Appendix Table A1.

Study Inclusion and Exclusion Criteria.

ELIGIBILITY CRITERIA

The following criteria must be met for the patient to be enrolled in the study:

1.  Age 4 to <7 years

2.  Amblyopia associated with strabismus, anisometropia, or both (previously treated or untreated)

a.  Criteria for strabismus: At least one of the following must be met:

• Presence of a heterotropia on examination at distance or near fixation (with or without optical correction), must be no more than 4pd by SPCT at near fixation.

• Documented history of strabismus which is no longer present

b.  Criteria for anisometropia: At least one of the following criteria must be met:

• ≥1.00 D difference between eyes in spherical equivalent

• ≥1.50 D difference in astigmatism between corresponding meridians in the two eyes

c.  Criteria for combined-mechanism amblyopia: Both of the following criteria must be met:

• Criteria for strabismus are met (see above)

• ≥1.00 D difference between eyes in spherical equivalent OR ≥1.50 D difference in astigmatism between corresponding meridians in the two eyes

3.  No amblyopia treatment in the past 2 weeks (patching, atropine, Bangerter, vision therapy, binocular treatment)

4.  Requirements for required refractive error correction (based on a cycloplegic refraction (CR) within the last 7 months:

• Hypermetropia of 2.50D or more by spherical equivalent (SE)

• Myopia of amblyopic eye of 0.50D or more SE

• Astigmatism of 1.00D or more

• Anisometropia of more than 0.50D SE

Note: Subjects with cycloplegic refractive errors that do not fall within the requirements above for spectacle correction may be given spectacles at investigator discretion but must follow the study-specified prescribing guidelines, as detailed below.

a.  Spectacle prescribing instructions referenced to the CR completed within the last 7 months:

•SE must be within 0.50D of fully correcting the anisometropia.

•SE must not be under corrected by more than 1.50D SE, and reduction in plus sphere must be symmetric in the two eyes.

•Cylinder power in both eyes must be within 0.50D of fully correcting the astigmatism.

•Cylinder axis must be within +/− 10 degrees if cylinder power is ≤1.00D, and within +/− 5 degrees if cylinder power is >1.00D.

•Myopia must not be under-corrected by more than 0.25D or over corrected by more than 0.50D SE, and any change must be symmetrical in the two eyes.

b.  Spectacle correction meeting the above criteria must be worn:

• 16 weeks OR until VA stability is documented (defined as <0.1 logMAR change by the same testing method measured on 2 consecutive exams at least 8 weeks apart).

o  Determining visual acuity stability (non-improvement):The first of two measurements may be made 1) in current correction, or 2) in trial frames with or without cycloplegia or 3) without correction (if new correction is prescribed),

o  The second measurement must be made without cycloplegia in the correct spectacles that have been worn for at least 8 weeks.

Note: since this determination is a pre-study procedure, the method of measuring visual acuity is not mandated.

5.  Visual acuity, measured in each eye without cycloplegia incurrent spectacle correction (if applicable) within 7 days prior to randomization using the ATS-HOTV VA protocol for children < 7 years on a study-approved device displaying single surrounded optotypes, as follows:

a.  VA in the amblyopic eye 20/40 to 20/200 inclusive (ATS-HOTV)

b.  Best-corrected fellow-eye VA meeting the following criteria:

• If age 4, 20/40 or better by ATS-HOTV

• If age 5 or 6, 20/32 or better by ATS-HOTV

c.  IOD ≥ 3 logMAR lines (ATS-HOTV)

6.  Heterotropia with a near deviation of < 5Δ (measured by SPCT) in habitual correction

7.  Subject able to play the Dig Rush game (at least level 3) on the study iPad® under binocular conditions (with red-green glasses). Subject must be able to see both the red “diggers” and blue “gold carts” when contrast is at 20% for the non- amblyopic eye.

8.  Investigator is willing to prescribe computer game play, or continue spectacle wear per protocol.

9.  Parent understands the protocol and is willing to accept randomization.

10.  Parent has phone (or access to phone) and is willing to be contacted by Jaeb Center staff or other study staff.

11.  Relocation outside of area of an active PEDIG site for this study within the next 8 weeks is not anticipated.

EXCLUSION CRITERIA

1.  Prism in the spectacle correction at time of enrollment (eligible only if prism is discontinued 2 weeks prior to enrollment).

2.  Myopia greater than −6.00D spherical equivalent in either eye.

3.  Previous intraocular or refractive surgery.

4.  Any treatment for amblyopia (patching, atropine, Bangerter filter, or previous binocular treatment) during the past 2 weeks. Previous amblyopia therapy is allowed regardless of type, but must have been discontinued at least 2 weeks prior to enrollment.

5.  Ocular co-morbidity that may reduce VA determined by an ocular examination performed within the past 7 months.

6.  (Note: nystagmus per se does not exclude the subject if the above visual acuity criteria are met).

7.  No Down syndrome or cerebral palsy

8.  No severe developmental delay that would interfere with treatment or evaluation (in the opinion of the investigator). Subjects with mild speech delay or reading and/or learning disabilities are not excluded.

9.  Subject has demonstrated previous low compliance with binocular treatment and/or spectacle treatment (as assessed by investigator)

logMAR = logarithm of minimum angle of resolution; Δ = prism diopters; SD = standard deviation; SPCT = simultaneous prism and cover testATS-HOTV = Amblyopia Treatment Study HOTV; VA = visual acuity; PEDIG = Pediatric Eye Disease Investigator Group