Augmenting Atropine Treatment for Amblyopia in Children 3 to < 8 Years Old

Study Overview
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Brief Summary
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This study is designed to evaluate the effectiveness of adding a plano lens to weekend atropine after visual acuity has stabilized with weekend atropine but amblyopia is still present. Children ages 3 to <8 years with visual acuity of 20/50 to 20/400 in the amblyopic eye will be enrolled in a run-in phase with weekend atropine until no improvement, followed by randomization of eligible patients to weekend atropine treatment with a plano lens over the sound eye versus without a plano lens over the sound eye. The primary objective is to determine if adding a plano lens to weekend atropine will improve visual acuity in patients with amblyopia still present after visual acuity has stabilized with initial treatment.

Detailed Description
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Amblyopia is the most common cause of monocular visual impairment in both children and young and middle-aged adults. Both patching and atropine are accepted treatment modalities for the management of moderate amblyopia in children.1 Many practitioners prescribe weekend atropine as initial therapy for amblyopia. However, many children fail to achieve normal visual acuity in the amblyopic eye after treatment with this regimen. In a randomized trial conducted by PEDIG comparing atropine regimens, 58 of 83 patients with moderate amblyopia (70%) had amblyopic eye visual acuity of 20/32 or worse after 4 months of treatment with weekend atropine.2 In another PEDIG randomized trial comparing atropine with a plano lens versus without a plano lens for initial treatment of amblyopia, 60 of 84 patients with moderate amblyopia (71%) had amblyopic eye visual acuity of 20/32 or worse after 16 weeks of treatment with weekend atropine.3 When improvement stops after initial therapy and amblyopia is still present, treatment options include increasing the dosage of current treatment, switching to another treatment, maintaining the same treatment and dosage, or combining treatments. Many clinicians will add a plano lens over the sound eye to atropine treatment, in part because families using atropine have become comfortable with its use. This option is limited to children with hypermetropia in the sound eye. However, it is unknown whether adding a plano lens over the sound eye will improve amblyopic eye visual acuity more than continuing atropine alone in patients who have shown no improvement after initial treatment with atropine. In a PEDIG randomized trial comparing patching to atropine for initial treatment of amblyopia, a plano lens was prescribed for the sound eye for 55 patients who had not improved to 20/30 or at least 3 lines after 4 months of daily atropine use.1, 4 Their mean acuity improvement prior to using the plano lens was 1.0 line, compared with 1.6 lines after prescribing the plano lens. We are unaware of any reports of the response of treatment of amblyopia still present after initial treatment with weekend atropine.

Official Title
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Augmenting Atropine Treatment for Amblyopia in Children 3 to < 8 Years Old

Conditions
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Amblyopia

Intervention / Treatment
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* Drug: Atropine
* Device: Plano lens
* Drug: Atropine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Major Eligibility Criteria for Run-in Phase Age 3 to < 8 years Amblyopia associated with strabismus, anisometropia, or both Visual acuity in the amblyopic eye between 20/50 and 20/400 inclusive Visual acuity in the sound eye 20/32 or better and inter-eye acuity difference >3 logMAR lines Amblyopia treatment within the past 6 months subject to the following stipulations: No more than 6 weeks of any amblyopia treatment other than spectacles (except for patients being treated with atropine who are entering the study on treatment) No simultaneous treatment with patching and atropine No use of atropine in combination with the sound eye spectacle lens reduced by more than 1.50 D Maximum level of treatment within the past 6 months: Patching: up to 2 hours daily Atropine: up to once daily Wearing spectacles with optimal correction (if amblyopic eye acuity is 20/80 or better, then VA must be stable in glasses; if amblyopic eye acuity is 20/100 or worse, then spectacles and atropine can be initiated simultaneously). Hypermetropia and spectacle correction in sound eye of +1.50 D or more Eligibility Criteria for Randomization: Amblyopic eye acuity of 20/40 to 20/160 with an inter-ocular difference of >2 lines, or amblyopic eye acuity of 20/32 with 3 lines of IOD. Compliance with weekend atropine treatment based on investigator judgment. Exclusion Criteria: Currently using vision therapy or orthoptics Ocular cause for reduced visual acuity (nystagmus per se does not exclude the patient if the above visual acuity criteria are met) Prior intraocular or refractive surgery Known allergy to atropine or other cycloplegic drugs Down Syndrome present

