Glasses Versus Observation for Moderate Hyperopia in Young Children (HTS1)
Phase: NA
Conditions: Hyperopia
Sponsor: Jaeb Center for Health Research

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GLASSES VERSUS OBSERVATION FOR 
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MODERATE HYPEROPIA IN YOUNG 
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CHILDREN (HTS1) 
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PROTOCOL 
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Version 3.0 
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28 January 2015 
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CONTACT INFORMATION  
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COORDINATING CENTER 
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Raymond T. Kraker, M.S.P.H. (Director) 
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Jaeb Center for Health Research 
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15310 Amberly Drive, Suite 350 
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Tampa, FL 33647 
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Phone (888) 79PEDIG or (813) 975-8690 
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Fax (888) 69PEDIG or (813) 975-8761 
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PROTOCOL CHAIRS 
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Donny W. Suh, M.D., FAAP 
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Wolfe Eye Clinic 
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6200 Westtown Parkway 
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West Des Moines, IA 50266 
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(800) 542-7957 
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(515) 988-7744 cell 
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dowsuh@gmail.com 
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Marjean Taylor Kulp, OD, MS 
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The Ohio State University 
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College of Optometry 
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338 W. 10th Ave 
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Columbus, OH 43210-1280 
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(614) 688-3336 
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(614) 578-3336 cell  
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MTkulp@optometry.osu.edu 
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Kulp.6@osu.edu  
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HYPEROPIA TREATMENT STUDY 1 (HTS1) 
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Glasses versus Observation for Moderate Hyperopia in Young Children 
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PROTOCOL AMENDMENT (8-19-13) 
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This amendment provides for the following protocol changes: 
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Protocol Change #1 
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Current Protocol 
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In the current protocol, eligibility is limited to children 12 to <60 months of age with two primary 
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cohorts divided by age (one younger primary cohort of children 12 to <36 months of age and 
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another older primary cohort of children 36 to <60 months of age).  
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Proposed Change 
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The age range for eligibility in the older primary cohort will be extended to <72 months; children 60 
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to <72 months of age will be included in the older primary cohort (section 2.2.1). For eligibility, 
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children 60 to <72 months of age must have age-normal visual acuity of 20/32 or better in both 
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eyes.   
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Rationale for Change 
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Expanding the older cohort age group is expected to increase recruitment without compromising the 
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validity of the results, given that there is no evidence that the treatment effect would differ between 
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36 to <60 month olds and 60 to <72 month olds.   
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Protocol Change #2 
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Current Protocol 
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A masked exam is required at every protocol-specified visit.  The masked examiner tests ocular 
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alignment, as well as visual acuity and stereoacuity for those subjects old enough to perform them.  
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The masked examiner tests each of these assessments twice, first with correction and then without 
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correction to maintain masking. The masked examiner also performs a retest if the subject shows 
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suspected deterioration on any of the initial masked assessments, regardless of whether or not their 
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poor test results are with their assigned treatment (e.g. observation group subjects are retested when 
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they test poorly with correction; glasses group subjects are retested when they test poorly without 
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correction).       
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Proposed Change 
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At interim visits prior to the 36-month primary outcome exam, a masked exam will be required only 
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if unmasked testing in the assigned correction shows suspected deterioration related to strabismus, 
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distance visual acuity, or stereoacuity in a subject who has not had deterioration confirmed by 
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masked exam at a previous visit. The only procedure(s) to be tested by the masked examiner are 
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those specific tests suggesting deterioration.  The masked examiner will test each required 
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assessment(s) twice, first with correction and then without correction. The masked examiner will 
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not perform any retests, given that the masked examiner’s initial testing (in the appropriate 
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correction status) may serve as confirmation (or not) of the suspected deterioration detected by 
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unmasked testing.  If a masked examiner is not available on the same day as the unmasked testing, a 
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separate masked exam will be scheduled within 2 weeks. See changes to sections 3.3.1 and 3.3.2.     
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No changes related to masking are proposed to the 36-month primary outcome visit--all testing 
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related to the classification of failure (i.e. ocular alignment, visual acuity, and stereoacuity) will 
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continue to be performed by the masked examiner.   
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Rationale for Change 
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Feedback from participating sites was that the testing burden associated with the current protocol is 
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excessive and that visits take too long to complete, issues which may be contributing to the study’s 
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poor recruitment.   
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Unmasking the initial testing eliminates the second set of testing that was done solely for the 
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purpose of maintaining masking, as well as retesting that is not related to classification of 
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deterioration, thus substantially reducing the testing burden on the site and subject.  Given that the 
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study population is children aged 1 to <6 years old, an additional benefit of less testing may be 
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reduced subject fatigue and better attention, particularly for the very young children.   
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Unmasking the initial testing also eliminates the need for a masked examiner at every follow up 
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visit, given that a masked examiner would now be needed only if the unmasked initial testing 
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suggests deterioration.  Reducing the testing burden for the subject may also help retention. 
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The Steering Committee acknowledges that the proposed change does have a potential 
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disadvantage.  The original purpose of the masking was not only to allow unbiased determination of 
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the 3-year failure outcome, but also to allow unbiased determination of deterioration during the 
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study.  The classification of deterioration triggers mandatory prescription of glasses in observation 
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group subjects and releases subjects in both groups to further treatment at investigator discretion.  
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The specific concern regarding deterioration is that it could be overcalled in the observation group, 
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resulting in glasses being prescribed earlier than necessary. This situation would make the 
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treatments received in each group more similar and thus bias against finding a treatment group 
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difference in the primary outcome at 3 years.   
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In the proposed change, the determination of deterioration remains sufficiently masked because the 
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trigger for the masked retest is the unmasked initial testing OR parental concern in the absence of 
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deterioration (see protocol change # 3 below).  Therefore, the masked examiner will not know 
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whether or not deterioration was found on unmasked testing and the proposed change should not 
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bias the masked examiner towards finding deterioration.  Consequently, the Steering Committee 
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feels that having a confirmatory retest by a masked examiner will be adequately rigorous.  
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Protocol Change #3 
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Current Protocol 
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When a subject first meets deterioration criterion (with the exception of deterioration for parental 
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concern), the criterion met must be retested by the masked examiner.   
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Proposed Change 
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If a parent indicates significant concern about the child’s eyes that would warrant starting treatment 
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in the absence of meeting formal deterioration criteria by unmasked examination; ocular alignment, 
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distance visual acuity, and stereoacuity must be assessed by a masked examiner.  
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Rationale for Change 
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Requiring such masked exams would keep masked examiners masked to whether there was 
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suspected deterioration on unmasked testing, because under this proposed protocol change a masked 
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exam would also performed if the parent expressed significant concern about the child’s eyes that 
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would warrant starting treatment.  
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Protocol Change #4 
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Current Protocol 
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Deterioration and failure criteria may be met if stereoacuity at near by the Randot Preschool 
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stereotest is below age normal values or has decreased 2 or more octaves (>0.6 log seconds of arc) 
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from the best previously recorded stereoacuity or to nil.   
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Proposed Change 
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The stereoacuity portion of deterioration and failure will be based solely on whether the 
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stereoacuity is below age normal values, removing the criteria based on whether stereoacuity has 
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decreased 2 or more octaves than the best previously recorded stereoacuity or a drop to nil (sections 
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3.3.3 and 5.2.1).    
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Rationale for Change 
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Because the study treatment (refractive correction) may affect stereoacuity, the distribution of best 
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previous stereoacuity may differ between treatment groups, thus compromising the validity of 
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treatment group comparisons based on a change from best stereoacuity. 
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Protocol Change #5 
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Current Protocol 
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The protocol does not address how the analysis will treat cases in which non-protocol treatment is 
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prescribed in the absence of meeting formal deterioration criteria.   
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Proposed Change 
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Specified that non-protocol treatment for refractive error, amblyopia, and/or ocular alignment 
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prescribed in the absence of meeting formal deterioration criteria (any treatment other than 
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refractive correction in the glasses group or any treatment in the observation group) will be 
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considered deterioration for analysis purposes (sections 3.3.3 and 4.5). Non-protocol treatment has 
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no impact on the primary outcome of failure at 36 months unless strabismus surgery was received, 
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in which case the subject is considered failed.     
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Rationale for Change 
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Subjects who have not met deterioration criteria but who receive treatment other than their 
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randomized treatment are not at the same risk of deterioration as subjects who have not started such 
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treatment.  For example, a subject who was started on amblyopia treatment even though 
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deterioration criteria were not met (e.g. subject was too young to have visual acuity tested or 
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subject’s interocular difference did not quite meet deterioration criteria) may be expected to be at 
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less risk of amblyopia that someone who did not receive such treatment.  
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Protocol Change #6 
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Current Protocol 
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Currently, binocular near visual acuity testing at the 36-month primary outcome exam is performed 
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with and without correction by the masked examiner. 
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Proposed Change 
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Binocular near visual acuity testing may be performed by an unmasked examiner (section 3.6.2).   
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Rationale for Change 
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Binocular near visual acuity is a secondary outcome and does not influence whether the subject ails 
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at the 36-month primary outcome visit.  To decrease the burden on the subject and the masked 
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examiner, this testing will not be completed during the masked portion of the exam. 
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Protocol Change #7 
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Current Protocol 
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Children with any prior refractive correction are ineligible for the study.  
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Proposed Change 
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The study will allow prior treatment of refractive correction that was one week or less and occurred 
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more than 2 months prior to enrollment (section 2.2.2)    
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Rationale for Change 
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We have precedent in our some of our previous amblyopia studies to allow a very minimal amount 
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of prior treatment to essentially count as ‘no treatment.’ We would not expect one week or less of 
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refractive correction to have a meaningful effect, particularly if it occurred more than two months 
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before enrollment. 
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This amendment also provides for the following minor protocol changes/clarifications:   
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 Clarified that the requirement that the examiner be a study-certified pediatric 
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ophthalmologist, pediatric optometrist, or certified orthoptist pertains only to the ocular 
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alignment testing. Visual acuity and stereoacuity testing may be performed by any masked 
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examiner who is PEDIG-certified to perform the specific assessment (section 3.7).   
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 Specified that a course of short-term, bilateral cycloplegia to assist in relaxing the subject’s 
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accommodation to adapt to the glasses can now be prescribed at investigator discretion and 
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will not require approval by the protocol chair (see sections 3.1.2 and 3.4) because this is 
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routine practice.  If bilateral cycloplegia is prescribed, it must be stopped at least two weeks 
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prior to any study visit.  Data regarding how often bilateral cycloplegia is prescribed will be 
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gathered at follow up visits.   
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 Specified that deterioration can occur at any follow up visit and is not limited to protocol-
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specified visits (section 3.3.3)  
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 Clarified procedures for the 36-month primary outcome exam.  If a subject meets any failure 
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criteria (with the exception of strabismus surgery prior to the 36-month outcome exam); the 
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visual condition that is considered to be failed must be retested by the masked examiner 
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(section 3.6.1).  This information was previously located only in the statistical analysis 
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chapter.     
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 Clarified that for each assessment in the masked exam, both with correction testing and 
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without correction testing should be completed before proceeding to the next assessment 
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(section 3.3.2 and 3.6.1)  
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 Specified that at interim follow up visits, the subjects current glasses must be verified as 
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correct by lensometry prior to any unmasked testing (section 3.3.1).   
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 Clarified what refractive correction should be used for testing at interim follow up visits and 
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whether or not deterioration has been confirmed by masked exam previously (section 3.3.1) 
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 Clarify deterioration criteria (section 3.3.3) 
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 Clarified what refractive correction should be used for testing at the 36-month primary 
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outcome visit (section 3.6.1)   
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 Clarified that full cylinder correction refers to both power and axis (sections 1.4, 3.1.2, 
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3.6.1)  
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 Specified that atropine is allowed for treatment of amblyopia but must be discontinued at 
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least 2 weeks before the 36-month primary outcome visit (section 4.5) 
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 Clarified that subjects who have not met deterioration criteria must continue with their 
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randomized treatment assignment (no correction for observation group subjects, hyperopic 
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correction per protocol for glasses group subjects) with no additional treatment (sections 
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3.1.1 and 3.1.2).  
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 Habitual correction has been clarified as randomized correction throughout the protocol.   
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 Clarified the method of payment to the parent for travel reimbursement as by check or by 
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merchandise or money-card (section 4.9) 
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 Clarified contact information for a change in protocol chairs on cover page 
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PROTOCOL AMENDMENT 2 (1-23-15) 
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This amendment provides for the following protocol changes: 
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Protocol Change #1 
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Current Protocol – section 3.6.1 
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The appropriate hyperopic correction for testing in trial frames at the 36-month primary outcome 
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exam is based on the cycloplegic refraction at 30 months defined as follows:  
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 If deterioration has not been confirmed by masked exam at a previous visit, subjects should 
