The Enhancement Via Accommodation (EVA) Study
Phase: NA
Conditions: Hyperopia
Sponsor: Donald O Mutti, OD, PhD

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Study Title: The Emmetropization Via Accommodation (EVA) Study 
NCT Number: NCT03669146 
Document Date:  January 6, 2024 
 

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Emmetropization Via Accommodation (EVA) Study 
I. 
Objective. The objective of this study is to determine if wearing a moderate spectacle 
under-correction (3.00D) and performing activities designed to stimulate accurate accommodation 
during a 15-month period will enhance emmetropization in highly hyperopic (≥+5.00D) 3-month old 
infants. Our hypothesis is that more active and accurate accommodation, promoted with spectacle 
under-correction and accommodative exercises, will increase the rate of axial elongation to reduce 
hyperopia. The prediction is that the eye will modulate axial length by modifying ocular shape, that 
more accurate accommodation will be associated with creating a less oblate, more prolate eye shape 
that accentuates elongation. The results of this study would be clinically relevant almost immediately. 
Results from the proposed study would represent evidence-based guidelines for effective infant 
refractive care. 
 
II. 
Background and Rationale. Most healthy human infants are born hyperopic, or farsighted 
(Mayer, Hansen, Moore, et al., 2001). The average cycloplegic refractive error for infants at birth ranges 
from +1.00D to +2.50D with standard deviations ranging from 1.50D to 2.50D (Cook and Glasscock, 
1951; Luyckx, 1966; Mayer et al., 2001; Santonastaso, 1930; Wood, Hodi and Morgan, 1995; Zonis and 
Miller, 1974). Infants undergo a process called emmetropization in which their normal early hyperopic 
refractive error decreases over time by coordination of the development of optical power and axial 
length of the eye.  
A majority of the emmetropization process occurs within the first 18 months of life, particularly 
between 3 months and 9 months of age, leaving a small window of opportunity for potential 
intervention (Mayer et al., 2001; Mutti, Mitchell, Jones, et al., 2005). At 18 months of age, the mean 
refractive error in infants is +1.10 ± 0.90D (Mutti, Mitchell, Jones, et al., 2009). Once the infant phase of 
the emmetropization process is complete, residual significant levels of hyperopia can persist into 
childhood. If hyperopia is present past the age of emmetropization, it is unlikely the child will have the 
ability to “grow out of” their hyperopia (Jones, Mitchell, Mutti, et al., 2005). Failure to emmetropize 
leaves between 7.5% and 10% of school-aged children with clinically significant hyperopia (> +2.00D) 
(Kleinstein, Jones, Hullett, et al., 2003; Laatikainen and Erkkila, 1980).  
Hyperopic children are more at risk for developing strabismus, specifically esotropia. Studies 
show a dose-dependent relationship between hyperopia and the risk of developing strabismus. Children 
than have a refractive error between +2.00D and +3.00D are 6.4 times more likely to develop an 
esotropia and those with a refractive error greater than +5.00 are 122 times more likely to develop 
esotropia (Cotter, Varma, Tarczy-Hornoch, et al., 2011). Anker et al. found that in children who 
developed esotropia, 18.4% were significantly hyperopic (+4.00D) and only 0.5% were emmetropic 
(Anker, Atkinson, Braddick, et al., 2004). Strabismus is a risk factor for the development of amblyopia, a 
decrease in visual acuity that creates impaired depth perception. Just as hyperopia shows a 
dose-response relationship with the development of strabismus, it shows a similar relationship with the 
development of amblyopia (Pascual, Huang, Maguire, et al., 2014).  
Uncorrected hyperopia may compromise visual comfort or visual acuity which could impede 
learning. Quaid and Simpson assessed school-aged children, some of which were on an Individualized 
Education Program (IEP) and others who were not. They found that children on IEPs had significantly 
greater amounts of hyperopia than children who were not on IEPs. All of the hyperopic children had 
poorer scores on the Convergence Insufficiency Symptom Survey, which was used off-label to determine 
what asthenopic complaints the children had. The hyperopic children also had a slower reading speed 
than non-hyperopic children (Quaid and Simpson, 2013). One group of researchers found a link between 
uncorrected hyperopia and academic standardized testing. Children in first through fifth grade who had 

