PEDIG Update

National Association of Vision ProfessionalsAnnual Conference

Coralville, IAAugust 7th, 2014

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Pediatric Eye Disease Investigator Group(PEDIG)

An Update from the Coordinating Center

Raymond Kraker, M.S.P.H.Director, PEDIG Coordinating Center

Jaeb Center for Health ResearchTampa, FL

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Disclosures

PEDIG Studies are Supported by the National Eye Institute

Grant Funding from NIH (EY011751 and EY018810)

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PEDIG Information

Public Website list of PEDIG studies and more

information

http://www.pedig.netEmail: [email protected]

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A network dedicated to conducting multi-center studies in strabismus, amblyopia, and other eye disorders that affect children.

Formed in 1997, the network is funded by the National Eye Institute.

Most recent five-year grant renewed for 2014 through 2018

Development of PEDIG

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The primary focus of PEDIG

Comparative effectiveness studies done by university- and community-based pediatric eye care practitioners as part of routine practice

To challenge consensus and provide evidence base for the practice of pediatric eye care

Primary Focus of PEDIG

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Benefits of a Network?

• Multicenter –recruit a large # of patients• Central coordinating center

– Multiple studies– Reduced expense

• Randomized clinical trials– Best design to answer research question– Minimizes bias and potential for confounding– Prospective standardized follow up and outcomes

• EVA visual acuity tester (ATS-HOTV/E-ETDRS)• Masked assessment of outcomes

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Structure of PEDIG

Director, PEDIG Coordinating CenterRaymond T. Kraker, M.S.P.H.

Jaeb Center for Health ResearchTampa, FL

Network Chair OfficeDavid K. Wallace, M.D., M.P.H.

Duke University

Operations CommitteeDavid K. Wallace, M.D.

Raymond K. Kraker MSPH

Jonathan M. Holmes, M.D.

Michael X. Repka, M.D.Susan A. Cotter, O.D.

Roy W. Beck M.D., Ph.D.Kathy Lee, M.D.

Eric Crouch, M.D.

Data Safety and Monitoring Committee

(DSMC)

Executive Committee

SteeringCommittees

AmblyopiaStrabismus

SitesInvestigatorsCoordinatorsTechniciansOrthoptists

Writing Committees

For each primary and secondary manuscript

ProtocolPlanning

Committees

Protocol MonitorsChristina Morales

Brooke FimbelDiana Rojas

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Continually solicits the participation of new sites and investigators

Collaboration between academic and community-based eye care providers

Open to Ophthalmologists or Optometrists completing pediatric fellowship or residency whose practice is at least 40% pediatric eye care and/or strabismus

Open Network

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Size of Network

• 105 Sites Actively Participating –85 (81%) Ophthalmology Based

– 50 Institutional, 35 Community –20 (19%) Optometry Based

– 15 Institutional, 5 Community• Over 700 study group members

– Eye care professionals including investigators, coordinators, technicians, orthoptists

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PEDIG Studies1997-2014

Completed Current UpcomingStrabismus 2 2 1Amblyopia 21 1NLD 3Hyperopia/Myopia 1 1CI 1Registry/Data Collection

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PEDIG Update

• Entering 17th year• 33 completed studies• 6 current studies recruiting or in follow up• Approaching 10000 patients• 86 manuscripts toward goal to change

clinical practice

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Amblyopia Treatment StudiesChanging Clinical Practice

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Does vision improve with glasses alone?How long does improvement continue?

• Some recommend initiating patching with glasses, while others wait a highly variable period of time.

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Spectacle-Only Phase (ATS5)• 3 to <7yr olds with no prior treatment for amblyopia• Glasses only until improvement stopped• Anisometropic amblyopia (n= 84)

– 20/40 to 20/250– 77% improved at least 2 lines– 27% resolved

• Strabismic amblyopia (n=25)– 72% improved at least 2 lines– 24% resolved

• Up to 30 weeks to plateau

146 patients (ATS13)75% improved at least

2 lines32% resolved

Ophthalmology 2006;113:895–903; AJO 2007;143:1060-317

ATS5 and ATS13 Lessons Learned

• Amblyopia from anisometropia, strabismus or both combined, improves with spectacles alone.

