Binocular Dig Rush Game Treatment for Amblyopia
Phase: NA
Conditions: Amblyopia
Sponsor: Jaeb Center for Health Research

 
ATS20ProtocolV4.0 04-30-18 
 
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AMBLYOPIA TREATMENT STUDY 
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(ATS20) 
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Binocular Dig Rush Game Treatment for 
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Amblyopia 
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PROTOCOL 
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Version 4.0 
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30 April 2018 
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ATS20ProtocolV4.0 04-30-18 
PROTOCOL AMENDMENT #1 
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13 September 2017 
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This amendment provides for the following protocol change: 
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Protocol Change  
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Current Protocol 
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The original sample size of 84 study participants for the older cohort assumed a standard deviation 
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of 5 letters after 4 weeks of treatment (see Section 5.2.2).   
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Although we believed that our estimate of 5 letters in the older cohort was reasonable, a sample size 
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re-estimation was planned once approximately 50% of the pre-planned number of subjects have 
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completed their 4-week outcome visit (see Section 5.3).  In summary, a pooled estimate of variance 
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without respect to treatment group will be calculated and used to re-estimate sample size.  If the 
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observed standard deviation of change is larger than the pre-study estimate of 5 letters, the sample 
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size will be increased, up to a maximum limit corresponding to a standard deviation of change of 8 
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letters for the older cohort (206 subjects) with a 5% adjustment for loss to follow-up. 
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Proposed Change 
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The pooled standard deviation for 42 subjects completing their 4-week outcome visit was observed 
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to be 6 letters (higher than the original estimate of 5 letters).  The sample size for the older cohort 
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will be increased to 116 study participants (58 per group) based on the results of the planned sample 
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size re-estimation.     
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Other Change: 
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A typographical error has been corrected in section 2.5.   
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ATS20ProtocolV4.0 04-30-18 
PROTOCOL AMENDMENT #2 
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12 February 2018 
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This amendment provides for the following protocol change: 
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Protocol Change  
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Current Protocol 
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The following criteria must be met for a child to be enrolled in the study:  
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• VA in the fellow eye 20/25 or better (ATS-HOTV) or >78 letters (E-ETDRS) 
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Proposed Change 
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Eligibility criteria with respect to fellow-eye visual acuity has been changed to depend upon the age 
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of the subject.  The following criteria must be met for a child to be enrolled in the study:  
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• Best-corrected fellow-eye VA meeting the following criteria:  
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o If age 4, 20/40 or better by ATS-HOTV 
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o If age 5 or 6, 20/32 or better by ATS-HOTV 
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o If age 7 or older, 20/25 or better by E-ETDRS (>78 letters) 
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The requirement for an interocular difference ≥3 logMAR lines (ATS-HOTV) or (>15 letters ( E-
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ETDRS) has not changed.   
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Rationale for Change 
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Normal visual acuity values depend upon the age of the subject. The eligibility values for the study have 
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been changed to match the normal values based upon age cited in the following table:  
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Table: Normal Visual Acuity Values Based on Age 
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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.29 Normal values for children aged >72 
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months based on a study by Drover et al.30 
 
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ATS20ProtocolV4.0 04-30-18 
PROTOCOL AMENDMENT #3 
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07 March 2018 
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This amendment provides for the following protocol change: 
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Protocol Change 
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References added to the protocol to support normal values for children aged 30-72 months based on 
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a study by Pan et al and normal values for children aged >72 months based on a study by Drover et 
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al added. 
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ATS20ProtocolV4.0 04-30-18 
PROTOCOL AMENDMENT #4 
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30 April 2018 
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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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The original sample size of 116 study participants for the younger cohort assumed a standard 
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deviation (SD) of 1.2 logMAR lines after 4 weeks of treatment (see Section 5.2.1).   
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Although we believed that our estimate of 1.2 logMAR lines in the younger cohort was reasonable, 
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as it was based on best available data, a sample size re-estimation was pre-specified once 
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approximately 50% of the pre-planned number of participants reached their 4-week outcome visit 
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(see Section 5.3):  Once approximately 50% of the pre-planned number of subjects have completed 
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the 4-week outcome visit, a pooled estimate of variance without respect to treatment group will be 
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calculated and used to re-estimate sample size using a procedure that maintains masking and has a 
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negligible effect on the Type I error rate. Within each age cohort, if the observed standard deviation 
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of change is larger than the pre-study estimate, the sample size will be increased, up to a maximum 
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limit corresponding to a standard deviation of change of 1.5 logMAR lines (182 subjects) for the 
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younger cohort. 
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Proposed Change 
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The pooled SD for 51 subjects completing their 4-week outcome visit was 1.6 logMAR lines (95% 
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confidence interval for SD = 1.2 to 2.0 logMAR).  Since the observed SD is much higher than the 
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1.2 logMAR lines used to estimate sample size, the sample size for the younger cohort will be 
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increased to 182 study participants (91 per group) based on the results of the planned sample size 
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re-estimation.     
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Protocol Change # 2 
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Current Protocol 
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Due to the short duration of the primary outcome at 4 weeks and expected rapid recruitment, no 
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interim monitoring will be conducted for either age cohort.  This decision will be re-evaluated if the 
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sample size is increased. 
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Proposed Change 
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Interim monitoring for futility will be conducted when approximately 50% of the revised sample 
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size (n=91) has completed the 4-week primary outcome visit.  Details of the interim analysis plan 
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will be developed in consultation with the DSMC and documented in the statistical analysis plan. 
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ATS20ProtocolV4.0 04-30-18 
 
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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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Jonathan M. Holmes, M.D. 
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Department of Ophthalmology 
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Mayo Clinic  
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Rochester, MN 55905 
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Phone: (507) 284-3760 
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Email: holmes.jonathan@mayo.edu  
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Ruth E. Manny, O.D., Ph.D., FAAO 
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University of Houston College of Optometry 
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Houston, TX 77004 
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Phone 713-743-1944 
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Mobile 281-782-1689 
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Email: RManny@central.uh.edu  
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ATS20ProtocolV4.0 04-30-18 
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 
Results of PEDIG study of binocular treatment (ATS18) ................................................................................. 1-2 
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1.3 
Rationale for Proposed Study Design ................................................................................................................ 1-2 
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1.4 
Study Objective ................................................................................................................................................. 1-3 
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1.5 
Synopsis of Study Design.................................................................................................................................. 1-3 
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CHAPTER 2: SUBJECT ENROLLMENT .......................................................................................................................... 2-1 
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2.1 
Eligibility Assessment and Informed Consent/Assent ...................................................................................... 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 ...................................................................................................................................... 2-3 
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2.3 
Historical Information ....................................................................................................................................... 2-3 
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2.4 
Procedures at the Enrollment Visit .................................................................................................................... 2-3 
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2.5 
Randomization of Eligible Subjects .................................................................................................................. 2-4 
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CHAPTER 3: TREATMENT AND FOLLOW-UP ............................................................................................................. 3-1 
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3.1 
Binocular Computer Game Treatment .............................................................................................................. 3-1 
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3.2 
Continued Spectacle Correction Group ............................................................................................................. 3-1 
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3.3 
Compliance ....................................................................................................................................................... 3-1 
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3.4 
Phone Call ......................................................................................................................................................... 3-1 
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3.5 
Follow-up Visit Schedule .................................................................................................................................. 3-1 
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3.6 
Resolution of Amblyopia .................................................................................................................................. 3-2 
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3.7 
Optional Post 8-week Treatment ....................................................................................................................... 3-2 
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3.8 
Follow-up Visit Testing Procedures .................................................................................................................. 3-2 
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3.8.1 
Masked Examiner ...................................................................................................................................... 3-3 
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3.9 
16-Week visit .................................................................................................................................................... 3-3 
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3.10 
Non-Study Visits and Treatment .................................................................................................................... 3-3 
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CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP ................................................................... 4-4 
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4.1 
Contacts by the Jaeb Center for Health Research and Sites .............................................................................. 4-4 
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4.2 
Subject Withdrawals ......................................................................................................................................... 4-4 
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4.3 
Management of Refractive Error ....................................................................................................................... 4-4 
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4.4 
Management of Strabismus ............................................................................................................................... 4-4 
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4.5 
Risks .................................................................................................................................................................. 4-4 
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4.5.1 
Development of Manifest Ocular Deviation or Diplopia ........................................................................... 4-4 
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4.5.2 
Risks of Examination Procedures .............................................................................................................. 4-5 
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4.5.3 
Delay in Use of Traditional Amblyopia Treatment ................................................................................... 4-5 
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4.6 
Reporting of Adverse Events ............................................................................................................................ 4-5 
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4.6.1 
Risk Assessment ........................................................................................................................................ 4-5 
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4.7 
Discontinuation of Study ................................................................................................................................... 4-5 
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4.8 
Travel Reimbursement ...................................................................................................................................... 4-5 
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4.9 
Study Costs ........................................................................................................................................................ 4-5 
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4.10 
General Considerations .................................................................................................................................. 4-5 
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CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .......................................................... 5-6 
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5.1 
Definition of Subject Cohorts ............................................................................................................................ 5-6 
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5.2 
Sample Size Estimation ..................................................................................................................................... 5-6 
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5.2.1 
Younger Cohort (Children 4 to <7 years of age) ....................................................................................... 5-6 
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5.2.2 
Older Cohort (Children 7 to <13 years of age) .......................................................................................... 5-8 
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5.3 
Interim Analysis and Sample Size Re-estimation ............................................................................................. 5-9 
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5.4 
Analyses .......................................................................................................................................................... 5-10 
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5.4.1 
Primary Analysis ..................................................................................................................................... 5-10 
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5.4.1.1 
Mean Amblyopic Eye VA at 4 Weeks ........................................................................................ 5-10 
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5.4.2 
Secondary Analyses ................................................................................................................................. 5-10 
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5.4.2.1 
VA Improvement at 4 Weeks Defined as a Binary Outcome ..................................................... 5-10 
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5.4.2.2 
Stereoacuity ................................................................................................................................ 5-10 
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5.4.2.3 
Treatment Compliance with Binocular Therapy ......................................................................... 5-10 
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5.4.2.4 
Fellow-eye Contrast with Binocular Therapy ............................................................................. 5-11 
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5.4.3 
Safety ....................................................................................................................................................... 5-11 
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5.4.3.1 
VA in Fellow Eye ....................................................................................................................... 5-11 
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5.4.3.2 
Ocular Alignment ....................................................................................................................... 5-11 
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ATS20ProtocolV4.0 04-30-18 
5.4.3.3 
Diplopia ...................................................................................................................................... 5-11 
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5.4.3.4 
Adverse Symptoms ..................................................................................................................... 5-11 
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5.4.4 
Outcomes at 8 Weeks .............................................................................................................................. 5-11 
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5.4.5 
Exploratory Analyses ............................................................................................................................... 5-11 
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5.4.5.1 
Subgroup Analysis at 4 Weeks ................................................................................................... 5-11 
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5.4.5.2 
Effect of Binocular Treatment in Children Randomized to Continued Spectacles ..................... 5-12 
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CHAPTER 6: REFERENCES ............................................................................................................................................. 6-13 
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ATS20ProtocolV4.0 04-30-18 
 