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a refractive error of +1.25D or more scored significantly lower on achievement test scores (Rosner and 
Rosner, 1997). A recent study assessed the early literacy in 4 and 5 year old uncorrected hyperopes and 
emmetropes in preschool and found that children with uncorrected hyperopia of +4.00D or greater, and 
children with +3.00D - +6.00D who had reduced near stereoacuity or binocular near acuity scored worse 
on the Test of Preschool Early Literacy compared to their emmetropic peers (VIP-HIP Study Group, Kulp, 
Ciner, et al., 2016). The association between uncorrected hyperopia and early literacy is important and 
alarming. One in six children who are not reading proficiently in third grade do not graduate from high 
school on time, a rate 4 times greater than for those who are proficient readers (Hernandez, 2012).  
There is a lot of clinical uncertainty about managing hyperopia in infants. Human studies suggest 
that correction of hyperopia will improve acuity and relieve the burden on accommodation. Animal 
studies suggest that early correction of hyperopia may impede the normal emmetropization process 
that reduces hyperopic refractive error during maturation (Hung, Crawford and Smith, 1995). Clinicians 
and researchers are often concerned that early correction of hyperopia may interfere with 
emmetropization’s natural process in humans. Human infant studies show conflicting results. One study 
found that early correction did not interfere with the emmetropization process while another did 
(Atkinson, Anker, Bobier, et al., 2000; Ingram, Gill and Lambert, 2000). 
The proposed protocol for this study differs from other early 
intervention studies. The current proposal will provide a greater 
amount of under-correction and will occur at a younger age. Results 
from a longitudinal study performed by the primary investigator of 
this study suggest that 1.00D of under-correction in a three-month old 
infant would result in a very small change between 3 and 9 months of 
age (Figure 1) (Mutti et al., 2005). Previous studies have used only 
1.00 to 2.00D of under-correction in early intervention (Atkinson et al., 
2000; Ingram et al., 2000). Based on the information provided in 
Figure 1, the range of effective emmetropization occurs between 
+1.00D and +4.00D of hyperopia. More aggressive under-correction 
(greater than 1.00D to 2.00D) would be needed in higher hyperopes to 
ensure that they reach the range of effective emmetropizaion between 
+1.00D and +4.00D. The effective range of emmetropization is 
addressed in more detail in Figure 2. If the emmetropization endpoint 
is defined as reaching a refractive error of ≤+2.00D by 18 months of age, then 80% or more of early 
refractive errors of +4.00D or less at 3 months of age will resolve by 18 months of age using no 
intervention. For early refractive error between +5.00D to +7.00D, which is what is proposed in this 
study, the percentage that reach the emmetropization endpoint of ≤+2.00D drops to between 50% and 
as low as 20%. The range of refractive errors outside of +5.00D 
and +7.00D appears to be outside of the effective range of 
emmetropization.  
Previous studies initiated early correction treatment in 
the latter half of of the first year of life (Atkinson et al., 2000; 
Ingram et al., 2000). The majority of the emmetropization 
process occurs before 9 months of age (Mutti et al., 2005). As 
children get older, hyperopia becomes less effective in 
promoting refractive changes. Hyperopic infants between 3 and 
9 months of age show a decrease of hyperopia by an average of 
0.81D while infants between 9 and 18 months show a decrease 
of only 0.23D (Mutti et al., 2009). Perhaps previous studies did 
not find a treatment effect because they initiated treatment too 
y = 0.028x3 – 0.18x2
– 0.20x + 0.17
-4.0
-3.0
-2.0
-1.0
0.0
1.0
2.0
-2.0
0.0
2.0
4.0
6.0
8.0
Change in Refractive Error (D)
Refractive Error at 3 Months (D)
R2 = 0.41
P<0.0001
Figure 2. The change in cycloplegic spherical
equivalent refractive error 
between 3 and 9
months as a function of refractive error at 3
months.
y = 0.028x3 – 0.18x2
– 0.20x + 0.17
Figure 1. The change in hyperopia 
between 3 and 9 months as a function of 
hyperopia at 3 months. 
0.0
0.1
0.2
0.3
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0.5
0.6
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0.8
0.9
1.0
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2.5
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4.5
5
5.5
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7
SEQ at 3 months (cycloplegic)
 Prob(emmetropization)
Refractive Error at 3 Months (D)
Probability of Emmetropization
2.0
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Figure 2. The probability of emme-
tropization at 18 months (≤+2.00D) as a 
function of refractive error at 3 months. 

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late. An animal study shows that refractive compensation occurred with moderate spectacle under-
correction at the human equivalent of 2.5 months of age, which provides support for the rationale 
behind this early intervention study (Smith and Hung, 1999).  
The foundation of this proposed project has been investigated in the past by the PI of this study, 
Dr. Don Mutti. The study found that partial spectacle correction and accommodation training to improve 
accommodative response is a promising treament in reducing high amounts of farsightedness which is 
illustrated in the graphs below: 
 
 In the figures, refractive error and eye focusing (accommodation) data from 4 subjects are 
plotted against age and time respectively. Subjects 003, 005, and 007 were given partial correction and 
accommodative training at 3 months of age. In Figure 3a, each of those subject’s farsightedness 
decreased over time at a faster rate than untreated subject 006 those in the Berkeley Infant Biometry 
Study (BIBS) study. Figure 3b shows that subjects who appeared to have the greatest decrease in the 
amount of hyperopia tended to have better eye focusing ability, which is one of the proposed 
mechanisms of emmetropization and something we will measure longitudinally throughout the study. 
 
