Trial Comparing Patching Versus Atropine for Amblyopia in 7 to < 13 Year Olds

Study Overview
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Brief Summary
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The purpose of this study is: To compare the effectiveness of weekend atropine plus near activities and daily patching plus near activities for moderate amblyopia (20/40 to 20/100) and severe amblyopia (20/125 to 20/400) in improving vision in the amblyopic eye of 7 to <13 year olds. To determine the maximum improvement in vision of the amblyopic eye with each treatment. To determine whether amblyopia is associated with structural abnormalities of optic nerve fiber layer.

Detailed Description
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Although there is consensus that amblyopia can be treated effectively in young children, many eye care practitioners believe that treatment beyond a certain age is ineffective. Some clinicians have believed that a treatment response is unlikely after the age of 6 or 7 years, while others have considered age 9 or 10 years to be the upper age limit for successful treatment. The American Academy of Ophthalmology Preferred Practice Pattern for amblyopia recommends treatment up to age 10 years. The opinion that amblyopia treatment is ineffective in older children may have arisen because the age of 6 to 7 years is thought to be the end of the critical period for visual development in humans. This belief, however, was not based on adequate prospectively-collected data. To address this issue of the response of amblyopia to treatment in children 7 years and older, the Pediatric Eye Disease Investigator Group (PEDIG) conducted a randomized trial of 507 patients (aged 7 to <18 years) with amblyopic eye visual acuity ranging from 20/40 to 20/400. Patients were provided with optimal optical correction and then randomized to a Treatment Group (2 to 6 hours per day of prescribed patching of the sound eye combined with near visual activities for all patients plus atropine one drop per day in the sound eye for 7 to <13 year olds) or an Optical Correction Group (optical correction alone). Patients whose amblyopic eye acuity improved 10 or more letters (2 lines) by 24 weeks were considered responders. In the 7 to <13 year olds (N=404), 53% of the Treatment Group were responders compared with 25% of the Optical Correction Group (P<0.001). In the 13 to <18 year olds (N=103), the responder rates were 25% and 23% respectively overall (adjusted P=0.22), but 47% and 20% respectively among patients not previously treated with patching and/or atropine for amblyopia (adjusted P=0.03). Most patients, including responders, were left with a residual visual acuity deficit. The use of multiple modalities (patching, atropine, near visual activities) in the treatment regimen for the 7 to <13 year olds in this trial (ATS3) was an effort to maximize the therapeutic response. Patients age 13 years and older were prescribed patching but not atropine because of concern that the continual optical blur from the atropine could have a deleterious effect on their ability to drive and perform other activities. Prescribed patching was 2 to 6 hours a day to limit patch wear to non-school hours and because our prior studies of 3 to <7 year olds demonstrated that as little as two hours of patching a day (when combined with near visual activities) is as effective as a greater number of hours. Instructing patients to perform at least one hour of near activities while wearing the patch was based on the unproven clinical opinion that near activities can augment the effect of the occlusion therapy. A PEDIG pilot study suggested that near activities are beneficial and this question of benefit of near activities is currently being studied in another randomized clinical trial. Atropine placed in the sound eye once a day and two days a week has been demonstrated in younger children to be beneficial to the acuity of the amblyopic eye, presumably due to its cycloplegic effect of blurring vision in the sound eye especially at near fixation. In a study comparing daily and weekend atropine, daily atropine was not found to be superior. The unanswered question from this completed clinical trial is whether prescribing patching or atropine alone could have produced a response similar to the combination therapy, or whether in this age group, one treatment is better than the other. A poll of PEDIG investigators at an investigator meeting on January 15, 2005 indicated that very few are following the treatment regimen used in the prior study (ATS3); rather, most are prescribing monotherapy-either patching or atropine-as the initial treatment for amblyopia in the 7 to <13 year age range. Thus, a trial comparing atropine and patching as amblyopia treatments in 7 to <13 year olds is needed. The study has been designed as a simple trial that, other than the type of amblyopia therapy being determined through the randomization process, approximates standard clinical practice. The two treatment regimes are: 1) Atropine 1% once each weekend day in the sound eye plus near activities for at least one hour every day without the aid of reading glasses (with increase to daily atropine at 5 weeks if acuity not improved by at least 5 letters) and 2) Patching 2 hours per day plus near activities for one hour while patching (with increase to 4 hours per day for moderate amblyopes and > 4 hours per day for severe amblyopes at 5 weeks if acuity not improved by at least 5 letters). Optional Ancillary Study As part of the optic nerve imaging ancillary study, retinal nerve fiber layer imaging using optical coherence tomography will be performed on some patients. This will be optional for patients at participating sites. The procedure is not part of standard care. The subject's pupils will need to be dilated, if not already dilated as part of the exam. Testing of both eyes can be completed in about 15 minutes.