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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Epidemiology & clinical characteristics 
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Amblyopia is the most common cause of reduced monocular VA (VA) in children and young 
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adults, with estimates of prevalence ranging from 1% to 5%.1,2  The most common associated 
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amblyogenic risk factors are uncorrected anisometropia, strabismus, or a combination of 
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anisometropia and strabismus.   
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Treatment –current methods and outcomes  
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The current mainstay of amblyopia treatment is spectacle correction (when there is uncorrected 
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refractive error) followed by part-time patching or atropine penalization of the fellow eye.3-8   
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Although current treatments using part-time occlusion and atropine drops are effective in many 
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younger children (3 to <7 years) 3-8 residual amblyopia (20/32 or worse) is still present in 54% 
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of children at age 10 years9 and 40% at age 15 years.10 In older children, age 7 to 12 years, 
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current treatments are less effective.11 The majority of older children still have residual 
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amblyopia after treatment; in 7- to 12-year-old children, 80% treated with atropine and 74% 
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treated with patching had residual amblyopia of 20/32 or worse.12 
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One possible reason for failure of part-time patching treatment in some younger children and 
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many older children is poor compliance with the prescribed treatment regimens.13,14 
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Nevertheless, data from studies using an occlusion dose monitor15,16 suggest that many children 
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successfully comply with prescribed part-time patching treatment and yet fail to respond to 
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treatment, supporting the assertion that part-time patching is ineffective for treating amblyopia 
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in some children. 
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In addition, patching has negative psychosocial effects for many children, and children often 
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resist wearing a patch.  Some children and their parents rate patching poorly from the standpoint 
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of adverse effects of treatment, treatment compliance, and social stigma.17,18 
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Based on the prevalence of residual amblyopia with current part-time patching treatment and the 
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challenges of compliance with patching, new treatments for amblyopia are needed, particularly 
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those that can be visually unobtrusive and that do not overtly interfere with the vision of the 
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fellow eye. 
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Binocular treatment 
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In 2010, Hess et al19 reported a binocular approach to treating amblyopia,  without patching, 
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atropine drops or blurring filters, consisting of dichoptic stimuli presented to each eye.  In 
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laboratory-based sessions, dichoptic motion coherence thresholds were measured by adjusting 
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contrast levels in the fellow eye to optimize combination of visual information from both eyes 
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and overcome suppression of the amblyopic eye. In these adult subjects mean amblyopia eye 
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VA and stereoacuity improved over several weeks.19 This method of binocular treatment was 
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then adapted to a “falling blocks” game, which was studied by Li et al,20 reporting a mean 
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amblyopic eye improvement of approximately 2 logMAR lines when treating adults in a 
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supervised setting for 1 hour/day over 2 weeks.  
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ATS20ProtocolV4.0 04-30-18 
 
1-2 
Recently, binocular treatment using a “falling blocks” game has been adapted to an iPad® 
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device, which uses red-green anaglyphic glasses. In children, non-randomized studies conducted 
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by Birch’s research group found an improvement in amblyopic-eye VA of approximately 1 
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logMAR line prescribing 4 hours/week of binocular treatment for 4 weeks in 4 to 12 year-
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olds,21,22 and in 3- to 6-year-olds.23  The studies21-23  conducted by Birch’s group in children 
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included 4 different binocular games, one of which was the falling blocks game, and allowed 
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concurrent patching at a different time of day at the eye care provider’s discretion, although a 
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sub-analysis of those only treated with binocular games yielded a similar magnitude of effect. 
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Knox et al24 also found a comparable improvement (approximately 1 logMAR line) in children 
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(mean age 8.5 years ) treated with a similar game, using a head-mounted display in a supervised 
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setting for 1 hour/day for 5 sessions over one week.  
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Based on these pilot studies, PEDIG performed a randomized clinical trial to compare 
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amblyopic-eye VA improvement over 16 weeks in children age 5 to <13 years, with 20/40 to 
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20/200 amblyopic-eye VA, comparing a binocular iPad game (prescribed 1 hour per day) with 
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patching of the fellow eye (prescribed 2 hours per day).  
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1.2 
Results of PEDIG study of binocular treatment (ATS18) 
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In a recently completed PEDIG RCT,25 385 subjects 5 to <13 years of age (mean 8.5 years) with 
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amblyopia (20/40 to 20/200, mean 20/63) resulting from strabismus, anisometropia, or both, 
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were randomly assigned to either 16 weeks of a binocular iPad game, prescribed for 1 hour a 
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day (n=190, binocular group), or patching of the fellow eye prescribed for 2 hours a day 
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(n=195, patching group).   
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At 16 weeks, the mean amblyopic-eye VA improved 1.05 lines (2-sided 95% confidence 
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interval (CI): 0.85 to 1.24 lines) in the binocular group and 1.35 lines (2-sided 95% CI: 1.17 to 
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1.54 lines) in the patching group, with an adjusted treatment group difference of 0.31 lines 
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favoring patching (upper limit of the 1-sided 95% CI 0.53 lines).  This upper limit exceeded the 
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pre-specified non-inferiority limit of 0.5 lines. In a post hoc analysis, the two-sided 95% CI for 
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the adjusted treatment group difference was 0.04 to 0.58 lines, favoring the patching group.  
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Only 22% of subjects randomized to the binocular game performed >75% of the prescribed 
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treatment (median 46%, interquartile range 20% to 72%). In younger subjects 5 to <7 years of 
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age, without prior amblyopia treatment, amblyopic-eye VA improved 2.5 ± 1.5 lines in the 
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binocular group and 2.8 ± 0.8 in the patching group.  Adverse effects (diplopia, reduction of 
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fellow-eye VA, new tropia) were uncommon and of similar frequency between groups.  
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We therefore concluded that in children 5 to <13 years of age, amblyopic-eye VA improved 
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with both binocular game play and patching, particularly in younger children age 5 to <7 years 
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without prior amblyopia treatment.  However, based on a post hoc analysis, VA improvement 
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with this particular binocular iPad treatment was not as good as with 2 hours of prescribed daily 
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patching. 
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1.3 
Rationale for Proposed Study Design 
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It is entirely possible that our failure to find non-inferiority of binocular treatment to part-time 
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patching in our recent RCT was due to poor compliance with the binocular treatment. Only 22% 
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of subjects randomized to the binocular game performed >75% of the prescribed treatment 
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(median 46%, interquartile range 20% to 72%). 
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ATS20ProtocolV4.0 04-30-18 
 
1-3 
Recently, a new binocular game has been developed for children, called “Dig Rush,” which is 
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much more interesting than the falling blocks game because it involves more interesting tasks 
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such as digging for gold and earning rewards.  It has 42 levels, and therefore the child remains 
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engaged for a much longer period of time than the falling blocks game. 
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The Birch group has studied the binocular Dig Rush game in children age 4 to <10 years and 
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found that compliance with the game is excellent, with a mean amblyopic eye VA improvement 
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of 1.5 lines at 2 weeks and 1.7 lines at 4 weeks.26  
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Based on several promising pilot studies of binocular treatment in children and in adults, a full 
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RCT is warranted, to investigate whether binocular treatment is an effective treatment for 
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amblyopia, and, analogous to the PEDIG RCT which investigated the effectiveness of 
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patching,27 the appropriate control group is continued spectacle treatment alone. 
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1.4 
Study Objective 
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To compare the efficacy of 1 hour/day of binocular game play 5 days per week plus spectacle 
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correction with spectacle correction only, for treatment of amblyopia in children 4 to <13 years 
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of age. 
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1.5 
Synopsis of Study Design 
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Major eligibility criteria: (see section 2.2 for a complete listing) 
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• Age 4 to <13 years  
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• Amblyopia associated with anisometropia, strabismus (<5∆ at near measured by SPCT), 
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or both 
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• No amblyopia treatment (atropine, patching, Bangerter, vision therapy, binocular 
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therapy) in the past 2 weeks  
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• Spectacle correction (if required) worn for at least 16 weeks, or until stability of VA is 
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demonstrated (<0.1 logMAR change by the same testing method measured on 2 exams 
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at least 8 weeks apart) 
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• VA in the amblyopic eye 20/40 to 20/200 (ATS-HOTV) or 33 to 72 letters (E-ETDRS) 
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• Best-corrected fellow-eye VA meeting the following criteria:  
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o If age 4, 20/40 or better by ATS-HOTV 
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o If age 5 or 6, 20/32 or better by ATS-HOTV 
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o If age 7 or older, 20/25 or better by E-ETDRS (>78 letters) 
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• Interocular difference ≥3 logMAR lines (ATS-HOTV) or (>15 letters ( E-ETDRS) 
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• No myopia greater than -6.00D spherical equivalent in either eye 
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• Demonstrate in-office ability to play the Dig Rush game under binocular conditions 
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(with red-green glasses) on at least level 3, including ability to see red “diggers” and 
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blue “gold carts” at 20% contrast in the non-amblyopic eye 
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Treatment Groups 
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Subjects will be randomly assigned with equal probability to either:  
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• Binocular treatment group: binocular computer game play prescribed 1 hour per day 5 
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days a week (treatment time can be split into shorter sessions totaling 1 hour each day) 
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with spectacles, if needed (see section 3.1) 
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• Continued spectacle correction, if needed (see section 3.2) 
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Sample Size – see details in Chapter 5 
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• Results will be analyzed separately in 2 age cohorts.   
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o 182 children aged 4 to < 7 years (younger cohort) 
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ATS20ProtocolV4.0 04-30-18 
 
