Study of Binocular Computer Activities for Treatment of Amblyopia

Study Overview
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Brief Summary
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The purpose of the study is to compare the effectiveness of 1 hour/day of binocular game play 7 days per week with 2 hours/day patching 7 days per week in children 5 to <17

Detailed Description
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The purpose of the study is to 1) compare the effectiveness of 1 hour/day of binocular game play 7 days per week (minimum of 4 days per week) with 2 hours/day patching 7 days per week, in children 5 to <13 years of age (younger cohort), as a non-inferiority study; and 2) to compare the effectiveness of 1 hour/day of binocular game play 7 days per week (minimum of 4 days per week) with 2 hours/day patching 7 days per week, in children 13 to <17 years of age (older cohort), as a superiority study.

Official Title
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Study of Binocular Computer Activities for Treatment of Amblyopia

Conditions
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Amblyopia

Intervention / Treatment
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* Device: iPad®
* Other: Patching 2 hours per day, 7 days per week


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 5 to <17 years Amblyopia associated with strabismus, anisometropia, or both (previously treated or untreated) 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 spectacles) Documented history of strabismus which is no longer present (which in the judgment of the investigator could have caused amblyopia) Criteria for anisometropia: At least one of the following criteria must be met: ≥0.50 diopter (D) difference between eyes in spherical equivalent ≥1.50 D difference between eyes in astigmatism in any meridian 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 between eyes in astigmatism in any meridian Note: the spherical equivalent requirement differs from that in the definition for refractive/anisometropic amblyopia No amblyopia treatment in the past 2 weeks (patching, atropine, Bangerter, vision therapy) Refractive correction (spectacles or contact lenses, if applicable) must meet the following criteria at enrollment and be based on a cycloplegic refraction that is not more than 7 months old. Requirements for Correction of Refractive Error: For subjects meeting criteria for strabismic (only) amblyopia (see 2.2.1 #2 above): • Hypermetropia, if corrected, must not be under-corrected by more than +1.50 D spherical equivalent, and the reduction in plus sphere must be symmetric in the two eyes. For subjects meeting criteria for anisometropic or combined-mechanism amblyopia (see 2.2.1 #2 above): Spherical equivalent must be within 0.50 D of fully correcting the anisometropia Hypermetropia must not be under-corrected by more than +1.50 D spherical equivalent, and reduction in plus must be symmetric in the two eyes Cylinder power in both eyes must be within 0.50 D of fully correcting the astigmatism Cylinder axis for both eyes must be within 6 degrees of the axis of the cycloplegic refraction when cylinder power is ≥1.00 D Refractive corrections meeting the above criteria must be worn for either: 16 weeks or more or Until visual acuity in amblyopic eye is stable (defined as 2 consecutive visual acuity measurements by the same testing method at least 4 weeks apart with <1 line change (<5 letters if E-ETDRS)) Monocular or binocular contact lens wear is allowed provided the contact lenses meet the above refractive requirements at the corneal plane. The same form of correction must be worn throughout the entire study during study procedures (i.e., no changing between contacts and spectacles while patching or while game-playing or study testing). Safety glasses are not required for subjects wearing contact lenses, but investigators are encouraged to suggest safety glasses be worn over contact lenses. Visual acuity, measured in each eye without cycloplegia in current refractive correction (if applicable) within 7 days prior to randomization using the Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children < 7 years and the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-approved device displaying single surrounded optotypes, as follows: Visual acuity in the amblyopic eye 20/40 to 20/200 inclusive (33 to 72 letters if E-ETDRS) Visual acuity in the fellow eye 20/25 or better (≥ 78 letters if E-ETDRS) Interocular difference ≥ 3 logMAR lines (≥ 15 letters if E-ETDRS) (i.e., amblyopic-eye acuity at least 3 logMAR lines worse than fellow-eye acuity) Heterotropia or heterophoria with a total near deviation of ≤ 10∆ (measured by PACT). Ability to align the nonius cross on the binocular game system (angles of ocular deviation >10∆ would require the nonius cross to be adjusted to such an extent that playing of the game would be compromised). Subject is able to play Hess Falling Blocks game on the study iPad® (on easy setting) under binocular conditions (with red-green glasses), as demonstrated by scoring at least 1 line in the office. Investigator is willing to prescribe computer game play or patching per protocol. Parent understands the protocol and is willing to accept randomization. Parent has phone (or access to phone) and is willing to be contacted by Jaeb Center staff. Relocation outside of area of an active Pediatric Eye Disease Investigator Group (PEDIG) site for this study within the next 16 weeks is not anticipated. Exclusion Criteria: A subject is excluded for any of the following reasons: Prism in the refractive correction at time of enrollment (eligible only if prism is discontinued 2 weeks prior to enrollment). Myopia greater than -6.00 D spherical equivalent in either eye. Previous intraocular or refractive surgery. Any treatment for amblyopia (patching, atropine, Bangerter filter, or vision therapy) during the past 2 weeks. Previous amblyopia therapy is allowed regardless of type, but must be discontinued at least 2 weeks immediately prior to enrollment. Ocular co-morbidity that may reduce visual acuity determined by an ocular examination performed within the past 7 months (Note: nystagmus per se does not exclude the subject if the above visual acuity criteria are met). No Down syndrome or cerebral palsy 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. Heterotropia or heterophoria with a total ocular deviation >10∆ (phoria plus tropia >10∆) at near (measured by PACT).