Official Title
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A Randomized Trial Comparing Patching Versus Atropine for Amblyopia in 7 to < 13 Year Olds

Conditions
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Amblyopia

Intervention / Treatment
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* Drug: Atropine
* Device: Patching
* Procedure: Near activities


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 7 to 12 years old (inclusive) Amblyopia associated with strabismus, anisometropia, or both Visual acuity in the amblyopic eye 19 to 71 letters on Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS©) (20/40 to 20/400 inclusive) Visual acuity in the sound eye 79 letters or better on E-ETDRS© (20/25 or better) Interocular difference >=15 letters (3 lines) Spectacles, if needed, worn for at least 16 weeks or visual acuity documented to be stable Inclusion Criteria for Optional Ancillary Study: Enrolled into the main study Refractive error in both eyes between -0.25 and +5.00D, inclusive (to avoid the need to adjust for refractive error) Birth weight >1500 grams No history of Central Nervous System (CNS) disease (e.g. intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), meningitis, developmental abnormalities of the brain, hydrocephalus, cerebral palsy, hypoxic ischemic encephalopathy Exclusion Criteria: Amblyopia treatment (other than spectacles) in the last 6 months Myopia (more than -0.25D spherical equivalent) in either eye

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 12 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Patching<br>Patching 2 hours per day plus near activities for one hour while patching (with increase to 4 hours per day for moderate amblyopes and >4 hours per day for severe amblyopes at 5 weeks if acuity not improved at least 5 letters) | Device: Patching<br>* Patching 2 hours per day<br>* Other names: Coverlet, 3M Opticlude, Ortopad®;Procedure: Near activities<br>* near visual activities for at least one hour per day<br>|
| Active Comparator: Atropine<br>Atropine 1% once each weekend day in the sound eye plus near activities for at least one hour every day (with increase to daily atropine at 5 weeks if acuity not improved by at least 5 letters) | Drug: Atropine<br>* Atropine 1% each weekend day in the sound eye<br>Procedure: Near activities<br>* near visual activities for at least one hour per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of Visual Acuity in the Amblyopic Eye at 17 Weeks | Visual acuity was measured in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. | 17 weeks | 
| Mean Visual Acuity in the Amblyopic Eye at 17 Weeks | Visual acuity was measured in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. | 17 weeks | 
| Distribution of Change in Visual Acuity in the Amblyopic Eye From Baseline to 17 Weeks | Visual acuity was measured at baseline and 17 weeks in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. A difference between the scores at baseline and 17 weeks was calculated. A positive difference indicates acuity was better at 17 weeks than at baseline; a negative difference indicates acuity was worse at 17 weeks. | Baseline to 17 weeks | 
| Mean Change in Visual Acuity in the Amblyopic Eye From Baseline to 17 Weeks | Visual acuity was measured at baseline and 17 weeks in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. A difference between the scores at baseline and 17 weeks was calculated. A positive difference indicates acuity was better at 17 weeks than at baseline; a negative difference indicates acuity was worse at 17 weeks. | Baseline to 17 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stereoacuity Measured by the Randot Preschool Test at 17 or 19 Weeks- Participants With All Causes of Moderate Amblyopia | The Randot Preschool Stereotest measures stereopsis from 800 to 40 seconds of arc on patients as young as 2 years of age. This Stereotest is designed as a matching game in which the patient matches pictures in a test booklet wearing special glasses. A subject can fail the pretest (not see any pictures) or can score >800 (the worst), 800, 400, 200, 100, 60, or 40 (the best) seconds of arc. If two shapes are identified correctly the patient progresses to the next lower stereoacuity level. A failed test occurs when the patient cannot identify any shapes. | 17 or 19 weeks | 
