Hyperopia Protocol v1 0 11-14-11

8/12/2019 Hyperopia Protocol v1 0 11-14-11

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Hyperopia Protocol v1.0 11-14-11

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GLASSES VERSUS OBSERVATION FOR5

MODERATE HYPEROPIA IN YOUNG6

CHILDREN (HTS1)78

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PROTOCOL13

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Version 1.01714 November 201118

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CONTACT INFORMATION23242526

27COORDINATING CENTER28

Raymond T. Kraker, M.S.P.H. (Director)29Jaeb Center for Health Research3015310 Amberly Drive, Suite 35031

Tampa, FL 3364732Phone (888) 79PEDIG or (813) 975-869033Fax (888) 69PEDIG or (813) 975-876134

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PROTOCOL CHAIRS3940

David B. Petersen, MD41Rocky Mountain Eye Care Associates42

4400 South 700 East, Suite 10043Salt Lake City, Utah 8410744

(801) 264-445045(801) 520-7420 cell46

[email protected]

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Marjean Taylor Kulp, OD, MS51The Ohio State University52

College of Optometry53338 W. 10th Ave54

Columbus, OH 43210-128055(614) 688-333656

(614) 578-3336 [email protected]

[email protected]
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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TABLE OF CONTENTS636465

CHAPTER 1:BACKGROUND AND SUMMARY ............................................................................................................. 1-1661.1 Background .................................................................................................................................................... 1-1671.2 Rationale for the Study ................................................................................................................................... 1-1681.3 Study Objectives ............................................................................................................................................ 1-2691.4 Synopsis of Study Design .............................................................................................................................. 1-2

70 CHAPTER 2:PATIENT ENROLLMENT ........................................................................................................................... 2-1712.1 Eligibility Assessment and Informed Consent ............................................................................................... 2-1722.2 Eligibility and Exclusion Criteria ................................................................................................................... 2-173

2.2.1 Eligibility Criteria ...................................................................................................................................... 2-1742.2.2 Exclusion Criteria ...................................................................................................................................... 2-175

2.3 Historical Information .................................................................................................................................... 2-2762.4 Procedures at the Enrollment Visit................................................................................................................. 2-2772.5 Randomization of Eligible Patients ................................................................................................................ 2-378

CHAPTER 3:TREATMENT AND FOLLOW-UP ............................................................................................................. 3-1793.1 Treatment ....................................................................................................................................................... 3-180

3.1.1 Observation Group ..................................................................................................................................... 3-1813.1.2 Glasses Group ............................................................................................................................................ 3-182

3.2 Follow-up Visit Schedule ............................................................................................................................... 3-1833.3 Follow-up Visit Testing Procedures at 6, 12, 18, 24, and 30 months ............................................................. 3-2843.4 Deterioration Criteria ..................................................................................................................................... 3-385

3.4.1 Masked Examiner ...................................................................................................................................... 3-4863.4.2 Deterioration Confirmation by Masked Examiner ..................................................................................... 3-4873.4.3 Pre-Approved Unmasked Sites .................................................................................................................. 3-588

3.5 Post-Deterioration Glasses Treatment ............................................................................................................ 3-6893.6 30-Month Follow-up Visit ............................................................................................................................. 3-6903.7 36-Month Masked Outcome Exam Testing Procedures ................................................................................. 3-6 913.8 Non-Study Visits and Treatment .................................................................................................................... 3-792

CHAPTER 4:MISCELLANEOUS CONSIDERATION IN FOLLOW-UP ..................................................................... 4-1934.1 Contacts by the Jaeb Center for Health Research .......................................................................................... 4-1944.2 Patient Withdrawals ....................................................................................................................................... 4-1954.3 Management of Refractive Error .................................................................................................................... 4-196

4.3.1 Bifocals ...................................................................................................................................................... 4-197 4.4 Management of Strabismus ............................................................................................................................ 4-1984.5 Management of Amblyopia ............................................................................................................................ 4-2994.6 Risks ............................................................................................................................................................... 4-2100

4.6.1 Risks of Examination Procedures .............................................................................................................. 4-21014.7 Reporting of Adverse Events ......................................................................................................................... 4-21024.8 Discontinuation of Study ................................................................................................................................ 4-21034.9 Travel Reimbursement ................................................................................................................................... 4-21044.10 Study Costs .................................................................................................................................................... 4-2105

CHAPTER 5:SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .......................................................... 5-11065.1 Definitions of Primary Cohorts ...................................................................................................................... 5-11075.2 Primary Data Analysis ................................................................................................................................... 5-1108

5.2.1 Classification of Outcome (Failure Criteria) ............................................................................................. 5-11095.3 Secondary Data Analyses ............................................................................................................................... 5-2110

5.3.1 Best Visual Acuity at 36 Months ............................................................................................................... 5-2 1115.3.2 Development of Strabismus ....................................................................................................................... 5-21125.3.3 Subgroup Analysis ..................................................................................................................................... 5-21135.3.4 Observation Group Deterioration .............................................................................................................. 5-21145.3.5 Development of Amblyopia ....................................................................................................................... 5-31155.3.6 Near Visual Acuity .................................................................................................................................... 5-3116

5.4 Exploratory Analyses ..................................................................................................................................... 5-31175.5 Sample Size Estimates ................................................................................................................................... 5-31185.6 Interim Analysis ............................................................................................................................................. 5-4119

CHAPTER 6: REFERENCES ............................................................................................................................................... 6-1120121


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Hyperopia Protocol v1.0 11-14-11 1-1