III. 
Procedures 
A. Research Design. This study will be a hybrid of a prospective, randomized, clinical trial for 
infants with farsightedness that is ≥ +5.00D to ≤ +7.00D and a case series for infants with 
farsightedness that is > +7.00D. The study will take place over 18 months.   
B. Sample. Subjects for this study will be recruited from Riverside Pediatrics Associates, a local 
private practice in Columbus, Ohio. The physicians, nurses, and staff will help recruit eligible 
subjects. The infants will be screened at their 2 month old well-baby visits at the practice. 
 
Entry Criteria are: 
• 
Age: between 8 weeks and 15 weeks at the baseline examination 
• 
Either gender, any ethnicity 
• 
Birthweight greater than 2500g 
Figure 3a. Refractive error changes over time (age, in months); Figure 3b. Accommodation (in 
Diopters) dynamic state over time (in seconds).The infants treated with the proposed 
intervention (glasses and training; subjects 003, 005, and 007) lost more farsightedness (left 
panel) and had more accurate accommodative responses to a 2 diopter stimulus than untreated 
subjects (006 and BIBS).

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• 
Normal pregnancy and delivery (including Cesarean section delivery but excluding 
serious complications or conditions such as eclampsia or rubella) 
• 
Hyperopia of ≥ +5.00D in the spherical component of refractive error (most 
hyperopic meridian) in one or both eyes measured with cycloplegic retinoscopy 
using 1% cyclopentolate 
o Infants with a refractive error of ≥ +5.00D to ≤ +7.00D will be randomized to 
treatment or standard therapy (which is observation only) 
o Infants with a refractive error of > +7.00D will receive treatment 
• 
No astigmatism greater than 2.00D in either eye 
• 
No anisometropia greater than 1.50D (spherical equivalent) 
• 
No strabismus or previous history of difficulty with pupillary dilation 
• 
No history of cardiac, liver, asthma, or other respiratory disease 
• 
No history of ocular disease, retinal detachment, severe macular dragging, 
intraocular surgery, optic nerve hypoplasia, malformations of the eye, cortical visual 
impairment or active ocular inflammation 
• 
No history of hydrocephalus, Down syndrome, or cerebral palsy, developmental 
delay, or seizure disorders. 
 
If a subject presents with conditions such as pathology, or refractive error that is 
significant and suggests the presence of a pathological condition, an appropriate referral will 
be made. 
Sample size calculations were performed using the formula adapted by Lindsey to take 
advantage of the power gained from obtaining repeated measurements across time and 
eyes (Lindsey, 2001). Data from the Berkeley Infant Biometry Study (BIBS) were used to 
obtain an estimate of the within-subject/within-visit repeatability of refractive error and the 
correlation of these measurements across time. The standard deviation for change in 
refractive error from 3 to 9 months of age from infants with hyperopia >+5.00D enrolled in 
BIBS was 1.17D. Data from Atkinson et al. suggests a standard deviation of 1.50D and 
Ingram et al. give a standard deviation for change is assumed to be 1.36D (Atkinson et al., 
2000; Ingram et al., 2000). To provide the most conservative estimate of sample size, the 
standard deviation of change is assumed to be 1.50D. If a new, difficult, expensive 
treatment strategy is to be adopted, the benefit must be substantial. The ordinary decrease 
in hyperopia in uncorrected, highly hyperopic infants might be 1.2D to 1.34D (Atkinson et 
al., 2000; Ingram et al., 2000). We would expect that there would be little enthusiasm for 
this new approach if the decrease in hyperopia in treated infants was not on the order of 
3.00D (an improvement compared to controls of 1.75D). Using these parameters, a sample 
size of 13 in each randomized group will be needed (α=0.05, β=0.1, two-sided test). If we 
estimate that 10% of the infants may not complete the follow up, 30 infants need to be 
enrolled with 15 randomly assigned to each of the two randomized groups. The rather large 
difference relative to its standard deviation to be detected (1.75/1.50 = 1.17) along with the 
increase in power obtained by taking repeated refractive error measurements help to keep 
the sample size low. However, given the prevalence of high hyperopia (more than +5.00D) in 
the population of 3 months old infants, a sample size of 30 eligible infants (for 
randomization, not including the case series) is not trivial. Up to 10 eligible infants will be 
enrolled in the case series portion of the study. One of the major efforts in this project will 
be screening the 900 infants needed to find those that are eligible.  
C. Measurement/Instrumentation 

