Observation Versus Occlusion Therapy for Intermittent Exotropia

Study Overview
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Brief Summary
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The present study is being conducted to assess the natural history of intermittent exotropia and to establish the effectiveness of occlusion in its treatment. Study Objectives: To determine the effectiveness of occlusion for the treatment of intermittent exotropia among patients aged 3 to < 11 years who have baseline near stereoacuity of 400 arcsec or better by Preschool Randot stereotest To determine the natural history of intermittent exotropia among patients aged 3 to < 11 years who have baseline near stereoacuity of 400 arcsec or better by Preschool Randot stereotest

Detailed Description
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Intermittent exotropia (IXT) is the most common form of childhood-onset exotropia with an incidence of 32.1 per 100,000 in children under 19 years of age. Intermittent exotropia is characterized by an exotropia that is not constant and is mainly present in the distance but may also be present at near. Many cases of IXT are treated using non-surgical interventions, such as part-time occlusion, fusional vergence exercises, and over-minus lenses. The rationale for such interventions is that they may improve the ability to control the IXT and preserve stereoacuity, thereby potentially addressing both visual function and social concerns, and may delay or eliminate the need for surgical correction of IXT. Nevertheless, the natural history of IXT is unknown and in many cases it is not known whether withholding treatment may in fact allow for spontaneous resolution or improvement in IXT, making non-surgical or surgical intervention unnecessary. Moreover, although non-surgical treatments for IXT are commonly prescribed, such treatments have not been subjected to rigorous study and their efficacy in improving visual function or social concerns remains unclear. One aim of the present study is to better understand the natural history of IXT. Available reports on the natural history of IXT disagree on the progression of the disease. A 1966 study by von Noorden (cited in von Noorden and Campos) found that over an average of 3.5 years of follow-up, 75% of 51 patients showed signs of IXT progression, 9% showed no change, and 16% improved without therapy. A 1968 retrospective study by Hiles et al found that after a minimum of 6 years follow up with observation and nonsurgical treatment, 81% of 48 patients showed no change in angle of deviation. The results of more recent retrospective studies show some reporting that the majority of cases improve over time, others reporting that most cases remain stable, and still others reporting that most cases deteriorate. It is therefore unclear what proportion of patients, if left untreated, is likely to deteriorate, improve, or remain stable over time. Natural history data acquired during this study will help determine not only what proportion of patients change over time, but whether there are associated prognostic indicators of deterioration or improvement. Such data will not only enable better identification of those patients with IXT likely to benefit from treatment and those for whom treatment is likely to be unnecessary, but will also improve the quality of medical advice to parents regarding the likely progression of the disease, thus alleviating anxiety. The aim of most forms of non-surgical treatments for IXT is to improve the strength and/or quality of binocular single vision by either eliminating suppression, increasing awareness of diplopia, and/or increasing positive fusional amplitudes. Commonly used non-surgical treatment methods include: occlusion, fusional vergence exercises (sometimes known as vision therapy or orthoptics), and over-minus lenses. When surveyed in 1990, members of the American Association for Pediatric Ophthalmology and Strabismus reported that occlusion was the most commonly used form of non-surgical treatment. More recently (2008), a poll of our investigator group revealed again that occlusion was the most widely prescribed non-surgical treatment for children affected by IXT. Occlusion is thought to work by interrupting the development of or eliminating already present suppression, an adaptation to avoid diplopia in IXT. Persistent or entrenched suppression prevents normal binocular vision and may lead to permanent loss of stereoacuity. If successful, occlusion may then result in improved binocular sensory fusion. As reported in recent reviews of treatment for IXT, previous studies of occlusion vary regarding the recommended occlusion dose (from 3 hours a day to full time), the optimum duration of occlusion treatment (from 6 weeks to 42 months), and which eye should be occluded (preferred/dominant eye or alternate eyes). For the majority of studies, part-time occlusion, rather than full-time occlusion was preferred. In the three occlusion studies conducted prospectively, the recommended dose was either 3 hours a day, 3 to 6 hours a day, or 4 to 6 hours a day, and the duration of occlusion ranged from 3 months to 6 months to up to 42 (mean 15) months. Nevertheless, these previous studies of occlusion for the treatment of IXT used a variety of outcome measures at a variety of non-standardized time points; therefore, no definite conclusions can be drawn from the existing literature. Although occlusion treatment for IXT treatment is widely used, there have been no randomized clinical trials evaluating its effectiveness. Understanding the degree of effectiveness of occlusion treatment for IXT and the natural history of IXT has important public health implications. Successful restoration of binocular alignment and normal binocular function with occlusion therapy, or spontaneous improvement, will reduce the proportion of children undergoing surgery. Defining the rate of success with either occlusion or observation is therefore important in planning treatment for children with IXT. Alternatively, evidence of low treatment effectiveness with occlusion will help avoid unnecessary treatment. The present study is being conducted to assess the natural history of IXT and to establish the effectiveness of occlusion in its treatment.