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be tested in partial plus (sphere cut symmetrically by 1.00D, with full cylinder).  
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 If deterioration has been confirmed by masked exam at a previous visit, subjects should be 
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tested in full sphere and cylinder correction (magnitude and axis) 
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Proposed Change – section 3.6.1 
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The appropriate hyperopic correction for testing in trial frames at the 36-month primary outcome 
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exam is based on the most recent cycloplegic refraction and most recent glasses-correction (if any) 
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defined as follows:  
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 If deterioration has been confirmed by masked exam at a previous visit, and refractive 
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correction with full plus was prescribed as glasses at the most recent visit, the subject 
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should be tested in trial frames with full sphere and cylinder correction (magnitude and axis) 
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from the most recent cycloplegic refraction 
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o Full plus prescribed at the most recent visit is defined as prescribed sphere within 
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0.25D of the cycloplegic refraction 
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 Otherwise, the subject should be tested in trial frames with partial plus (sphere cut 
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symmetrically by 1.00D, with full cylinder correction magnitude and axis) from the most 
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recent cycloplegic refraction 
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Rationale for Change 
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The current protocol would require testing in full plus for all subjects who previously deteriorated 
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(regardless of the cause of the deterioration or the current glasses correction). However, full plus is 
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only appropriate for certain conditions (for subjects who have been wearing full plus e.g. subjects 
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who deteriorate due to development of an ET).  If a subject who has not been wearing full plus is 
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tested in full plus, reduced distance acuity may be found because the subject may not be able to 
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instantaneously relax into the full plus prescription.  Therefore, we are requesting to change the 
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current protocol such that if the subject has deteriorated previously and full plus was prescribed at 
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the last visit, then the subject will be tested at the 36-month visit in full plus.  Otherwise the subject 
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will be tested in partial plus.  This change will provide the most reasonable assessment of true 
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outcome.  
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This amendment also provides for the following minor protocol changes/clarifications:   
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 Section 3.6.2 - The criteria for repeat testing 4 weeks following the 36-month visit for 
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subjects suspected of meeting failure criteria with a change in cycloplegic refraction were 
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clarified to make clearer that 1) glasses are prescribed at the 36 month visit and 2) 
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assessments are repeated wearing the new glasses at the repeat outcome visit. Testing 
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without correction does not need to be repeated at the repeat outcome visit.   
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 Section 5.2.1 – Clarified that for children that return for a repeat outcome visit, the final 
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assessment of failure for the study will be based upon the assessments without trial frames at 
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36 months and the assessments in new glasses 4 weeks later.      
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TABLE OF CONTENTS 
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CHAPTER 1: BACKGROUND AND SUMMARY ............................................................................................................. 1-1 
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1.1 
Background .................................................................................................................................................... 1-1 
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1.2 
Rationale for the Study ................................................................................................................................... 1-1 
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1.3 
Study Objectives ............................................................................................................................................ 1-2 
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1.4 
Synopsis of Study Design .............................................................................................................................. 1-2 
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CHAPTER 2: PATIENT ENROLLMENT ........................................................................................................................... 2-1 
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2.1 
Eligibility Assessment and Informed Consent ............................................................................................... 2-1 
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2.2 
Eligibility and Exclusion Criteria ................................................................................................................... 2-1 
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2.2.1 
Eligibility Criteria ...................................................................................................................................... 2-1 
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2.2.2 
Exclusion Criteria ...................................................................................................................................... 2-1 
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2.3 
Historical Information .................................................................................................................................... 2-2 
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2.4 
Procedures at the Enrollment Visit ................................................................................................................. 2-2 
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2.5 
Randomization of Eligible Patients ................................................................................................................ 2-3 
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CHAPTER 3: TREATMENT AND FOLLOW-UP ............................................................................................................. 3-1 
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3.1 
Treatment ....................................................................................................................................................... 3-1 
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3.1.1 
Observation Group ..................................................................................................................................... 3-1 
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3.1.2 
Glasses Group ............................................................................................................................................ 3-1 
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3.2 
Follow-up Visit Schedule ............................................................................................................................... 3-1 
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3.3 
Follow-up Visits at 6, 12, 18, 24, and 30 months ........................................................................................... 3-2 
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3.3.1 
Unmasked Exam ........................................................................................................................................ 3-2 
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3.3.2 
Masked Exams for Subjects with Newly Suspected Deterioration ............................................................ 3-3 
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3.3.3 
Deterioration Criteria ................................................................................................................................. 3-4 
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3.3.4 
Pre-Approved Unmasked Sites .................................................................................................................. 3-5 
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3.4 
Post-Deterioration Glasses Treatment ............................................................................................................ 3-5 
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3.5 
30-Month Follow-up Visit ............................................................................................................................. 3-6 
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3.6 
36-Month Primary Outcome Exam ................................................................................................................ 3-6 
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3.6.1 
Masked Exam ............................................................................................................................................ 3-6 
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3.6.2 
Unmasked Exam ........................................................................................................................................ 3-7 
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3.7 
Examiner Qualifications ................................................................................................................................. 3-8 
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3.8 
Non-Study Visits and Treatment .................................................................................................................... 3-8 
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CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ................................................................... 4-1 
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4.1 
Contacts by the Jaeb Center for Health Research .......................................................................................... 4-1 
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4.2 
Patient Withdrawals ....................................................................................................................................... 4-1 
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4.3 
Management of Refractive Error .................................................................................................................... 4-1 
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4.3.1 
Bifocals ...................................................................................................................................................... 4-1 
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4.4 
Management of Strabismus ............................................................................................................................ 4-1 
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4.5 
Management of Amblyopia ............................................................................................................................ 4-2 
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4.6 
Risks ............................................................................................................................................................... 4-2 
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4.6.1 
Risks of Examination Procedures .............................................................................................................. 4-2 
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4.7 
Reporting of Adverse Events ......................................................................................................................... 4-2 
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4.8 
Discontinuation of Study ................................................................................................................................ 4-2 
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4.9 
Travel Reimbursement ................................................................................................................................... 4-2 
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4.10 
Study Costs .................................................................................................................................................... 4-2 
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CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .......................................................... 5-1 
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5.1 
Definitions of Primary Cohorts ...................................................................................................................... 5-1 
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5.2 
Primary Data Analysis ................................................................................................................................... 5-1 
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5.2.1 
Classification of Primary Outcome (Failure Criteria) ................................................................................ 5-1 
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5.3 
Secondary Data Analyses ............................................................................................................................... 5-2 
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5.3.1 
Best Visual Acuity at 36 Months ............................................................................................................... 5-2 
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5.3.2 
Development of Strabismus ....................................................................................................................... 5-2 
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5.3.3 
Subgroup Analysis ..................................................................................................................................... 5-2 
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5.3.4 
Observation Group Deterioration .............................................................................................................. 5-2 
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5.3.5 
Development of Amblyopia ....................................................................................................................... 5-3 
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5.3.6 
Near Visual Acuity .................................................................................................................................... 5-3 
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5.4 
Exploratory Analyses ..................................................................................................................................... 5-3 
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5.5 
Sample Size Estimates ................................................................................................................................... 5-3 
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5.6 
Interim Analysis ............................................................................................................................................. 5-4 
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CHAPTER 6: REFERENCES ............................................................................................................................................... 6-1 
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1-1 
CHAPTER 1: BACKGROUND AND SUMMARY 
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This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is 
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funded through a cooperative agreement from the National Eye Institute.   
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1.1 
Background 
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The prevalence of hyperopia was reported in recent population-based studies in 6- to 72-month-
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old children.1, 2  In white children the prevalence of hyperopia was 31.5% with ≥+2.00D, 13.2% 
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with ≥+3.00D, 5.2% with ≥+4.00D, and 2.4% with ≥+5.00D.  Hyperopia prevalence was lower 
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for African-American children (relative prevalence white to African-American = 1.62; 95% CI 
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1.52 to 1.74).1  The prevalence of hyperopia ≥+2.00D (in the better eye) was slightly higher in 
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Hispanic children (19.6%) than in African American children (15.2%). 
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Moderate and high hyperopia are associated with the development of strabismus and amblyopia.  
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Atkinson et al3 found that children with greater than +3.50D in any meridian at 6 to 8 months of 
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age were 13 times more likely to develop strabismus by 4 years of age and 6 times more likely 
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to have amblyopia, compared to infants with low hyperopia or emmetropia.  Similarly, a study 
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by Ingram et al4 found that the presence of +2.50D or more of hyperopia at 1 year of age was 
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significantly associated with the development of strabismus and/or amblyopia by 3.5 years of 
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age.  The American Academy of Ophthalmology consensus guidelines state that hyperopia of 
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≥+6.00 D in 0- to 1-year olds; ≥ +5.00 D in 1-to 2-year olds; and ≥ +4.50 D in 2- to 3-year olds 
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is amblyogenic.5  A threshold of greater than +3.50 D in any meridian has been suggested as a 
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referral criterion for vision screening.6 
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Nevertheless, the question of whether to prescribe glasses for hyperopia remains controversial.  
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1.2 
Rationale for the Study 
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The primary aims of treatment for asymptomatic moderate and high hyperopia in preschool 
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children are to facilitate the development of normal visual acuity and to prevent the 
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development of esotropia and amblyopia.  Treatment consists of optical correction, typically 
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using glasses.  For children with high hyperopia (>+5.00D) and without strabismus or 
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amblyopia, there is general consensus that a correction (usually partial plus) should be 
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prescribed.7 Nevertheless, for children with moderate hyperopia (+3.00D to +5.00D) without 
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strabismus or amblyopia, there is less consensus among pediatric eye care professionals.  A 
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survey by Lyons et al7 found that for a 2-year-old child with hyperopia greater than +3.00D, 
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65% of optometrists would prescribe glasses compared to 25% of ophthalmologists; for a 4-year 
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old with hyperopia greater than +3.00D, 67% of optometrists would prescribe compared with 
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42% of ophthalmologists.  The American Association for Pediatric Ophthalmology and 
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Strabismus (AAPOS) recommends correcting +4.00D or more in 2 to 7 year olds8 and the 
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American Academy of Ophthalmology recommends a threshold of +4.50D for correction in 2-to 
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3-year olds.5  Unlike ophthalmology, optometry does not provide specific recommendations 
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based on age and level of refractive error.9  Such variation in practice highlights the lack of 
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rigorously collected scientific evidence for the management of this condition.  Across all levels 
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of hyperopia, most ophthalmologists and optometrists usually prescribe less than the full 
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cycloplegic refraction (71% in the Lyons survey) when no strabismus or amblyopia is present.7 
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The rationale for proactively correcting moderate hyperopia in an asymptomatic child is the 
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prevention of esotropia, amblyopia3, 4 or asthenopia.  The argument against correcting moderate 
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hyperopia in an asymptomatic child is the expense and inconvenience of glasses that might be 
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1-2 
unnecessary and the potential disruption of emmetropization in infants and toddlers.  At present, 
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it remains uncertain whether correction of moderate hyperopia is beneficial in terms of visual 
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acuity outcomes or strabismus development.  There is some evidence that using partial 
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correction of hyperopia allows emmetropization to take place.10  
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There are some previous data comparing no spectacle correction of moderate hyperopia to 
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partial correction.  Ingram et al11 randomized 6-month-old children (n=372) with +4.00D or 
457 
more of hyperopia to glasses or no glasses and found no difference in the rate of strabismus 
458 
development (23.5% vs. 26% respectively) by 3.5 years of age.  Nevertheless, there was a 
459 
difference in visual acuity outcome between groups: 97% of the glasses group achieved 20/40 
460 
or better compared to 87% in the non-glasses group.  A study by Atkinson et al12 allocated 
461 
infants with +3.50D or more of hyperopia to glasses or no glasses and, in contrast with the 
462 
Ingram study,11 found that there was a significant difference in the rate of strabismus 
463 
development (6.3% vs. 21% respectively).  Atkinson et al also found that the rate of amblyopia 
464 
was lower in the glasses group compared to the non-glasses group (28.6% vs. 68% 
465 
respectively).  In a second study by the Atkinson group,13 the strabismus findings were not 
466 
replicated (no difference in rate of strabismus development between glasses [n=58] and non-
467 
glasses wearers [n=18]) whereas the visual acuity outcomes were replicated (amblyopia was 
468 
found in 17% of children in glasses group and 67% of children in non-glasses group).13  There 
469 
is unfortunately a lack of standardization in these previous studies, especially regarding visual 
470 
acuity testing methods  In addition, it is not always clear how amblyopia was defined and 
471 
whether visual acuity was assessed with or without hyperopic correction (in no-spectacles 
472 
patients).  Furthermore, some reported outcomes include data only for subjects considered to be 
473 
‘compliant’ with glasses. 
474 
 