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a. Cycloplegic refractive error. Refractive error will be measured using cycloplegic 
autorefraction and retinoscopy (1% tropicamide at the screening visit and 1% 
cyclopentolate at all follow up visits). Refractive error will also be measured with the 
following FDA-approved commercially available instrument: 
i. Welch Allyn Sure Sight Autorefractor 
b. Accommodative accuracy. Accommodation will be assessed with the following FDA-
approved commercially available instrument: 
i. PowerRefractor 
D. Detailed study procedures 
a. Screening. Topical tropicamide (1%) will be administered to an infant at their 2 
month well-baby visit. Thirty minutes after instillation of tropicamide, the infant is 
placed the appropriate distance from the autorefractor and from the screener 
(35cm from the Welch Allyn SureSight, 67 cm for retinoscopy) for measurement of 
central cycloplegic refractive error. If the subject measures ≥+5.00D sphere in one or 
both eyes via retinoscopy, the subject’s parent will be given information regarding 
the study. If the parent(s) decides to participate, Dr. Ann Morrison (co-investigator) 
will schedule the patient and infant for the treatment phase of the study. 
b. Treatment 
i. Randomization. Subjects will be randomized to treatment or placebo 
(control) if their refractive error is ≥ +5.00D to ≤ +7.00D via retinoscopy. A 
random number generator will be run in SAS using the RANUNI function 
prior to the start of the study. Random numbers will be generated for 30 
subjects (15 for each arm of the study), in a manner in which half of the 
numbers are even and half of the numbers are odd. In the program, it will 
be specified that there should be 15 subjects in each arm of the study giving 
a total of 30 subjects. The program will then scramble numbers in random 
to provide 15 subjects in each arm. In order from the sequence of random 
numbers, even numbers will represent subjects assigned to treatment and 
odd numbers will represent subjects assigned to the control group 
(standard therapy – observation). 
Subjects with a refractive error of +7.00D or higher will receive 
treatment as a Case Series. 
ii. Treatment group. Infants randomized to the treatment will receive 
spectacles with 3.00D of under-correction relative to the spherical 
equivalent in each eye as measured by cycloplegic retinoscopy performed at 
baseline. The level of correction of astigmatism is more complicated. 
Clinicians report a wide range of philosophies with respect to the correction 
of astigmatism in the young patient (Lyons, Jones, Walline, et al., 2004; 
Miller and Harvey, 1998). These philosophies tend to differ between the 
professions of optometry and ophthalmology; the majority of optometrists 
prescribe less than the full amount of astigmatism while the majority of 
ophthalmologists prescribe the full amount of astigmatism. Neither the 
American Academy of Ophthalmology nor the American Optometric 
Association make explicit recommendations in their practice guidelines as to 
whether to provide the full cylindrical correction or to reduce this correction 
by some formula. Anker et al. only provided half the measured cylindrical 
error in the spectacles while Ingram et al. fully corrected the astigmatism 
(Anker et al., 2004; Ingram et al., 2000). Considering the lack of consensus 

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and that advantages may accrue from having the most in-focus retinal 
image, the treatment group in the current study will receive the full amount 
of measured astigmatism in their glasses. 
Children with anisometropia > 1.50D will be excluded from the study as 
this amount is a risk factor for accommodative esotropia (Weakley, Birch 
and Kip, 2001). Present in only 1% of infants, this amount of anisometropia 
is rare (Mayer et al., 2001). Changes in spectacle lens power will be made as 
needed at any follow-up visit to keep the level of under-correction within 
0.50D of the target 3.00D. Follow-up will occur with a phone call to the 
subject’s parent(s) after the first week of spectacle wear to assess the 
adaptation to the spectacles and to address their acceptability. If the 
subject’s parent(s) feel that there is an issue with spectacle wear 
adaptation, they can return to the clinic to assess the prescription and fit of 
the spectacles. If the parent(s) feel that spectacle wear is going well, follow-
up will then continue at 4.5 months of age, 6 months of age, 9 months of 
age, 12 months of age, 15 months of age and 18 months of age. If an infant 
in the treatment group develops a spherical equivalent refractive error less 
than +3.00D in both eyes, he or she will be considered to have 
emmetropized, be taken out of spectacles, and then followed until the 
conclusion of the study (when the subject is 18 months of age). If only one 
eye achieves the emmetropization endpoint, the non-emmetropizing eye 
will remain under treatment with correction equal to the difference in 
refractive error between the two eyes, up to and including 1.00D. For 
example, an infant who is +3.50D OD and +2.75D OS would receive a +0.75D 
for the right eye and a plano lens for the left eye. While this places the level 
of under-correction below 3D, the importance of maintaining a balanced 
correction requires such an adjustment. Aggressive under-correction is 
intended to be only temporary, ending when the potential for 
emmetropization is complete. Regular clinical care will replace any 
investigational treatment at the conclusion of the 15 month follow up at 18 
months of age.  
Parents of the subjects in the intervention group will be instructed to 
provide 20 minutes per day of visual engagement with their infant to 
encourage accurate accommodation.  The visual engagement exercises are 
listed specifically on the “Visual Engagement Activities” form that will be 
given to parents at the initiation of treatment. Parents are instructed that 
the subject should wear his or her correction when possible while 
performing visual engagement activities.  
Compliance of glasses wear will be encouraged with parents. A calendar 
will be given to the parents at each visit to help keep track of the subject’s 
compliance with glasses wear and prescribed vision therapy. Compliance 
will be monitored but infants will not be discontinued from the study for 
non-compliance with glasses wear. 
iii. Control group – Standard Therapy. Infants typically do not receive 
comprehensive eye examinations. Therefore infant hyperopia is most often 
neither detected nor corrected in the US at this time. Uncorrected infant 
hyperopia has no symptoms. Infant eye examinations are typically done 
only when a child presents with strabismus or pathology. As an example, 

