Amblyopia and Strabismus Testing in Pediatrics
Conditions: Amblyopia, Strabismus
Sponsor: Rebiscan, Inc.

NCT Number: NCT02536963 
 
Study Title: Improving Quality Vision Outcomes in Managed Care Setting While Reducing Cost 
by Use of Accurate, Automated Screening 
 
Document: Study Protocol 
 
Date Created: August 2015 
 
 

Objectives and Purpose 
2.1 
The purpose of this study is to assess the performance of the Pediatric Vision Scanner at 
identifying amblyopia/strabismus on children older or equal to 2 years of age, and less than 6 
years of age in a busy pediatric clinic setting and to compare it to an examination comprised of 
visual acuity testing, stereopsis, eye alignment, and cycloplegic refraction. 
 
2.2 
The hypothesis is that the false positive rate of REBIScan is 10% or less. The proportion 
of patients without amblyopia or strabismus will be less than 10% of patients screened positive 
by the device.  
• Amblyopia will be defined as a two or more line difference between the 
eyes or a clear fixation preference in either eye, in the presence of a 
known amblyogenic factor.  
o 2-3 year old: vision >20/50  
o 4 year old - vision > 20/40  
o 5 year old - vision > 20/30 
• Strabismus is defined as misalignment of the eyes. 
 
3.0 
Study Design 
 
Cohort study of children tested with the REBIScan device followed by a vision examination.  
 
The data will be collected using one PVS device during the child’s regularly scheduled 
examination or on a single examination on another day at a pediatric center within the KP 
system. The additional examination following PVS will consist of an eye examination by a 
pediatric ophthalmologist. Parents and patients will be given the opportunity to complete all of 
the study testing during their initial visit.  
 
4.0 
Device Information 
 
 
4.1 
Description of Device 
 
 
The Pediatric Vision Scanner is a binocular scanner, which detects fixation in both eyes 
simultaneously. It detects fixation of the human eye remotely by scanning the eye with an 
annulus of low-intensity, polarized laser light. Previous studies have shown that it is capable of 
detecting strabismus in children as young as 2 years of age. Additional studies showed it could 
detect amblyopia in apparently straight-eyed subjects due to the high accuracy of fixation 
detection. REBIScan has built hand-held prototypes for clinical testing.  
 
To allow easy operation, the PVS was equipped with a simple two-button interface and binary 
red-light/green light output. The device displays a binocularity score to indicate the accuracy of 
fixation on an internal target. A binocularity score of 60% and above (with 2 green lights) gives a 
“pass” recommendation; lower binocularity (with one or two red lights) results in a “refer” 
recommendation. 
 

For PVS data collection, the child will be seated approximately 40 cm from the instrument 
fixation target. Room lights will be dimmed to enhance interest in the illuminated target and to 
increase pupil size. A background measurement will be obtained with eyes closed, and 
subtracted from subsequent readings to improve the signal to noise ratio. Data collection will 
last between 2.5 and 5 seconds of attention to the fixation target. Results will be recorded on 
the data form, but the patient, parents, and ophthalmologists will not be informed of the 
results. 
 
The PVS can be operated by lay users, but some training is required, and it is possible that some 
individuals may have difficulty following the protocol. The Contact PI has extensive experience 
training users of all backgrounds in use of the device. Regular site visits by REBIScan study 
personnel will ensure that testing is being performed according to instruction and allow for 
correction of any observed problems.  
 
In the event that meaning of the results is conveyed to a participant, caregivers, or providers, 
the participant will be excluded from the study and recruitment will continue until at least 300 
participants who are eligible for analysis have been tested.  
 
 
4.2 
IND/IDE Number 
 
The FDA has determined that the Pediatric Vision Scanner is a non-significant risk (NSR) device 
because it does not meet the definition of a significant risk (SR) device under § 812.3(m) of the 
investigational device exemptions (IDE) regulation (21 CFR 812). As a result, an IDE application 
is not required to be submitted to, or approved by, the FDA for a NSR study. 
 