CHAPTER 1:BACKGROUND AND SUMMARY122123

This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is124funded through a cooperative agreement from the National Eye Institute.125

1.1 Background126The prevalence of hyperopia was reported in recent population-based studies in 6- to 72-month-127

old children.1, 2 In white children the prevalence of hyperopia was 31.5% with +2.00D, 13.2%128with +3.00D, 5.2% with +4.00D, and 2.4% with +5.00D. Hyperopia prevalence was lower129for African-American children (relative prevalence white to African-American = 1.62; 95% CI1301.52 to 1.74).1 The prevalence of hyperopia +2.00D (in the better eye) was slightly higher in131Hispanic children (19.6%) than in African American children (15.2%).132

133Moderate and high hyperopia are associated with the development of strabismus and amblyopia.134Atkinson et al3found that children with greater than +3.50D in any meridian at 6 to 8 months of135age were 13 times more likely to develop strabismus by 4 years of age and 6 times more likely136to have amblyopia, compared to infants with low hyperopia or emmetropia. Similarly, a study137by Ingram et al4found that the presence of +2.50D or more of hyperopia at 1 year of age was138

significantly associated with the development of strabismus and/or amblyopia by 3.5 years of139age. The American Academy of Ophthalmology consensus guidelines state that hyperopia of140+6.00 D in 0- to 1-year olds; +5.00 D in 1-to 2-year olds; and +4.50 D in 2- to 3-year olds141is amblyogenic.5 A threshold of greater than +3.50 D in any meridian has been suggested as a142referral criterion for vision screening.6143

144Nevertheless, the question of whether to prescribe glasses for hyperopia remains controversial.145

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1.2 Rationale for the Study147The primary aims of treatment for asymptomatic moderate and high hyperopia in preschool148

children are to facilitate the development of normal visual acuity and to prevent the149development of esotropia and amblyopia. Treatment consists of optical correction, typically150using glasses. For children with high hyperopia (>+5.00D) and without strabismus or151amblyopia, there is general consensus that a correction (usually partial plus) should be152prescribed.7Nevertheless, for children with moderate hyperopia (+3.00D to +5.00D) without153strabismus or amblyopia, there is less consensus among pediatric eye care professionals. A154survey by Lyons et al7found that for a 2-year-old child with hyperopia greater than +3.00D,15565% of optometrists would prescribe glasses compared to 25% of ophthalmologists; for a 4-year156old with hyperopia greater than +3.00D, 67% of optometrists would prescribe compared with15742% of ophthalmologists. The American Association for Pediatric Ophthalmology and158Strabismus (AAPOS) recommends correcting +4.00D or more in 2 to 7 year olds8and the159

American Academy of Ophthalmology recommends a threshold of +4.50D for correction in 2-to1603-year olds.5 Unlike ophthalmology, optometry does not provide specific recommendations161based on age and level of refractive error.9 Such variation in practice highlights the lack of162rigorously collected scientific evidence for the management of this condition. Across all levels163of hyperopia, most ophthalmologists and optometrists usually prescribe less than the full164cycloplegic refraction (71% in the Lyons survey) when no strabismus or amblyopia is present.7165

166The rationale for proactively correcting moderate hyperopia in an asymptomatic child is the167prevention of esotropia, amblyopia3, 4or asthenopia. The argument against correcting moderate168hyperopia in an asymptomatic child is the expense and inconvenience of glasses that might be169


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unnecessary and the potential disruption of emmetropization in infants and toddlers. At present,170it remains uncertain whether correction of moderate hyperopia is beneficial in terms of visual171acuity outcomes or strabismus development. There is some evidence that using partial172correction of hyperopia allows emmetropization to take place.10173

174There are some previous data comparing no spectacle correction of moderate hyperopia to175

partial correction. Ingram et al

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randomized 6-month-old children (n=372) with +4.00D or176 more of hyperopia to glasses or no glasses and found no difference in the rate of strabismus177development (23.5% vs. 26% respectively) by 3.5 years of age. Nevertheless, there was a178difference in visual acuity outcome between groups: 97% of the glasses group achieved 20/40179or better compared to 87% in the non-glasses group. A study by Atkinson et al12allocated180infants with +3.50D or more of hyperopia to glasses or no glasses and, in contrast with the181Ingram study,11found that there was a significant difference in the rate of strabismus182development (6.3% vs. 21% respectively). Atkinson et al also found that the rate of amblyopia183was lower in the glasses group compared to the non-glasses group (28.6% vs. 68%184respectively). In a second study by the Atkinson group,13the strabismus findings were not185replicated (no difference in rate of strabismus development between glasses [n=58] and non-186glasses wearers [n=18]) whereas the visual acuity outcomes were replicated (amblyopia was187found in 17% of children in glasses group and 67% of children in non-glasses group).13 There188is unfortunately a lack of standardization in these previous studies, especially regarding visual189acuity testing methods In addition, it is not always clear how amblyopia was defined and190whether visual acuity was assessed with or without hyperopic correction (in no-spectacles191patients). Furthermore, some reported outcomes include data only for subjects considered to be192compliant with glasses.193

194If refractive correction of moderate hyperopia does not reduce the incidence of amblyopia195and/or esotropia compared to no refractive correction, then glasses can be avoided. However, if196correcting moderate hyperopia does reduce the development of amblyopia and/or esotropia,197then the benefits of preemptive refractive correction will have been identified.198

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1.3 Study Objectives200To compare visual acuity outcomes and development of strabismus after a 3-year follow-up201period in children age 12 to