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none of highly hyperopic (>+4.00D) three-month-olds from the BIBS study 
referred for clinical assessment received at correction from community 
eyecare providers. Therefore the current standard for treating hyperopia 
against which any new treatment must be judged is observation without 
correction. The alternative would be to provide full or 1.00D under-
correction. It has already been shown that infants may not emmetropize 
with these corrections (Atkinson et al., 2000). Any inhibition of 
emmetropization may be accentuated if infants are corrected in this way at 
three months rather than later. Infants with no correction may occasionally 
emmetropize (Ingram et al., 2000). This suggests that the most ethical and 
informative form of standard therapy for infant hyperopia would be to 
provide no correction for the infants within the range of eligibility (≥+5.00D 
to ≤+7.00D). Beyond the upper limit of eligibility for randomization 
(≥+7.00D), the majority of both optometrists and ophthalmologists would 
recommend providing a refractive correction, making randomization of 
infants to observation only questionable ethically (Lyons et al., 2004; Miller 
et al., 1998). Therefore, these infants will be given treatment (like the 
treatment group) and observed as a Case Series to better understand the 
nature of their refractive error development. 
Infants with refractive errors from +5.00D up to +7.00D who are 
randomized to standard therapy will receive no correction. Follow-up will 
occur on the same schedule as infants randomized to treatment: 1.5 months 
after the baseline examination and then every 3 months until completion at 
18 months of age (6 follow-up visits after the baseline exam). Regular 
clinical care, if any is needed, will begin at the conclusion of follow up at 18 
months. Infants in either the treatment or control group who have not 
achieved a refractive error of <+3.50D in each eye by 18 months of age will 
be referred outside the study for an independent evaluation. This level of 
hyperopia is selected for referral at 18 months because of its association 
with an elevated level of risk for strabismus (Atkinson, Braddick, Robier, et 
al., 1996) 
iv. Case Series Group. Infants with a refractive error of ≥+7.00D will receive 
treatment (same protocol as infants randomized to the treatment group of 
this study). The follow-up of the infants in this case series group is the same 
for those who are randomized to treatment.  
c. Measurements. The subject will be examined while seated in the parent’s lap for all 
tests. 
i. Visual Acuity. Preferential looking visual acuity with Teller acuity cards will 
be used to determine visual acuity without refractive correction. The Teller 
acuity cards will be presented at 55cm. The subject is observed through a 
center peephole of the acuity cards for preferential looking. Successively 
smaller patterns are presented until the subject either no longer displays 
preferential looking, or loses interest. Testing will be first be attempted 
monocularly but if the subject is resistant to occlusion, testing will be done 
binocularly. Final results are recorded in the subject’s chart as the 
cycles/degree of the last card at which a response is noted in each eye.  
ii. Pupil testing. Pupillary function is tested with a penlight for size, equality, 
shape, response to direct light, and consensual response. 

