Trial of Overminus Spectacle Therapy for Intermittent Exotropia

Study Overview
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Brief Summary
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The main objectives of this randomized trial comparing overminus lens treatment to non-overminus (spectacles without overminus or spectacles with plano lenses) are to determine: The long-term on-treatment effect of overminus treatment on distance intermittent exotropia (IXT) control score. The off-treatment effect of overminus treatment on distance IXT control score (following weaning and 3 months off treatment).

Detailed Description
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The main objectives of this randomized trial comparing overminus lens treatment to non-overminus (spectacles without overminus or spectacles with plano lenses) are to determine: The long-term on-treatment effect of overminus treatment on distance IXT control score. The off-treatment effect of overminus treatment on distance IXT control score (following weaning and 3 months off treatment). The recently completed IXT3 pilot study (NCT02223650) addressed the question of whether overminus lens therapy has an initial short-term therapeutic effect for IXT while wearing overminus spectacles. There have been no rigorous studies that address the following important questions related to overminus lens therapy: Does overminus lens therapy have a long-term therapeutic effect for IXT while wearing overminus spectacles (over many months or years)? Does overminus lens therapy have a long-term therapeutic effect for IXT when overminus spectacles are discontinued? In November 2019, a protocol amendment discontinued overminus lens treatment and extended the study for an additional 18 months after the 18-month randomized trial has ended. The objective of the extension study is to compare long-term refractive error between subjects originally treated with either overminus spectacles or non-overminus spectacles as part of the 18-month randomized trial; treatment is at investigator discretion.

Official Title
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A Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia

Conditions
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Intermittent Exotropia

Intervention / Treatment
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* Device: Overminus treatment
* Device: Non-overminus treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 3 years to < 11 years Intermittent exotropia (manifest deviation) meeting all of the following criteria: At distance: intermittent exotropia or constant exotropia o Mean distance control score of 2 points or more (mean of 3 assessments over the exam) At near: intermittent exotropia, exophoria, or orthophoria o Subject cannot have a score of 5 points on all 3 near assessments of control Exodeviation at least 15∆ at distance measured by PACT Near deviation does not exceed distance deviation by more than 10∆ by PACT (convergence insufficiency type IXT excluded) Distance visual acuity (any optotype method) in each eye of 0.4 logMAR (20/50) or better if age 3 years and 0.3 logMAR (20/40) or better if 4 years or older. Interocular difference of distance visual acuity ≤0.2 logMAR (2 lines on a logMAR chart) Refractive error between -6.00 diopters (D) standard error (SE) and +1.00D SE (inclusive) in the most myopic / least hyperopic eye based on a cycloplegic refraction performed within the past 2 months or at the end of the enrollment exam. If refractive error (based on cycloplegic refraction performed within past 2 months or at the end of the enrollment exam) meets any of the following criteria, then pre-study spectacles are required and must have been worn for at least 1 week prior to enrollment: SE anisometropia ≥1.00D Astigmatism ≥1.50D in either eye SE myopia ≥-1.00D in either eye Pre-study refractive correction, if worn, must meet the following criteria relative to the cycloplegic refraction performed within past 2 months or at the end of the enrollment exam: SE anisometropia must be corrected within <1.00D of the SE anisometropic difference Astigmatism must be corrected within <1.00D of full magnitude; axis must be within 10 degrees. The SE of the spectacles must not meet the definition of substantial overminus (see exclusion criteria below) Gestational age ≥ 32 weeks Birth weight > 1500 grams Parent understands the protocol and is willing to accept randomization to overminus spectacles or non-overminus spectacles Parent has home phone (or access to phone) and is willing to be contacted by Jaeb Center staff and Investigator's site staff Relocation outside of area of an active PEDIG site within next 18 months is not anticipated Exclusion Criteria: Treatment for IXT or amblyopia (other than refractive correction) within the past 4 weeks, including vision therapy, patching, atropine, or other penalization. Current contact lens wear Substantial deliberate overminus treatment within the past 6 months, defined as spectacles overminused by more than 1.00D SE than the cycloplegic refractive error (within 2 months or at the end of the enrollment exam) Prior strabismus, intraocular, or refractive surgery (including BOTOX injection) Abnormality of the cornea, lens, or central retina Down syndrome or cerebral palsy Severe developmental delay which would interfere with treatment or evaluation (in the opinion of the investigator). Subjects with mild speech delays or reading and/or learning disabilities are not excluded. Any disease known to affect accommodation, vergence, and ocular motility such as multiple sclerosis, Graves orbitopathy, dysautonomia, myasthenia gravis, or current use of atropine for amblyopia Anti-seizure medications [e.g., carbamazepine (Tegretol, Carbatrol, Epitol, or Equetro), diazepam (Valium or Diastat), clobazam (Frisium or Onfri), clonazepam (Klonopin), lorazepam (Ativan), ethosuximide (Zarontin), felbamate (Felbatol), lacosamide (VIMPAT), gabapentin (Neurontin), oxcarbazepine (Oxtellar XR or Trileptal), phenobarbital, phenytoin (Dilantin or Phenytek), pregabalin (Lyrica), tiagabine (Gabitril), topiramate (Topamax), valproate (Depakote), or zonisamide (Zonegran), vigabatrin (Sabril)]