1-4 
o 116 children aged 7 to <13 years (older cohort) based on results of the sample 
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size re-estimation 
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i. A maximum of 20% of enrolled subjects in each age cohort may have had 
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previous binocular therapy. 
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Visit Schedule  
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• Enrollment exam and randomization  
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• 1-week phone call (7 to 13 days from randomization) to inquire about issues with the 
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binocular game (if applicable) and to encourage compliance with treatment for all 
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groups (to be completed by site personnel) 
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• 4 weeks ± 1 week (primary outcome)   
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• 8 weeks ± 1 week (secondary outcome) 
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• Binocular group final visit 
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• Spectacle group switched to binocular treatment and followed for 8 weeks 
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• 9-week phone call (Spectacle group only: 7 to 13 days from 8-week exam) to inquire 
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about issues with the binocular game (if applicable) and to encourage compliance with 
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treatment for all groups (to be completed by site personnel) 
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• 16 weeks ± 1 week (final visit for  group originally randomized to continued spectacle 
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treatment who were switched to binocular treatment) 
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Testing Procedures 
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At each follow-up visit, distance VA will be measured in each eye using ATS-HOTV for 
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children <7 years at enrollment and the E-ETDRS for children ≥7 years at enrollment (VA 
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method used at enrollment will be used over the course of the trial).  We will also assess near 
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stereoacuity using the Randot Butterfly Stereoacuity test and Randot Preschool Stereoacuity 
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test, history of diplopia, symptoms, and ocular alignment (distance and near) by cover test, 
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simultaneous prism cover test (SPCT) (if manifest deviation present), and prism and alternate 
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cover test (PACT) (for all subjects).   
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Analysis 
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The primary analysis will compare mean change in amblyopic-eye VA from enrollment to 4 
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weeks in the binocular computer treatment group with the continued spectacle treatment group.    
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ATS20ProtocolV4.0 04-30-18 
 
1-5 
Study Summary Flow Chart 
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Baseline Measurements (with best correction) 
Diplopia Questionnaire (must be performed prior to other testing) 
Symptom survey 
Monocular distance VA 
Randot stereoacuity (Butterfly and Preschool) 
Ocular alignment (cover/uncover, SPCT, PACT) 
Demonstrate in-office ability to play the Dig Rush game  
Major Eligibility Criteria 
Age 4 to <13 years 
Amblyopia associated with anisometropia, strabismus (<5∆ at near, measured by SPCT) or both 
No amblyopia treatment in the past 2 weeks 
Spectacles (if required) worn for at least 16 weeks, or demonstrated stability of VA (<0.1 logMAR change by the 
same testing method measured on 2 exams at least 8 weeks apart) 
VA in the amblyopic eye 20/40 to 20/200 inclusive (33 to 72 letters if E-ETDRS) 
 
Best-corrected fellow-eye VA meeting the following criteria:  
o 
If age 4, 20/40 or better by ATS-HOTV 
o 
If age 5 or 6, 20/32 or better by ATS-HOTV 
o 
If age 7 or older, 20/25 or better by E-ETDRS (>78 letters) 
Interocular difference ≥3 logMAR lines (≥15 letters if E-ETDRS) 
No myopia greater than -6 00D SE in either eye
Randomize 
Binocular computer game 
play 1 hour/ day, 5 days 
per week 
Continued spectacle 
correction  
(if needed) 
1-Week Call  
Inquire if any problems with game play (binocular group only) and to encourage compliance 
(Completed by site personnel) 
16 weeks ± 1 week: Follow-up Exam (Continued Spectacle Correction group opting to 
have binocular computer game treatment) 
Diplopia Questionnaire (must be performed prior to other testing) 
Symptom survey 
Monocular distance VA 
Randot stereoacuity (Butterfly and Preschool) 
Ocular alignment (cover/uncover, SPCT, PACT) 
Study Ends 
Offer binocular computer 
game play 1 hour/ day, 5 
days per week 
Continued spectacle 
correction group 
Binocular computer game 
group 
8 weeks ± 1 week: Follow-up Exam (Secondary Outcome) 
Diplopia Questionnaire (must be performed prior to other testing) 
Symptom survey 
Monocular distance VA (Masked) 
Randot stereoacuity (Butterfly and Preschool) (Masked) 
Ocular alignment (cover/uncover, SPCT, PACT) 
4 weeks ± 1 week: Follow-up Exam (Primary Outcome) 
Diplopia Questionnaire (must be performed prior to other testing) 
Symptom survey 
Monocular distance VA (Masked) 
Randot stereoacuity (Butterfly and Preschool) (Masked) 
Ocular alignment (cover/uncover, SPCT, PACT) 
9-Week Call  
Inquire if any problems with game play and to encourage 
compliance (Completed by site personnel) 

 
ATS20ProtocolV4.0 04-30-18 
 
2-1 
CHAPTER 2: SUBJECT ENROLLMENT 
417 
 
418 
2.1 
Eligibility Assessment and Informed Consent/Assent 
419 
The study plans to enroll a minimum of 182 subjects aged 4 to < 7 years and 116 subjects aged 7 to 
420 
<13 years (based on results of the sample size re-estimation).  Up to 20% of enrolled subjects in 
421 
each age cohort can have had previous binocular therapy. As the enrollment goal approaches, sites 
422 
will be notified of the end date for recruitment. Subjects who have signed an informed consent form 
423 
can be randomized until the end date, which means the expected recruitment might be exceeded.   
424 
 
425 
A child is considered for the study after undergoing a routine eye examination (by a study 
426 
investigator as part of standard of care) that identifies amblyopia appearing to meet the eligibility 
427 
criteria. The study will be discussed with the child’s parent(s) or guardian(s) (referred to 
428 
subsequently as parent(s)). Parent(s) who express an interest in the study will be given a copy of the 
429 
informed consent form to read. Written informed consent / assent must be obtained from a parent 
430 
and child (depending on age and local IRB requirements) prior to performing any study-specific 
431 
procedures that are not part of the child’s routine care. 
432 
2.2 
Eligibility and Exclusion Criteria 
433 
2.2.1 Eligibility Criteria  
434 
The following criteria must be met for a child to be enrolled in the study: 
435 
1. Age 4 to <13 years  
436 
2. Amblyopia associated with strabismus, anisometropia, or both (previously treated or 
437 
untreated) 
438 
a. Criteria for strabismic amblyopia: At least one of the following must be met: 
439 
• Presence of a heterotropia on examination at distance or near fixation (with or without 
440 
optical correction, must be no more than 4pd by SPCT at near fixation (see #6 below) 
441 
• Documented history of strabismus which is no longer present (which in the judgment of 
442 
the investigator could have caused amblyopia) 
443 
b. Criteria for anisometropia: At least one of the following criteria must be met: 
444 
• ≥1.00 D difference between eyes in spherical equivalent 
445 
• ≥1.50 D difference in astigmatism between corresponding meridians in the two eyes 
446 
c. Criteria for combined-mechanism amblyopia: Both of the following criteria must be met: 
447 
• Criteria for strabismus are met (see above) 
448 
• ≥1.00 D difference between eyes in spherical equivalent OR ≥1.50 D difference in 
449 
astigmatism between corresponding meridians in the two eyes 
450 
3. No amblyopia treatment other than optical correction in the past 2 weeks (patching, atropine, 
451 
Bangerter, vision therapy, binocular treatment) 
452 
4. Requirements for required refractive error correction (based on a cycloplegic refraction 
453 
completed within the last 7 months): 
454 
• Hypermetropia of 2.50 D or more by spherical equivalent (SE) 
455 
• Myopia of amblyopic eye of 0.50D or more SE 
456 
• Astigmatism of 1.00D or more  
457 
• Anisometropia of more than 0.50D SE 
458 
 
459 
NOTE: Subjects with cycloplegic refractive errors that do not fall within the 
460 
requirements above for spectacle correction may be given spectacles at investigator 
461 
discretion but must follow the study-specified prescribing guidelines, as detailed below. 
462 
 
463 

 
ATS20ProtocolV4.0 04-30-18 
 
2-2 
a. Spectacle prescribing instructions referenced to the cycloplegic refraction completed within 
464 
the last 7 months: 
465 
• SE must be within 0.50D of fully correcting the anisometropia. 
466 
• SE must not be under corrected by more than 1.50D SE, and reduction in plus sphere 
467 
must be symmetric in the two eyes. 
468 
• Cylinder power in both eyes must be within 0.50D of fully correcting the 
469 
astigmatism. 
470 
• Axis must be within +/- 10 degrees if cylinder power is ≤1.00D, and within +/- 5 
471 
degrees if cylinder power is >1.00D. 
472 
• Myopia must not be undercorrected by more than 0.25D or over corrected by more 
473 
than 0.50D SE, and any change must be symmetrical in the two eyes.  
474 
 