475 
If refractive correction of moderate hyperopia does not reduce the incidence of amblyopia 
476 
and/or esotropia compared to no refractive correction, then glasses can be avoided.  However, if 
477 
correcting moderate hyperopia does reduce the development of amblyopia and/or esotropia, 
478 
then the benefits of preemptive refractive correction will have been identified. 
479 
 
480 
1.3 
Study Objectives 
481 
To compare visual acuity outcomes and development of strabismus after a 3-year follow-up 
482 
period in children age 12 to <72 months with moderate hyperopia (spherical equivalent +3.00D 
483 
to +6.00D) who are prescribed glasses either immediately or only after confirmation of pre-
484 
specified deterioration criteria.  
485 
 
486 
1.4 
Synopsis of Study Design 
487 
Major eligibility criteria: (See section 2.2 for a complete listing) 
488 
 Age 12 to <72 months  
489 
o The study will consist of two primary cohorts divided by age.  One primary 
490 
cohort will consist of children 12 to <36 months of age and another primary 
491 
cohort will consist of children 36 to <72 months of age.  
492 
 Cycloplegic refraction:  
493 
o +3.00D to +6.00D of spherical equivalent (SE) in either eye 
494 
o Astigmatism ≤1.50D in both eyes 
495 
o Spherical equivalent anisometropia ≤ +1.50D 
496 
 No prior treatment for refractive error with glasses or contacts (unless treatment was one 
497 
week or less in duration and occurred more than 2 months prior to enrollment) 
498 

HTS1v3 0 1-30-15 
 
1-3 
 No prior treatment for amblyopia or strabismus (e.g., surgery, patching, vision therapy, 
499 
etc.) 
500 
 No measurable heterotropia at distance (3 meters) or at near (1/3 meter) by 
501 
cover/uncover testing 
502 
 No known neurological anomalies (e.g. cerebral palsy, Down syndrome) 
503 
 For children 36 to <72 months of age: 
504 
o No evidence of subnormal visual acuity - Uncorrected monocular visual acuity in 
505 
both eyes of 20/50 or better for age 36 to <48 months,20/40 or better for age 48 
506 
to <60 months, and 20/32 or better for ages 60 to <72 months measured without 
507 
cycloplegia using the ATS-HOTV© visual acuity testing protocol  
508 
o Zero (0) or 1 logMAR line interocular difference (IOD) in uncorrected visual 
509 
acuity measured without cycloplegia using the ATS-HOTV© visual acuity testing 
510 
protocol  
511 
o Age-normal stereoacuity on the Randot Preschool Stereotest (see Table 2) 
512 
 
513 
Primary Cohorts 
514 
 One primary cohort consists of patients aged 12 to <36 months. 
515 
 A second primary cohort consists of patients aged 36 to <72 months.   
516 
 
517 
Treatment Groups 
518 
For each primary cohort, patients will be randomized (1:1) to either: 
519 
 Observation: glasses will not be prescribed unless the patient has confirmation of one or 
520 
more deterioration criteria (defined in section 3.3.3.3) 
521 
 Glasses: glasses are prescribed at enrollment and worn per protocol throughout the duration 
522 
of the study (unless the glasses correction decreases to +1.00D SE or less during follow-up; 
523 
then glasses are at investigator discretion) 
524 
 
525 
For patients in the glasses group, the sphere will be cut symmetrically by 1.00D (partial plus) 
526 
and the full cylinder (magnitude and axis) will be prescribed.  Patients in either group who have 
527 
confirmation of one or more deterioration criteria (defined in section 3.3.3.3) will be prescribed 
528 
glasses with amount of sphere and cylinder correction according to guidelines suggested in 
529 
section 3.4.  
530 
 
531 
Sample Size 
532 
The study will enroll 336 patients aged 12 to <36 months and 336 patients aged 36 to <72 
533 
months in the primary cohorts. 
534 
 
535 
Visit Schedule (timed from randomization) 
536 
 Enrollment exam 
537 
 6 months ± 1 month 
538 
 12 months ± 1month 
539 
 18 months ± 1 month  
540 
 24 months ± 1 month  
541 
 30 months ± 1 month 
542 
 36 months ± 1 month 
543 
 Repeat 36-month outcome exam within 4 weeks for subjects meeting failure criteria 
544 
(section 5.2) and requiring change in glasses (section 4.3). 
545 
 
546 

HTS1v3 0 1-30-15 
 
1-4 
At each 6-month follow-up visit, monocular distance visual acuity using the ATS-HOTV (if old 
547 
enough to perform), cover uncover test, simultaneous prism cover test (SPCT) (if deviation 
548 
present), prism and alternate cover test (PACT), the Randot Preschool Stereoacuity test (if old 
549 
enough to perform), and dynamic retinoscopy (optional) will be performed. Near visual acuity 
550 
will be tested at 36 months. 
551 
 
552 
The primary outcome exam will be 36 months after randomization.  Cycloplegic refraction will 
553 
be performed yearly (or more frequently if clinically indicated); a mandatory cycloplegic 
554 
refraction will be performed at the 30-month follow-up visit and again at the 36-month outcome 
555 
exam.  Subjects meeting failure criteria and requiring a change in glasses at the 36-month 
556 
outcome exam will return for a repeat outcome exam in the updated glasses within 4 weeks. 
557 
 
558 
Primary Analysis 
559 
For each of the two primary cohorts, the proportion meeting failure criteria at 3 years post-
560 
randomization will be compared between treatment groups using the Fisher’s exact test. 
561 
 Failure (confirmed by a retest at the same visit) will be determined at the 36-month primary 
562 
outcome visit and is defined in section 5.2.1. 
563 
564 

HTS1v3 0 1-30-15 
 
1-5 
Study Summary Flow Chart 
565 
 
566 
567 
6, 12, 18, 24, and 30 month exams ± 1 month (unmasked in randomized correction*) 
 Randot Preschool stereoacuity (children 36 months and older) 
 Ocular alignment (cover/uncover, SPCT if tropic, and PACT) 
 Monocular distance visual acuity (ATS-HOTV in children 36 months and older) 
 Dynamic retinoscopy (optional)  
 Cycloplegic refraction (if not performed in last 12 months) -Mandatory at 30-month exam 
Randomize 
Observation 
Glasses 
 
 
 
 Measurable heterotropia  
 Stereoacuity below age norms  
 Measurable heterotropia 
 Parent reports problems with function due to vision 
 
 
 
 
 Monocular VA below age norm 
 ≥2 lines of IOD if Dist VA 20/25 or worse in better eye 
 ≥3 lines of IOD if Dist VA 20/20 or better in better eye  
 
Is deterioration newly suspected? 
(any of the following findings in a subject who has not had deterioration confirmed at a prior visit) 
Yes – Masked Exam* * 
(same day or within 2 weeks)  
 If same day as unmasked testing, give 10-minute break 
 Test only the procedures related to suspected deterioration 
 Test each procedure twice--first with correction, then without correction   
Observation Group  
Glasses Group  
No 
 Continue in current 
group (glasses or 
observation) 
Not confirmed 
continue 
observation 
Baseline Measurements (without correction, without cycloplegia) 
 Randot Preschool stereoacuity (children 36 months and older) 
 Ocular alignment (cover/uncover, PACT) 
 Monocular distance visual acuity (ATS-HOTV in children 36 months and older) 
 Binocular near visual acuity 
 Dynamic retinoscopy (optional) 
Not confirmed 
continue 
current glasses 
If > 30 mo 
Confirmed deterioration 
(Either Group) 
 Cycloplegic refraction (if not performed within previous 6 months) 
 Subject is released to best clinical care (defined as any care at investigator 
discretion but must include prescribing glasses according to guidelines suggested 
in section 3.4) 
 The subject will return for all study-specified follow-up visits 
* Testing is performed in child’s glasses and no masked exam is needed at interim follow 
up visits for children who have previously been classified as deteriorated 
** - Unless site is pre-authorized for non-masked 6-12, 18, 24, and 30 month visits in 
which case retest is performed by non-masked personnel. 
If > 30 mo 
If > 30 mo 
If > 30 mo 