 
4.3 
Device Supplier Information 
 
 
 
During Phase II, REBIScan will provide one unit upon study commencement, and 
will have a second device available for use, if necessary and mutually agreed upon, by study 
personnel.  
 
 
5.0  
Selection and withdrawal of subjects 
 
 
5.1 
Inclusion Criteria 
 
Children who present to the pediatric clinic will be invited to participate in the study if they are 
aged older or equal to 2 years of age, and less than 6 years of age. 
 
5.2 
Exclusion Criteria 
 
o Developmental delay or cognitive deficit 
o Visually obvious ocular conditions that would warrant specialist referral 

§ The PVS is designed to identify patients requiring referral to a specialist 
for evaluation of amblyopia or strabismus. Patients with these conditions 
often have no external signs of an abnormality, and thus will not be 
referred if they are not tested. In contrast, children with, for example, 
ptosis, periocular masses, ocular discharge, active conjunctivitis, corneal 
scarring, abnormal pupils, anterior polar or total cataracts, orbital 
cellulitis, ocular trauma, or large-angle strabismus will need to be 
referred to a specialist regardless of the results of the PVS scan. For this 
reason there is no benefit to enrolling such patients in a study of how 
effective the PVS is at referring children with amblyopia and strabismus 
(including microstrabismus.) Each of these excludable conditions would 
be easily recognized by a pediatrician. 
 
5.3 
Withdrawal Criteria 
 
If a participant is unable to complete the PVS scan due to lack of cooperation, such as refusing 
to open one’s eyes or take further direction, then the inability to participate will be recorded, 
and the participant will be excluded from the study, post-hoc, and not considered a part of the 
300-participant cohort.  
 
A participant may also be excluded from the study post-hoc if study personnel vocally share 
results of the PVS with the participant, parent, or provider prior to the Ophthalmic Examination. 
General observation of device indicator lights by the participant, parent, or provider is not 
justification for exclusion.  
 
Finally, a participant can be excluded post-hoc if unable to complete the ophthalmic 
examination. 
 
All excluded participants will be documented in the final analysis to compare how many 
participants were unable to perform the screening. Post-hoc exclusions at this stage will be 
determined by the study coordinator prior to review of the PVS screening results. 
 
6.0 
Stratification / Descriptive Factors / Randomization Scheme 
 
KP staff will manage all recruitment efforts for participation, as well as completing consent and 
data forms for all enrollees. Children who present to the pediatric clinic and meet the inclusion 
criteria will be invited to participate in the study until 300 participants have been enrolled and 
are eligible for analysis. The researcher will describe the study to their parents and obtain 
informed consent. The consent form will be written at a level simple enough for parents to read 
meaningfully and for older children to understand.  
 
 
 
7.0 
Study Agent administration or intervention and toxicity management plan 
 
 
Not applicable  

 
 
8.0 
Assessment of efficacy and safety 
 
The primary efficacy outcome is amblyopia, defined as as a two or more line difference 
between the eyes or a clear fixation preference in either eye:  
o 2-3 year old: vision >20/50  
o 4 year old - vision > 20/40  
o 5 year old - vision > 20/30 
; and/or the presence of strabismus, defined as the misalignment of the eyes. 
 
The device is considered a non-significant risk device. As such, no risk is expected with its use.  
 
 
9.0 
Clinical and laboratory evaluations and study calendar 
 
 
See Appendix IV, Study Workflow. 
 
 
 
The Informed Consent, Pediatric Vision Screener (PVS) exam and Ophthalmic 
Exam are to be performed on the same day unless otherwise desired by the patient and/or 
parent/legal guardian. 
 