475 
b. Spectacle correction meeting the above criteria must be worn: 
476 
• For at least 16 weeks OR until VA stability is documented (defined as <0.1 logMAR 
477 
change by the same testing method measured on 2 consecutive exams at least 8 
478 
weeks apart).   
479 
• For determining VA stability (non-improvement): 
480 
o The first of two measurements may be made 1) in current spectacles, or 
481 
2) in trial frames with or without cycloplegia or 3) without correction (if 
482 
new correction is prescribed),   
483 
o The second measurement must be made without cycloplegia in the correct 
484 
spectacles that have been worn for at least 8 weeks.   
485 
o Note: since this determination is a pre-study procedure, the method of 
486 
measuring VA is not mandated. 
487 
5. VA, measured in each eye without cycloplegia in current spectacle correction (if applicable) 
488 
within 7 days prior to randomization using the ATS-HOTV VA protocol for children < 7 
489 
years and the E-ETDRS VA protocol for children ≥ 7 years on a study-approved device 
490 
displaying single surrounded optotypes, as follows: 
491 
a. VA in the amblyopic eye 20/40 to 20/200 inclusive (ATS-HOTV) or 33 to 72 letters (E-
492 
ETDRS) 
493 
b. Best-corrected fellow-eye VA meeting the following criteria:  
494 
o If age 4, 20/40 or better by ATS-HOTV 
495 
o If age 5 or 6, 20/32 or better by ATS-HOTV 
496 
o If age 7 or older, 20/25 or better by E-ETDRS (>78 letters) 
497 
c. Interocular difference ≥ 3 logMAR lines (ATS-HOTV) or ≥ 15 letters (E-ETDRS)   
498 
6. Heterotropia with a near deviation of <5∆ (measured by SPCT) in habitual correction 
499 
(Angles of ocular deviation >4∆ are not allowed because large magnitudes of the deviation 
500 
would compromise successful playing of the game.)  
501 
7. Subject is able to play the Dig Rush game (at least level 3) on the study iPad under binocular 
502 
conditions (with red-green glasses). Subject must be able to see both the red “diggers” and 
503 
blue “gold carts” when contrast for the non-amblyopic eye is at 20%. 
504 
8. Investigator is willing to prescribe computer game play, or continued spectacle wear per 
505 
protocol.  
506 
9. Parent understands the protocol and is willing to accept randomization. 
507 
10. Parent has phone (or access to phone) and is willing to be contacted by Jaeb Center staff or 
508 
other study staff. 
509 
11. Relocation outside of area of an active PEDIG site for this study within the next 8 weeks is 
510 
not anticipated. 
511 

 
ATS20ProtocolV4.0 04-30-18 
 
2-3 
2.2.2 Exclusion Criteria 
512 
A subject is excluded for any of the following reasons: 
513 
1. Prism in the spectacle correction at time of enrollment (eligible only if prism is discontinued 
514 
2 weeks prior to enrollment). 
515 
2. Myopia greater than -6.00D spherical equivalent in either eye. 
516 
3. Previous intraocular or refractive surgery. 
517 
4. Any treatment for amblyopia (patching, atropine, Bangerter filter, vision therapy or previous 
518 
binocular treatment) during the past 2 weeks. Previous amblyopia therapy is allowed 
519 
regardless of type, but must be discontinued at least 2 weeks prior to enrollment. 
520 
5. Ocular co-morbidity that may reduce VA determined by an ocular examination performed 
521 
within the past 7 months (Note: nystagmus per se does not exclude the subject if the above 
522 
VA criteria are met). 
523 
6. No Down syndrome or cerebral palsy 
524 
7. No severe developmental delay that would interfere with treatment or evaluation (in the 
525 
opinion of the investigator).  Subjects with mild speech delay or reading and/or learning 
526 
disabilities are not excluded. 
527 
8. Subject has demonstrated previous low compliance with binocular treatment and/or 
528 
spectacle treatment (as assessed informally by the investigator) 
529 
2.3 
Historical Information 
530 
Historical information to be elicited will include the following: date of birth, sex, race, ethnicity, 
531 
and history of prior eye-related treatment (including length of spectacle correction).   
532 
2.4 
Procedures at the Enrollment Visit 
533 
All examination procedures must be tested within 7 days prior to the date of enrollment, except the 
534 
cycloplegic refraction and ocular examination, which may be performed within 7 months prior to 
535 
enrollment.  
536 
 
537 
All examination procedures at enrollment are performed in the subject’s current spectacle 
538 
correction, if required (testing in trial frames is not permitted), and without cycloplegia: 
539 
 
540 
1. ATS Diplopia Questionnaire 
541 
• The child and parent(s) will be specifically questioned regarding the presence and 
542 
frequency of any diplopia within the last 2 weeks using a standardized diplopia 
543 
assessment (see ATS Miscellaneous Testing Procedures Manual).  The diplopia 
544 
assessment must be performed prior to any other testing during the exam. 
545 
 
546 
2. Symptom Survey  
547 
• The child and parent(s) will complete a 5-item symptom survey regarding the presence 
548 
of various ocular symptoms within the past 2 weeks (see ATS Miscellaneous Testing 
549 
Procedures Manual).  The symptom survey must be performed prior to any other testing 
550 
during the exam. 
551 
 
552 
3. Distance VA Testing:  Monocular distance VA testing will be performed in current 
553 
refractive correction (if required) in each eye by a certified examiner using the electronic 
554 
ATS-HOTV VA protocol for children <7 years and the E-ETDRS VA protocol for children 
555 
≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes as 
556 
described in the ATS Testing Procedures Manual.  
557 
• The same VA protocol used at enrollment will be used throughout the study regardless 
558 
of age at follow-up. 
559 

 
ATS20ProtocolV4.0 04-30-18 
 
2-4 
 
560 
4. Stereoacuity Testing:  
561 
• Stereoacuity will be tested at near in current spectacle correction using the Randot 
562 
Butterfly and Randot Preschool stereoacuity tests. 
563 
 
564 
5. Ocular Alignment Testing: 
565 
• Ocular alignment will be assessed in current spectacle correction by the cover test, 
566 
simultaneous prism and cover test (SPCT) (in cases of strabismus detected by cover 
567 
test), and prism and alternate cover test (PACT) in primary gaze at distance (3 meters) 
568 
and at near (1/3 meter) as outlined in the ATS Procedures Manual. 
569 
o See section 2.2.1 for eligibility criteria related to ocular alignment. 
570 
 
571 
6. Additional Clinical Testing: 
572 
• Ocular examination as per investigator’s clinical routine (if not performed within 7 
573 
months) 
574 
 
575 
7. Demonstration of Game Understanding 
576 
• The subject must be able to see both the red “diggers” and blue “gold carts” when 
577 
contrast is at 20% for the non-amblyopic eye. Subjects must demonstrate that they 
578 
understand the game by playing the game in the office on at least level 3. Subjects 
579 
unable to play the game are not eligible for the study.  
580 
2.5 
Randomization of Eligible Subjects 
581 
For each age cohort, the Jaeb Center will construct a Master Randomization List using a permutated 
582 
block design stratified by visual acuity in the amblyopic eye as moderate 20/40 to 20/80 (53 to 67 
583 
letters) versus severe 20/100 to 20/400 (18 to 52 letters), which will specify the order of treatment 
584 
group assignments.   
585 
 
586 
All eligible subjects enrolled in the study will be followed for 8 weeks.  Subjects will be randomly 
587 
assigned in a 1:1 allocation to one of the following treatment groups for 8 weeks:  
588 
 
589 
1. Binocular game play 1 hour per day, 5 days per week with spectacle correction (see section 
590 
3.1), if needed 
591 
2. Continued spectacle correction (see section 3.2), if needed 
592 
 
593 
Once a child is assigned to treatment, he/she will be included in the analysis regardless of whether 
594 
or not the assigned treatment is received.  Thus, the investigator must not randomly assign a subject 
595 
to treatment unless convinced that the parent will accept either of the treatments.  
596 

 
ATS20ProtocolV4.0 04-30-18 
 
3-1 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
597 
 
598 
3.1 
Binocular Computer Game Treatment 
599 
Subjects assigned to the binocular treatment group will be prescribed the Dig Rush game to play for 
600 
1 hour per day, 5 days a week for 8 weeks.  Parents of subjects will be instructed that the 1 hour of 
601 
daily treatment should be completed in a single 60-minute session, but if this is not possible for 
602 
whatever reason, the treatment may be divided into shorter sessions totaling 1 hour per day.   
603 
 
604 
All subjects in the study will play the Dig Rush game presented on an iPad while wearing red/green 
605 
(anaglyph) glasses (over current spectacle correction, if applicable) with the green filter placed over 
606 
the amblyopic eye.  The subject should be instructed to hold the iPad at his/her usual reading 
607 
distance. Some game elements are only visible to the fellow eye viewing through the red lens, while 
608 
other game elements are only visible to the amblyopic eye viewing through the green lens.  Image 
609 
contrast varies depending on depth of amblyopia to ensure stimulation of the amblyopic eye and 
610 
binocular game play. 
611 
 
612 
Contrast of the game elements in the amblyopic eye will be at 100% throughout the study.  Contrast 
613 
of game elements seen by the fellow eye will begin at 20% at the start of the study and will increase 
614 
or decrease automatically in increments from the last contrast level (e.g., 20% to 22%) based on the 
615 
subject’s performance and duration of game play.   
616 
3.2 
Continued Spectacle Correction Group 
617 
Subjects assigned to the continued spectacle wear group will continue wearing their appropriate 
618 
spectacle correction (if required) for all waking hours, 7 days per week for 8 weeks.  Subjects 
619 
assigned to the continued spectacle wear group will be offered binocular treatment for 8 weeks after 
620 
the initial 8 weeks of the study has been completed.  Subjects in the continued spectacle correction 
621 
group that choose to continue with binocular treatment after 8 weeks will return for a follow-up 
622 
visit at 16 weeks. 
623 
3.3 
Compliance 
624 
Parents will be asked to complete a compliance calendar by manually recording the number of 
625 
minutes that the child played the game each day, and/or how long the child has worn the spectacle 
626 
correction.  The investigator will review the calendars at each follow-up visit.  The amount of time 
627 
the game is played will also be recorded automatically during game play by the iPad.  These data 
628 
will be downloaded at the Jaeb Center when the iPad is returned after the study. 
629 
3.4 
Phone Call   
630 
Site personnel will call all subjects at 1 week (7 to 13 days) to encourage compliance with treatment 
631 
and to confirm that there are no technical problems playing the binocular game for those assigned to 
632 
binocular treatment.  Site personnel will call subjects in the continued spectacle treatment group 
633 
who switch to binocular treatment at 9 weeks (7 to 13 days after the 8-week visit), again to 
634 
encourage compliance with treatment and to confirm that there are no technical problems playing 
635 
the binocular game for those assigned to binocular treatment. 
636 
3.5 
Follow-up Visit Schedule 
637 
The follow-up schedule is timed from randomization as follows: 
638 
• 1-week phone call (7 to 13 days from randomization) to inquire about issues with the 
639 
binocular game (if applicable) and to encourage compliance with treatment for all groups (to 
640 
be completed by site personnel) 
641 
• 4 weeks ± 1 week (primary outcome)   
642 