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Binocular Treatment<br>Binocular computer game play 1 hour per day, 7 days per week (minimum of 4 days per week) | Device: iPad®<br>* Binocular therapy on iPad®<br>|
| Active Comparator: Patching Treatment<br>Patching 2 hours per day, 7 days per week | Other: Patching 2 hours per day, 7 days per week<br> <br> * Other names: Patching;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Distance Visual Acuity From Baseline in the Younger Cohort (5 to <13 Years) | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the younger cohort, the level of visual acuity is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (approximate range: -0.2 to 1.7) such that higher scores indicate poorer VA. Change in VA is computed as logMAR lines (positive values indicate improvement), defined as the difference between the enrollment and 16-week acuities (logMAR) multiplied by 10. | Baseline and 16 weeks | 
| Mean Amblyopic Eye Visual Acuity (Younger Cohort) | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the younger cohort, the level of visual acuity is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (approximate range: -0.2 to 1.7) such that higher scores indicate poorer VA. | 16 Weeks from baseline | 
| Mean Change in Amblyopic-eye Visual Acuity in the Older Cohort (13 to <17 Years) | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the analyses in the older cohort, the level of VA is measured as letter scores (approximate range: 0 to 97 letters, lower scores indicate poorer VA) and change in VA from baseline is measured in letters (positive values indicate improvement), defined as the difference in letter scores between enrollment and follow-up. | Baseline and 16 weeks | 
| Mean Amblyopic-eye Visual Acuity in the Older Cohort (13 to <17 Years) | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the analyses in the older cohort, the level of VA is measured as letter scores (approximate range: 0 to 97 letters, lower scores indicate poorer VA) and change in VA from baseline is measured in letters (positive values indicate improvement), defined as the difference in letter scores between enrollment and follow-up. | 16 weeks | 
| Distribution of Change in Amblyopic-eye Visual Acuity | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. Younger cohort: The level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (previously defined) and change in VA from baseline as logMAR lines (previously defined). Older cohort: The level of VA is measured as letter scores (previously defined) and VA change from baseline is measured in letters (previously defined). | Baseline and 16 weeks | 
| Distribution of Amblyopic-eye Visual Acuity | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. Younger cohort: The level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (previously defined) and change in VA from baseline as logMAR lines (previously defined). Older cohort: The level of VA is measured as letter scores (previously defined) and VA change from baseline is measured in letters (previously defined). | At 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Amblyopic-eye VA Improvement of 2 or More logMAR Lines (10 or More Letters if E-ETDRS) From Baseline | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. Younger cohort: The level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (previously defined) and change in VA from baseline as logMAR lines (previously defined). Older cohort: The level of VA is measured as letter scores (previously defined) and VA change from baseline is measured in letters (previously defined). | Baseline and 16-week visit | 
| Number of Participants With Resolution of Amblyopia | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. The level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (previously defined) for the younger cohort and as letter scores (previously defined) for the older cohort. Resolution of amblyopia was defined as having an amblyopic-eye VA of 20/25 or better (≥ 78 letters if E-ETDRS) and within 1 logMAR line (5 letters if E-ETDRS) of the fellow eye VA. | 16-week visit | 