Official Title
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A Randomized Clinical Trial of Observation Versus Occlusion Therapy for Intermittent Exotropia

Conditions
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Exotropia

Intervention / Treatment
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* Device: occlusion treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12 months to < 11 years Intermittent exotropia (manifest deviation) meeting all of the following criteria: Intermittent exotropia at distance OR constant exotropia at distance and either intermittent exotropia or exophoria at near Exodeviation at least 15PD at distance OR near measured by prism and alternate cover test (PACT) Exodeviation at least 10PD at distance measured by PACT No previous surgical or non-surgical treatment for IXT (other than refractive correction) Visual acuity in the worse eye at least 0.3 logMAR (20/40 on ATS HOTV or 70 letters on E-ETDRS) for children ≥ 3 years of age No interocular difference of visual acuity more than 0.2 logMAR (2 lines on ATS HOTV or 10 letters on E-ETDRS) for children ≥ 3 years of age No hyperopia greater than +3.50 D spherical equivalent in either eye No myopia greater than -6.00 D spherical equivalent in either eye No prior strabismus, intraocular, or refractive surgery No abnormality of the cornea, lens, or central retina Investigator willing to observe the IXT untreated for 3 years unless specific criteria for deterioration are met Exclusion Criteria: Pure phoria at both distance and near Prior non-surgical treatment for IXT other than refractive correction (e.g., vergence therapy, occlusion, vision therapy/orthoptics, or deliberate over-minus with spectacles more than 0.50D) Previous amblyopia treatment other than refractive correction within 1 year Vision therapy/orthoptics for any reason within the last year Interocular visual acuity difference more than 0.2 logMAR (2 lines on ATS HOTV for patients 3 to < 7 years old or 10 letters on E-ETDRS for patients ≥ 7 years old) (patients ≥ 3 years only) and/or investigator plans to initiate amblyopia treatment at this time. Limitation of ocular rotations due to restrictive or paretic strabismus Craniofacial malformations affecting the orbits Ocular disorders which would reduce visual acuity (except refractive error) Prior strabismus surgery or botulinum injection, intraocular surgery, or refractive surgery Strabismus surgery planned Known skin reactions to patch or bandage adhesives Significant neurological impairment such as cerebral palsy. Patients with mild speech delays or common reading and/or learning disabilities are not excluded. Investigator planning to change refractive correction at this time (if the patient is otherwise eligible, the investigator should consider prescribing refractive correction and bringing the patient back at a later time for enrollment)

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 10 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 |
| --- | --- |
| No Intervention: Observation<br>Patients randomized to the observation group will receive no treatment (other than refractive correction). | |
| Active Comparator: Occlusion Therapy<br>Patients randomized to the occlusion treatment group will receive occlusion (patching) for 3 hours per day for at least 3 months. Choice of which eye to occlude, or whether to alternate daily, is at investigator's discretion. | Device: occlusion treatment<br>* Patients randomized to the occlusion treatment group will receive occlusion (patching) for 3 hours per day for at least 3 months. Choice of which eye to occlude, or whether to alternate daily, is at investigator's discretion.<br>* Other names: patching;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deterioration by 6 Months - Older Cohort | The primary outcome measure for this study was whether the participant's condition had deteriorated within 6 months after randomization. Deterioration was defined as meeting one or both of the following criteria during a masked examination at either the 3-month or 6-month visit: 1) a constant exotropia (throughout the exam) of 10∆ or greater at distance and near by SPCT, confirmed by a retest, or 2) loss of near stereoacuity of 2 octaves (0.6 log arcsec) or more from the better of a test and retest of Preschool Randot stereoacuity at baseline, confirmed by a retest. In addition, participants were classified as deteriorated for the primary analysis if they started using non-randomized treatment (i.e., any treatment in the observation group; any treatment other than patching in the patching group) without first meeting one of the two protocol-specified deterioration criteria. | 6 months | 