 
ATS20ProtocolV4.0 04-30-18 
 
3-2 
• 8 weeks ± 1 week (secondary outcome) 
643 
• Binocular final visit 
644 
• Spectacle group switched to binocular treatment and followed for 8 weeks 
645 
• 9-week phone call (Spectacle group only: 7 to 13 days from 8-week exam) to inquire about 
646 
issues with the binocular game (if applicable) and to encourage compliance with treatment 
647 
for all groups (to be completed by site personnel) 
648 
• 16 weeks ± 1 week (final visit for  group originally randomized to continued spectacle 
649 
treatment who were switched to binocular treatment) 
650 
 
651 
Additional non-study visits can be performed at the discretion of the investigator. 
652 
3.6 
Resolution of Amblyopia 
653 
Subjects achieving amblyopic-eye VA equal to or better (0 lines or more lines better) than the better 
654 
of the fellow-eye VA at baseline or 4-week visit, will be considered to have resolved and may 
655 
discontinue binocular treatment, although these subjects will still return for all remaining follow-up 
656 
exams.  
657 
3.7 
Optional Post 8-week Treatment 
658 
For children originally randomized to binocular treatment, the study ends at 8 weeks. 
659 
 
660 
Children who were originally assigned to continued spectacle treatment will be offered binocular 
661 
treatment for 8 weeks following the 8-week visit.  The study will end at the 8-week exam for 
662 
children who choose not to receive binocular treatment.  Children receiving binocular treatment at 
663 
the 8 week exam will return at 16 weeks for a follow-up visit. The study will end for these children 
664 
at the 16-week visit.   
665 
3.8 
Follow-up Visit Testing Procedures 
666 
Subjects will be seen at follow-up visits as outlined in section 3.5.  A Masked Examiner must 
667 
complete distance VA and stereoacuity testing at these visits (section 3.8.1).  All procedures will be 
668 
performed with the subject’s current spectacle correction.  If a subject currently wears spectacles 
669 
but is not wearing them at the follow-up examination for whatever reason, testing must be 
670 
performed in trial frames. 
671 
 
672 
Prior to the Masked Examiner entering the room, subjects and parents should be instructed not to 
673 
discuss their treatment with the Masked Examiner.   
674 
 
675 
The following study procedures are performed at each visit: 
676 
 
677 
1. ATS Diplopia Questionnaire 
678 
• The child and parent(s) will be specifically questioned regarding the presence and 
679 
frequency of any diplopia within the last 2 weeks using a standardized diplopia 
680 
assessment (see ATS Miscellaneous Testing Procedures Manual).  The diplopia 
681 
assessment must be performed prior to any other testing during the exam. 
682 
 
 
683 

 
ATS20ProtocolV4.0 04-30-18 
 
3-3 
 
684 
2. Symptom Survey  
685 
o The child and parent(s) will complete a 5-item symptom survey regarding the 
686 
presence of various ocular symptoms within the past 2 weeks (see ATS 
687 
Miscellaneous Testing Procedures Manual).  The symptom survey must be 
688 
performed prior to any other testing during the exam. 
689 
 
690 
3. Distance VA Testing (masked):   
691 
• Monocular distance VA testing will be performed in the current spectacle correction in 
692 
each eye using the same VA testing method that was used at enrollment, as described in 
693 
the ATS Testing Procedures Manual. 
694 
o 
The ATS HOTV testing protocol will always be used to test VA in the younger 
695 
age cohort (4 to <7 years at enrollment) whereas the E-ETDRS protocol will 
696 
always be used to test VA in the older cohort (7 to<13 years at enrollment). 
697 
o 
Testing must be completed without cycloplegia. 
698 
 
699 
4. Stereoacuity Testing (masked):  
700 
• Near stereoacuity will be tested in habitual current refractive correction using the Randot 
701 
Butterfly test and Randot Preschool Stereoacuity test at near (1/3 meter). 
702 
 
703 
5. Ocular Alignment Testing:   
704 
• Ocular alignment will be assessed in the current spectacle correction by the cover test, 
705 
simultaneous prism and cover test (SPCT) (if strabismus is present on cover testing), and 
706 
prism and alternate cover test (PACT) in primary gaze at distance (3 meters) and at near 
707 
(1/3 meter) as outlined in the ATS Procedures Manual. 
708 
3.8.1 Masked Examiner 
709 
The Masked Examiner must be certified to test VA and stereoacuity.  Because the Masked 
710 
Examiner must be masked to the subject’s treatment group, he/she must be someone other than the 
711 
managing clinician (in many cases the managing clinician will be the investigator but this is not 
712 
required). 
713 
3.9 
16-Week visit 
714 
This visit is only for children randomized to continued spectacle treatment who opt to receive 
715 
binocular treatment at the 8-week visit. At the 16-week visit, children will have the same testing as 
716 
described in section 3.8; however, testing does not need to be completed by a masked examiner.  
717 
Following this visit, the study will end for these children. 
718 
3.10 
Non-Study Visits and Treatment 
719 
Investigators may schedule additional visits at their own discretion.  Subjects will continue to 
720 
follow the study-specified follow-up schedule regardless of any non-study visits.  No data will be 
721 
collected at non-study visits for the purpose of the study. 
722 
 
723 
Investigators must not start any additional treatment (other than that outlined in section 3.1) prior to 
724 
the 8-week outcome visit.   
725 
 
 
726 

 
ATS20ProtocolV4.0 04-30-18 
 
4-4 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
727 
4.1 
Contacts by the Jaeb Center for Health Research and Sites 
728 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided with 
729 
the parent’s contact information.  The Jaeb Center may contact the parents of the subjects.  
730 
Permission for such contacts will be included in the Informed Consent Form.  The principal purpose 
731 
of the contacts will be to develop and maintain rapport with the subject and/or family and to help 
732 
coordinate scheduling of the outcome examinations.   
733 
 
734 
The site investigator or coordinator will contact the parents of each subject after the first week of 
735 
the study to encourage compliance with treatment (spectacle or binocular) and to confirm that there 
736 
are no technical problems playing the binocular game for those assigned to binocular treatment.   
737 
4.2 
Subject Withdrawals 
738 
Parents may withdraw their child from the study at any time.  This is expected to be a very 
739 
infrequent occurrence in view of the study design’s similarity to routine clinical practice and short 
740 
duration.  If the parents indicate that they want to withdraw their child from the study, the 
741 
investigator personally should attempt to speak with them to determine the reason.  If their interest 
742 
is in transferring the child’s care to another eye care provider, every effort should be made to 
743 
comply with this and at the same time try to keep the child in the study under the new provider’s 
744 
care. 
745 
4.3 
Management of Refractive Error 
746 
Because of the short duration of the study and the requirement to have a cycloplegic refraction 
747 
within 7 months prior to enrollment, no cycloplegic refraction is mandated during the study.  
748 
Nevertheless, whenever the investigator suspects that refractive error may not be corrected 
749 
according to study guidelines, a cycloplegic refraction should be performed.  Change in spectacle 
750 
correction is at investigator discretion, but must be prescribed according to the guidelines described 
751 
in section 2.2.1. and spectacles will be paid for by the study. 
752 
 
753 
Contact lenses are not allowed during the study. 
754 
4.4 
Management of Strabismus  
755 
Because of the short duration of the study and the age group being studied, strabismus surgery is not 
756 
allowed prior to the end of the study.  If surgery is performed, the date and type of surgery will be 
757 
recorded in the comment section of the Follow-up Examination Form. 
758 
4.5 
Risks 
759 
4.5.1 Development of Manifest Ocular Deviation or Diplopia 
760 
Diplopia is expected to be rare based on our experience during the previous ATS18 study 
761 
comparing binocular treatment with patching. 25 
762 
 
763 
Data on frequency of diplopia will be collected from the child and parent(s) at each study visit. 
764 
 
765 
If treatment precipitates the development of a manifest ocular deviation (e.g., esotropia) and/or 
766 
diplopia, the parent will be advised to have the subject see the investigator as soon as possible. If a 
767 
new manifest deviation is confirmed on examination, the decision as to whether to continue or 
768 
discontinue therapy will be left to the investigator’s and parent’s decision. If the investigator 
769 
determines that binocular diplopia is present, continuation of treatment is also at the discretion of 
770 
the investigator and parent(s). If amblyopia treatment is to be discontinued during the study, a 
771 