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No prior treatment for amblyopia or strabismus (e.g., surgery, patching, vision therapy,217etc.)218

No measurable heterotropia in primary gaze at distance (3 meters) or at near (1/3 meter)219by cover/uncover testing220

No known neurological anomalies (e.g. cerebral palsy, Down syndrome)221 For children 36 to


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present), prism and alternate cover test (PACT), the Randot Preschool Stereoacuity test, and266dynamic retinoscopy (optional) will be performed. Near visual acuity will be tested at 36267months.268

269The primary outcome exam will be 36 months after randomization. Cycloplegic refraction will270be performed yearly (or more frequently if clinically indicated); a mandatory cycloplegic271

refraction will be performed at the 30-month follow-up visit and again at the 36-month outcome272 exam. Subjects meeting failure criteria and requiring a change in glasses at the 36-month273outcome exam will return for a repeat outcome exam in the updated glasses within 4 weeks.274

275Primary Analysis276For each of the two primary cohorts, the proportion meeting failure criteria at 3 years post-277randomization will be compared between treatment groups using the Fishers exact test.278

Failure (confirmed by a retest at the same visit) will be determined at the 36-month primary279outcome visit and is defined insection 5.2.1.280

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Study Summary Flow Chart282

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6 months 1 month exams (Masked* - -with and without correction in trial frames) Randot Preschool stereoacuity Ocular alignment (cover/uncover, SPCT if tropic and PACT) Monocular distance visual acuity (ATS-HOTV in children 36 months and older) Cycloplegic refraction (if not performed in last 12 months) -Mandatory at 30-month exam Dynamic retinoscopy (optional and NOT masked) in habitual correction

Randomize

Observation Glasses

Measurable heterotropiaStereoacuity below age normsStereo >2 octaves below previous best or drop to nilParent reports problems with function due to vision

Monocular VA in habitual correction below age norm2 lines of IODif Dist VA 20/25 or worse in better eye3 lines of IOD if Dist VA 20/20 or better in better eye

Are any of the following new findings present, suggestive of deterioration?

Yes

10-minute break Confirm with a retest by the maskedexaminer

Observation Group Glasses Group

No

Continue in currentgroup (glasses orobservation)

Not confirmed

continueobservation

Baseline Measurements (without correction)

Randot Preschool stereoacuity Ocular alignment (cover/uncover, PACT) Monocular distance visual acuity (ATS-HOTV in children 36 months and older) Binocular near visual acuity Dynamic retinoscopy (optional)

Not confirmed

continuecurrent glassesIf > 30 mo

Confirmed deterioration

(Either Group)

Cycloplegic refraction (if not performed within previous 6 months) Subject is released to best clinical care (defined as any care at investigator

discretion but must include prescribing glasses according to guidelines suggestedinsection 3.5)

3-Year Primary Outcome Exam: 36 months 1 month (Masked)

Randot Preschool stereoacuity with and without correction

Ocular alignment (cover/uncover, SPCT (if tropic), and PACT) with and without correctiono Retest ocular alignment at near with +3.00D lens if strabismus present at near through distance correction

Monocular distance visual acuity (ATS-HOTV) with and without correction Binocular near visual acuity with and without correction Dynamic retinoscopy (optional and NOT masked) in habitual correction Cycloplegic refraction

* - Unless pre-authorized for non-masked

6-month visits.

If > 30 mo

If > 30 mo

If > 30 mo


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285

286287288

NoStudy ends

Has the cycloplegic refraction changed significantly since refraction at 30 months?

(>0.75D sphere, >0.75D cylinder, or axis change of >6 degrees when cylinder is >+1.50D)

Repeat Outcome Exam 4 Weeks 1 Week from 36- Month Exam with Updated Glasses (Masked)

Randot Preschool stereoacuity with and without correction Ocular alignment (cover/uncover, SPCT (if tropic), and PACT) with and without correction

o Retest ocular alignment at near with +3.00D lens if strabismus present at near Monocular distance visual acuity (ATS-HOTV) with and without correction Binocular near visual acuity with and without correction Dynamic retinoscopy (optional and NOT masked) in habitual correction

Yes Update glasses Repeat Outcome Exam 4 weeks 1 week

Measureable heterotropiaStereoacuity below age normsStereo >2 octaves below previous best or drop to nilParent reports problems with function due to vision

Best monocular VA in either eye below age norm2 lines of IODif Dist VA 20/25 or worse in better eye3 lines of IOD if Dist VA 20/20 or better in better eye

No

Study endsYes

Are any of the following new findings suggestive of failure detected and confirmed by a masked examiner?


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CHAPTER 2:PATIENT ENROLLMENT289290

2.1 Eligibility Assessment and Informed Consent291The study will enroll a minimum of 336 subjects for the primary cohort of patients aged 12 to


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5. Previous intraocular, refractive, or extraocular muscle surgery3376. Previous amblyopia treatment3387. Previous vergence/accommodative therapy3398. Parental concerns over learning or development3409. Ocular co-morbidity that may reduce visual acuity34110.Symptoms of blur or asthenopia34211.

