Trial of Overminus Spectacle Therapy for Intermittent Exotropia (IXT5)

A Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia

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).

Study Overview

• Status: Completed
• Conditions: Intermittent Exotropia
• Intervention / Treatment: Device: Overminus treatment; Device: Non-overminus treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 386
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Alberta Children's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • CHU - Sainte-Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Glendale, Arizona, United States, 85308
      • Midwestern University Eye Institute
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Childrens
  • California
    • Anaheim, California, United States, 92807
      • University Eye Center at Ketchum Health
    • Fullerton, California, United States, 92831
      • Marshall B. Ketchum University
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Dept. of Ophthalmology
    • Mission Viejo, California, United States, 92691
      • Saddleback Eye Medical Associates
    • Palo Alto, California, United States, 94303
      • Stanford University
    • Pomona, California, United States, 91766
      • Western University College of Optometry
    • San Francisco, California, United States, 94143
      • University of California San Francisco Department of Ophthalmology
  • Florida
    • Fort Lauderdale, Florida, United States, 33382
      • Nova Southeastern University College of Optometry, The Eye Institute
    • Gainesville, Florida, United States, 32608
      • University of Florida Shands Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Eye Center
  • Idaho
    • Boise, Idaho, United States, 83702
      • St Luke's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Chicago, Illinois, United States, 60616
      • Illinois College of Optometry
    • Chicago Ridge, Illinois, United States, 60415
      • The Eye Specialists Center, LLC
    • Downers Grove, Illinois, United States, 60515
      • Midwestern U Chicago College of Optometry
    • Wilmette, Illinois, United States, 60091
      • Pediatric Eye Associates
  • Indiana
    • Bloomington, Indiana, United States, 47405
      • Indiana University School of Optometry
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Munster, Indiana, United States, 46321
      • The Eye Specialist Center, LLC
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Wolfe Eye Clinic
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Department of Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21287-9028
      • Wilmer Eye Institute
    • Baltimore, Maryland, United States, 21204-5809
      • Greater Baltimore Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital Pediatric Ophthalmology
    • Grand Rapids, Michigan, United States, 49546
      • Pediatric Ophthalmology, P.C.
    • West Bloomfield, Michigan, United States, 48322
      • Children's Eye Care PC
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Department of Ophthalmology
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63121
      • U of MO St. Louis College of Optometry
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • University of Nebraska Medical Center
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Concord Ophthalmologic Associates
  • New York
    • New York, New York, United States, 10036
      • State University of New York, College of Optometry
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Eye Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Columbus, Ohio, United States, 43210-1280
      • The Ohio State University College of Optometry
    • Poland, Ohio, United States, 44514
      • Eye Care Associates, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Dean A. McGee Eye Institute, University of Oklahoma
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute
    • Portland, Oregon, United States, 97205
      • Pacific University College of Optometry
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17601
      • Conestoga Eye
    • Philadelphia, Pennsylvania, United States, 19141
      • Salus University/Pennsylvania College of Optometry
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Eye Center of Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, Storm Eye Institute
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Pediatric Eye Specialists
    • Memphis, Tennessee, United States, 38104
      • Southern College of Optometry
  • Texas
    • Houston, Texas, United States, 77204
      • University of Houston College of Optometry
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital - Dept. Of Ophthalmology
    • Lubbock, Texas, United States, 79430
      • Texas Tech University Health Science Center
    • The Woodlands, Texas, United States, 77381
      • Houston Eye Associates
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Pediatric Eye Center
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Overminus Treatment; spectacles with full cycloplegic refraction plus 2.50 D overminus added to the sphere	Device: Overminus treatment; spectacles with full cycloplegic refraction plus 2.50 D overminus added to the sphere; Other Names: Overminus spectacles; Overminus glasses; Overminus therapy
Active Comparator: Non-overminus Treatment; spectacles with full cycloplegic refraction without overminus	Device: Non-overminus treatment; spectacles with full cycloplegic refraction without overminus

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research
• Collaborators: National Eye Institute (NEI); Pediatric Eye Disease Investigator Group
• Investigators: Study Chair: Angela M Chen, OD, MS, Marshall B. Ketchum University; Study Chair: S. Ayse Erzurum, MD, Eye Care Associates, Inc.

Publications and helpful links

General Publications

• Chen AM, Erzurum SA, Chandler DL, Hercinovic A, Melia BM, Bhatt AR, Suh DW, Vricella M, Erickson JW, Miller AM, Marsh JD, Bodack MI, Martinson SR, Titelbaum JR, Gray ME, Holtorf HL, Kong L, Kraker RT, Rahmani B, Shah BK, Holmes JM, Cotter SA; Pediatric Eye Disease Investigator Group. Overminus Lens Therapy for Children 3 to 10 Years of Age With Intermittent Exotropia: A Randomized Clinical Trial. JAMA Ophthalmol. 2021 Apr 1;139(4):464-476. doi: 10.1001/jamaophthalmol.2021.0082.
• Holmes JM, Leske DA, Hercinovic A, Hatt SR, Chandler DL, Li Z, Melia BM, Chen AM, Erzurum SA, Crouch ER, Jenewein EC, Kraker RT, Cotter SA; Pediatric Eye Disease Investigator Group. Rasch-calibrated Intermittent Exotropia Symptom Questionnaire for Children. Optom Vis Sci. 2022 Jun 1;99(6):513-520. doi: 10.1097/OPX.0000000000001901. Epub 2022 Apr 12.

Helpful Links

• PEDIG public website

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2017
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): February 15, 2022

Study Registration Dates

• First Submitted: June 16, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimate): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): June 3, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Intermittent Exotropia; IXT; overminus
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Cranial Nerve Diseases; Ocular Motility Disorders; Strabismus; Exotropia
• Other Study ID Numbers: IXT5; 2U10EY011751 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: In accordance with the NIH data sharing policy, a de-identified database is placed in the public domain on the PEDIG public website after the completion of each protocol and publication of the primary manuscript.
• IPD Sharing Time Frame: Data will be made available after publication of each primary manuscript.
• IPD Sharing Access Criteria: Users accessing the data must enter an email address.