HTS1v3 0 1-30-15 
 
1-6 
  
568 
 
569 
 
570 
 
571 
 
572 
 
573 
 
574 
575 
No 
Study ends 
Has the cycloplegic refraction changed significantly since 
refraction at 30 months?  
(>0.75D sphere, >0.75D cylinder, >0.75D in SE 
anisometropia or axis change of >6 degrees when cylinder is 
>+1.50D) 
Repeat Outcome Exam 4 Weeks  1 Week from 36- Month Exam with Updated Glasses (Masked) 
 Randot Preschool stereoacuity with correction 
 Ocular alignment (cover/uncover, SPCT (if tropic), and PACT) with correction 
o 
Retest ocular alignment at near with +3.00D lens if strabismus present at near 
 Monocular distance visual acuity (ATS-HOTV) with correction 
 Binocular near visual acuity (Not masked) 
 Dynamic retinoscopy (optional, Not masked) 
Yes 
 Update glasses 
 Repeat Outcome Exam 4 weeks  1 
 
 Measureable heterotropia  
 Stereoacuity below age norms  
 
 
 Best monocular VA in either eye below age norm 
 ≥2 lines of IOD if Dist VA 20/25 or worse in better eye 
 ≥3 lines of IOD if Dist VA 20/20 or better in better eye  
No 
Study ends 
Yes 
 
10-minute break 
 
Confirm with a retest by masked examiner (with exception of 
strabismus surgery prior to 36mo)  
Did subject have strabismus surgery or are any of the following findings suggestive of failure found on masked exam? 
No Confirmed Failure  
Study ends 
Confirmed 
Failure 
3-Year Primary Outcome Exam: 36 months ± 1 month (Masked) 
 Randot Preschool stereoacuity with and without correction 
 Ocular alignment (cover/uncover, SPCT (if tropic), and PACT) with and without correction 
o 
Retest ocular alignment at near with +3.00D lens if strabismus present at near through distance correction 
 Monocular distance visual acuity (ATS-HOTV) with and without correction 
 Binocular near visual acuity  (NOT masked) 
 Dynamic retinoscopy (optional and NOT masked)  
 Cycloplegic refraction (NOT masked) 

HTS1v3 0 1-30-15 
 
2-1 
CHAPTER 2: PATIENT ENROLLMENT 
576 
 
577 
2.1 
Eligibility Assessment and Informed Consent 
578 
The study will enroll a minimum of 336 subjects for the primary cohort of patients aged 12 to <36 
579 
months at enrollment, and a minimum of 336 subjects for a separate primary cohort of patients aged 
580 
36 to <72 months at enrollment.  As the enrollment goal approaches, sites will be notified of the end 
581 
date for recruitment.  Subjects who have signed an informed consent form can be randomized up 
582 
until the end date, which means the expected recruitment might be exceeded. 
583 
 
584 
A patient is considered for the study after undergoing a routine eye examination (by a study 
585 
investigator as part of standard of care), or a referral, that identifies hyperopia that appears to meet 
586 
the eligibility criteria.  The study will be discussed with the child’s parent(s) or guardian(s) (referred 
587 
to subsequently as parent(s)).  Parent(s) who express an interest in the study will be given a copy of 
588 
the informed consent form to read.  Written informed consent must be obtained from the parent 
589 
prior to performing any study-specific procedures that are not part of the patient’s routine care. 
590 
 
591 
2.2 
Eligibility and Exclusion Criteria 
592 
2.2.1 Eligibility Criteria  
593 
The following criteria must be met for the patient to be enrolled in the study: 
594 
1. Age 12 to <72 months  
595 
2. Refractive error between +3.00D and +6.00D SE (by cycloplegic refraction) in either eye 
596 
3. Astigmatism <1.50D in both eyes 
597 
4. Spherical equivalent anisometropia ≤ +1.50D 
598 
5. For children 36 to <72 months of age: 
599 
a. Normal visual acuity for age - Uncorrected monocular visual acuity in both eyes using 
600 
the ATS-HOTV© visual acuity testing protocol without cycloplegia (see section 3.3.3, 
601 
Table 1) 
602 
b. No amblyopia - Zero (0) or 1 logMAR line interocular difference (IOD) in uncorrected 
603 
visual acuity without cycloplegia using the ATS-HOTV© visual acuity testing protocol 
604 
c. Normal near stereoacuity for age using the Randot Preschool Stereoacuity test (see 
605 
section 3.3.3, Table 2) 
606 
6. Gestational age >32 weeks 
607 
7. Investigator is willing to prescribe glasses per protocol or observe the hyperopia untreated for 3 
608 
years unless specific criteria for deterioration outlined in section 3.3.3 are confirmed.   
609 
8. Parent understands the protocol and is willing to accept randomization to either glasses or no 
610 
glasses initially, and is willing to wear glasses as prescribed or accept that glasses will not be 
611 
prescribed by the investigator unless specific deterioration criteria outlined in section 3.3.3 are 
612 
confirmed. 
613 
9. Parent has phone (or access to phone) and is willing to be contacted by Jaeb Center staff. 
614 
10. Relocation outside of area of an active PEDIG site for this study within the next 36 months is 
615 
not anticipated. 
616 
2.2.2 Exclusion Criteria 
617 
A patient is excluded for any of the following reasons: 
618 
1. Any measurable heterotropia at distance (3 meters) or at near (1/3 meter) by cover/uncover 
619 
testing. Note that patients with heterophoria are eligible.  
620 
2. Previous documented strabismus (parental report must be confirmed by investigator) 
621 
3. Manifest or latent nystagmus evident clinically 
622 

HTS1v3 0 1-30-15 
 
2-2 
4. Previous treatment of refractive error with glasses or contacts unless duration of glasses or 
623 
contacts wear was one week or less and occurred more than 2 months prior to enrollment.  
624 
5. Previous intraocular, refractive, or extraocular muscle surgery 
625 
6. Previous amblyopia treatment 
626 
7. Previous vergence/accommodative therapy 
627 
8. Parental concerns over learning or development 
628 
9. Ocular co-morbidity that may reduce visual acuity 
629 
10. Symptoms of blur or asthenopia 
630 
11. Developmental delay diagnosed by pediatrician or Individualized Education Program (IEP) 
631 
12. Known neurological anomalies (e.g. cerebral palsy, Down syndrome) 
632 
13. Inability to perform visual acuity ATS-HOTV testing if ≥ 36 months of age 
633 
2.3 
Historical Information 
634 
Historical information to be elicited will include the following: date of birth, gender, race, ethnicity, 
635 
reason for coming for exam, history of prior eye-related treatment, and diagnosis and current 
636 
treatment of ADHD.  Family history of strabismus and/or amblyopia, patching, or glasses before the 
637 
age of 7 years will also be collected. 
638 
 
639 
2.4 
Procedures at the Enrollment Visit 
640 
All examination procedures must be tested within 14 days prior to enrollment, except a cycloplegic 
641 
refraction, which must be tested within 2 months prior to enrollment.  All examination procedures at 
642 
enrollment are performed without correction and without cycloplegia in the following order: 
643 
 
644 
1. Stereoacuity Testing (patients >=36 months of age only):  
645 
 Stereoacuity will be tested at near without correction using the Randot Preschool 
646 
Stereoacuity test. 
647 
 
648 
2. Ocular Alignment Testing: 
649 
 Ocular alignment will be assessed without correction by the cover/uncover test and prism 
650 
and alternate cover test (PACT) in primary gaze at distance (3 meters) and at near (1/3 
651 
meter) as outlined in the Hyperopia Testing Procedures Manual. 
652 
o See section 2.2.1 for eligibility criteria related to ocular alignment. 
653 
 A parental report of strabismus must be confirmed by clinical testing performed by the 
654 
investigator.  If the investigator fails to find strabismus, the subject may be brought back at 
655 
investigator discretion.  If the return visit is within two weeks, other clinical measures made 
656 
within 14 days of this repeated ocular alignment testing may be used for enrollment. 
657 
 
658 
3. Distance Visual Acuity Testing (patients >= 36 months of age only):  Monocular distance visual 
659 
acuity testing will be performed without correction in each eye by a certified examiner using the 
660 
ATS single-surround HOTV protocol on a study-certified acuity tester as described in the ATS 
661 
Testing Procedures Manual.  ATS single-surround HOTV protocol will be used throughout the 
662 
study. 
663 
 No visual acuity data (including fixation preference) will be collected on children <36 
664 
months old. 
665 
 Testing must be completed without cycloplegia. 
666 
 At investigator discretion acuity may be retested on the same day or subsequent day to 
667 
assess eligibility.  
668 
 
669 

HTS1v3 0 1-30-15 
 
2-3 
4. Binocular Near Visual Acuity Testing (patients ≥36 months only): Binocular near visual acuity 
670 
testing will be performed without correction as described in the Hyperopia Study Testing 
671 
Procedures Manual. 
672 
 
673 
5. Additional Clinical Testing: 
674 
 Undilated dynamic retinoscopy (optional) at near without correction as outlined in the 
675 
Hyperopia Testing Procedures Manual.   
676 
 Ocular examination as per investigator’s clinical routine (if not performed within 6 months) 
677 
 Cycloplegic refraction (if not performed within 2 months) using drops containing 
678 
cyclopentolate (must achieve stable retinoscopy reflex) 
679 
o See section 2.2.1 for eligibility criteria for refractive error 
680 
 
681 
2.5 
Randomization of Eligible Patients 
682 
The Jaeb Center will construct a Master Randomization List using a permutated block design 
683 
stratified by primary cohort (age 12 to <36 months and age 36 to <72 months) and by site which 
684 
will specify the order of treatment group assignments.  All eligible patients enrolled in the study 
685 
will be randomized to one of the following groups:  
686 
1. Observation: glasses not prescribed unless confirmation of one or more deterioration 
687 
criteria 
688 
2. Glasses: glasses prescribed immediately 
689 
 
690 
Patients will be randomized in a 1:1 ratio.  
691 
 
692 
Once a patient is randomized, that subject will be included in the analysis regardless of whether the 
693 
assigned treatment is received or not.  They will also remain in the study and return for the protocol-
694 
specified follow-up visits.  Thus, the investigator must not randomize a patient until he/she is 
695 
convinced that the parent will accept either of the treatment groups.  
696 
 
697 
Parents of children randomized to glasses should be encouraged to fill the glasses prescription as 
698 
soon as possible following randomization but glasses must begin within 30 days of randomization. 
699 

HTS1v3 0 1-30-15 
 
3-1 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
700 
3.1 
Treatment 
701 
3.1.1 Observation Group 
702 
Subjects randomized to the observation group will receive no glasses to correct the child’s 
703 
refractive error or any other treatment unless one or more deterioration criteria are confirmed.   
704 
 
705 
If a subject meets deterioration criteria (section 3.3.3) at any visit, the subject will then be released 
706 
to best clinical care, which is defined as care at the investigator’s discretion, but must include 
707 
prescribing glasses according to guidelines suggested in section 3.4.  The subject will return for all 
708 
study-specified follow-up visits, including masked examination at the 36-month primary outcome 
709 
exam. 
710 
 