| Deterioration by 3 Years - Older Cohort | The primary outcome measure for this study was whether the participant's condition had deteriorated within 3 years after randomization. Deterioration was defined as meeting one or both of the following criteria during any masked examination between 3 months and 3 years after randomization: 1) a constant exotropia (throughout the exam) of 10∆ or greater at distance and near by SPCT, confirmed by a retest, or 2) loss of near stereoacuity of 2 octaves (0.6 log arcsec) or more from the better of a test and retest of Preschool Randot stereoacuity at baseline, confirmed by a retest. In addition, participants were classified as deteriorated for the primary analysis if they started using non-randomized treatment (i.e., any treatment in the observation group; any treatment other than patching in the patching group) without first meeting one of the two protocol-specified deterioration criteria. | 3 years | 
| Deterioration by 6 Months - Younger Cohort | The primary outcome measure was deterioration of the intermittent exotropia (IXT) within 6 months after randomization. Motor deterioration was deﬁned as a constant exotropia of 10 D or more at distance and near by SPCT, conﬁrmed by a retest, at either the 3- or 6-month visit. | 6 months | 
| Deterioration by 3 Years - Younger Cohort | The primary outcome measure was deterioration of the intermittent exotropia (IXT) within 6 months after randomization. Motor deterioration was deﬁned as a constant exotropia of 10 D or more at distance and near by SPCT, conﬁrmed by a retest, during any masked examination between 3 months and 3 years after randomization. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distance Stereoacuity - 3 Years | Stereoacuity scores (seconds of arc) were calculated based on the Randot Preschool stereoacuity test (scores: 800, 400, 200, 100, 60 and 40). Seconds of arc refers to the visual angle that is being measured in order to determine depth perception. Lower scores indicate better stereoacuity. A logarithm base 10 transformation was used to convert stereoacuity scores to the log scale to calculate descriptive statistics (reported as log of seconds of arc, or log arcsec). The stereoacuity at distance is reported at 3 years, as is the change in distance stereoacuity from baseline to 3 years. Both were reported as log of seconds of arc, or log arcsec. For change in stereo, positive change indicates improvement in stereo. | Between baseline and 3 years | 
| Near Stereoacuity - 6 Months | Stereoacuity scores (seconds of arc) were calculated based on the Randot Preschool stereoacuity test (scores: 800, 400, 200, 100, 60 and 40). Seconds of arc refers to the visual angle that is being measured in order to determine depth perception. Lower scores indicate better stereoacuity. A logarithm base 10 transformation was used to convert stereoacuity scores to the log scale to calculate descriptive statistics (reported as log of seconds of arc, or log arcsec). The stereoacuity at near is reported at 3 years, as is the change in near stereoacuity from baseline to 3 years. Both were reported as log of seconds of arc, or log arcsec. Outcome based on initial testing regardless of whether a retest was completed for suspected deterioration. Change is calculated as baseline level minus 6-month level. For change in stereo, positive change indicates improvement in stereo. | 6 months | 
| Near Stereoacuity - 3 Years | Stereoacuity scores (seconds of arc) were calculated based on the Randot Preschool stereoacuity test (scores: 800, 400, 200, 100, 60 and 40). Seconds of arc refers to the visual angle that is being measured in order to determine depth perception. Lower scores indicate better stereoacuity. A logarithm base 10 transformation was used to convert stereoacuity scores to the log scale to calculate descriptive statistics (reported as log of seconds of arc, or log arcsec). The stereoacuity at near is reported at 3 years, as is the change in near stereoacuity from baseline to 3 years. Both were reported as log of seconds of arc, or log arcsec. For change in stereo, positive change indicates improvement in stereo. | between baseline and 3 years | 
| Exotropia Control at Distance - 6 Months | Change in control is calculated as baseline level minus 3-year level, so positive change = improvement. Scale Range: 0 to 5. Improvement in control was defined as an improvement of 3 points based on the 3-point threshold for real change. Numeric values for exotropia control were assigned so that the following categories were created: Not applicable (no exodeviation) 0: No exotropia unless dissociated, recovers <1 secs (phoria) No exotropia unless dissociated, recovers 1-5 secs No exotropia unless dissociated, recovers >5 secs Exotropia <50% of 30-second observation Exotropia >50% of 30-second observation Constant exotropia Lower scores indicate better control. | 6 months | 