| Time Course of Visual Acuity Improvement | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the younger cohort, the level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (approximate range: -0.2 to 1.7, higher values indicate poorer VA) and change in VA from baseline as logMAR lines (positive values indicate improvement), defined as the difference between the enrollment and follow-up acuities (logMAR) multiplied by 10. | Baseline, 4 weeks, 8 weeks, 12 weeks and 16 weeks | 
| Younger Cohort: Change in Distance Visual Acuity From Baseline According to Subgroups | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the electronic Amblyopia Treatment Study single-surround HOTV (ATS-HOTV) visual acuity protocol for children <7 years and the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the younger cohort, the level of VA is analyzed in the log of the Minimum Angle of Resolution (logMAR) scale (previously defined) and change in VA from baseline as logMAR lines (previously defined, positive values indicate improvement), For both descriptive and formal subgroup analyses, all subgroup factors were pre-specified except for baseline stereoacuity (nil, better than nil). We performed post hoc descriptive analyses to explore treatment effect by baseline age (5 to <7 yrs, 7 to <13 yrs) and prior amblyopia treatment (yes/no). | Baseline and 16 weeks | 
| Older Cohort: Change in Distance Visual Acuity From Baseline According to Subgroups | Monocular distance visual acuity (VA) in current refractive correction (if required) in each eye by a certified examiner using the Electronic Early Treatment Diabetic Retinoscopy Study (E-ETDRS) visual acuity protocol for children ≥ 7 years on a study-certified acuity tester displaying single surrounded optotypes. For the analyses in the older cohort, the level of VA is measured as letter scores (previously defined) and change in VA from baseline is measured in letters (positive values indicate improvement), defined as the difference in letter scores between enrollment and follow-up. Subgroup factors of interest were pre-specified except for baseline stereoacuity (nil, better than nil). | Baseline and 16 weeks | 
| Distribution of Stereoacuity Scores | Stereoacuity was tested at near in current refractive correction. Stereoacuity scores (measure as seconds of arc) were calculated based on the Randot Butterfly (scores: 2000, Nil) and Randot Preschool stereoacuity (scores: 800, 400, 200, 100, 60 and 40) test methods. Lower scores indicate better stereoacuity. Results of the Randot Butterfly test were analyzed as 2000 seconds of arc (if correct response). Nil was assigned a score of 4000 seconds of arc and was defined as (1) an incorrect response on the butterfly in absence of a correct response on the 800 seconds of arc level of the Randot Preschool stereoacuity test or (2) an incorrect response on the 800 seconds of arc level if the butterfly was not attempted. | 16 weeks | 
| Median Stereoacuity Score (Seconds of Arc) | Stereoacuity was tested at near in current refractive correction. Stereoacuity scores (measure as seconds of arc) were calculated based on the Randot Butterfly (scores: 2000, Nil) and Randot Preschool stereoacuity (scores: 800, 400, 200, 100, 60 and 40) test methods. Lower scores indicate better stereoacuity. Results of the Randot Butterfly test were analyzed as 2000 seconds of arc (if correct response). Nil was assigned a score of 4000 seconds of arc and was defined as (1) an incorrect response on the butterfly in absence of a correct response on the 800 seconds of arc level of the Randot Preschool stereoacuity test or (2) an incorrect response on the 800 seconds of arc level if the butterfly was not attempted. A logarithm base 10 transformation was used to convert stereoacuity scores (seconds of arc) to the log scale (conversion reference listed below), which was used to calculate descriptive statistics. Results of the descriptive analyses are reported as seconds of arc. | 16 weeks | 