Developmental delay diagnosed by pediatrician or Individualized Education Program (IEP)343 12.Known neurological anomalies (e.g. cerebral palsy, Down syndrome)344

13.Inability to perform visual acuity ATS-HOTV testing if 36 months of age3452.3 Historical Information346

Historical information to be elicited will include the following: date of birth, gender, race, ethnicity,347reason for coming for exam, history of prior eye-related treatment, and diagnosis and current348treatment of ADHD. Family history of strabismus and/or amblyopia, patching, or glasses before the349age of 7 years will also be collected.350

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2.4 Procedures at the Enrollment Visit352All examination procedures must be tested within 14 days prior to enrollment, except a cycloplegic353refraction, which must be tested within 2 months prior to enrollment. All examination procedures at354enrollment are performed without correction in the following order:355

3561. Stereoacuity Testing (patients >=36 months of age only):357

Stereoacuity will be tested at near without correction using the Randot Preschool358Stereoacuity test.359

3602. Ocular Alignment Testing:361

Ocular alignment will be assessed without correction by the cover/uncover test and prism362and alternate cover test (PACT) in primary gaze at distance (3 meters) and at near (1/3363

meter) as outlined in theHyperopia Testing Procedures Manual.364o Seesection 2.2.1for eligibility criteria related to ocular alignment.365

A parental report of strabismus must be confirmed by clinical testing performed by the366investigator. If the investigator fails to find strabismus, the subject may be brought back at367investigator discretion. If the return visit is within two weeks, other clinical measures made368within 14 days of this repeated ocular alignment testing may be used for enrollment.369

3703. Distance Visual Acuity Testing (patients >= 36 months of age only): Monocular distance visual371

acuity testing will be performed without correction in each eye by a certified examiner using the372ATS single-surround HOTV protocol on a study-certified acuity tester as described in theATS373Testing Procedures Manual. ATS single-surround HOTV protocol will be used throughout the374

study.375 No visual acuity data (including fixation preference) will be collected on children


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CHAPTER 3:TREATMENT AND FOLLOW-UP412413414

3.1 Treatment4153.1.1 Observation Group416

Subjects randomized to the observation group will receive no glasses to correct the childs417refractive error or any other treatment unless one or more deterioration criteria are confirmed.418

419If a subject meets deterioration criteria (section 3.4)at any visit, any newly failed criteria will be420retested by the masked examiner (section3.4.1) after a 10-minute break, first with correction placed421in a trial frame and second without correction. If retesting confirms deterioration, a cycloplegic422refraction must be performed if not done within 6 months of deterioration. The subject will then be423released to best clinical care, which is defined as care at the investigators discretion, but must424include prescribing glasses according to guidelines suggested insection 3.5. The subject will return425for all study-specified follow-up visits.426

427If a subject does not meet deterioration criteria, the subject will continue to be observed without428glasses and return for all study-specified follow-up visits.429

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3.1.2 Glasses Group431Subjects randomized to the glasses group will receive partial plus glasses, i.e., with sphere cut432symmetrically by 1.00D (from a cycloplegic refraction within 2 months prior to enrollment) and full433cylinder correction. The site investigator or coordinator will directly contact the parents of each434participant who is assigned to glasses treatment within the first 2 weeks of the study to inquire about435any issues with obtaining glasses and to encourage treatment compliance.436

437If the investigator feels that the subject is not compliant with wearing his/her glasses and/or needs438

assistance relaxing his/her accommodation to adapt to the glasses, the investigator must call a439Protocol Chair to discuss management options, which may include a short course of bilateral440cycloplegia.441

442If a subject meets deterioration criteria (section 3.4)at any visit, any newly failed criteria will be443retested by the masked examiner (section3.4.1) after a 10-minute break, first with correction and444second without correction. If retesting confirms deterioration, a cycloplegic refraction must be445performed if not done within 6 months of deterioration. The subject will then be released to best446clinical care, which is defined as care at the investigators discretion, but must include continued447used of glasses according to guidelines suggested insection 3.5. The subject will return for all448study-specified follow-up visits.449

450 If a subject does not meet deterioration criteria, the subject will continue treatment in his/her451habitual glasses and return for all study-specified follow up visits.452

453Subjects in the glasses group will continue to wear glasses throughout the study unless the glasses454correction decreases to +1.00D spherical equivalent (SE) or less (then glasses may be discontinued455at investigators discretion).456

3.2 Follow-up Visit Schedule457The follow-up schedule is timed from randomization as follows:458

6-month: 6 months 1 month459


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12-month: 12 months 1 month460 18-month: 18 months 1 month461 24-month: 24 months 1 month462 30-month: 30 months 1 month463 36-month: 36 months 1 month (masked primary outcome examination)464

o Repeat 36-month outcome exam 4 weeks 1 week for subjects meeting failure465criteria (section5.2) and requiring change in glasses (section3.7).466467

Additional non-specified visits can be performed at the discretion of the investigator; however, the468decision to schedule non-specified visits may not be based on group assignment (e.g., additional469non-specified visits cannot be routinely scheduled for subjects in the observation group but not the470glasses group).471

472At follow-up visits, Randot Preschool Stereoacuity at near, cover/uncover, SPCT (if tropic), PACT,473distance visual acuity, near visual acuity (primary outcome visit only), and dynamic retinoscopy474(optional) will be performed. All testing at non-outcome follow-up visits should be performed both475with and without correction (with correction defined as the subjects habitual correction if already476

in glasses or partial plus (i.e., cut by +1.00D from full cycloplegic refraction) if not wearing477 glasses). Cycloplegic refraction will be performed yearly (or more frequently if clinically478indicated) and upon confirmation of a new deterioration criterion (if not performed within 6479months); a mandatory cycloplegic refraction will be performed at the 30-month follow-up visit and480the 36-month outcome exam. History of diagnosis of ADHD and associated medications will be481elicited and recorded at each follow-up visit.482

483

3.3 Follow-up Visit Testing Procedures at 6, 12, 18, 24, and 30 months484Subjects will be seen every 6 months 1 month as outlined insection3.2. All procedures must be485completed by the masked examiner (section 3.4.1).486