711 
If a subject does not meet deterioration criteria, the subject will continue to be observed without 
712 
glasses or any other treatment for amblyopia and ocular alignment, and will return for all study-
713 
specified follow-up visits. 
714 
 
715 
3.1.2 Glasses Group 
716 
Subjects randomized to the glasses group will receive partial plus glasses, i.e., with sphere cut 
717 
symmetrically by 1.00D (from a cycloplegic refraction within 2 months prior to enrollment) and full 
718 
cylinder correction (magnitude and axis).  Unmasked personnel at the site (e.g. site investigator or 
719 
coordinator) will directly contact the parents of each participant who is assigned to glasses 
720 
treatment within the first 2 weeks of the study to inquire about any issues with obtaining glasses and 
721 
to encourage treatment compliance. 
722 
 
723 
If the investigator feels that the subject is not compliant with wearing his/her glasses and/or needs 
724 
assistance relaxing his/her accommodation to adapt to the glasses, the investigator is encouraged to 
725 
prescribe a short course of bilateral cycloplegia.  If bilateral cycloplegia is prescribed, it must be 
726 
stopped at least two weeks prior to any study visit.   
727 
 
728 
If a subject meets deterioration criteria (section 3.3.3) at any visit, the subject will then be released 
729 
to best clinical care, which is defined as care at the investigator’s discretion, but must include 
730 
continued use of glasses according to guidelines suggested in section 3.4.  The subject will return 
731 
for all study-specified follow-up visits, including masked examination at the 36-month primary 
732 
outcome exam.  
733 
 
734 
If a subject does not meet deterioration criteria, the subject will continue treatment with glasses only 
735 
(any other treatment for amblyopia or ocular alignment is prohibited) and return for all study-
736 
specified follow up visits. 
737 
 
738 
Subjects in the glasses group will continue to wear glasses throughout the study unless the glasses 
739 
correction decreases to +1.00D spherical equivalent (SE) or less (then glasses may be discontinued 
740 
at investigator’s discretion). 
741 
3.2 
Follow-up Visit Schedule 
742 
The follow-up schedule is timed from randomization as follows: 
743 
 
6-month: 6 months  1 month 
744 
 
12-month: 12 months ± 1 month 
745 
 
18-month: 18 months ± 1 month 
746 
 
24-month: 24 months ± 1 month 
747 

HTS1v3 0 1-30-15 
 
3-2 
 
30-month: 30 months ± 1 month 
748 
 
36-month: 36 months ± 1 month (masked primary outcome examination) 
749 
o Repeat 36-month outcome exam 4 weeks  1 week for subjects meeting failure 
750 
criteria (section 5.2) and requiring change in glasses (section 4.3). 
751 
 
752 
If unmasked testing at any visit before 36 months shows suspected deterioration related to 
753 
strabismus, distance visual acuity, stereoacuity, or parental concern (section 3.3.3), and the subject 
754 
has not had deterioration confirmed at a previous visit, a separate masked exam (section 3.3.2) must 
755 
be completed within 2 weeks if it cannot be completed on the same day as the unmasked testing.   
756 
 
757 
Additional non-specified visits can be performed at the discretion of the investigator; however, the 
758 
decision to schedule non-specified visits may not be based on group assignment (e.g., additional 
759 
non-specified visits cannot be routinely scheduled for subjects in the observation group but not the 
760 
glasses group). 
761 
 
762 
 
763 
3.3 
Follow-up Visits at 6, 12, 18, 24, and 30 months 
764 
Subjects will be seen every 6 months  1 month as outlined in section 3.2.   
765 
3.3.1 Unmasked Exam  
766 
Each protocol-specified visit between 6 and 30 months will have an unmasked exam.   
767 
 
768 
Prior to performing any testing, unmasked personnel will verify the current glasses prescription using a 
769 
lensometer.   
770 
 
771 
The testing procedures below should be performed as follows:  
772 
 If deterioration has not been confirmed by masked exam at a previous visit, subjects should 
773 
be tested in randomized correction. 
774 
o Subjects in the observation group will be tested with no refractive correction.  
775 
o Subjects in the glasses group will be tested in appropriate hyperopic correction.  The 
776 
subject’s current glasses may be worn for testing provided lensometry completed prior to 
777 
testing verifies that the plus cut symmetrically by +1.00D based on most recent 
778 
cycloplegic refraction, otherwise, trial frames should be used.   
779 
 If deterioration has been confirmed by masked exam at a previous visit: 
780 
o Subjects will be tested in their current refractive correction.  
781 
Note: for subjects wearing bifocals, only the appropriate distance correction will be placed in the 
782 
trial frame.   
783 
 
784 
The following procedures should be performed by an unmasked examiner in the following order at 
785 
each visit: 
786 
1. Stereoacuity Testing (subjects >=36 months only):  
787 
 Stereoacuity will be tested using the Randot Preschool Stereoacuity test at near (1/3 
788 
meter). 
789 
 
790 
2. Ocular Alignment Testing:   
791 
 Ocular alignment will be assessed using cover/uncover, SPCT (if tropia is present and of 
792 
sufficient duration to measure), and PACT, both in primary gaze at distance (3 meters) 
793 
and at near (1/3 meter). 
794 
 
795 

HTS1v3 0 1-30-15 
 
3-3 
3. Distance Visual Acuity Testing (subjects >= 36 months only):   
796 
 Monocular visual acuity testing at all follow-up exams will be done without cycloplegia 
797 
using the ATS single-surround HOTV letter protocol on study-certified visual acuity 
798 
system.   
799 
 
800 
4. Cycloplegic Refraction (see section 2.4): 
801 
 A mandatory cycloplegic refraction will be performed at the 30-month follow-up visit, 
802 
even if cycloplegia has been performed within the past 12 months.   
803 
 A cycloplegic refraction will be performed at all other follow-up exams if not 
804 
performed within the last 12 months.  If a new deterioration criterion is confirmed, 
805 
cycloplegic refraction must be performed if one has not been done within the past 6 
806 
months. 
807 
 If a cycloplegic refraction is performed, it will be performed only after all clinical 
808 
testing listed (including any retests if deterioration criteria are met (section 3.3.3)) is 
809 
completed. 
810 
 
811 
5. Other Testing/Data Collection: 
812 
 Dynamic retinoscopy (optional) at near is performed as outlined in the Hyperopia 
813 
Testing Procedures Manual.  This must be done without cycloplegia. 
814 
 At each visit, data will be collected on glasses wear compliance based on interviews with 
815 
the parent and child. 
816 
 At each visit, parents will be asked if they have concerns about their child’s vision, 
817 
asking, “Do you have concerns with your child’s vision or ability to see well close up?” 
818 
 History of diagnosis of ADHD and the use of medications associated with the disorder 
819 
will be elicited and recorded at each follow-up visit. 
820 
 History of use of bilateral cycloplegia in children assigned to glasses will be elicited and 
821 
recorded at each follow-up visit.  
822 
 
823 
If unmasked testing shows suspected deterioration related to strabismus, distance visual acuity, 
824 
stereoacuity, or parental concern (section 3.3.3), and the subject has not had deterioration confirmed 
825 
at a previous visit, a masked exam (section 3.3.2) must be completed either the same day or within 2 
826 
weeks.   If a child >=36 months of age shows no deterioration related to strabismus but is unable to 
827 
perform distance visual acuity and/or stereoacuity testing, the investigator may, at their discretion, 
828 
attempt to repeat testing on the same day or continue in follow-up until the next protocol specified 
829 
follow-up visit.       
830 
3.3.2 Masked Exams for Subjects with Newly Suspected Deterioration 
831 
A masked exam is required if unmasked testing shows suspected deterioration related to strabismus, 
832 
distance visual acuity, stereoacuity, or parent concern (section 3.3.3), and the subject has not 
833 
already had deterioration confirmed at a previous visit.  The masked exam should be completed 
834 
either the same day as the unmasked testing (after a 10-minute break) or within 2 weeks.  
835 
 
836 
Because the masked examiner must be masked to the subject’s treatment group, he/she must be 
837 
someone other than the treating investigator. 
838 
 
839 
The only procedure(s) to be tested by the masked examiner are those which relate to the visual 
840 
condition with suspected deterioration (section 3.3.3).  If parental concern is expressed that would 
841 
warrant starting treatment in the absence of suspected deterioration by unmasked examination; 
842 
ocular alignment, distance visual acuity (if >36 months old), and stereoacuity (if >36 months old) 
843 
must be assessed by the masked examiner.  
844 

HTS1v3 0 1-30-15 
 
3-4 
 
845 
Unmasked personnel will specify on the masked exam worksheet what assessment(s) the masked 
846 
examiner needs to test.  
847 
 
848 
All required procedures will be performed twice to facilitate masking, first with appropriate 
849 
hyperopic correction in trial frames and second without correction.  Appropriate hyperopic 
850 
correction is defined as follows:  
851 
o Refractive correction in which the plus is cut symmetrically by +1.00D based on most recent 
852 
cycloplegic refraction.   
853 
 
854 
For each assessment, the testing with correction and testing without correction should be completed 
855 
before proceeding to the next assessment. 
856 
 
857 
The trial frame lenses must be placed in the trial frame by someone other than the masked examiner 
858 
and the trial frame must be placed on the subject before the masked examiner enters the room.  Prior 
859 
to the masked examiner entering the room, subjects and parents should be instructed not to discuss 
860 
their treatment with the masked examiner. 
861 
 
862 
The unmasked investigator will review the findings from the masked testing to determine if one or 
863 
more deterioration criteria were confirmed.  Deterioration is confirmed if one or more deterioration 
864 
criteria below (section 3.3.3) are met.   
865 
 
866 
3.3.3 Deterioration Criteria 
867 
A subject’s condition will be considered to have deteriorated if any of the following criteria are met 
868 
during testing while wearing their randomized correction* at any protocol-specified or unspecified 
869 
visit after randomization, based on unmasked testing (3.3.1) and confirmed by a retest performed by 
870 
a masked examiner (section 3.3.2).  
871 
 
872 
1. Strabismus -any measurable heterotropia detected by a cover/uncover test in primary gaze at 
873 
distance (3 meters) or at near (1/3 meter)  in the randomized correction 
874 
2. Distance visual acuity meeting any of the following criteria: 
875 
 Distance visual acuity below age normal values in either eye (see Table 1) 
876 
 ≥2 logMAR lines of IOD if visual acuity is 20/25 or worse in the better eye  
877 
 >3 logMAR lines of IOD if visual acuity is 20/20 or better in the better eye  
878 
3. Stereoacuity in randomized correction at near by the Randot Preschool stereotest below age 
879 
normal values (see Table 2). 
880 
4. Investigator determines that the parent has significant concern about the child’s eyes that 
881 
would warrant starting treatment in the absence of meeting formal deterioration criteria 
882 
(after discussing any concerns raised with the parent).  In the case of parental concern, the 
883 
patient will be classified as deteriorated if the parental concern persists and non-protocol 
884 
treatment is begun regardless of the results of the masked examination.  
885 
 