 
ATS20ProtocolV4.0 04-30-18 
 
4-5 
Protocol Chair should be called to discuss the case. Subjects discontinuing treatment during the 
772 
study will continue to be seen for the remaining regularly scheduled study visits. 
773 
4.5.2 Risks of Examination Procedures 
774 
The procedures in this study are part of daily eye care practice in the United States and pose no 
775 
known risks. As part of a routine usual-care exam, the subject may receive cycloplegic/dilating eye 
776 
drops. 
777 
4.5.3 Delay in Use of Traditional Amblyopia Treatment 
778 
The subjects in the either treatment group will not be able to perform any patching, atropine, 
779 
Bangerter filter, or additional vision therapy treatment during the study. 
780 
4.6 
Reporting of Adverse Events 
781 
No surgical procedures are part of the protocol.  There are no expected long-term adverse events 
782 
associated with playing the computer game on the iPad.  Investigators will abide by local IRB 
783 
reporting requirements. 
784 
4.6.1 Risk Assessment  
785 
It is the investigators’ opinion that the protocol’s level of risk falls under DHHS 46.404 which is 
786 
research not involving greater than minimal risk.  
787 
4.7 
Discontinuation of Study 
788 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
789 
Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 
790 
subjects. 
791 
4.8 
Travel Reimbursement 
792 
Parents of each subject will be compensated $40 per visit (by check or money-card) for completion 
793 
of each protocol-specified visit, for a maximum of $160.  If there are extenuating circumstances, 
794 
and the subject is unable to complete study visits without additional funds for travel costs, 
795 
additional funds may be provided. 
796 
4.9 
Study Costs  
797 
The subject or his/her insurance provider will be responsible for the costs that are considered 
798 
standard care.  
799 
 
800 
Because the treatment used in the study is not standard of care, the enrollment, 4-, 8, and 16-week 
801 
follow-up visits will be paid for by the study.  The cost of the binocular game treatment related 
802 
equipment will also be paid for by the study; however the iPad will need to be returned upon study 
803 
completion.   
804 
 
805 
Changes in spectacle correction if done (see section 4.3) will be paid for by the study.  
806 
 
807 
4.10 
General Considerations 
808 
The study is being conducted in compliance with the policies described in the study policies 
809 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
810 
protocol described herein, and with the standards of Good Clinical Practice. 
811 
 
812 
Data will be directly collected in electronic CRFs, which will be considered the source data. 
813 
 
814 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
815 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
816 
2013). 
817 

 
ATS20ProtocolV4.0 04-30-18 
 
5-6 
CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
818 
 
819 
The approach to sample size estimation and the statistical analyses are summarized below.  A 
820 
detailed Statistical Analysis Plan document will be written and finalized prior to any tabulation or 
821 
analysis of study outcome data.   
822 
5.1 
Definition of Subject Cohorts 
823 
The study will enroll two cohorts of subjects with identical eligibility criteria, apart from age at time 
824 
of randomization: 
825 
• Younger cohort: Children aged 4 to <7 years 
826 
• Older cohort: Children aged 7 to <13 years 
827 
 
828 
Compliance may differ by age; therefore, we believe that there could be a differential treatment 
829 
effect between age groups.  If the binocular game is not as appealing to younger children with some 
830 
not being able to play the game very well, it is possible that the treatment response with binocular 
831 
therapy may be reduced in this age group due to poorer compliance with game play compared with 
832 
the older cohort.   The opposite may be true as well.  Therefore, the current study will be powered 
833 
for two separate age cohorts according to the criteria listed above. 
834 
5.2 
Sample Size Estimation 
835 
Sample size estimates for each age cohort were based on data from previous PEDIG studies 
836 
(ATS328, ATS527, and ATS1825), and data from a preliminary pilot study for subjects treated with 
837 
the Dig Rush game on an iPad device (E. Birch Study26) limited to subjects meeting the eligibility 
838 
criteria for the current protocol.  
839 
5.2.1 Younger Cohort (Children 4 to <7 years of age) 
840 
Control Group – Continued Spectacle Correction Alone 
841 
To estimate the treatment effect in our study for those randomized to continued spectacles alone 
842 
after stability, data were reviewed from subjects aged 3 to <7 years who were randomly assigned to 
843 
continue spectacle correction alone in a previous PEDIG study (ATS5, see Table 1).  After 
844 
adjusting for baseline VA, the mean change in VA at 5 weeks was 0.55 logMAR lines (95% 
845 
confidence interval (CI): 0.19 to 0.90 logMAR lines) with standard deviation 1.28 logMAR lines 
846 
(95% confidence interval (CI): 1.07 to 1.58 logMAR lines).   
847 
 
848 
Given the more stringent criteria for assessing VA stability with spectacles and shorter outcome 
849 
time in the current study as compared to the previous study, we anticipate that the magnitude and 
850 
standard deviation of VA improvement after 4 weeks in the current study will be smaller than those 
851 
in Table 1.  
852 
 
853 
Binocular Treatment Group (Dig Rush Game): 
854 
Data from 2 studies were reviewed: (1) preliminary pilot data for subjects randomly assigned to 4 
855 
weeks of binocular treatment with the Dig Rush game on an iPad device (E. Birch Study) and (2) 
856 
data from a previous PEDIG trial (ATS18) for subjects randomly assigned to binocular treatment 
857 
with the Hess falling blocks game on an iPad device (Table 1).  Based on the more conservative 
858 
estimates from ATS18, a mean VA change at 4 weeks of 1.09 lines (95% CI: 0.63 to 1.55 lines), 
859 
with standard deviation 1.32 logMAR lines (95% CI: 1.06 to 1.74 logMAR lines) after adjusting for 
860 
baseline VA might be expected.  However, we anticipate that the magnitude of VA improvement 
861 
after 4 weeks in the current study will be somewhat larger than that in ATS18, due to better 
862 
compliance. 
863 
 
864 
 
865 

 
ATS20ProtocolV4.0 04-30-18 
 
5-7 
Table 1: Previous Study Data from Subjects Aged 3 to <7 Years of Age   
866 
Cohort 
N 
Change in Amblyopic Eye VA 
at the 4 or 5 Week Visit 
(logMAR Lines) ‡ 
Mean Change (95% CI) 
SD Change (95% CI) 
Spectacle Correction Alone: 
 
 
 
ATS5: Age 3 to <7 years † 
53 
0.55 (0.19 to 0.90) 
1.28 (1.07 to 1.58) 
      No prior amblyopia treatment 
50 
0.54 (0.17 to 0.91) 
1.32 (1.10 to 1.64) 
      Prior amblyopia treatment 
3 
0.67 (-2.21 to 3.54) 
0.39 (0.20 to 2.45) 
Binocular Treatment: 
 
 
 
E. Birch Study (Age 4 to <7 years) ^ 
9 
1.67 (0.73 to 2.61) 
1.19 (0.80 to 2.28) 
 
 
 
 
ATS18 (Age 5 to <7 years) § 
34 
1.09 (0.63 to 1.55) 
1.32 (1.06 to 1.74) 
      No prior amblyopia treatment 
19 
1.47 (0.73 to 2.22) 
1.54 (1.16 to 2.28) 
            Prior amblyopia treatment 
15 
0.60 (0.15 to 1.05) 
0.81 (0.59 to 1.28) 
‡ Positive values indicate improvement.   Mean and SD adjusted for baseline visual acuity.  
867 
† ATS5 data were limited to randomized subjects with an amblyopic-eye VA of 20/40 to 20/200 inclusive with ≥ 3 lines of interocular difference and 
868 
a fellow-eye VA of 20/25 or better who had stabilized with spectacle correction prior to randomization.  The baseline magnitude of tropia at near (as 
869 
measured by SPCT) was limited to <5pd.  The outcome data reported were based on the 5-week primary masked outcome visit.  
870 
^ E. Birch study enrolled children aged 4 to <7 years of age.  Change in VA after 4 weeks of binocular therapy was computed for subjects randomly 
871 
assigned to receive binocular treatment using the Dig Rush game on an iPad device for 4 weeks (prescribed 1 hour per day, 5 days per week without 
872 
patching).  Subjects with >4pd magnitude of strabismus (measured by PACT) were excluded from the study. 
873 
§ ATS18 study subjects were prescribed binocular treatment for 1 hour per day, 7 days per week.  The binocular game, Hess falling blocks, was 
874 
played on an iPad device.  The outcome data reported are from the 4-week masked outcome visit.   
875 
 
876 
Summary: 
877 
Based on data from previous studies (Table 1), the treatment group difference for the current study 
878 
for the mean change in VA at 4 weeks was estimated to be 0.75 logMAR lines with a pooled  
879 
standard deviation of 1.2 logMAR lines. Although the expected group difference in the current 
880 
study is larger than 0.75 logMAR lines (Table 1), there is limited data available on the Dig Rush 
881 
binocular game and this estimate is consistent with the results of the previous ATS5 study 
882 
comparing spectacle correction alone versus patching (treatment group difference of 0.7 line) after 5 
883 
weeks of treatment.   
884 
 
885 
Sample Size Estimation: 
886 
Assuming a true difference in mean VA change between the two groups of 0.75 logMAR line after 
887 
4 weeks of treatment and a pooled standard deviation of 1.2 logMAR lines, a total sample size of 
888 
110 subjects (55 per group) has 90% power with a type I error rate of 5% to detect a treatment 
889 
group difference between binocular treatment and spectacle correction alone (Table 2).  Adjusting 
890 
for 5% loss to follow-up, a total sample size of 182 (91 per group) is needed. 
891 
 
892 
Table 2. Total Sample Size Estimates for a 2-Arm Study *    
893 
SD of Change 
(LogMAR lines) 
Treatment Group Difference in Mean VA Change from Baseline at 4 weeks (LogMAR lines) 
0.50 
0.75 
1.00 
1.25 
1.50 
1.0 
172 
78 
46 
30 
22 
1.1 
206 
94 
54 
36 
26 
1.2 
246 
110 
64 
42 
30 
1.3 
288 
130 
74 
48 
34 
1.4 
332 
150 
86 
56 
40 
1.5 
382 
172 
98 
64 
46 
* Number in cells represents the total number of subjects required to detect a treatment group difference in amblyopic-eye VA change from baseline 
894 
to 4 weeks using a t-test with a 2-sided alpha=0.05 and power 90% for a range of pooled SD of change in VA (logMAR lines). 
895 
 