All procedures will be performed first with correction (subjects habitual correction if already in487 glasses or partial plus if not wearing glasses) placed in trial frames and second without glasses. For488subjects wearing bifocals (subject has met deterioration on a previous visit and has been prescribed489bifocals), only the appropriate distance correction will be placed in the trial frame. All trial frame490lenses must be placed in the trial frame by someone other than the masked examiner before the491masked examiner enters the room. Distance correction will be defined according to treatment as492outlined below:493

For subjects in the glasses group who have not had confirmation of one or more494deterioration criteria (see section 3.4), testing should be completed with partial plus (cut495+1.00D based on most recent cycloplegic refraction).496

Subjects in the observation group who have not had confirmation of one or more497deterioration criteria will be tested with partial plus.498

Subjects with confirmed deterioration will be tested in their habitual correction.499500

Prior to the masked examiner entering the room, subjects and parents should be instructed not to501discuss their treatment with the masked examiner. The masked exam should be performed prior to502examination by the investigator.503

504The following procedures should be performed in the following order at each visit:505

1. Stereoacuity Testing (subjects >=36 months only; masked):506


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Stereoacuity will be tested using the Randot Preschool Stereoacuity test at near (1/3507meter).508

5092. Ocular Alignment Testing (masked):510

Ocular alignment will be assessed using cover/uncover, SPCT (if tropia is present and of511sufficient duration to measure), and PACT, both in primary gaze at distance (3 meters)512

and at near (1/3 meter).5135143. Distance Visual Acuity Testing (subjects >= 36 months only; masked):515

Monocular visual acuity testing at all follow-up exams will be done without cycloplegia516using the ATS single-surround HOTV letter protocol on study-certified visual acuity517system.518

No visual acuity data will be collected on subjects 3 logMAR lines of IOD if visual acuity is 20/20 or better in the better eye554


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need to be confirmed at subsequent visits if previously confirmed by the masked examiner at a581previous visit.582

583Before retesting, the subject should be given a 10-minute break. All procedures will be performed584first with correction (subjects current correction for subjects already wearing glasses, or partial plus585if the subject is not already wearing glasses, as defined insection 3.3) placed in trial frames, and586

second without glasses.587588The following procedures should be performed for the specified deterioration criterion:589

1. Any measureable heterotropia detected by a cover/uncover test:590 Ocular alignment will be assessed using cover/uncover, both in primary gaze at591

distance (3 meters) and at near (1/3 meter).592

Deterioration is confirmed if any measurable heterotropia is detected while wearing593the habitual correction.594

2. Distance visual acuity below age normal values in either eye (see Table 1)595 Monocular visual acuity testing of the eye not meeting age normal values will be596

done without cycloplegia by the masked examiner using the ATS single-surround597

HOTV letter protocol as described in theATS Testing Procedures Manual.598 Deterioration is confirmed if visual acuity is below age normal values when tested599

while wearing the habitual correction.6003. 2 logMAR lines of IOD if visual acuity is 20/25 or worse in the better eye; 3 logMAR601

lines of IOD if visual acuity is 20/20 or better in the better eye602

Monocular visual acuity testing of both eyes will be done without cycloplegia by the603masked examiner using the ATS single-surround HOTV letter protocol as described604in theATS Testing Procedures Manual.605

Deterioration is confirmed if 2 logMAR lines of IOD if visual acuity is 20/25 or606worse in the better eye, or 3 logMAR lines of IOD if visual acuity is 20/20 or better607in the better eye while wearing the habitual correction.608

4. Stereoacuity in habitual correction at near by Randot Preschool stereotest is below age609 normal values, or 2 or more octaves worse than best previous stereoacuity, or drops to nil610 Stereoacuity will be tested at near (1/3 meter) with distance correction placed in a611

trial frame and then without glasses using the Randot Preschool Stereoacuity test.612

Deterioration is confirmed if stereoacuity while wearing the habitual correction is613below age normal values, or 2 or more octaves worse than best stereoacuity at614previous visits, or drops to nil615

616If the masked examiner fails to confirm deterioration, the subject will not be considered to have met617deterioration criteria and follow-up continues without a change in treatment.618

619

If the masked examiner is unable to complete the exam on the same day, the subject may be brought620back for a masked exam within 2 weeks of the scheduled exam where deterioration criteria621appeared to be met.622

623

3.4.3 Pre-Approved Unmasked Sites624Prior to the start of the study, the Hyperopia Treatment Study Steering Committee will determine625sites that will be authorized to perform non-masked exams at 6, 12, 18, 24, and 30 month visits.626Non-masked exams will follow the same procedures outlined above (testing both with and without627correction) and examiners must be either a study-certified pediatric ophthalmologists, pediatric628


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optometrists, or certified orthoptists. The 36-month outcome exam will continue to be masked for629all sites (seesection 3.7).630

631

3.5 Post-Deterioration Glasses Treatment632All subjects with confirmation of one or more deterioration criteria prior to the 36-month outcome633visit will be provided refractive correction and continue to return for additional follow-up at the634

study-specified 6-month intervals. All subjects with confirmation of one or more deterioration635criteria must be treated with glasses; correction with contact lenses is not allowed. The amount of636sphere and cylinder to prescribe is at investigator discretion, but should follow the guidelines637suggested in Table 4. Additional treatment and management is at investigator discretion and may638include (but is not limited to): lenses, prism, surgery, amblyopia treatment, bifocals, and639vergence/accommodative therapy. The prescription of prisms and bifocals is at investigator640discretion.641