Ages Eligible for Study
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Minimum Age: 3 Years
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 |
| --- | --- |
| Experimental: Overminus Treatment<br>spectacles with full cycloplegic refraction plus 2.50 D overminus added to the sphere | Device: Overminus treatment<br>* spectacles with full cycloplegic refraction plus 2.50 D overminus added to the sphere<br>* Other names: Overminus therapy;|
| Active Comparator: Non-overminus Treatment<br>spectacles with full cycloplegic refraction without overminus | Device: Non-overminus treatment<br>* spectacles with full cycloplegic refraction without overminus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Distance Control at 12-Months (On-Treatment Visit) | A comparison of mean control of the distance exodeviation (average of 3 measurements over the exam) between the 2.50 diopters (D) overminus group and the non-overminus group (spectacles without overminus or no spectacles) at 12 months. The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 12 months | 
| Mean Distance Control at 18-Months (Off-Treatment Visit) | A comparison of mean control of the distance exodeviation (average of 3 measurements over the exam) between the 2.50D overminus group and the non-overminus group (spectacles without overminus or no spectacles) at 18 months (after treatment discontinuation). The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With No Spontaneous Tropia | The number of subjects with no spontaneous tropia at 12 months and at 18 months will be compared between treatment groups. | 12 months | 
| No Spontaneous Tropia | The proportion of subjects with no spontaneous tropia at 12 months and at 18 months will be compared between treatment groups. | At 18 months | 
| Change in Distance Control | The proportion of subjects with ≥1 point improvement in distance control between baseline and 12 months will be compared between treatment groups. The proportion of subjects with ≥2 points improvement in distance control will be similarly compared between treatment groups. The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 12 months | 
| Change in Distance Control | The proportion of subjects with ≥1 point improvement in distance control between baseline and 18 months will be compared between treatment groups. The proportion of subjects with ≥2 points improvement in distance control will be similarly compared between treatment groups. The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 18 months | 
| Deterioration as Assessed by Motor Alignment and Stereoacuity at Near (12 Months) | The cumulative proportion of subjects who meet deterioration criteria by the time point will be estimated for each treatment group. Participants who meet either of the following at any visit by a specific timepoint (e.g., 12 months, 18 months) will be considered to have met deterioration criteria by that timepoint. Motor deterioration: Control of the exodeviation measures 5 (constant exotropia) on all three assessments at distance and near. The exodeviation does not need to be constant throughout the entire exam provided that it is constant during all three assessments of control. Stereoacuity deterioration: Drop in near stereoacuity of at least 2 octaves from enrollment stereoacuity, or to nil, confirmed by a retest by a Masked Examiner on a subsequent day. Note: participants with nil stereoacuity at enrollment will not be able to deteriorate with respect to a drop in near stereoacuity. | 12 months | 
| Deterioration as Assessed by Motor Alignment and Stereoacuity at Near (18 Months) | The cumulative proportion of subjects who meet deterioration criteria by the time point will be estimated for each treatment group. Participants who meet either of the following at any visit by a specific timepoint (e.g., 12 months, 18 months) will be considered to have met deterioration criteria by that timepoint. Motor deterioration: Control of the exodeviation measures 5 (constant exotropia) on all three assessments at distance and near. The exodeviation does not need to be constant throughout the entire exam provided that it is constant during all three assessments of control. Stereoacuity deterioration: Drop in near stereoacuity of at least 2 octaves from enrollment stereoacuity, or to nil, confirmed by a retest by a Masked Examiner on a subsequent day. Note: participants with nil stereoacuity at enrollment will not be able to deteriorate with respect to a drop in near stereoacuity. | 18 months | 