896 

 
ATS20ProtocolV4.0 04-30-18 
 
5-8 
5.2.2 Older Cohort (Children 7 to <13 years of age) 
897 
Control Group – Continued Spectacle Correction Alone 
898 
To estimate the treatment effect in our study for those randomized to continued spectacles alone 
899 
after stability, data were reviewed from subjects aged 7 to <13 years who were randomly assigned 
900 
to continued spectacle correction alone in a previous PEDIG study (ATS3, see Table 3).  Similar to 
901 
ATS18, the proportion of subjects with prior treatment in the current study is expected to be higher 
902 
than the proportion observed in ATS3.  Therefore, the proportions with and without prior treatment 
903 
from ATS18 were used to weight ATS3 outcome data.  After adjusting for baseline acuity, the 
904 
weighted mean change in VA at 6 weeks was 1.3 letters (95% CI: 0.01 to 2.6 letters) with standard 
905 
deviation of 5.3 letters (95% confidence interval (CI): 4.5 to 6.4 letters).   
906 
 
907 
Given the more stringent criteria for assessing VA stability with spectacles and shorter outcome 
908 
time than the previous study, we anticipate that the magnitude of VA change after 4 weeks will be 
909 
close to zero, with standard deviation somewhat smaller than in Table 3. 
910 
 
911 
Binocular Treatment Group (Dig Rush Game): 
912 
Data from 2 studies were reviewed: (1) preliminary pilot data26 for subjects randomly assigned to 4 
913 
weeks of binocular treatment using the Dig Rush game on an iPad device and (2) data from a 
914 
previous PEDIG trial25 of subjects who were randomly assigned to binocular treatment using the 
915 
Hess falling blocks game on an iPad device (Table 3).     
916 
 
917 
A larger treatment effect at 4 weeks in the current study than in ATS18 is expected due to better 
918 
compliance.  Therefore, we used the 16-week data from ATS1825 to estimate the expected mean and 
919 
standard deviation of change in VA (4.1 letters, 95% CI: 3.0 to 5.1 letters) and (6.0 letters, 95% CI: 
920 
5.3 to 6.9 letters), respectively, adjusted for baseline acuity. 
921 
 
922 
Table 3: Previous Study Data from Subjects Aged 7 to <13 Years of Age  
923 
Cohort 
 
% of Enrolled 
Subgroup * 
Change in Amblyopic Eye VA 
at the 4 or 6 Week Visit 
(Letters) ‡ 
N 
Actual 
Expected 
Mean Change  
(95% CI) 
SD Change  
(95% CI) 
Spectacle Correction Alone: 
 
 
 
 
 
ATS3 (Age 7 to <13 years) † 
67 
 
 
1.3 (0.004 to 2.6) 
5.3 (4.5 to 6.4) 
      No prior amblyopia treatment 
27 
40% 
17% 
3.4 (-0.1 to 6.8) 
5.7 (4.5 to 7.8) 
      Prior amblyopia treatment 
40 
60% 
83% 
0.9 (-0.4 to 2.1) 
4.6 (3.8 to 5.9) 
Weighted Estimate** 
 
 
 
1.3 (0.01 to 2.6) 
5.3 (4.5 to 6.4) 
Binocular Treatment: 
 
 
 
 
 
E. Birch Study26 (Age 7 to <10 years)^  
5 
 
 
9.0 (5.5 to 12.6) 
2.5 (1.5 to 7.2) 
 
 
 
 
 
 
ATS18 (Age 7 to <13 years) † § 
118 
 
 
1.8 (0.9 to 2.8) 
5.1 (4.5 to 5.8) 
      No prior amblyopia treatment 
22 
 
 
2.3 (-0.4 to 5.1) 
6.2 (4.8 to 8.9) 
      Prior amblyopia treatment 
96 
 
 
1.7 (0.7 to 2.7) 
4.8 (4.2 to 5.6) 
* For the percentage of enrolled subjects within each subgroup of prior amblyopia treatment status, the actual percentage is based on the ATS3 
924 
enrollment characteristics while the expected percentage projects the characteristics of the cohort for the current study, which was based on ATS18 
925 
(younger cohort trial).  
926 
‡ Positive values indicate improvement.   Mean and SD adjusted for baseline visual acuity. 
927 
† ATS3 data were limited to randomized subjects aged 7 to <13 years with an amblyopic-eye VA of 20/40 to 20/200 inclusive (33 to 72 letters if E-
928 
ETDRS), ≥ 3 lines of interocular difference (≥ 15 letters) and a fellow-eye VA of 20/25 or better (≥ 78 letters if E-ETDRS).  The baseline magnitude 
929 
of tropia at near (as measured by SPCT) was limited to <5pd.  The outcome data reported were based on the 6-week visit.  
930 

 
ATS20ProtocolV4.0 04-30-18 
 
5-9 
** A weight was calculated for each subject in the ATS3 study based on prior amblyopia treatment status (no prior amblyopia treatment, prior 
931 
amblyopia treatment) by computing the ratio of the expected to the actual percentage (Weight = Expected % / Actual %). 
932 
^ E. Birch study enrolled children aged 7 to <10 years of age and all of these study subjects had prior amblyopia treatment at enrollment. Change in 
933 
VA after 4 weeks of binocular therapy was computed as logMAR lines for subjects randomly assigned to receive binocular treatment using the Dig 
934 
Rush game on an iPad device for 4 weeks (prescribed 1 hour per day, 5 days per week without patching).  Subjects with >4pd magnitude of 
935 
strabismus (measured by PACT) were excluded from the study. 
936 
§ ATS18 study subjects were prescribed binocular treatment for 1 hour per day, 7 days per week.  The binocular game, Hess falling blocks, was 
937 
played on an iPad device.  The outcome data reported are from the 4-week masked outcome visit.  
938 
 
939 
Summary: 
940 
Due to the limited data available on the Dig Rush binocular game, ATS18 data were used to 
941 
estimate a treatment group difference in mean change in VA at 4 weeks of 3.75 letters (0.75 
942 
logMAR line) with a pooled standard deviation of 5 letters (1.0 logMAR line) for the current study. 
943 
 
944 
Sample Size Estimation: 
945 
Assuming a standard deviation of 5 letters, a total sample size of 78 subjects (39 per group) has 
946 
90% power with a type I error rate of 5% to detect a treatment group difference between binocular 
947 
treatment and spectacle correction alone assuming the true difference in mean VA change between 
948 
the two groups is 3.75 letters (0.75 logMAR line) after 4 weeks of treatment (Table 4).  Adjusting 
949 
for 5% loss to follow-up, a total sample size of 84 (42 per group) is needed. 
950 
 
951 
Table 4. Total Sample Size Estimates for a 2-Arm Study *    
952 
* Number in cells represents the total number of subjects required to detect a treatment group difference in amblyopic-eye VA change from baseline 
953 
to 4 weeks using a t-test with a 2-sided alpha=0.05 and power 90% for a range of pooled SD of change in VA (letters). 
954 
5.3 
Interim Analysis and Sample Size Re-estimation 
955 
The sample size estimates for both the younger and older age cohorts are based on previous studies 
956 
of spectacle correction and binocular treatment. Although we believe that our estimates of variation 
957 
are reasonable for both cohorts, a sample size re-estimation will be performed once approximately 
958 
50% of the pre-planned number of subjects have completed the 4-week outcome visit.  A pooled 
959 
estimate of variance without respect to treatment group will be calculated and used to re-estimate 
960 
sample size using a procedure that maintains masking and has a negligible effect on the Type I error 
961 
rate.28  Within each age cohort, if the observed standard deviation of change is larger than the pre-
962 
study estimate, the sample size will be increased, up to a maximum limit corresponding to a 
963 
standard deviation of change of 1.5 logMAR lines (182 subjects) for the younger cohort and 8 
964 
letters for the older cohort (206 subjects) with a 5% adjustment for loss to follow-up. 
965 
 
966 
Due to the short duration of the primary outcome at 4 weeks and expected rapid recruitment, no 
967 
interim monitoring will be conducted for either age cohort.  This decision will be re-evaluated if the 
968 
sample size is increased. 
969 
 
 
970 
SD of Change  
(Letters) 
Treatment Group Difference in Mean VA Change from Baseline at 4 weeks (Letters) 
2.50 
3.75 
5.00 
6.25 
7.50 
5 
172 
78 
46 
30 
22 
6 
246 
110 
64 
42 
30 
7 
332 
150 
86 
56 
40 
8 
434 
194 
110 
72 
50 

 
ATS20ProtocolV4.0 04-30-18 
 
5-10 
5.4 
Analyses 
971 
All analyses described below will be conducted separately for both of the age cohorts.  
972 
5.4.1 Primary Analysis 
973 
5.4.1.1 Mean Amblyopic Eye VA at 4 Weeks 
974 
For both age cohorts, the primary objective is to compare the efficacy of 4 weeks of treatment with 
975 
1 hour/day of binocular game play 5 days per week plus spectacle correction  to treatment with 
976 
spectacle correction alone (subsequently referred to as “control” treatment). 
977 
 
978 
An analysis of covariance (ANCOVA) will be performed to compute the 4-week mean change in 
979 
amblyopic-eye VA for the binocular and control treatments, adjusted for baseline acuity, and a 95% 
980 
confidence interval will be constructed on the treatment group difference.  
981 
 
982 
The primary analysis will follow a modified intent-to-treat principle.  Data will be included only 
983 
from subjects who complete the 4-week exam within the pre-defined analysis window.  There will 
984 
be no imputation of data for subjects who are lost to follow-up or withdraw from the study prior to 
985 
the 4-week exam.  Multiple imputation for missing data will be performed as a secondary approach, 
986 
and results of the analysis with imputation of missing data assessed for consistency with the primary 
987 
analysis.   
988 
 
989 
Additional approaches to the primary analysis include the following: 
990 
• Limit the analysis to subjects whose 4-week outcome exams were performed within the 
991 
protocol window (3 to 5 weeks post-randomization) 
992 
• Include subjects who completed the 4-week exam outside of the pre-defined analysis 
993 
window 
994 
5.4.2 Secondary Analyses  
995 
5.4.2.1 VA Improvement at 4 Weeks Defined as a Binary Outcome 
996 
A secondary analysis will estimate the proportion of subjects with amblyopic-eye VA improvement 
997 
of ≥ 2 logMAR lines (≥ 10 letters if E-ETDRS) at 4 weeks after baseline.  
998 
 