 
 
 
Responsibility 
 
MD 
MD 
Tech 
Tech 
MD – 
indepe
ndent  
Informed Consent Discussion 
X 
X 
X 
X 
 
Perform Physical Examination 
X 
X 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
X 
X 
 
CRF Completion & Correction 
X 
X 
X 
X 
 
CRF Review & Signature 
X 
X 
 
 
 
Obtain Medical History 
X 
X 
X 
X 
 
Ophthalmic Exam 
X 
X 
 
 
 
PVS Exam 
 
 
X 
 
 
Oversight 
 
 
 
 
X 
 
 
 
Study Calendar 
Month Task 
1 
Work out clinical logistics and test patient flow 
2 
Commence subject enrollment, 1-2 days per week 
6 
Submit AAPOS abstract on preliminary data 
20 
Complete subject enrollment 
20-22 
Data analysis 
22-24 
Report to device maker and draft JAMA manuscript  
 

10.0 
Criteria for evaluation and endpoint definitions  
 
 
The following results will be obtained when performing the PVS scan: Test length in seconds 
(time required to obtain a reliable scan), Yield, Tries and Binocular Score. Timing will begin once 
the study subject is in the chair and ready, and will conclude upon placing instrument down 
after all steps to acquire measurement have been completed.  
 
At age 2-5, visual acuity testing is not always reliable or possible, and so the gold standard for 
this group for detection of amblyopia will be imperfect. However the goal of the study is to 
implement this screening tool in a pediatric practice in an effort to identify cases of strabismus 
and amblyopia at an early age, and therefore it is important to attempt screening at this age. 
Where possible, visual acuity testing will be used. In the absence of this, clinical judgement will 
be used to determine whether a patient has amblyopia, including fixation preference (if 
present), stereopsis testing, and cycloplegic refraction. It may be necessary to analyze the 
group in which visual acuity could be obtained separately from the group in which visual acuity 
could not be obtained, leaving the gold standard diagnosis uncertain. Future studies will be able 
to follow up on these patients later to determine whether they developed amblyopia or 
strabismus after referral. To standardize the way in which vision is tested all patients whose 
acuity is checked will be assessed using HOTV with crowding bar. Regarding logMAR testing, the 
problem is that the clinic is not currently set up with the acuity charts in logMAR mode, but all 
methods (LEA, HOTV, and Snellen) use the same standard sequence of 20/100, 20/80, 20/70, 
20/50, 20/40, 20/30, 20/25, and 20/20. 
 
The ophthalmic exam consisting of visual acuity, sensorimotor status (including stereopsis), 
color vision, and cycloplegic refraction will be performed by a pediatric ophthalmologist. The 
individual performing the ophthalmic exam will be masked to the PVS results. Stereopsis will be 
measured using the Preschool Random Dot Stereogram test (Stereo Optical), with the 
published norms to be used as the definition of reduced stereo: 
Ages 2-3 
≥400 arcsec 
Ages 4-5 
≥200 arcsec 
 
The test consists of a book wth 3 pairs of pages. Each pair contains two sets of four random dot 
shapes (one is blank, the other three contain shapes) that can be named or matched to the 
easily visible black-and-white shapes on the other side of the book. Page 1 is presented first to 
test 200 arcsec and 100 arcsec levels of disparity. If the child is able to correctly identify two of 
three shapes at both of these disparity levels, Page 2 is presented next to test 60 arcsec and 40 
arcsec disparity. If the child is unable to identify two of the three shapes at 200 arcsec disparity, 
Book 3 is presented instead to test 800 arcsec and 400 arcsec disparity. Stereoacuity is defined 
as the smallest disparity at which the child is able to correctly identify at least two of three 
shapes. Visual acuity will be measured monocularly using a standard eye chart at standard 
testing distance. An adhesive patch will cover one eye during acuity testing. Cover-uncover and 
alternate cover testing will be performed at distance and at 40 cm (the testing distance of the 
PVS device) by asking the subject to focus on a letter target or sticker while alternately covering 

the two eyes; the observer watches for movement of the eyes as cover alternates. A cycloplegic 
refraction will be performed on all children.   
 
KP study personnel will compile all data forms and KP biostatisticians will perform the statistical 
analysis.  
 
Feasibility acceptance is for non-ophthalmic personnel to perform PVS testing in less than 2 
minutes, and with fewer than 3 attempts, on 90% of the enrolled cohort.  
 