| Distribution of Stereoacuity Scores (Participants With no History of Strabismus) | Stereoacuity was tested at near in current refractive correction. Stereoacuity scores (measure as seconds of arc) were calculated based on the Randot Butterfly (scores: 2000, Nil) and Randot Preschool stereoacuity (scores: 800, 400, 200, 100, 60 and 40) test methods. Lower scores indicate better stereoacuity. Results of the Randot Butterfly test were analyzed as 2000 seconds of arc (if correct response). Nil was assigned a score of 4000 seconds of arc and was defined as (1) an incorrect response on the butterfly in absence of a correct response on the 800 seconds of arc level of the Randot Preschool stereoacuity test or (2) an incorrect response on the 800 seconds of arc level if the butterfly was not attempted. | 16 weeks | 
| Distribution of Change in Stereoacuity Scores From Baseline | Stereoacuity was tested at near in current refractive correction. Stereoacuity scores (seconds of arc) were calculated based on the Randot Butterfly (scores: 2000, Nil) and Randot Preschool stereoacuity (scores: 800, 400, 200, 100, 60 and 40) test methods. Lower scores indicate better stereoacuity. Results of the Randot Butterfly test were analyzed as 2000 (if correct response). Nil (4000 ) was defined as (1) an incorrect response on the butterfly in absence of a correct response on the 800 seconds of arc level of the Randot Preschool stereoacuity test or (2) an incorrect response on the 800 seconds of arc level if the butterfly was not attempted. For each visit, stereoacuity scores were ordered and assigned a rank score. Change in stereoacuity was calculated as the difference in ranked score between the enrollment and 16-week stereoacuity scores. | Baseline and 16 weeks | 
| Distribution of Change in Stereoacuity Scores From Baseline (Participants With no History of Strabismus) | Stereoacuity was tested at near in current refractive correction. Stereoacuity scores (seconds of arc) were calculated based on the Randot Butterfly (scores: 2000, Nil) and Randot Preschool stereoacuity (scores: 800, 400, 200, 100, 60 and 40) test methods. Lower scores indicate better stereoacuity. Results of the Randot Butterfly test were analyzed as 2000 (if correct response). Nil (4000 ) was defined as (1) an incorrect response on the butterfly in absence of a correct response on the 800 seconds of arc level of the Randot Preschool stereoacuity test or (2) an incorrect response on the 800 seconds of arc level if the butterfly was not attempted. For each visit, stereoacuity scores were ordered and assigned a rank score. Change in stereoacuity was calculated as the difference in ranked score between the enrollment and 16-week stereoacuity scores. | Baseline and 16 weeks | 
| Binocular Treatment Group: Adherence and Fellow-eye Contrast (iPad Log File Data) | Participants assigned to binocular treatment were prescribed the binocular falling blocks game for 1 hour per day (allowing division into shorter sessions), 7 days per week for 16 weeks, with instructions to perform therapy a minimum of 4 days per week if unable to play for 7 days per week. The iPad device automatically recorded duration of game play, fellow-eye contrast, and performance. Adherence was calculated as the total hours of game play since baseline divided by the total prescribed hours (based on intended dose of 1 hour a day, 7 days per week) since baseline. The fellow-eye contrast was initially set to 20% (amblyopic eye always at 100%) and automatically increased or decreased by 10% increments (lowest level of 10%) or left unchanged from the last contrast level, based on the previous day's game play duration (at least 30 minutes required for contrast change) and performance (increased if scored 1000 points or more). Post hoc analysis: 4-week fellow-eye contrast. | Entire study period, up to 16 weeks | 
| Binocular Treatment Group: Median Adherence With Prescribed Game Play (iPad Log File Data) | Participants assigned to binocular treatment were prescribed the binocular falling blocks game for 1 hour per day (allowing division into shorter sessions), 7 days per week for 16 weeks, with instructions to perform therapy a minimum of 4 days per week if unable to play for 7 days per week. The iPad device automatically recorded duration of game play, fellow-eye contrast, and performance. Adherence was calculated as the % of prescribed treatment actually completed: total hours of game play since baseline divided by the total prescribed hours (based on intended dose of 1 hour a day, 7 days per week) since baseline. | Entire study period, up to 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amblyopia