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iii. Version testing. Versions are tested, with the examiner looking for any 
restrictions of yoked eye movements as the baby looks in different fields of 
gaze. 
iv. Binocularity testing. The examiner will determine if strabismus is present 
using a unilateral cover tests as well as Hirschberg evaluation. Subjects with 
an existing strabismus are not eligible. Subjects who develop a strabismus 
during the study period will be refereed for further evaluation and retained 
for follow up.  
v. Accommodative response and lag will be measured with the Schaeffel 
PowerRefactor and by dynamic retinoscopy with no refractive correction 
worn.  
The Schaeffel PowerRefractor is an infrared, binocular photoretinoscope 
capable of measuring the meridional refractive error, and therefore the 
dynamic accommodative response, of both eyes simultaneously at 25 Hz. 
Photorefraction in general and this instrument specifically have been shown 
to compare well to conventional retinoscopic measures of accommodation 
with the added advantage of measuring accommodative response and its 
variability in both eyes over a more extended period of time (Blade and 
Candy, 2006; Braddick, Atkinson, French, et al., 1979; Howland, Dobson and 
Sayles, 1987; Rosenfield, Portello, Blustein, et al., 1996; Seidemann and 
Schaeffel, 2003). The PI’s experience with this instrument is that 
maintaining attention is critical to the validity of measurements. Inattention 
and the drifting of gaze from central fixation on the accommodative target 
interfered with the comparability of measurements to conventional 
dynamic retinoscopy (Gabriel and Mutti, 2009). To filter out readings that 
might be obtained when fixation is poor, the “Gaze Control” setting on the 
PowerRefractor will be set to 15° in “Binocular” refraction mode.  
The accommodative targets are a set of plush stuffed toys. The texture 
of the toy maintains a range of spatial frequencies available to the baby that 
scale with fixation distance to drive the accommodative response. Such 
targets have been used successfully by the PI and another laboratory in 
studies of infant accommodation (Blade et al., 2006). A large circular “hot” 
infrared reflecting mirror is positioned at 45° in front of the infant. The 
reflecting mirror allows the accommodative target to be positioned in real 
space in front of the infant along the line of sight and coincident with the 
axis of the photorefractor. This avoids problems with fixation drifting from 
the 15° limit set on the machine. The PowerRefractor is placed on an 
instrument table 1 meter away from the subject on the other side of the 
mirror. The proximity of the mirror to the infant means that only a 
maximum of 4D of accommodation can be stimulated. Readings will be 
taken for approximately one minute at each of two distances: 6 meters and 
0.33 meters. Filtering of the data will remove blink artifacts or non-
physiologically rapid changes in accommodative response (>10D/sec) (Harb, 
Thorn and Troilo, 2006).  
Dynamic Retinoscopy will be assessed like a modified monocular 
estimation method (MEM), which is commonly used in clinical practice. 
Dynamic retinoscopy has been found to be similar to objective 
accommodative measurements, which we are measuring with the 

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PowerRefractor (Gabriel et al., 2009). Dynamic retinoscopy would be more 
directly applicable to clinicians who see patients regularly and do not have 
access to an instrument that can measure accommodation objectively in a 
clinical setting.  Measurements will be obtained at 0.33 meters.  
There is no universally accepted outcome measure for infant 
accommodative response, therefore the analysis in this phase will be 
somewhat exploratory. The simplest metric to calculate would be the 
average accommodative response. However, variability in that response 
provides a useful perspective that distinguishes the infant with stable 
accommodation from the one that is less well-controlled or exhibits more of 
a searching accommodative behavior. Variability will be added as a 
covariate in analyses of the accommodative response. The simple standard 
deviation in accommodation is one measure of this variability. Another 
approach would be to look for periodic variability through Fourier analysis 
of the response. This analysis would be exploratory. Analyses are typically of 
10 second segments of response. If infants are too unsteady to give such 
lengths of uninterrupted data, then the analysis may not be feasible. If the 
analysis can be done, then power at low, mid, and high temporal 
frequencies will be used as covariates in the analyses of accommodative 
response. Other potential metrics might be lag-minutes or diopter-minutes, 
essentially area-under-the-curve summary measures of diopters of lag, or 
alternatively, diopters of accommodative response per minute of recording.  
vi. Cycloplegic refractive error will be measured at all visits. Refractive error 
will be measured by cycloplegic retinoscopy by a masked examiner (primary 
outcome of the treatment phase of the study). The parents of the subject 
will be instructed not to discuss the treatment group the patient is in to the 
masked examiner. Measurements will occur 30 minutes after drop 
instillation. One drop of proparacaine 0.5% will be instilled in each eye, 
followed by two drops of cyclopegic agents. The drops used for cycloplegia 
are the following: 
1. Tropicamide (1%) will be used only at the screening visit 
2. Cyclopentolate (1%) will be used during all remaining visits 
The neutral point for the horizontal meridian is recorded first, then the 
neutral point for the vertical meridian. If the axes are oblique, the true 
meridian is measured by projecting the retinoscopy beam on to a protractor 
on the wall. SureSight autorefraction will be also be performed on both 
eyes from 35cm by the investigator (unmasked).  
vii. Peripheral refractive error. Peripheral refractive error will be assessed by 
the examiner using the SureSight autorefractor as an estimate of the ocular 
shape during emmetropization. The subject’s gaze is directed towards toys 
or interesting targets. Measurements will be made at 30° in both left and 
right gaze (a total of 2 peripheral gazes). This will be measured at the 
baseline, 9 month, and 18 month visit. 
viii. Parental refractive error status. The parent(s) refractive error will be 
obtained as in the Berkeley Infant Biometry Study (BIBS), from the 
prescription for glasses provided by the eye care provider for parents who 
wear refractive correction. If the parents report not having had a recent eye 