642Table 4: Guidelines for Post-Deterioration Glasses Prescription643

Hypermetropia should not be undercorrected by more than +1.00Dspherical equivalent

Reduction in plus sphere should be symmetric in the two eyes

Cylinder power in both eyes should be within 0.50D of fully correcting theastigmatism

Cylinder axis in the spectacle lenses in both eyes should be within 6 degreesof the axis of the cycloplegic refraction when cylinder power is >1.00D

If a patient develops an ET, he or she should be given a trial of full plus

644If the calculated glasses correction is +1.00D SE or less, prescribing glasses is at the investigators645discretion.646

647If the investigator feels that the subject is not compliant with wearing his/her glasses and needs648assistance relaxing his/her accommodation, the investigator must call a Protocol Chair to discuss649management options, which may include bilateral cycloplegia.650

651

3.6 30-Month Follow-up Visit652Subjects will be seen 30 months 1 month from enrollment. The exam will follow all procedures653as outlined insection 3.3. Each participant will receive a mandatory cycloplegic refraction (section6542.4), even if a cycloplegic refraction has been performed within the prior 12 months, and glasses655will be updated if refractive error meets the criteria outlined insection 4.3.656

657

3.7

36-Month Masked Outcome Exam Testing Procedures658Subjects will be seen 36 months 1 month from enrollment for a masked outcome exam (section6593.4.2). All procedures must be completed by a masked examiner (section 3.4.1) and be completed660on the same day.661

662All procedures will be performed first with correction (full sphere and cylinder correction for663subjects with confirmed deterioration otherwise partial plus; correction from cycloplegic refraction664at 30 months) placed in trial frames and second without glasses. For subjects wearing bifocals at665the time of the masked outcome exam, only the appropriate distance correction will be placed in the666


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trial frame. All trial frame lenses must be placed in the trial frame by someone other than the667masked examiner before the masked examiner enters the room.668

669The following procedures will be performed in the specified order at the 36-month masked outcome670exam according to the procedures as outlined insection3.3.671

672

1.

Stereoacuity Testing: (masked)673 Stereoacuity will be tested at near (1/3 meter) with distance correction placed in a trial frame674

and then without glasses using the Randot Preschool Stereoacuity test.675676

2. Ocular Alignment Testing: (masked)677 Ocular alignment will be assessed using cover/uncover, SPCT (if a tropia is present and of678

sufficient duration to measure), and PACT, both in primary gaze at distance (3 meters) and679at near (1/3 meter), with distance correction placed in a trial frame and then without glasses.680

If a subject has a measureable heterotropia at near in his/her distance correction, +3.00D681lenses OD/OS will be added to the trial frames and the subjects ocular alignment at near682will be retested.683

684 3. Distance Visual Acuity: (masked) by ATS-HOTV: Monocular visual acuity testing at the 36-685month outcome exam will be done without cycloplegia by a certified examiner using the ATS686single-surround HOTV letter protocol on a study-certified visual acuity system. Distance687visual acuity will be measured both with correction placed in a trial frame and without688correction.689

6904. Binocular Near Visual Acuity Testing (masked):691

Binocular near visual acuity will be performed by the masked examiner as described in the692Hyperopia Testing Procedures Manual. Binocular near visual acuity will be measured both693with correction placed in a trial frame and without correction.694

695 5. Other Testing/Data Collection:696 Undilated dynamic retinoscopy (optional and not masked) at near will be performed in697

habitual correction as outlined in theHyperopia Testing Procedures Manual.698

Data will be collected on glasses wear compliance based on interviews with the parent and699child700

History of diagnosisof ADHD and the current use of medications associated with the701disorder will be elicited and recorded.702

7036. Cycloplegic Refraction:704

A cycloplegic refraction (Section 2.4)will be performed only after all clinical testing listed705(including any retests if one or more failure criteria are met (section 5.2)) is completed.706

For subjects with confirmation of one or more failure criteria, if the cycloplegic refraction707has changed significantly since the refraction at 30 months (section 4.3), the subject will708

return on a different day 4 weeks 1 week later and all tests performed at the 36-month709outcome exam will be repeated by the masked examiner with the child wearing the new710correction.711

712

3.8 Non-Study Visits and Treatment713Investigators may schedule additional visits at their own discretion. Subjects will continue to714follow the study-specified follow-up schedule regardless of any non-study visits.715


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716Investigators must not start any additional treatment (other than that outlinedinsection 3.1) prior to717the 36-month outcome visit unless one or more deterioration criteria (section 3.4) have been met718and confirmed by the masked examiner.719

720721


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CHAPTER 4:MISCELLANEOUS CONSIDERATION IN FOLLOW-UP722723

4.1 Contacts by the Jaeb Center for Health Research724The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided with725the parentscontact information. The Jaeb Center will contact the parents of the participants only726when necessary. Permission for such contacts will be included in the Informed Consent Form. The727

principal purpose of the contacts will be to develop and maintain rapport with the participant and/or728family and to help coordinate scheduling of the outcome examinations.729

730The site investigator or coordinator will directly contact the parents of each participant who is731assigned to glasses treatment within the first 2 weeks of the study to inquire about any issues with732obtaining glasses and to encourage treatment compliance.733

734

4.2 Patient Withdrawals735Parents may withdraw their child from the study at any time. This is expected to be a very736infrequent occurrence in view of the study designs similarity to routine clinical practice. If the737

parents indicate that they want to withdraw their child from the study, the investigator personally738should attempt to speak with them to determine the reason. If their interest is in transferring the739childs care to another eye care provider, every effort should be made to comply with this and at the740same time try to keep the participant in the study under the new providers care.741