886 
*Randomized correction is defined as follows:  
887 
o No refractive correction for subjects in the observation group. 
888 
o Appropriate hyperopic correction for subjects in the glasses group.  Appropriate hyperopic 
889 
correction is that in which the plus is cut symmetrically by +1.00D based on most recent 
890 
cycloplegic refraction.   
891 
 
892 

HTS1v3 0 1-30-15 
 
3-5 
For analysis, subjects will also be classified as deteriorated if for any reason non-protocol treatment 
893 
is prescribed AND received without first meeting one of the deterioration criteria above. Non-
894 
protocol treatment includes any treatment for refractive error, amblyopia, and/or ocular alignment 
895 
other than refractive correction in the glasses group or any treatment in the observation group.    
896 
Increasing plus (including prescribing full plus) for subjects in the glasses group is not considered 
897 
non-protocol treatment and will not be considered deterioration.   
898 
 
899 
Table 1: Normal Visual Acuity Values Based on Age (ATS-HOTV) 
900 
Age range 
Subnormal if worse than 
36-47 months 
20/50 
48-59 months 
20/40 
60-83 months 
20/32 
>84 months 
20/25 
Normal values for children aged 30-72 months based on a study by Pan et al.14 Normal 
901 
values for children aged >72 months based on a study by Drover et al.15 
902 
 
903 
Table 2: Normal Randot Preschool Stereoacuity Values at Near Based on Age 
904 
Age range 
Subnormal if worse than (arcsec) 
3 years 
400” 
4 years 
200” 
5 years 
200” 
6 years 
100” 
7 years 
60” 
8+ years 
60” 
Normal values based on Birch et al.16 
905 
 
906 
3.3.4 Pre-Approved Unmasked Sites 
907 
Prior to the start of the study, the Hyperopia Treatment Study Steering Committee will determine 
908 
sites that will be authorized to perform non-masked exams at 6, 12, 18, 24, and 30 month visits.  
909 
Unlike at the masked sites, confirmatory retesting for suspected deterioration at these visits will be 
910 
performed by an examiner unmasked to treatment group.  The 36-month outcome exam will 
911 
continue to be masked for all subjects at all sites (see section 3.6).  
912 
 
913 
 
914 
 
915 
 
916 
 
917 
3.4 
Post-Deterioration Glasses Treatment 
918 
All subjects with confirmation of one or more deterioration criteria (section 3.3.3) prior to the 36-
919 
month outcome visit will be provided refractive correction and continue to return for additional 
920 
follow-up at the study-specified 6-month intervals.  All subjects with confirmation of one or more 
921 
deterioration criteria must be treated with glasses; correction with contact lenses is not allowed.  
922 
The amount of sphere and cylinder to prescribe is at investigator discretion, but should follow the 
923 
guidelines suggested in Table 4.  Additional treatment and management is at investigator discretion 
924 
and may include (but is not limited to): lenses, prism, surgery, amblyopia treatment, bifocals, and 
925 
vergence/accommodative therapy.  The prescription of prisms and bifocals is at investigator 
926 
discretion.   
927 
 
928 

HTS1v3 0 1-30-15 
 
3-6 
Table 4: Guidelines for Post-Deterioration Glasses Prescription  
929 
Hypermetropia should not be undercorrected by more than +1.00D 
spherical equivalent 
Reduction in plus sphere should be symmetric in the two eyes 
Cylinder power in both eyes should be within 0.50D of fully correcting the 
astigmatism 
Cylinder axis in the spectacle lenses in both eyes should be within 6 degrees 
of the axis of the cycloplegic refraction when cylinder power is >1.00D 
If a patient develops an ET, he or she should be given a trial of full plus 
 
930 
If the calculated glasses correction is +1.00D SE or less, prescribing glasses is at the investigator’s 
931 
discretion. 
932 
 
933 
If the investigator feels that the subject is not compliant with wearing his/her glasses and needs 
934 
assistance relaxing his/her accommodation, the investigator is encouraged to prescribe bilateral 
935 
cycloplegia.  If bilateral cycloplegia is prescribed, it must be stopped at least two weeks prior to the 
936 
36-month primary outcome exam.   
937 
 
938 
3.5 
30-Month Follow-up Visit 
939 
Subjects will be seen 30 months  1 month from enrollment.  The exam will follow all procedures 
940 
as outlined in section 3.3.  Each participant will receive a mandatory cycloplegic refraction (section 
941 
2.4), even if a cycloplegic refraction has been performed within the prior 12 months, and glasses 
942 
will be updated if refractive error meets the criteria outlined in section 4.3. 
943 
 
944 
3.6 
36-Month Primary Outcome Exam  
945 
Subjects will be seen 36 months  1 month from enrollment.   Subjects will be seen first by a 
946 
masked examiner who will complete outcome-related testing including any required retests (section 
947 
3.6.1), then will have unmasked testing performed (section 3.6.2).  
948 
3.6.1 Masked Exam 
949 
All required procedures will be performed twice to facilitate masking, first with appropriate 
950 
hyperopic correction in trial frames and second without correction.  The appropriate hyperopic 
951 
correction for testing in trial frames at the 36-month primary outcome exam is based on the most 
952 
recent cycloplegic refraction and most recent glasses-correction (if any) defined as follows:  
953 
 
954 
 If deterioration has been confirmed by masked exam at a previous visit, and refractive 
955 
correction with full plus was prescribed as glasses at the most recent visit, the subject 
956 
should be tested in trial frames with full sphere and cylinder correction (magnitude and axis) 
957 
from the most recent cycloplegic refraction 
958 
o Full plus prescribed at the most recent visit is defined as prescribed sphere within 
959 
0.25D of the cycloplegic refraction 
960 
 Otherwise, the subject should be tested in trial frames with partial plus (sphere cut 
961 
symmetrically by 1.00D, with full cylinder correction magnitude and axis) from the most 
962 
recent cycloplegic refraction 
963 
 
964 
For subjects wearing bifocals at the time of the masked outcome exam, only the appropriate 
965 
distance correction will be placed in the trial frame.  All trial frame lenses must be placed in the trial 
966 

HTS1v3 0 1-30-15 
 
3-7 
frame by someone other than the masked examiner and the trial frame should be placed on the 
967 
subject before the masked examiner enters the room.   
968 
 
969 
The following procedures will be performed in the specified order at the 36-month masked outcome 
970 
exam according to the procedures as outlined in section 3.3. 
971 
 
972 
1. Stereoacuity Testing: (masked) 
973 
 Stereoacuity will be tested at near (1/3 meter) with distance correction placed in a trial frame 
974 
and then without correction using the Randot Preschool Stereoacuity test. 
975 
 
976 
2. Ocular Alignment Testing: (masked)  
977 
 Ocular alignment will be assessed using cover/uncover, SPCT (if a tropia is present and of 
978 
sufficient duration to measure), and PACT, both in primary gaze at distance (3 meters) and 
979 
at near (1/3 meter), with distance correction placed in a trial frame and then without 
980 
correction. 
981 
 If a subject has a measureable heterotropia at near in his/her distance correction, +3.00D 
982 
lenses OD/OS will be added to the trial frames and the subject’s ocular alignment at near 
983 
will be retested. 
984 
 
985 
3. Distance Visual Acuity: (masked) by ATS-HOTV: Monocular visual acuity testing at the 36-
986 
month outcome exam will be done without cycloplegia by a certified examiner using the ATS 
987 
single-surround HOTV letter protocol on a study-certified visual acuity system.  Distance 
988 
visual acuity will be measured both with correction placed in a trial frame and without 
989 
correction. 
990 
 
991 
For each assessment, the testing with correction and testing without correction should be completed 
992 
before proceeding to the next assessment. 
993 
 
994 
If a subject meets any failure criteria (section 5.2.1) with the exception of strabismus surgery prior 
995 
to the 36-month outcome exam, the visual condition that is considered to be failed must be retested 
996 
by the masked examiner after a 10 minute break.   
997 
 If suspected failure relates to strabismus, ocular alignment will be assessed using the 
998 
cover/uncover test in primary gaze at distance (3 meters) and/or at near (1/3 meter). 
999 
 If suspected failure relates to distance visual acuity, monocular visual acuity testing at will 
1000 
be tested without cycloplegia using the ATS single-surround HOTV letter protocol on study-
1001 
certified visual acuity system.   
1002 
 If suspected failure relates to stereoacuity, stereoacuity will be tested using the Randot 
1003 
Preschool Stereoacuity test at near (1/3 meter). 
1004 
 
1005 
 
1006 
3.6.2 Unmasked Exam  
1007 
Following the masked exam, the following procedures will be assessed by an unmasked examiner in 
1008 
the same correction used for masked testing as described in 3.6.1:  
1009 
 
1010 
1. Binocular Near Visual Acuity Testing :  
1011 
 Binocular near visual acuity will be performed as described in the Hyperopia Testing 
1012 
Procedures Manual.   
1013 
 
1014 
2. Other Testing/Data Collection: 
1015 

HTS1v3 0 1-30-15 
 
3-8 
 Undilated dynamic retinoscopy (optional) at near will be performed as outlined in the 
1016 
Hyperopia Testing Procedures Manual.   
1017 
 Data will be collected on glasses wear compliance based on interviews with the parent and 
1018 
child 
1019 
 History of diagnosis of ADHD and the current use of medications associated with the 
1020 
disorder will be elicited and recorded. 
1021 
 
1022 
3. Cycloplegic Refraction: 
1023 
 A cycloplegic refraction (Section 2.4) will be performed only after all clinical testing listed 
1024 
(including any retests if one or more failure criteria are met (section 5.2)) is completed. 
1025 
 If the subject meets any failure criteria* with the exception of strabismus surgery prior to the 
1026 
36-month outcome exam AND the cycloplegic refraction is significantly different from the 
1027 
cycloplegic refraction used to determine the correction used for testing (section 4.3), a new 
1028 
refractive correction should be prescribed according to the guidelines in Section 3.4, Table 
1029 
4.  The subject will return 4 weeks  1 week later and all tests performed at the 36-month 
1030 
outcome exam will be repeated with the child wearing their new glasses (testing without 
1031 
correction to facilitate masking does NOT need to be repeated).      
1032 
o * Failure criteria met for strabismus, visual acuity, or stereoacuity as defined in 5.2.1 
1033 
BOTH with and without trial frames for that criterion 
1034 
 
1035 
3.7 
Examiner Qualifications  
1036 
Examiner qualifications are as follows:  
1037 
 Ocular alignment must be assessed by a study-certified pediatric ophthalmologist, pediatric 
1038 
optometrist, or certified orthoptist.  
1039 
 Visual acuity and stereoacuity testing can be performed by any examiner who is PEDIG 
1040 
certified to perform the specific assessment.  
1041 
 
1042 
Unmasked testing can be performed by the investigator or by any other examiner who meets the 
1043 
above criteria.  Because the masked examiner must be masked to the subject’s treatment group, 
1044 
he/she must be someone other than the treating investigator, who is masked to treatment group and 
1045 
meets the criteria above. 
1046 
 
1047 
3.8 
Non-Study Visits and Treatment 
1048 
Investigators may schedule additional visits at their own discretion.  Subjects will continue to 
1049 
follow the study-specified follow-up schedule regardless of any non-study visits.  
1050 
 