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examination, refractive error status will be estimated with the autorefractor 
without cycloplegia. 
ix. Survey. Additional data will be collected via a survey administered at the 
baseline visit and will request information regarding: 
1. Parental age at the infant’s birth 
2. Parental smoking status 
3. Alcohol consumption 
4. Infant birthweight 
5. Birth order 
6. Minor complications of pregnancy and delivery 
7. Years of education completed for each parent 
8. Family income 
9. Ethnic identification for each parent and for the child (assigned by 
the parent) 
x. Additional data. The following data will be obtained at each visit: 
1. Significant infant illness 
2. Medications given to the infant 
3. Nutritional history 
4. Compliance with spectacle wear. Parents will fill out a form at each 
follow up visit listing how compliant the subject was wearing 
spectacles. Parents of the subjects will be able to classify 
compliance as very good (>75% of the time), good (>50% of the time 
but less than 75% of the time), fair (>25% of the time but less than 
50% of the time), or poor (<25% of the time). Parents will be given a 
pre-printed calendar to help them keep track of compliance on a 
daily basis. This will be turned into the investigator at the next 
follow up. 
5. Compliance with visual engagement and vision therapy exercises. 
Parents will out a form at each follow up visit listing how compliant 
they were with performing accommodative therapy with the 
subject. Parents of the subjects will list how many minutes they 
were able to engage in the recommended visual activity each day. 
Parents will be given a pre-printed calendar to help them keep track 
of compliance on a daily basis. This will be turned in to the 
investigator at the next follow up.  
xi. Ocular health. The ocular health will be assessed at the baseline 
examination and at the final visit with a direct ophthalmoscope, 
transilluminator with a 20 Diopter condensing lens, or binocular indirect 
ophthalmoscope.  
d. Measurement and Visit Schedule 
 
Measurement 
S V1/B 
V2 
V3 V4 V5 V6 V7 
Target Age (months) 
2 
3 
4.5 
6 
9 
12 
15 
18 
Cycloplegic refractive error w/ SureSight 
X 
 
X 
X 
X 
X 
X 
X 
Cycloplegic refractive error w/ Retinoscopy 
X 
X 
M 
M 
M 
M 
M 
M 
Peripheral Refractive error w/ Sure Sight 
 
X 
 
 
X 
 
 
X 
Accommodative response and lag w/ Power Refractor 
 
X 
X 
X 
X 
X 
X 
X 

12 | P a g e  
 
Accommodative response and lag w/ MEM 
 
X 
X 
X 
X 
X 
X 
X 
Ocular Health 
 
X 
 
 
 
 
 
X 
Ocular Motility 
 
X 
X 
X 
X 
X 
X 
X 
Ocular Alignment 
 
X 
X 
X 
X 
X 
X 
X 
 
LEGEND: 
S = Screening visit at Pediatrician’s office 
 
 
 
V1/B = Baseline Examination 
V2 = Visit 2, 4.5 months of age  
V3 = Visit 3, 6 months of age 
V4 = Visit 4, 9 months of age 
 
V5 = Visit 5, 12 months of age 
V6 = Visit 6, 15 months of age  
V7 = Visit 7, 18 months of age 
M = Performed by an examiner masked to the infant’s group assignment 
 
e. Visit Schedule. The target and acceptable dates for each study visit are given below. 
If a monthly examination cannot be completed within the acceptable range, that 
visit will be considered as missed. It will be important to stress to parents at 
enrollment the importance of attending each of these scheduled visits. The 
acceptable range for the 6 and 18 month examinations has been extended to 14 
days after the target date to maximize the probability that this examination can be 
completed. 
An attempt will be made to dispense spectacles at the baseline examination. A 
stock of frames and lenses will be kept on site. If available, the investigator will edge 
lenses the day of the baseline examination (Visit 1) and dispense the glasses the 
same day. If the frame and/or lenses are not in stock, they will be ordered the day 
of the baseline examination (Visit 1) and the subject will return for a dispensing visit. 
The investigator will call the parents of the subject a week after glasses wear to 
make sure the glasses fit acceptably and the subject is not having difficulty adapting 
to glasses wear. A spectacle recheck visit will only occur if there are problems with 
adaptation to glasses wear. The investigator will decide at that visit if a cycloplegic 
refraction needs to occur with 1% cyclopentolate and if the lenses or frame need to 
be replaced. 
 