742

4.3 Management of Refractive Error743A cycloplegic refraction should be performed every 12 months during follow-up, unless the subject744has confirmation of one or more deterioration criteria, in which case a cycloplegic refraction must745be performed if not done within the previous 6 months. A mandatory cycloplegic refraction must746also be completed at the 30-month and 36-month exams. In addition, a cycloplegic refraction747

should be performed whenever the investigator suspects that refractive error may not be corrected748 according to study guidelines (see below).749750

If cycloplegic refraction reveals a change in refractive error of >0.75 D sphere or >0.75D cylinder751or > 0.75D in SE anisometropia or axis change of 6 degrees or more when cylinder is 1.00D or752more from the previous cycloplegic refraction, the glasses must be updated. Whether to update the753correction for smaller changes in refraction is at investigator discretion. If updated, the glasses754correction must meet the requirements described insections 3.1.2and 3.5.755

756If the glasses correction drops to +1.00D SE or lower, the use of glasses is at the investigators757discretion.758

7594.3.1 Bifocals760

Bifocal treatment is allowed only following confirmation of deterioration criteria. Subjects will be761tested in their distance correction placed in a trial frame at the 36-month outcome exam.762

763

4.4 Management of Strabismus764Strabismus surgery is not allowed prior to the 36-month outcome exam unless one or more765deterioration criteria are confirmed. Subjects who undergo strabismus surgery will return for766follow-up at the protocol-specific follow-up visits. Subjects who receive strabismus surgery prior767to the 36-month outcome exam will be considered a failure for analysis purposes (seesection5.2.1).768


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769

4.5 Management of Amblyopia770Amblyopia treatment is not allowed prior to the 36-month outcome exam unless one or more771deterioration criteria are confirmed. Amblyopia treatment for subjects with confirmation of one or772more deterioration criteria is at investigator discretion, but must start with prescribing refractive773correction (described insection3.5). Method used for amblyopia treatment is at investigator774

discretion. Subjects receiving amblyopia treatment prior to the 36-month outcome exam will not be775considered a failure for analysis purposes unless the amblyopia is present at the time of the outcome776exam.777

778

4.6 Risks779There are no risks involved in this study that would not be part of usual care.780

781

4.6.1 Risks of Examination Procedures782The procedures in this study are part of daily eye care practice in the United States and pose no783known risks. As part of a routine usual-care exam, the participant will receive cycloplegic/dilating784eye drops.785

786

4.7 Reporting of Adverse Events787No surgical procedures are part of the protocol and no treatments are being prescribed that are not788part of usual care. Investigators will abide by local IRB reporting requirements.789

790

4.8 Discontinuation of Study791The study may be discontinued by the Steering Committee (with approval of the Data and Safety792Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all793

participants.794795

4.9 Travel Reimbursement796Parents of each participant will be compensated $40 per visit for completion of each protocol-797specified follow-up visit, for a maximum of $280. If there are extenuating circumstances, and the798participant is unable to complete study visits without additional funds due to travel costs, additional799funds may be provided.800

801

4.10 Study Costs802The participant or his/her insurance will be responsible for the costs that are considered standard803

care.804805

Standard care visits (paid for by participant or his/her insurance) include:806

Initial examination807 12-month follow-up visit808 24-month follow-up visit809 36-month follow-up visit810

811Non-standard of care visits (paid for by the study) include:812

6-month follow-up visit813


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18-month follow-up visit814 30-month follow-up visit815 Return for repeat masked exam within 4 weeks of 36-month exam816

817All glasses and any changes to glasses that are mandated by the study protocol during the course of818the study and are required for further testing will be paid for by the study. A change in glasses819

prescribed at the 36-month exam when the subject will not be seen back for study purposes will not820be paid for by the study. Additional treatment offered at the investigators discretion during the821study will not be paid for by the study.822


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871Not Failure = NONE of the criteria for failure are met872

873If a subject meets any failure criteria (with the exception of strabismus surgery prior to the 36-874month outcome exam), the visual condition that is considered to be failed must be retested by the875masked examiner (section 3.4.1) using the same procedures outlined insection 3.4.2. The subject876

must be given a 10-minute break prior to retesting each failed criterion. Failure criterion must be877 confirmed with and without correction to be considered a failure.878879

If failure is confirmed and the subject requires a change in glasses (section 3.7), the 36-month880outcome exam is repeated on a different day 4 weeks 1 week later by the masked examiner.881Failure will be assessed at this post-36 month exam, and the subject will be classified as a failure if882he/she meets any of the failure criteria above. If the subject meets any failure criteria (with the883exception of strabismus surgery), the visual condition that is considered to be failed must be884retested by the masked examiner using the same procedures outlined above. Failure must be885confirmed with and without correction to be considered a failure.886

887

5.3 Secondary Data Analyses888All secondary analyses will be performed separately for each of the two primary cohorts (section8895.1).890

891

5.3.1 Best Visual Acuity at 36 Months892A treatment group comparison of the mean maximum visual acuity per subject at the masked 36-893month visit (best visual acuity on any test with and without correction) will be performed using a t-894test.895

896

5.3.2 Development of Strabismus897A treatment group comparison of the proportion of subjects who develop a measurable heterotropia898not correctable with glasses alone at the 36 month masked outcome will be performed using the899Fishers exact test. The cumulative proportion of subjects who develop a measureable heterotropia900at any time during follow-up will be compared between treatment groups using the log-rank test.901