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 7 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: Intensified treatment<br>Weekend atropine 1% with plano lens over the sound eye | Drug: Atropine<br>* Weekend atropine 1%<br>Device: Plano lens<br>* plano lens over the sound eye<br>|
| Active Comparator: Control<br>Weekend atropine 1% | Drug: Atropine<br>* Weekend atropine 1%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of 10-week Amblyopic-Eye Visual Acuity | The masked 10-week amblyopic eye visual acuity scores were tabulated for both treatment groups, and included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) with no imputation for missing data. The primary outcome analysis followed the intent-to-treat principle. Therefore, data from randomized participants were included in the analysis regardless of whether the assigned treatment was actually received or whether they deviated from treatment against protocol. In addition, randomized participants who were found to be ineligible upon subsequent review of enrollment data were included in the primary outcome analysis. | 10 weeks after randomization | 
| Mean 10-week Amblyopic-Eye Visual Acuity | The primary outcome analysis was a treatment group comparison of the masked 10-week amblyopic eye visual acuity using an analysis of covariance (ANCOVA) model, adjusting for visual acuity at randomization. The analysis included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) with no imputation for missing data. The primary outcome analysis followed the intent-to-treat principle. Therefore, data from randomized participants were included in the analysis regardless of whether the assigned treatment was actually received or whether they deviated from treatment against protocol. In addition, randomized participants who were found to be ineligible upon subsequent review of enrollment data were included in the primary outcome analysis. | 10 weeks after randomization | 
| Distribution of the Change in Amblyopic-Eye Visual Acuity | The change in 10-week amblyopic eye visual acuity scores since randomization was tabulated for both treatment groups, and included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) with no imputation for missing data. The primary outcome analysis followed the intent-to-treat principle. Therefore, data from randomized participants were included in the analysis regardless of whether the assigned treatment was actually received or whether they deviated from treatment against protocol. In addition, randomized participants who were found to be ineligible upon subsequent review of enrollment data were included in the primary outcome analysis. | Randomization to 10 weeks | 
| Mean Change in Amblyopic-Eye Visual Acuity at 10 Weeks From Randomization | The change in 10-week amblyopic eye visual acuity was computed for both treatment groups and included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) with no imputation for missing data. The primary outcome analysis followed the intent-to-treat principle. Therefore, data from randomized participants were included in the analysis regardless of whether the assigned treatment was actually received or whether they deviated from treatment against protocol. In addition, randomized participants who were found to be ineligible upon subsequent review of enrollment data were included in the primary outcome analysis. | Randomization to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Group Comparison of the Proportion of Participants Who Achieved 20/25 or Better Visual Acuity at 10 Weeks Since Randomization | The proportion of participants who achieved 20/25 or better visual acuity since randomization was computed at the 10-week outcome. The secondary outcome analysis was a treatment group comparison of the proportion of participants whose 10-week masked amblyopic eye visual acuity was 20/25 or better since randomization. The analysis included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) according to the principles specified in the primary outcome analysis. | 10 weeks after randomization | 
| Treatment Group Comparison of the Proportion of Participants Who Have Improved by 2 or More logMAR Visual Acuity Lines at 10 Weeks Since Randomization | The proportion of participants who improved at least 2 logMAR lines since randomization was computed at the 10-week outcome. The secondary outcome analysis was a treatment group comparison of the proportion of participants whose 10-week masked amblyopic eye visual acuity improved at least 2 logMAR lines since randomization using logistic regression, adjusting for visual acuity at randomization. The analysis included data from 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) according to the principles specified in the primary outcome analysis. | 10 weeks after randomization | 
| Spectacle Compliance at 10 Weeks by Treatment Group | The distribution of compliance with prescribed treatment was tabulated for the 10-week outcome. Compliance was evaluated as excellent (>75%), good (51%-75%), fair (26%-50%), or poor (<26%) based on discussions with the parent and by reviewing study calendars maintained by the parent, who recorded the frequency of atropine administration. | 10 weeks after randomization | 
| Average Spectacle Compliance by Treatment Group | The distribution of compliance with prescribed treatment was tabulated for the 10-week outcome and as averaged scores across all study follow-up visits. Compliance was evaluated as excellent (>75%), good (51%-75%), fair (26%-50%), or poor (<26%) based on discussions with the parent and by reviewing study calendars maintained by the parent, who recorded the frequency of atropine administration. | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Atropine Compliance at 10 Weeks by Treatment Group | The distribution of compliance with prescribed treatment was tabulated for the 10-week outcome. Compliance was evaluated as excellent (>75%), good (51%-75%), fair (26%-50%), or poor (<26%) based on discussions with the parent and by reviewing study calendars maintained by the parent, who recorded the frequency of atropine administration. | 10 weeks after randomization | 