1051 
Investigators must not start any additional treatment (other than that outlined in section 3.1) prior to 
1052 
the 36-month outcome visit unless one or more deterioration criteria (section 3.3.3) have been met 
1053 
and confirmed by the masked examiner. 
1054 
 
1055 
 
1056 

HTS1v3 0 1-30-15 
 
4-1 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1057 
 
1058 
4.1 
Contacts by the Jaeb Center for Health Research 
1059 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided with 
1060 
the parent’s contact information.  The Jaeb Center will contact the parents of the participants only 
1061 
when necessary.  Permission for such contacts will be included in the Informed Consent Form.  The 
1062 
principal purpose of the contacts will be to develop and maintain rapport with the participant and/or 
1063 
family and to help coordinate scheduling of the outcome examinations.   
1064 
 
1065 
The site investigator or coordinator will directly contact the parents of each participant who is 
1066 
assigned to glasses treatment within the first 2 weeks of the study to inquire about any issues with 
1067 
obtaining glasses and to encourage treatment compliance. 
1068 
 
1069 
4.2 
Patient Withdrawals 
1070 
Parents may withdraw their child from the study at any time.  This is expected to be a very 
1071 
infrequent occurrence in view of the study design’s similarity to routine clinical practice.  If the 
1072 
parents indicate that they want to withdraw their child from the study, the investigator personally 
1073 
should attempt to speak with them to determine the reason.  If their interest is in transferring the 
1074 
child’s care to another eye care provider, every effort should be made to comply with this and at the 
1075 
same time try to keep the participant in the study under the new provider’s care. 
1076 
 
1077 
4.3 
Management of Refractive Error 
1078 
A cycloplegic refraction should be performed every 12 months during follow-up, unless the subject 
1079 
has confirmation of one or more deterioration criteria (section 3.3.3), in which case a cycloplegic 
1080 
refraction must be performed if not done within the previous 6 months.  A mandatory cycloplegic 
1081 
refraction must also be completed at the 30-month and 36-month exams.  In addition, a cycloplegic 
1082 
refraction should be performed whenever the investigator suspects that refractive error may not be 
1083 
corrected according to study guidelines (see below). 
1084 
 
1085 
If cycloplegic refraction reveals a change in refractive error of >0.75 D sphere or >0.75D cylinder 
1086 
or > 0.75D in SE anisometropia or axis change of 6 degrees or more when cylinder is 1.00D or 
1087 
more from the previous cycloplegic refraction, the glasses must be updated.  Whether to update the 
1088 
correction for smaller changes in refraction is at investigator discretion.  If updated, the glasses 
1089 
correction must meet the requirements described in sections 3.1.2 and 3.4. 
1090 
 
1091 
If the glasses correction drops to +1.00D SE or lower, the use of glasses is at the investigator’s 
1092 
discretion.   
1093 
 
1094 
4.3.1 Bifocals 
1095 
Bifocal treatment is allowed only following confirmation of deterioration criteria (section 3.3.3).  
1096 
Subjects will be tested in their distance correction placed in a trial frame at the 36-month outcome 
1097 
exam. 
1098 
 
1099 
4.4 
Management of Strabismus  
1100 
Strabismus surgery is not allowed prior to the 36-month outcome exam unless one or more 
1101 
deterioration criteria are confirmed.  Subjects who undergo strabismus surgery will return for 
1102 

HTS1v3 0 1-30-15 
 
4-2 
follow-up at the protocol-specific follow-up visits.  Subjects who receive strabismus surgery prior 
1103 
to the 36-month outcome exam will be considered a failure for analysis purposes (see section 5.2.1). 
1104 
 
1105 
4.5 
Management of Amblyopia 
1106 
Amblyopia treatment is not allowed prior to the 36-month outcome exam unless one or more 
1107 
deterioration criteria are confirmed.  For subjects for whom amblyopia treatment is permitted, 
1108 
treatment is at investigator discretion, but must start with prescribing refractive correction 
1109 
(described in section 3.4).  Method used for amblyopia treatment is at investigator discretion. If 
1110 
atropine is being used, it must be discontinued at least 2 weeks before the 36-month visit.   
1111 
 
1112 
Subjects receiving amblyopia treatment prior to the 36-month outcome exam will be considered a 
1113 
deterioration for analysis (regardless of whether a formal deterioration criterion had first been met) 
1114 
but will not be considered a failure for analysis purposes unless the amblyopia is present at the time 
1115 
of the 36-month outcome exam. 
1116 
 
1117 
4.6 
Risks 
1118 
There are no risks involved in this study that would not be part of usual care.   
1119 
 
1120 
4.6.1 Risks of Examination Procedures 
1121 
The procedures in this study are part of daily eye care practice in the United States and pose no 
1122 
known risks.  As part of a routine usual-care exam, the participant will receive cycloplegic/dilating 
1123 
eye drops. 
1124 
 
1125 
4.7 
Reporting of Adverse Events 
1126 
No surgical procedures are part of the protocol and no treatments are being prescribed that are not 
1127 
part of usual care.  Investigators will abide by local IRB reporting requirements. 
1128 
 
1129 
4.8 
Discontinuation of Study 
1130 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
1131 
Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 
1132 
participants. 
1133 
 
1134 
4.9 
Travel Reimbursement 
1135 
Parents of each participant will be compensated $40 (by check or by merchandise or money-card)   
1136 
per visit for completion of each protocol-specified follow-up visit.  If there are extenuating 
1137 
circumstances, and the participant is unable to complete study visits without additional funds due to 
1138 
travel costs, additional funds may be provided. 
1139 
 
1140 
4.10 
Study Costs  
1141 
The participant or his/her insurance will be responsible for the costs that are considered standard 
1142 
care.   
1143 
 
1144 
Standard care visits (paid for by participant or his/her insurance) include: 
1145 
 Initial examination 
1146 
 12-month follow-up visit 
1147 

HTS1v3 0 1-30-15 
 
4-3 
 24-month follow-up visit 
1148 
 36-month follow-up visit 
1149 
 
1150 
Non-standard of care visits (paid for by the study) include: 
1151 
 6-month follow-up visit 
1152 
 18-month follow-up visit 
1153 
 30-month follow-up visit 
1154 
 Return for masked exam within 2 weeks after the 6, 12, 18, 24, or 30 month visits or within 
1155 
4 weeks of 36-month exam  
1156 
 
1157 
All glasses and any changes to glasses that are mandated by the study protocol during the course of 
1158 
the study and are required for further testing will be paid for by the study.  A change in glasses 
1159 
prescribed at the 36-month exam when the subject will not be seen back for study purposes will not 
1160 
be paid for by the study.  Additional treatment offered at the investigator’s discretion during the 
1161 
study will not be paid for by the study. 
1162 
 
1163 
 
1164 
 
1165 

HTS1v3 0 1-30-15 
 
5-1 
CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL 
1166 
ANALYSIS 
1167 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1168 
analysis plan will be written and finalized prior to the completion of the study.  The analysis plan 
1169 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1170 
 
1171 
5.1 
Definitions of Primary Cohorts 
1172 
All analyses will be performed separately for each of the two primary cohorts: 
1173 
 Subjects aged 12 to <36 months  
1174 
 Subjects aged 36 to <72 months  
1175 
 
1176 
5.2 
Primary Data Analysis 
1177 
The primary analysis will be a treatment group comparison of the proportion with confirmation of 
1178 
one or more failure criteria (below) at 36 months post-randomization.   
1179 
 
1180 
The null hypothesis of no difference between the treatment groups will be rejected if the proportion 
1181 
with confirmation of one or more failure criteria in immediate glasses is significantly (higher or) 
1182 
lower than the proportion in observation, based on the 2-sided Fisher’s exact test with probability of 
1183 
Type I error of 5%. 
1184 
 
1185 
The primary analysis will follow the intent-to-treat principle.  The primary analysis will not include 
1186 
those patients not completing the 36-month visit.  Secondary analyses will be conducted using the 
1187 
last-observation-carried-forward and using multiple imputation with logistic regression for failure 
1188 
status for subjects who fail to complete the 36-month outcome visit.  If these secondary results yield 
1189 
similar results to the primary analysis, they will be used to provide supportive evidence for the 
1190 
primary analysis conclusion.  If results differ, exploratory analyses will be conducted to evaluate the 
1191 
reasons for the difference. 
1192 
 
1193 
5.2.1 Classification of Primary Outcome (Failure Criteria) 
1194 
At the 36-month visit, each subject’s condition will be classified as either failure or not a failure as 
1195 
follows: 
1196 
 
1197 
Failure = ANY of the following criteria are met at the masked 36-month visit both with and without 
1198 
trial frames (without prism or bifocal): 
1199 
1. Any measurable heterotropia in primary gaze in the distance (3 meters) or at near (1/3 
1200 
meter)  not correctable with distance refractive correction alone  
1201 
2. Strabismus surgery prior to the 36-month outcome exam 
1202 
3. Visual acuity below age norms (see Table 1) in either eye  
1203 
4. ≥2 logMAR lines of IOD if visual acuity is 20/25 or worse in the better eye (applies to IOD 
1204 
either with or without correction but not one eye with and one eye without)  
1205 
5. >3 logMAR lines of IOD if visual acuity is 20/20 or better in the better eye (applies to IOD 
1206 
either with or without correction, but not one eye with and one eye without)  
1207 
6. Stereoacuity at near by Randot Preschool test below age normal values (see Table 2) : 
1208 
 
1209 
 
1210 
Not Failure = NONE of the criteria for failure are met 
1211 
 
1212 

HTS1v3 0 1-30-15 
 
5-2 
If a subject meets any failure criteria (with the exception of strabismus surgery prior to the 36-
1213 
month outcome exam), the visual condition that is considered to be failed must be retested by the 
1214 
masked examiner (section 3.6.1) using the same procedures outlined in section 3.6.1.  The subject 
1215 
must be given a 10-minute break prior to retesting each failed criterion.  Failure criterion must be 
1216 
confirmed with and without correction to be considered a failure. 
1217 
 
1218 
If failure is confirmed and the subject requires a change in glasses (section 4.3), the 36-month 
1219 
outcome exam is repeated on a different day 4 weeks ±1 week later by the masked examiner, with 
1220 
the child wearing their new glasses.  Testing without correction does NOT need to be repeated.  
1221 
Failure will be assessed at this post-36 month exam, and the subject will be classified as a failure if 
1222 
he/she meets any of the failure criteria above.  If the subject meets any failure criteria wearing their 
1223 
new glasses, the visual condition that is considered to be failed must be retested by the masked 
1224 
examiner using the same procedures outlined above.  Failure must be confirmed without trial frames 
1225 
at the 36-month exam and with correction at this repeat outcome exam 4-weeks later to be 
1226 
considered a failure. 
1227 
 
1228 
5.3 
Secondary Data Analyses 
1229 
All secondary analyses will be performed separately for each of the two primary cohorts (section 
1230 
5.1). 
1231 
 