902

5.3.3 Subgroup Analysis903Treatment effect in subgroups based on baseline factors will be assessed. The subgroups of interest904include baseline spherical equivalent anisometropia and baseline spherical equivalent refractive905error. Outcome failure status at 36 months post-randomization will be tabulated by subgroup and906reviewed for consistency. The subgroup definitions for the planned subgroup analyses are as907follows:908

Spherical equivalent anisometropia: +1.00D, >+1.00D909 Spherical equivalent refractive error: +3.00D to


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918

5.3.5 Development of Amblyopia919A treatment group comparison of the proportion of subjects who develop amblyopia during the920course of the study will be performed using the Fishers exact test.921

922

5.3.6 Near Visual Acuity923A treatment group comparison of the mean near visual acuity at the masked 36-month outcome924exam will be performed using a t-test.925

5.4 Exploratory Analyses926Exploratory analysis will be described fully in the formal analysis plan.927

928

5.5 Sample Size Estimates929Sample size has been estimated separately for each of the two primary cohorts. The study is930powered for an appropriate number of patients in each primary cohort.931

932

Table 5 provides sample size estimates per treatment group to detect specific differences in the933proportion of patients meeting failure criteria at 36 months (section 5.2.1) with 90% power and a934two-sided type I error rate of 5% using a Fishers exact test.935

936

Table 5: Sample Size Estimates Per Group for Various Failure Proportions937938

Failure Proportion:

Observation

Failure Proportion: Glasses

0.05 0.10 0.15 0.20

0.15 198 951 - -

0.20 107 282 1248 -

0.25 71 143 352 1502

0.30 51 90 173 4110.35 40 63 105 197

0.40 32 47 72 118

939

Subjects aged 12 to


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There is essentially no literature to base sample size estimates for 36 to


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CHAPTER 6:REFERENCES995996

1. Giordano L, Friedman DS, Repka MX, et al. Prevalence of refractive error among preschool997children in an urban population: the Baltimore Pediatric Eye Disease Study. Ophthalmology9982009;116:739-746.999

2. Multi-Ethnic Pediatric Eye Disease Study Group. Prevalence of myopia and hyperopia in 6- to1000

72-month-old african american and Hispanic children: the multi-ethnic pediatric eye disease1001 study. Ophthalmology2010;117:140-147.10023. Atkinson J, Braddick O, Robier B, et al. Two infant vision screening programmes: prediction1003

and prevention of strabismus and amblyopia from photo- and videorefractive screening.Eye10041996;10:189-198.1005

4. Ingram RM, Walker C, Wilson JM, Arnold PE, Dally S. Prediction of amblyopia and squint by1006means of refraction at age 1 year.British Journal of Ophthalmology1986;70:12-15.1007

5. American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel.Preferred1008practice pattern guidelines: Amblyopia. San Francisco, CA: American Academy of1009Ophthalmology; 2007:Available at:http://www.aao.org/ppp.1010

6. Donahue SP, Arnold RW, Ruben JB, Committee AVS. Preschool vision screening: what should1011we be detecting and how should we report it? Uniform guidelines for reporting results of1012preschool vision screening studies.Journal of AAPOS: American Association for Pediatric1013Ophthalmology & Strabismus2003;7:314-316.1014

7. Lyons SA, Jones LA, Walline JJ, et al. A survey of clinical prescribing philosophies for1015hyperopia. Optometry and Vision Science2004;81:233-237.1016

8. Miller JM, Harvey EM. Spectacle prescribing recommendations of AAPOS members.Journal1017of Pediatric Ophthalmology and Strabismus1998;35:51-52.1018

9. American Optometric Association. Optometric clinical practice guideline: Care of the patient1019with hyperopia. St. Louis, MO: American Optometric Association; 1997:Available at:1020http://www.aoa.org/x4813.xml1021

10. Atkinson J, Anker S, Bobier W, et al. Normal emmetropization in infants with spectacle1022correction for hyperopia.Investigative Ophthalmology & Visual Science2000;41:3726-3731.1023

11. Ingram RM, Arnold PE, Dally S, Lucas J. Results of a randomised trial of treating abnormal1024hypermetropia from the age of 6 months.British Journal of Ophthalmology1990;74:158-159.1025

12. Atkinson J, Braddick O, Nardini M, Anker S. Infant hyperopia: detection, distribution, changes1026and correlates-outcomes from the cambridge infant screening programs. Optometry and Vision1027Science2007;84:84-96.1028

13. Anker S, Atkinson J, Braddick O, Nardini M, Ehrlich D. Non-cycloplegic refractive screening1029can identify infants whose visual outcome at 4 years is improved by spectacle correction.1030Strabismus2004;12:227-245.1031

14. Pan Y, Tarczy-Hornoch K, Cotter SA, et al. Visual acuity norms in pre-school children: the1032Multi-Ethnic Pediatric Eye Disease Study. Optometry and Vision Science2009;86:607-612.1033

15. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE. Normative pediatric visual1034acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester1035following the Amblyopia Treatment Study protocol.Journal of AAPOS: American Association1036for Pediatric Ophthalmology & Strabismus2008;12:145-149.1037

16. Birch E, Williams C, Drover J, et al. Randot Preschool Stereoacuity Test: normative data and1038validity.Journal of AAPOS: American Association for Pediatric Ophthalmology & Strabismus10392008;12:23-26.1040

17. Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Boca1041Raton, FL: Chapman and Hall/CRC; 2000.1042

1043
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