• May treat with glasses alone until improvement stops

• Some still have amblyopia after period of treatment with glasses

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ATS1 - Patching or Atropine? • PEDIG’s 1st Randomized Trial

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ATS1 Rationale• In 1997, the available data on initial treatment for

amblyopia were largely retrospective and uncontrolled

• Amblyopia is the most common cause of visual impairment in children

• Amblyopia was usually treated with patching of the sound eye, though data suggested that atropine therapy may also be effective

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• Age < 7 years

• Moderate amblyopia 20/40 to 20/100

• 2 treatment groups

• Primary outcome: Visual acuity at 6 months

6hrs to FT Patching

Daily atropine

ATS1 Study Design

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0%

20%

40%

60%

80%

100% Patching

0%

20%

40%

60%

80%

100%

Atropine

ATS1 ResultsA

mbl

yopi

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6-month Amblyopic Eye Visual Acuity

>20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160

N=208

N=194

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ATS1 Lessons Learned

• There was substantial improvement in amblyopic eye visual acuity with both treatments

• The difference between groups in amblyopic eye acuity at six months was small

• The initial choice of treatment with patching or atropine can be made by the eye care provider and parent.

Arch Ophthalmol 2002;120:268-78

If Choose to Patch, How Much?

• Intuition and tradition– more must be better– Fulltime had been standard in texts and practice

guidelines• Real practice

– Not always suggested– Inconvenient– Can not be done

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ATS1 Led to Randomized Patching Dosage Studies (ATS2 A & B)

• Moderate amblyopia (20/40 – 20/80)– 2 hours versus 6 hours

• Severe amblyopia (20/100 – 20/400)– 6 hours versus full-time

• Primary outcome at 4 months• 3 to <7 years of age• Anisometropic, strabismic or combined amblyopia

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ATS2 B Moderate Amblyopia (20/40-20/80)

20/32

20/40

20/50

20/63

20/80

20/63+20/63+

Mea

n V

isua

l Acu

ity S

core 20/32-220/32-2

2 hr/d N=95

6 hr/d N=94

2 hr/d N=87

6 hr/d N=85

2 hr/dN=92

6 hr/d N=89

Baseline 5 Weeks 4 Months

20/40-20/40-

Arch Ophthalmol 2003;121:603-1126

ATS2 A Severe Amblyopia (20/100 - 20/125)

20/160

20/200

20/125

20/063

20/080

20/100

20/250

20/050

20/040

Mea

n V

isua

l Acu

ity S

core

FTN=90

6 hr/dN=85

Baseline

20/16020/160+

FTN=77

6 hr/dN=75

5 Weeks

20/63-220/63-2

FTN=84

6 hr/dN=73

4 Months

20/5020/50-2

Mean improvement4.8 lines in 6h group4.7 lines in FT group

Ophthalmology 2003;110:2075-8727

ATS2 A/B Lessons Learned

• As initial therapy– Improvement associated with all doses– In moderate amblyopia, prescribing 6 hours/day

patching is no more effective than 2 hours/day– In severe amblyopia, prescribing full-time

patching is no more effective than 6 hours/day

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If Choose Atropine, is Daily Atropine Required?

• Daily works; cycloplegia lasts a long time– Simons et al suggested a benefit of reduced

frequency• How frequent is a drop of atropine

necessary for a beneficial effect on amblyopia?

Simons et al. Ophthalmology 1997; 104:2143-55 29

ATS4 RCT Daily vs Weekend Atropine

• Moderate amblyopia (20/40 – 20/80)– Daily atropine vs weekend atropine

• Primary outcome at 4 months• 3 to <7 years of age

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5 Weeks

20/40+120/40

ATS4 Amblyopic EyeMean Acuity at Each Visit

20/32

20/40

20/50

20/63Mea

n V

isua

l Acu

ity S

core

DailyN=83

WeekendN=85

Baseline

Daily N=78

Weekend N=81

DailyN=77

WeekendN=83

20/63+220/63+2

4 Months

20/32-120/32-1

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0%

20%

40%

60%

80%

100%

Weekend Atropine

0%

20%

40%

60%

80%

100% Daily Atropine

ATS4 Amblyopic Eye at 4 MonthsA

mbl

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>20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160