| Near Control (12 Months) | Mean control of the near exodeviation (average of 3 measurements over the exam). The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 12 months | 
| Near Control (18 Months) | Mean control of the near exodeviation (average of 3 measurements over the exam). The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 18 months | 
| Change in Near Control (12 Months) | For each timepoint, the change in near control since baseline will be reported. The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 12 months | 
| Change in Near Control (18 Months) | For each timepoint, the change in near control since baseline will be reported. The Office Control Score provides a rating of exodeviation control on a 0 to 5 scale, in subjects with intermittent exotropia. Scores 3 to 5 reflect the proportion of time a spontaneous manifest exotropia is present during 30 seconds of observation (<50% score 3; >50% score 4; 100% score 5). If no spontaneous manifest exotropia is observed, scores 0 to 2 reflect the longest time to regain fusion after three, 10-second dissociations (>5 seconds score 2; 1-5 seconds score 1; <1 second score 0). | 18 months | 
| Angle Magnitude (12 Months) | The magnitude of the deviation by Prism Alternate Cover Test (PACT) will be compared between treatment groups. | 12 months | 
| Angle Magnitude (18 Months) | The magnitude of the deviation by Prism Alternate Cover Test (PACT) will be compared between treatment groups. | 18 months | 
| Stereoacuity at 12 Months | A comparison of near stereoacuity will be assessed using the Randot Preschool stereotest at near (performed at 40 cm) between treatment groups. | 12 months | 
| Stereoacuity at 18 Months | A comparison of near stereoacuity will be assessed using the Randot Preschool stereotest at near (performed at 40 cm) between treatment groups. | 18 months | 
| Compliance With Spectacle Wear (12 Months) | Compliance with spectacle wear will be assessed at the 12-month and 18-month outcome exam. Parents will give an estimate of the proportion of the time their children wore their spectacles. Proportion of time worn will be described as excellent (76% to 100%), good (51% to 75%), fair (26% to 50%), or poor (≤ 25%). The distribution of compliance will be assessed for each treatment group at the outcome exam. | 12 months | 
| Compliance With Spectacle Wear (18 Months) | Compliance with spectacle wear will be assessed at the 12-month and 18-month outcome exam. Parents will give an estimate of the proportion of the time their children wore their spectacles. Proportion of time worn will be described as excellent (76% to 100%), good (51% to 75%), fair (26% to 50%), or poor (≤ 25%). The distribution of compliance will be assessed for each treatment group at the outcome exam. | 18 months | 
| Parent Symptom Survey [12 Months] | A brief survey of symptoms that may be associated with overminus such as headaches, eye strain, and problems with spectacle wear will be administered to the parents of the subjects. Parents are asked to respond to the survey questions based on their observations of their child in the past 2 weeks. Response options are based on frequency of observations; never, rarely, sometimes, often, always, and not applicable. | At 12 months | 
| Parent Symptom Survey [18 Months] | A brief survey of symptoms that may be associated with overminus such as headaches, eye strain, and problems with spectacle wear will be administered to the parents of the subjects. Parents are asked to respond to the survey questions based on their observations of their child in the past 2 weeks. Response options are based on frequency of observations; never, rarely, sometimes, often, always, and not applicable. | At 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IXT, Intermittent Exotropia, overminus