| Exotropia Control at Distance - 3 Years | Change in control is calculated as baseline level minus 3-year level, so positive change = improvement. Scale Range: 0 to 5. Improvement in control was defined as an improvement of 3 points based on the 3-point threshold for real change. Numeric values for exotropia control were assigned so that the following categories were created: Not applicable (no exodeviation) 0: No exotropia unless dissociated, recovers <1 secs (phoria) No exotropia unless dissociated, recovers 1-5 secs No exotropia unless dissociated, recovers >5 secs Exotropia <50% of 30-second observation Exotropia >50% of 30-second observation Constant exotropia Lower scores indicate better control. | 3 years | 
| Exotropia Control at Near - 6 Months | Change in control is calculated as baseline level minus 3-year level, so positive change = improvement. Scale Range: 0 to 5. Improvement in control was defined as an improvement of 3 points based on the 3-point threshold for real change. Numeric values for exotropia control were assigned so that the following categories were created: Not applicable (no exodeviation) 0: No exotropia unless dissociated, recovers <1 secs (phoria) No exotropia unless dissociated, recovers 1-5 secs No exotropia unless dissociated, recovers >5 secs Exotropia <50% of 30-second observation Exotropia >50% of 30-second observation Constant exotropia Lower scores indicate better control. | 6 months | 
| Exotropia Control at Near - 3 Years | Change in control is calculated as baseline level minus 3-year level, so positive change = improvement. Scale Range: 0 to 5. Improvement in control was defined as an improvement of 3 points based on the 3-point threshold for real change. Numeric values for exotropia control were assigned so that the following categories were created: Not applicable (no exodeviation) 0: No exotropia unless dissociated, recovers <1 secs (phoria) No exotropia unless dissociated, recovers 1-5 secs No exotropia unless dissociated, recovers >5 secs Exotropia <50% of 30-second observation Exotropia >50% of 30-second observation Constant exotropia Lower scores indicate better control. | 3 years | 
| PACT Exodeviation at Distance - 6 Months | The prism and alternate cover test (PACT) is used to measure the angle of strabismus, or deviation, in prism diopters. This is measured separately at distance and at near. Smaller numbers are better because they indicate a smaller angle of deviation. For change in PACT, positive change indicates improvement (i.e. decrease in angle over time). log arcsec = logarithm of seconds of arc; Δ = prism diopter | 6 months | 
| PACT at Distance - 3 Years | The prism and alternate cover test (PACT) is used to measure the angle of strabismus, or deviation, in prism diopters. This is measured separately at distance and at near. Smaller numbers are better because they indicate a smaller angle of deviation. For change in PACT, positive change indicates improvement (i.e. decrease in angle over time). Improvement in PACT at distance was defined as a decrease of ≥8∆ because this amount exceed the repeatability coefficient of 7.2∆ for PACT angles larger than 20∆ at distance. log arcsec = logarithm of seconds of arc; Δ = prism diopter | 3 years | 
| PACT at Near - 6 Months | The prism and alternate cover test (PACT) is used to measure the angle of strabismus, or deviation, in prism diopters. This is measured separately at distance and at near. Smaller numbers are better because they indicate a smaller angle of deviation. For change in PACT, positive change indicates improvement (i.e. decrease in angle over time). log arcsec = logarithm of seconds of arc; Δ = prism diopter | 6 months | 
| PACT at Near - 3 Years | The prism and alternate cover test (PACT) is used to measure the angle of strabismus, or deviation, in prism diopters. This is measured separately at distance and at near. Smaller numbers are better because they indicate a smaller angle of deviation. For change in PACT, positive change indicates improvement (i.e. decrease in angle over time). Improvement in PACT at near was defined as a decrease of ≥13∆ because this amount exceed the repeatability coefficient of 12.8∆ for PACT angles larger than 20∆ at near. log arcsec = logarithm of seconds of arc; Δ = prism diopter | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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strabismus treatment, intermittent exotropia, IXT, natural history, occlusion therapy, occlusion, patching, strabismus, stereoacuity, motor alignment