Study Visit 
Target Date 
Visit Window 
Visit 1/Baseline examination (V1) 
Age 3 months 
±21 days 
Dispensing visit 
Within 3 days (B) 
±7 days (B) 
Spectacle recheck visit* 
7 days (D) 
4 to 10 days (D) 
Month 1.5 examination (V2) 
45 days (B) 
38 to 52 days (B) 
Month 3 examination (V3) 
90 days (B) 
83 to 97 days (B) 
Month 6 examination (V4) 
180 days (B) 
173 to 194 days (B) 
Month 9 examination (V5) 
270 days (B) 
263 to 277 days (B) 
Month 12 examination (V6) 
360 days (B) 
353 to 367 days (B) 
Month 15 examination (V7) 
450 days (B) 
443 to 464 days (B) 
 
 
LEGEND: 
B = from date of Baseline Examination 
 
 
 
D = from date of Dispensing visit 
 
 
* = not required 
 

13 | P a g e  
 
f. Development of Strabismus. The subject population of this study is at risk for 
developing strabismus (Anker et al., 2004; Cotter, 2007; Pascual et al., 2014). This 
will be discussed with the parents of potential subjects during screenings and during 
the consent process prior to the baseline examination. If a subject develops a 
strabismus, the subject will be discontinued from treatment in the study. The 
subject cannot remain in either arm of the study because of the different standard 
of care in prescribing philosophy that occurs with the development of strabismus 
(typically providing a full refractive correction for hyperopia). The subject will 
remain in the study and will continue to be followed for observation of all study 
measurements and outcomes. The subject’s parents will have the option of their 
child remaining under the care of Dr. Ann Morrison in the Ohio State University 
College of Optometry Pediatric clinic, or any other doctor within the Ohio State 
University College of Optometry, or seek or be referred to another provider for a 
second opinion or for patient care. Any visits or treatment of strabismus or any 
clinical sequelae of the strabismus would be at the discretion of the licensed eye 
care provider and separate from the study. Follow up visits related to the study will 
follow the same schedule and contain the same measurements listed in the 
protocol.  
 
E. Internal Validity. There are no threats to internal validity. All procedures performed in the 
examination are standard procedures that have been performed frequently in other studies. 
Threats to external validity might be present in selection bias. The sample of patients to be 
recruited will be identified at Riverside Pediatrics Associates by screenings of age 
appropriate infants. The screenings will be performed by Dr. Ann Morrison, Dr. Mike 
DiBartola, or a nurse that has been adequately trained. The age, gender, and ethnicity of 
these patients might not be a true representation of the general population of full term, 
healthy infants. 
 
F. Data Analysis. All data analysis will be performed using SPSS (Version 24). Statistical 
significance will be assessed using two-sided tests with an alpha level of 0.05. Data from 
both eyes will be included in all analyses and techniques to control for intra-subject 
correlations will be used.  
 
The basic analysis will be a two-sample t-test comparison of the change in refractive error 
between the two groups at 9 months and again at 18 months of age. Analysis of Covariance 
(ANCOVA) will be used to compare the change in refractive error between the two 
treatment groups adjusting for any possible confounding variables. Refractive error at 3 
months along with any other identified confounders will be included as covariates in the 
analysis. Randomization of infants into the two treatment groups should protect against 
confounding, however, testing will be performed and adjustments made for imbalances in 
confounders between groups.  
 
The relationship of accommodative effort and accommodative lag with change in refractive 
error between 3 and 9, or 3 and 18 months will be analyzed by repeated measures analysis 
of variance. We will fit a linear functions describing the relationship between change in 
refractive error and accommodation as the repeated factor, either effort or lag. A significant 
effect for type of accommodation will indicate that the greater slope is the better 
explanation of the driving force for change in refractive error.  

14 | P a g e  
 
 
Relative peripheral refractive error will be calculated as the difference in peripheral and 
central cycloplegic refractive error. This relative peripheral refractive error calculation will 
give insight into the ocular shape of the subject. If the relative peripheral refractive error is 
relatively myopic compared to the central refractive error, the eye has a more oblate shape. 
If the relative peripheral refractive error is relatively hyperopic compared to the central 
refractive error, the eye has a less oblate or more prolate shape. The relationship of the 
change in peripheral refractive error and central refractive error (relative peripheral 
refractive error) will be analyzed by a two-sample t-test comparison of the change in the 
relative peripheral refractive error between the two groups at 9 months and again at 18 
months of age. Analysis of Covariance will be used to compare the change in relative 
peripheral refractive error between the two treatment groups adjusting for any other 
possible confounding factors. Peripheral refractive error at 3 months along with any other 
identified confounders will be included as covariates in the analysis. Randomization of 
infants into the two treatment groups should protect against confounding, however, testing 
will be performed and adjustments made for imbalances in confounders between groups. 
 
 
IV. 
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