
difference in the proportion of subjects with no spontaneous tropia might be 15%.  
1915 
 
1916 
Accounting for up to 10% loss to follow-up over 12 months, the total sample size of 364 would 
1917 
provide 74% power to detect a difference if the true difference in the proportion of subjects with 
1918 
a control score of 2 or better on all three 8-week distance control between treatment groups was 
1919 
15% or larger; the maximum width of the 95% confidence interval on an observed 15% 
1920 
difference in proportions between treatment group would be ±11%. 
1921 
 
1922 
5.7.2 
Sample Size for Objective #2: Efficacy of Overminus After Treatment 
1923 
Discontinuation    
1924 
 
1925 
Primary Outcome – Comparison of Mean Distance Control at 18 Months 
1926 
The IXT3 pilot study of overminus treatment did not have an off-treatment period on which to 
1927 
base estimates of the 18-month off-treatment effect.  Because the 18-month off-treatment effect 
1928 
could potentially be smaller or larger than the 12-month on-treatment effect, using the same  
1929 
-0.65 point estimate (section 5.6.1) was felt reasonable.   
1930 
 
1931 
Under the same assumptions for the 12-month outcome (assuming a conservative standard 
1932 
deviation of 1.8 points and using a 2-sided t-test with alpha = 0.05 and 90% power), a sample 
1933 
size of 326 subjects (163 per treatment group) is needed to detect a mean difference in 18-month 
1934 
distance control scores (overminus – non-overminus) if the magnitude of true mean difference is 
1935 
-0.65 points or larger. 
1936 
 
1937 
Accounting for up to 10% loss to follow-up expected in the first 12 months of the study, and up 
1938 
to 5% additional loss to follow-up between 12 to 18 months, the total sample size is 384 subjects 
1939 
overall (192 per group). 
1940 

IXT5 Protocol v3.0 (11-22-19) 
5-8 
 
1941 
Secondary Outcome – No Spontaneous Tropia at 18 Months  
1942 
Because the 18-month off-treatment effect could potentially be smaller or larger than the 12-
1943 
month on-treatment effect (section 5.6.1), the same 15% difference in proportion of patients with 
1944 
no spontaneous tropia is assumed.   
1945 
 
1946 
Accounting for up to 15% loss to follow-up over 18 months, the total sample size of 384 would 
1947 
provide 74% power to detect a difference if the true difference in the proportion of subjects with 
1948 
a control score of 2 or better on all three 8-week distance control between treatment groups was 
1949 
15% or larger; the maximum width of the 95% confidence interval on an observed 15% 
1950 
difference in proportions between treatment group would be ±11%. 
1951 

IXT5 Protocol v3.0 (11-22-19) 
6-1 
CHAPTER 6: REFERENCES 
1952 
 
1953 
 
1954 
 
1955 
1. 
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exotropia: A population-based study. Ophthalmology 2005;112:104-8. 
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2. 
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1958 
Strabismic Ophthalmic Symposium. St. Louis: Mosby Year Book; 1950:353. 
1959 
3. 
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1 to 2 ½  years, in child welfare clinics. J Pediatr Ophthalmol Strabismus 1980;17:261-7. 
1961 
4. 
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Systematic Reviews 2006;3:CD003737. 
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5. 
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exotropia: a critical appraisal. Optometry and Vision Science 1992;69:386-404. 
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6. 
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Vision & Strabismus Quarterly 1993;8:187-216. 
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7. 
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patching with observation for children 3 to 10 years of age with intermittent exotropia. 
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8. 
Landolt H. Behandlung der Divergenz durch überkorrigierende Konkavgla¨ser. Klinische 
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Monatsblätter für Augenheilkunde 1913;51:47. 
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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: The 
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Macmillan Press; 1990:391-6. 
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10. 
Romano PE, Robinson JA. Intermittent exotropia: survey of clinical management. In: 
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Tillson G, editor. Transactions of the VIIth International Orthoptic Congress; 1991; Nurnburg, 
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Germany: Fahner Verlag Lauf. p. 227-31. 
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11. 
Reynolds JD, Wackerhagen M, Olitsky SE. Overminus lens therapy for intermittent 
1979 
exotropia American Orthoptic Journal 1994;44:86-91. 
1980 
12. 
Horwood AM, Riddell PM. Evidence that convergence rather than accommodation 
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controls intermittent distance exotropia. Acta Ophthalmologica 2012;90:e109-e17. 
1982 
13. 
Kennedy JR. The correction of divergent strabismus with concave lenses. Am J Optom 
1983 
Arch Am Acad Optom 1954;31:605-14. 
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14. 
Caltrider N, Jampolsky A. Overcorrecting minus lens therapy for treatment of 
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intermittent exotropia. Ophthalmology 1983;90:1160-5. 
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15. 
Goodacre H. Minus overcorrection: conservative treatment of intermittent exotropia in 
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the young child--a comparative study. Australian Orthoptic Journal 1985;22:9-17. 
1988 
16. 
Rutstein RP, Marsh-Tootle W, London R. Changes in refractive error for exotropes 
1989 
treated with overminus lenses. Optometry and Vision Science 1989;66:487-91. 
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17. 
Donaldson PJ, Kemp EG. An initial study of the treatment of intermittent exotropia by 
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minus overcorrection. British Orthoptic Journal 1991;48:41-3. 
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18. 
Kushner BJ. Does overcorrecting minus lens therapy for intermittent exotropia cause 
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myopia? Archives of Ophthalmology 1999;117:638-42. 
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19. 
Watts P, Tippings E, Al-Madfai H. Intermittent exotropia, overcorrecting minus lenses, 
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and the Newcastle scoring system. Journal of AAPOS: American Association for Pediatric 
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Ophthalmology & Strabismus 2005;9:460-4. 
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Rowe FJ, Noonan CP, Freeman G, DeBell J. Intervention for intermittent distance 
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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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Hatt SR, Mohney BG, Leske DA, Holmes JM. Variability of control in intermittent 
2002 
exotropia. Ophthalmology 2008;115:371-6. 
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Control in Intermittent Exotropia Using Multiple Measures. Am J Ophthalmol 2011;152:872-6. 
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2026