 
11.0 
Data collection and monitoring 
 
Name, date of birth, and medical record number will be recorded on an enrollment form (see 
appendix), which will also include a numeric study identification code. Subject confidentiality 
will be maintained by utilizing this code in lieu of identifiable subject information. A study 
identification log will be utilized as the only link between a subject’s study identification code 
and their identifiable information such as name and medical record number. The study 
identification log will be kept in a locked file accessible only to study staff for the purposes of 
enrolling subjects. 
 
Data forms will be completed for each PVS screen. Key data collected include PVS binocularity 
score and total time spent testing. Timing will begin once the study subject is in the chair and 
ready, and will conclude upon placing instrument down after all steps to acquire measurement 
have been completed. Data acquisition procedures and collection updates will be reviewed 
during site visits.  
 
Data collected on case report forms will be entered into a database periodically. The data 
capture screens will be designed to capture the information from the data collection case 
report forms. System security will be maintained by requiring user authentication to gain access 
to the file on the site’s private secure network. Only authorized users will be permitted access 
to the data files. Only de-identified information will be transferred to REBIScan. All study data 
that was agreed to be shared with REBIScan will be given only to authorized study personnel in 
compliance with IRB and HIPAA requirements.  
 
Subject Safety and Data Monitoring 
 
Study patients will be monitored for the occurrence of events defined as any undesirable 
experience. Adverse events will be classified and handled according to Kaiser Permanente 
Standard Operating Procedures (document attached). Patients will be monitored during the day 
of enrollment. All adverse events will be recorded on an adverse event case report form and 
will include a description of all undesirable experiences, required interventions, patient’s 
condition after the event, an estimate of the extent of injury and potential strategies to prevent 
future occurrences. The principal investigator will classify the relationship of the study protocol 
to the event. The principal investigator is responsible for reporting serious adverse events 
(death, life threatening, new, serious or permanent disability) to the Kaiser Permanente IRB.  

 
 
12.0 
Statistical considerations  
 
This study is the second of a two-phased study. The first phase was a pilot and feasibility study 
to understand the utility of using the PVS device within Kaiser Permanente. This second phase is 
to determine the sensitivity and specificity of the device and its feasibility for widespread 
deployment in a primary care setting. 
 
The collected data will generate patient demographic and clinical descriptives to describe the 
study population. 
 
The outputs that will be calculated are sensitivity and specificity for detecting amblyopia or 
strabismus. The current published data on PVS sensitivity and specificity is 97% and 87% 
respectively.Error! Bookmark not defined. It is anticipated that sensitivity will be within 5% of the 
published results; that is, 92% sensitivity and 82% specificity (contained within the calculated 
95% confidence intervals.) Assuming a 5% prevalence rate of the conditions, in a sample size of 
300 children we anticipate 15-20 children presenting with amblyopia or strabismus; therefore 
we expect to identify 14-18 cases, while having no more than 45 false referrals.  
 
13.0 
Registration guideline  
 
 
14.1 
Recruitment 
 
 
 
Patients will be recruited at the time of their visit. Patients may be contacted at 
the request of the patient or parent.  
 
 
14.2 
Forms and Records for Recruitment: Source Document, Informed Consent, Case 
Report Form 
 
 
 
At the time of registration, two copies of a signed and dated patient Informed 
Consent form with Bill of Rights must be available (an original for patient’s medical chart; one 
copy for the patient; and the other for the PI’s file). 
 
The forms and records needed for registration are: 
§ Source Document 
§ Informed Consent (1 original, 2 copies): original for patient’s medical 
chart, one copy for the patient, one copy for the PI’s file 
§ Case Report Form 
 
  
 
14.0 
Ethical and regulatory considerations  
 
 
All institutional and Federal regulations concerning the Informed Consent form will be 
fulfilled. The study will be conducted in adherence to ICH Good Clinical Practice. 

 
 
 
 

15.0 
References 
 
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3. Guyton DL, Hunter DG, Sandruck JC, Patel SN, Fry RL, inventors; The Johns Hopkins 
University School of Medicine, assignee. “Eye fixation monitor and tracker”, US 
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