999 
The proportion of subjects who achieve this outcome will be tabulated by treatment group and an 
1000 
exact 95% confidence interval will be computed on the group proportion.  A p-value for the 
1001 
treatment group comparison will be computed using binomial regression with adjustment for 
1002 
baseline VA.  If the binomial regression model does not converge, Poisson regression with robust 
1003 
variance estimation or an exact method (without baseline adjustment) will be used to derive a p-
1004 
value for the treatment group comparison. 
1005 
5.4.2.2 Stereoacuity 
1006 
Stereoacuity will be tabulated at baseline and 4 weeks according to treatment group with 
1007 
computation of descriptive statistics.  The change in stereoacuity from baseline to 4 weeks will be 
1008 
tabulated for each group and compared between treatment groups using the exact Wilcoxon rank-
1009 
sum test.   
1010 
5.4.2.3 Treatment Compliance with Binocular Therapy 
1011 
Data from the automated iPad log files will be used to provide an objective measure of compliance 
1012 
with binocular treatment.  The total amount of game play will be computed for the initial 4 weeks of 
1013 
treatment for the binocular treatment group.  Secondary analyses will evaluate the relationship 
1014 
between the total amount of game play with (1) change in VA and (2) change in stereoacuity after 
1015 
the first 4 weeks of binocular treatment.  
1016 
 
1017 

 
ATS20ProtocolV4.0 04-30-18 
 
5-11 
5.4.2.4 Fellow-eye Contrast with Binocular Therapy 
1018 
Data from the automated iPad log files will be used to assess game performance as measured by the 
1019 
fellow-eye contrast.  The level and change in fellow-eye contrast will be computed for the initial 4 
1020 
weeks of treatment for the binocular treatment group.  Secondary analyses will evaluate the 
1021 
relationship between the change in fellow-eye contrast with (1) change in VA and (2) change in 
1022 
stereoacuity after the first 4 weeks of binocular treatment.     
1023 
5.4.3 Safety 
1024 
5.4.3.1 VA in Fellow Eye 
1025 
The mean change in fellow-eye VA from baseline to 4 weeks will be calculated and compared 
1026 
between treatment groups using ANCOVA with adjustment for baseline VA. The proportion of 
1027 
subjects with loss of 2 or more logMAR lines (10 or more letters) of VA in the fellow eye from 
1028 
baseline to the 4-week exam will be reported for each treatment group and compared using 
1029 
Barnard’s exact test. 
1030 
5.4.3.2 Ocular Alignment 
1031 
The proportion of subjects with development of new strabismus (no heterotropia at baseline and the 
1032 
presence of near and/or distance heterotropia at 4 weeks) or an increase from baseline ≥10∆ in a 
1033 
pre-existing strabismus at 4 weeks will be reported by treatment group and compared using 
1034 
Barnard’s exact test. 
1035 
5.4.3.3 Diplopia  
1036 
The proportion of subjects with each level of diplopia frequency will be reported by treatment group 
1037 
at 4 weeks.  Data will also be tabulated based on the maximum frequency of diplopia reported by 
1038 
treatment group. The change in diplopia frequency level from baseline to 4 weeks will be compared 
1039 
between treatment groups using the exact Wilcoxon rank-sum test.   
1040 
5.4.3.4 Adverse Symptoms 
1041 
The child and parent(s) will complete a 5-item symptom survey regarding the presence of various 
1042 
ocular symptoms within the past 2 weeks at enrollment and at each visit.  The distribution of scores 
1043 
on each symptom survey item will be described for the enrollment exam and the 4-week exam for 
1044 
each treatment group.  The distribution of change in scores on each symptom survey item will also 
1045 
be described for each treatment group.   
1046 
5.4.4 Outcomes at 8 Weeks 
1047 
As secondary analyses, all analyses described above will be repeated using data obtained from the 
1048 
8-week visit.  
1049 
5.4.5 Exploratory Analyses 
1050 
5.4.5.1 Subgroup Analysis at 4 Weeks  
1051 
The treatment effect after 4 weeks in subgroups based on baseline factors will be assessed in 
1052 
exploratory analyses and used to suggest hypotheses for further investigation in future studies. The 
1053 
following baseline factors are of interest: amblyopic-eye VA, stereoacuity, the presence of a tropia 
1054 
at near, and prior amblyopia treatment (other than spectacle correction).  In accordance with NIH 
1055 
guidelines, subgroup analyses of treatment effect according to gender and race/ethnicity will be 
1056 
conducted.  However, based on results from previous studies, a differential treatment effect by these 
1057 
variables is not expected. 
1058 
 
1059 
The general approach for these exploratory analyses will be to conduct an analysis of covariance 
1060 
similar to the primary analysis adding an interaction for treatment and the subgroup covariate of 
1061 
interest.   
1062 
 
1063 
The subgroup definitions for the planned subgroup analyses are as follows: 
1064 
1. Amblyopic-eye VA at baseline (20/40, 20/50, 20/63, 20/80 or worse) 
1065 
2. Age group (specified for each age cohort separately in the Statistical Analysis Plan) 
1066 

 
ATS20ProtocolV4.0 04-30-18 
 
5-12 
3. Stereoacuity (nil versus better than nil) 
1067 
4. Presence of a near heterotropia at baseline (yes/no) 
1068 
5. Prior amblyopia treatment (yes/no)  
1069 
 
1070 
5.4.5.2 Effect of Binocular Treatment in Children Randomized to Continued 
1071 
Spectacles 
1072 
The following exploratory analyses will evaluate the effect of binocular treatment in children 
1073 
randomized to continued spectacles alone who are prescribed binocular treatment at the 8-week 
1074 
visit.   
1075 
• A point estimate and 95% confidence interval will be calculated for the mean change in 
1076 
amblyopic eye VA between the 8-week and 16-week visits while on binocular treatment.  
1077 
• The total amount of game play will be computed for the duration of binocular treatment as 
1078 
an estimate of compliance.    
1079 
• The distribution of scores on each symptom survey item will be described for the 8-week 
1080 
exam prior to starting binocular treatment and the 16-week exam after a period of binocular 
1081 
treatment.  The distribution of change in scores between 8 and 16 weeks on each symptom 
1082 
survey item will also be described 
1083 
 
 
1084 

 
ATS20ProtocolV4.0 04-30-18 
 
6-13 
CHAPTER 6: REFERENCES 
1085 
1. 
Holmes JM, Clarke MP. Amblyopia. Lancet. 2006;367(9519):1343-1351. 
1086 
2. 
Webber AL, Wood J. Amblyopia: Prevalence, natural history, functional effects and 
1087 
treatment. Clinical & Experimental Optometry. 2005;88(6):365-375. 
1088 
3. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 
1089 
treatment of moderate amblyopia in children. Arch Ophthalmol. 2002;120(3):268-278. 
1090 
4. 
Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized 
1091 
trial of atropine vs patching for treatment of moderate amblyopia in children. Arch 
1092 
Ophthalmol. 2005;123(2):149-157. 
1093 
5. 
Pediatric Eye Disease Investigator Group. A comparison of atropine and patching treatments 
1094 
for moderate amblyopia by patient age, cause of amblyopia, depth of amblyopia, and other 
1095 
factors. Ophthalmology. 2003;110(8):1632-1638. 
1096 
6. 
Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for 
1097 
treatment of moderate amblyopia in children. Arch Ophthalmol. 2003;121(5):603-611. 
1098 
7. 
Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching 
1099 
regimens for treatment of severe amblyopia in children. Ophthalmology. 
1100 
2003;110(11):2075-2087. 
1101 
8. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine regimens for 
1102 
treatment of moderate amblyopia in children. Ophthalmology. 2004;111(11):2076-2085. 
1103 
9. 
Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 
1104 
treatment of moderate amblyopia: Follow-up at age 10 years Arch Ophthalmol. 
1105 
2008;126(8):1039-1044. 
1106 
10. 
Repka MX, Kraker RT, Holmes JM, et al. Atropine vs patching for treatment of moderate 
1107 
amblyopia: Follow-up at 15 years of age of a randomized clinical trial. JAMA Ophthalmol. 
1108 
2014;132(7):799-805. 
1109 
11. 
Holmes JM, Lazar EL, Melia BM, et al. Effect of age on response to amblyopia treatment in 
1110 
children. Arch Ophthalmol. 2011;129(11):1451-1457. 
1111 
12. 
Pediatric Eye Disease Investigator Group. Patching vs atropine to treat amblyopia in 
1112 
children aged 7 to 12 years: A randomized trial. Arch Ophthalmol. 2008;126(12):1634-1642. 
1113 
13. 
Oliver M, Neumann R, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and results 
1114 
of treatment for amblyopia in children more than 8 years old. Am J Ophthalmol. 
1115 
1986;102(3):340-345. 
1116 
14. 
Pritchard C. Why won't you treat my 10 year old's lazy eye? Am Orthopt J. 1990;40:15-18. 
1117 
15. 
Loudon SE, Polling JR, Simonsz HJ. Electronically measured compliance with occlusion 
1118 
therapy for amblyopia is related to visual acuity increase. Graefes Arch Clin Exp 
1119 
Ophthalmol. 2003;241(3):176-180. 
1120 
16. 
Stewart CE, Moseley MJ, Stephens DA, Fielder AR, MOTAS Cooperative. Treatment dose-
1121 
response in amblyopia therapy: The monitored occlusion treatment of amblyopia study 
1122 
(motas). Invest Ophthalmol Vis Sci. 2004;45(9):3048-3054. 
1123 
17. 
Pediatric Eye Disease Investigator Group. Impact of patching and atropine treatment on the 
1124 
child and family in the amblyopia treatment study. Arch Ophthalmol. 2003;121(11):1625-
1125 
1632. 
1126 
18. 
Felius J, Chandler DL, Holmes JM, et al. Evaluating the burden of amblyopia treatment 
1127 
from the parent and child's perspective. J AAPOS. 2010;14(5):389-395. 
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