1232 
5.3.1 Best Visual Acuity at 36 Months 
1233 
A treatment group comparison of the mean maximum visual acuity per subject at the masked 36-
1234 
month visit (best visual acuity on any test with and without correction) will be performed using a t-
1235 
test. 
1236 
 
1237 
5.3.2 Development of Strabismus 
1238 
A treatment group comparison of the proportion of subjects who develop a measurable heterotropia 
1239 
not correctable with glasses alone at the 36 month masked outcome will be performed using the 
1240 
Fisher’s exact test.  The cumulative proportion of subjects who develop a measureable heterotropia 
1241 
at any time during follow-up will be compared between treatment groups using the log-rank test.   
1242 
 
1243 
5.3.3 Subgroup Analysis 
1244 
Treatment effect in subgroups based on baseline factors will be assessed.  The subgroups of interest 
1245 
include baseline spherical equivalent anisometropia and baseline spherical equivalent refractive 
1246 
error.  Outcome failure status at 36 months post-randomization will be tabulated by subgroup and 
1247 
reviewed for consistency.  The subgroup definitions for the planned subgroup analyses are as 
1248 
follows: 
1249 
 Spherical equivalent anisometropia: ≤+1.00D, >+1.00D 
1250 
 Spherical equivalent refractive error: +3.00D to <+4.00D, +4.00D to <+5.00D, +5.00D to 
1251 
+6.00D 
1252 
 Masking: unmasked sites, masked sites (including those subjects where masking was not 
1253 
completed) 
1254 
 
1255 
5.3.4 Observation Group Deterioration 
1256 
Proportion of subjects in the observation group who deteriorated during the course of the study will 
1257 
be evaluated and a 95% confidence interval for the proportion will be calculated. 
1258 
 
1259 

HTS1v3 0 1-30-15 
 
5-3 
5.3.5 Development of Amblyopia 
1260 
A treatment group comparison of the proportion of subjects who develop amblyopia during the 
1261 
course of the study will be performed using the Fisher’s exact test.  
1262 
 
1263 
5.3.6 Near Visual Acuity 
1264 
A treatment group comparison of the mean near visual acuity at the masked 36-month outcome 
1265 
exam will be performed using a t-test.  
1266 
5.4 
Exploratory Analyses 
1267 
Exploratory analysis will be described fully in the formal analysis plan. 
1268 
 
1269 
5.5 
Sample Size Estimates 
1270 
Sample size has been estimated separately for each of the two primary cohorts.  The study is 
1271 
powered for an appropriate number of patients in each primary cohort.   
1272 
 
1273 
Table 5 provides sample size estimates per treatment group to detect specific differences in the 
1274 
proportion of patients meeting failure criteria at 36 months (section 5.2.1) with 90% power and a 
1275 
two-sided type I error rate of 5% using a Fisher’s exact test.   
1276 
 
1277 
Table 5: Sample Size Estimates Per Group for Various Failure Proportions 
1278 
 
1279 
Failure Proportion: 
Observation 
Failure Proportion: Glasses 
0.05 
0.10 
0.15 
0.20 
0.15 
198 
951 
- 
- 
0.20 
107 
282 
1248 
- 
0.25 
71 
143 
352 
1502 
0.30 
51 
90 
173 
411 
0.35 
40 
63 
105 
197 
0.40 
32 
47 
72 
118 
 
1280 
Subjects aged 12 to <36 months  
1281 
Based upon estimates in the literature, the proportion of infants developing a heterotropia or 
1282 
amblyopia after glasses ranged from 6% to 29%.4, 12, 13  The proportion of infants developing a 
1283 
heterotropia or amblyopia after no glasses ranged from 21 to 68%.4, 12, 13  Unfortunately, there was a 
1284 
lack of standardization of outcomes in these prior studies.  Since failure criteria will be more 
1285 
stringent in this study, and since children will be followed more closely in the current study, we 
1286 
estimate that the failure proportions in the current study will be toward the lower end of these 
1287 
estimates from the literature.  
1288 
 
1289 
Following discussion with clinicians, the anticipated failure proportion is 10% in the glasses group 
1290 
and 25% in the observation group.  Given these failure proportions, a sample size of 143 per 
1291 
treatment group would provide 90% power to detect a difference between the treatment groups, 
1292 
using a 2-sided probability of Type I error of 5%.  Adjusting for 10% loss to follow up, and a 5% 
1293 
adjustment for interim monitoring, the study would need to enroll approximately 336 subjects 12 to 
1294 
<36 months old.  
1295 
 
1296 
Subjects aged 36 to <72 months  
1297 
There is essentially no literature to base sample size estimates for 36 to <72 month olds.  A sample 
1298 
size of 336 subjects 36 to <72 months old was chosen, the same as that for the younger cohort.   
1299 

HTS1v3 0 1-30-15 
 
5-4 
 
1300 
We could speculate that outcome proportions in both treatment groups might be less frequent in the 
1301 
older cohort since children in the younger cohort may have amblyopia or reduced stereoacuity at 
1302 
randomization that is undetected due to inability to test in this age group, or children in the older 
1303 
cohort may have an inherently lower risk of amblyopia, heterotropia, and reduced stereoacuity.  
1304 
Assuming the same anticipated failure proportions as the younger cohort (10% in the glasses group 
1305 
and 25% in the observation group), with the sample size of 143 subjects completing outcome in 
1306 
each treatment group (the same as the younger cohort) the study would have over 90% power to 
1307 
detect a difference between the treatment groups (the study would have 97% power to detect a 
1308 
difference if the true proportions were 5% in the glasses group and 20% in the observation group).    
1309 
 
1310 
As the enrollment goal approaches, sites will be notified of the end date for recruitment.  Subjects 
1311 
who have signed an informed consent form can be randomized up until the end date, which means 
1312 
the expected recruitment might be exceeded.  The maximum number of randomized subjects will be 
1313 
700. 
1314 
 
1315 
Subjects from Unmasked Sites 
1316 
The study will allow up to 20% of subjects in each primary cohort (67 subjects) to be enrolled at 
1317 
unmasked sites.  
1318 
 
1319 
5.6 
Interim Analysis 
1320 
This study will include a separate interim monitoring plan for each primary cohort that incorporates 
1321 
at least one and up to three interim analyses, consisting of a treatment group comparison of 
1322 
proportion meeting failure criteria at 36 months post-randomization.  The monitoring plan will 
1323 
consist of a two-sided boundary for efficacy.17  This will allow for early stopping to be considered 
1324 
in the event that interim data strongly support a treatment effect favoring glasses.  The interim 
1325 
monitoring is unlikely to affect study recruitment since recruitment is likely to end before the 36-
1326 
month outcome is reached; only study follow-up of enrolled subjects will be affected. 
1327 
 
1328 
The DSMC will monitor the cumulative proportion of subjects that deteriorate within treatment 
1329 
group, by masking status.  If the cumulative proportion that deteriorates appears to differ by 
1330 
masking status within treatment group, recruitment may be stopped in unmasked sites. 
1331 
 
1332 
A formal statistical plan for interim monitoring of primary outcome data will be developed in 
1333 
conjunction with the DSMC and incorporated into the statistical analysis plan prior to any analysis 
1334 
of primary or secondary outcome data.  
1335 
 
1336 
 
1337 

HTS1v3 0 1-30-15 
 
6-1 
CHAPTER 6: REFERENCES 
1338 
 
1339 
1. Giordano L, Friedman DS, Repka MX, et al. Prevalence of refractive error among preschool 
1340 
children in an urban population: the Baltimore Pediatric Eye Disease Study. Ophthalmology 
1341 
2009;116:739-746. 
1342 
2. Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of myopia and hyperopia in 6- to 
1343 
72-month-old african american and Hispanic children: the multi-ethnic pediatric eye disease 
1344 
study. Ophthalmology 2010;117:140-147. 
1345 
3. Atkinson J, Braddick O, Robier B, et al. Two infant vision screening programmes: prediction 
1346 
and prevention of strabismus and amblyopia from photo- and videorefractive screening. Eye 
1347 
1996;10:189-198. 
1348 
4. Ingram RM, Walker C, Wilson JM, Arnold PE, Dally S. Prediction of amblyopia and squint by 
1349 
means of refraction at age 1 year. British Journal of Ophthalmology 1986;70:12-15. 
1350 
5. American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. Preferred 
1351 
practice pattern guidelines: Amblyopia. San Francisco, CA: American Academy of 
1352 
Ophthalmology; 2007:Available at: http://www.aao.org/ppp. 
1353 
6. Donahue SP, Arnold RW, Ruben JB, Committee AVS. Preschool vision screening: what should 
1354 
we be detecting and how should we report it? Uniform guidelines for reporting results of 
1355 
preschool vision screening studies. Journal of AAPOS: American Association for Pediatric 
1356 
Ophthalmology & Strabismus 2003;7:314-316. 
1357 
7. Lyons SA, Jones LA, Walline JJ, et al. A survey of clinical prescribing philosophies for 
1358 
hyperopia. Optometry and Vision Science 2004;81:233-237. 
1359 
8. Miller JM, Harvey EM. Spectacle prescribing recommendations of AAPOS members. Journal 
1360 
of Pediatric Ophthalmology and Strabismus 1998;35:51-52. 
1361 
9. American Optometric Association. Optometric clinical practice guideline: Care of the patient 
1362 
with hyperopia. St. Louis, MO: American Optometric Association; 1997:Available at: 
1363 
http://www.aoa.org/x4813.xml  
1364 
10. Atkinson J, Anker S, Bobier W, et al. Normal emmetropization in infants with spectacle 
1365 
correction for hyperopia. Investigative Ophthalmology & Visual Science 2000;41:3726-3731. 
1366 
11. Ingram RM, Arnold PE, Dally S, Lucas J. Results of a randomised trial of treating abnormal 
1367 
hypermetropia from the age of 6 months. British Journal of Ophthalmology 1990;74:158-159. 
1368 
12. Atkinson J, Braddick O, Nardini M, Anker S. Infant hyperopia: detection, distribution, changes 
1369 
and correlates-outcomes from the cambridge infant screening programs. Optometry and Vision 
1370 
Science 2007;84:84-96. 
1371 
13. Anker S, Atkinson J, Braddick O, Nardini M, Ehrlich D. Non-cycloplegic refractive screening 
1372 
can identify infants whose visual outcome at 4 years is improved by spectacle correction. 
1373 
Strabismus 2004;12:227-245. 
1374 
14. Pan Y, Tarczy-Hornoch K, Cotter SA, et al. Visual acuity norms in pre-school children: the 
1375 
Multi-Ethnic Pediatric Eye Disease Study. Optometry and Vision Science 2009;86:607-612. 
1376 
15. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual 
1377 
acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester 
1378 
following the Amblyopia Treatment Study protocol. Journal of AAPOS: American Association 
1379 
for Pediatric Ophthalmology & Strabismus 2008;12:145-149. 
1380 
16. Birch E, Williams C, Drover J, et al. Randot Preschool Stereoacuity Test: normative data and 
1381 
validity. Journal of AAPOS: American Association for Pediatric Ophthalmology & Strabismus 
1382 
2008;12:23-26. 
1383 
17. Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Boca 
1384 
Raton, FL: Chapman and Hall/CRC; 2000. 
1385 
 
1386