| Average Atropine Compliance by Treatment Group | The distribution of compliance with prescribed treatment was tabulated for the 10-week outcome and as averaged scores across all study follow-up visits. Compliance was evaluated as excellent (>75%), good (51%-75%), fair (26%-50%), or poor (<26%) based on discussions with the parent and by reviewing study calendars maintained by the parent, who recorded the frequency of atropine administration. | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Distribution of Interocular Difference at 12-week Exam | Distribution of Interocular Difference Between Eyes at 12-week Exam | 12 weeks after randomization | 
| Mean Interocular Difference at 12-week Exam | Mean Interocular Difference Between Eyes at 12-week Exam | 12 weeks after randomization | 
| Distribution of 12-week Fellow-Eye Visual Acuity | Following the 10-week primary outcome exam, participants discontinued the randomized treatment and returned 2 weeks later for a 12-week visit to measure off-treatment fellow-eye visual acuity. | 12 weeks after randomization | 
| Mean Fellow-Eye Visual Acuity at 12-week Exam |  | 12 weeks after randomization | 
| Distribution of Change in Fellow-Eye Visual Acuity at 12 Weeks From Randomization |  | 12 weeks after randomization | 
| Mean Change in Fellow-Eye Visual Acuity at 12 Weeks From Randomization |  | 12 weeks after randomization | 
| Distribution of Baseline Characteristics at the 10-week Outcome | The number of participants was tabulated by treatment group within categorical levels of prespecified baseline subgroup factors for participants with 10-week visual acuity exams completed between 8 to 15 weeks (inclusive) according to principles specified in the primary outcome analysis. | 10 weeks after randomization | 
| Mean Amblyopic Eye Visual at Randomization According to Baseline Characteristics for 10-week Outcome | Mean amblyopic eye visual acuity at randomization was computed by treatment group within categorical levels of prespecified baseline subgroup factors. The analysis included data from participants with 10-week exams completed between 8 to 15 weeks (inclusive) according to the principles specified in the primary outcome analysis. | 10 weeks after randomization | 
| Treatment Comparison of Mean Amblyopic Eye Visual Acuity Change at 10-weeks According to Baseline Characteristics | A treatment comparison of mean amblyopic eye visual acuity change since randomization was performed at the 10-week outcome according to categorical levels of prespecified baseline subgroup factors. The analysis included data from participants with 10-week exams completed between 8 to 15 weeks (inclusive) according to the principles specified in the primary outcome analysis. | 10 weeks after randomization | 
| Distribution of Amblyopic-Eye Visual Acuity at Best Outcome Visit | Participants in both groups who have improved by one or more lines from randomization to the 10-week outcome exam will continue in the study and visits will occur every 10 weeks until no improvement of one or more lines from the previous visit. The distribution of best post-randomization (10 weeks or later) visual acuity scores in the amblyopic eye was tabulated for both treatment groups using the initial visual acuity score (if a retest was obtained.) | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Mean Amblyopic-Eye Visual Acuity at Best Outcome Visit | Participants in both groups who have improved by one or more lines from randomization to the 10-week outcome exam will continue in the study and visits will occur every 10 weeks until no improvement of one or more lines from the previous visit. A treatment comparison of mean amblyopic eye visual acuity at the visit of best post-randomization visual acuity (10 weeks or later) was performed using an analysis of covariance, adjusting for amblyopic eye visual acuity at randomization. | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Distribution of Change in Amblyopic-Eye Visual Acuity From Randomization to Best Outcome Visit | Participants in both groups who have improved by one or more lines from randomization to the 10-week outcome exam will continue in the study and visits will occur every 10 weeks until no improvement of one or more lines from the previous visit. The distribution of change in best post-randomization (10 weeks or later) visual acuity in the amblyopic eye since randomization was tabulated for both treatment groups using the initial visual acuity score (if a retest was obtained.) | Randomization to 10 weeks or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Mean Change in Amblyopic-Eye Visual Acuity at Best Outcome Visit | Participants in both groups who have improved by one or more lines from randomization to the 10-week outcome exam will continue in the study and visits will occur every 10 weeks until no improvement of one or more lines from the previous visit. The mean change in amblyopic eye visual acuity since randomization was computed for both treatment groups based on the visit of best post-randomization visual acuity (10 weeks or later) using the initial visual acuity score (if a retest was obtained.) | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Treatment Group Comparison of the Proportion of Participants Who Have Improved by 2 or More logMAR Visual Acuity Lines Based on Visual Acuity at Best Outcome Visit |  | 10 weeks after randomization or later (until no further VA improvement, up to maximum of 84 weeks for one subject) | 
| Distribution of Randot Preschool Stereoacuity Score at 12 Weeks | Distribution of Randot Preschool Stereoacuity Score at 12 Weeks; Participants with a Randot Preschool test of >800 seconds of arc were classified as having a stereoacuity of 3000 seconds of arc if the Titmus fly test was positive or as nil if the Titmus fly test was negative. | 12 weeks after randomization | 
| Distribution of Randot Preschool Stereoacuity Scores at 12 Weeks for Participants With Anisometropic Amblyopia |  | 12 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amblyopia, atropine, Plano lens