| Stereoacuity Measured by the Randot Preschool Test at 17 or 19 Weeks- Anisometropic Participants With Moderate Amblyopia Only | The Randot Preschool Stereotest measures stereopsis from 800 to 40 seconds of arc on patients as young as 2 years of age. This Stereotest is designed as a matching game in which the patient matches pictures in a test booklet wearing special glasses. A subject can fail the pretest (not see any pictures) or can score >800 (the worst), 800, 400, 200, 100, 60, or 40 (the best) seconds of arc. If two shapes are identified correctly the patient progresses to the next lower stereoacuity level. A failed test occurs when the patient cannot identify any shapes. | 17 or 19 weeks | 
| Stereoacuity Measured by the Randot Preschool Test at 17 or 19 Weeks- Participants With Moderate Amblyopia From Strabismus Only or Combined Mechanism | The Randot Preschool Stereotest measures stereopsis from 800 to 40 seconds of arc on patients as young as 2 years of age. This Stereotest is designed as a matching game in which the patient matches pictures in a test booklet wearing special glasses. A subject can fail the pretest (not see any pictures) or can score >800 (the worst), 800, 400, 200, 100, 60, or 40 (the best) seconds of arc. If two shapes are identified correctly the patient progresses to the next lower stereoacuity level. A failed test occurs when the patient cannot identify any shapes. | 17 or 19 weeks | 
| Stereoacuity Measured by the Randot Preschool Test at 17 or 19 Weeks- Participants With All Causes of Moderate Amblyopia | Stereoacuity is scored as seconds of arc with values of: <800, 800, 400, 200, 100, 60, 40. The lower the arc second value, the better the score (i.e. 40 arc sec is best stereoacuity; <800 is the worst). A change score was defined as the difference between baseline and outcome in score level (i.e. moving from 800 at baseline to 400 at outcome is one level change, moving from 800 to 200 is two levels, etc.) change in levels was categorized as within one level meaning change was -1, 0, or +1. | 17 or 19 weeks | 
| Amblyopia Treatment Index - Social Stigma (Moderate Amblyopia Only) | Questionnaire scores on the Social Stigma subscale of the Amblyopia Treatment Index. Questions were evaluated on a likert type scale as strongly agree (5) to strongly disagree (1), with a higher number indicating worse response. | 17 weeks | 
| Amblyopia Treatment Index - Compliance (Moderate Amblyopia Only) | Questionnaire scores on the compliance subscale of the Amblyopia Treatment Index. Questions were evaluated on a likert type scale as strongly agree (5) to strongly disagree (1), with a higher number indicating worse response. | 17 weeks | 
| Amblyopia Treatment Index - Adverse Effects Scale (Moderate Amblyopia Only) | Questionnaire scores on the adverse events subscale of the Amblyopia Treatment Index. Questions were evaluated on a likert type scale as strongly agree (5) to strongly disagree (1), with a higher number indicating worse response. | 17 weeks | 
| Distribution of Visual Acuity in the Fellow Eye at 17 Weeks | Visual acuity was measured in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. | 17 weeks | 
| Mean Visual Acuity in the Fellow Eye at 17 Weeks | Visual acuity was measured in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. | 17 weeks | 
| Distribution of Change in Visual Acuity in the Fellow Eye From Baseline to 17 Weeks | Visual acuity was measured at baseline and 17 weeks in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. A difference between the scores at baseline and 17 weeks was calculated. A positive difference indicates acuity was better at 17 weeks than at baseline; a negative difference indicates acuity was worse at 17 weeks. | Baseline to 17 weeks | 
| Mean Change in Visual Acuity in the Fellow Eye From Baseline to 17 Weeks | Visual acuity was measured at baseline and 17 weeks in each eye using the electronic early treatment diabetic retinopathy study (E-ETDRS) method which resulted in a letter score that could range from 0 to 97 letters, with 0 being the worst and 97 being the best. A difference between the scores at baseline and 17 weeks was calculated. A positive difference indicates acuity was better at 17 weeks than at baseline; a negative difference indicates acuity was worse at 17 weeks. | Baseline to 17 weeks | 

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