N=77

N=83

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0%

20%

40%

60%

80%

100%

6-Hours Patching

0%

20%

40%

60%

80%

100% 2-Hours Patching

ATS2B - Amblyopic Eye at 4 MonthsA

mbl

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>20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160

N=92

N=89

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0%

20%

40%

60%

80%

100%

6-Hours Patching

0%

20%

40%

60%

80%

100% 2-Hours Patching

ATS2B and ATS4Amblyopic Eye at 4 Months

Am

blyo

pic

Eye

Vis

ual A

cuity

Cum

ulat

ive

Dis

tribu

tion


>20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160

N=92

N=89

0%

20%

40%

60%

80%

100%

Weekend Atropine

0%

20%

40%

60%

80%

100%

Daily AtropineN=77

N=83


• Daily atropine is no more effective than weekend atropine (twice a week) as initial therapy for moderate amblyopia.

• Reduced frequency is another alternative treatment for amblyopia

• Magnitude of improvement similar to that seen with patching in ATS2B

Ophthalmology 2004;111:2076-2085 35

Augmenting Atropine with a Plano Lens (ATS8)

• Some atropine advocates enhance atropine with a plano lens for the sound eye– Cycloplegia (blur at near) and optical

penalization (blur at distance and near)– Might be very powerful

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ATS8 RCT Atropine vs Atropine Plus Plano Lens

• Moderate amblyopia (20/40 – 20/100)– Weekend atropine vs weekend atropine

plus plano lens

• Primary outcome at 18 weeks• 3 to <7 years of age

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ATS8 - Amblyopic Eye at 18 WeeksAtropine

Only GroupN=84

Atropine + Plano GroupN=88

Mean acuity at baseline 20/63+2 20/63Mean improvement from baseline 2.4 lines 2.8 lines

Mean acuity at 18 wks 20/32-2 20/32-1

Mean Difference (95% CI)0.3 lines

(-0.2, 0.8) 38

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ATS8 Amblyopic Eye at 18 Weeks


• Prescribing a plano lens for the fellow eye is no more effective than weekend atropine alone.

Archives Ophthalmology 2009;127:22-3040

Older Children and Teens7 to 18 years (ATS3)

• Traditionally not always offered treatment• Randomization

– spectacles only– spectacles plus therapy

• Occlusion 2 hours per day• Daily atropine (up to 13 years)

• Enrolled 507 patients at 49 sites

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Average Maximum Improvement

• Augmented treatment compared with optical alone– 13.3 and 7.3 letters, p < 0.001

Arch Ophthalmol 2005;123:437-47 42

Two or More Lines Improvement

0102030405060708090

100

Perc

enta

ge

Augmented TreatmentOptical Treatment

7 to 8yrs 9 to 10yrs 11 to 12yrs 13 to 17yrs

86 86 75 75 40 44 55 48 43


• Children 7 to <13 years of age respond to conventional treatment

• Some teenagers 13 to <17 years respond, particularly if previously untreated.

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How about older children - patching versus atropine monotherapy?

(ATS9)• 7 to 12 years• Moderate amblyopia (20/40 to 20/100)• Randomization

– Patching 2 hours per day– Atropine twice weekly

Arch Ophthalmol. 2008;126:1634-1642 45

ATS9 RCTAmblyopic Eye at 17 Weeks

Atropine GroupN=89

Patching GroupN=84

Mean acuity at baseline 61.7 letters 62.4 letters

Mean acuity at 17 wks 69.4 letters 71.0 lettersMean improvement from baseline 7.6 letters 8.6 letters

Mean Difference*95% CI

1.1 letters(-0.8 to 3.0)

* Controlling for baseline acuity. Patching – Atropine interval shown46

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ATS9 Amblyopic Eye at 17 Weeks

0%

20%

40%

60%

80%

100%

Patching

0%

20%

40%

60%

80%

100%

Atropine

Am

blyo

pic

Eye

Vis

ual A

cuity

Cum

ulat

ive

Dis

tribu

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Amblyopic Eye Visual Acuity at Four-month Outcome Exam

>20/16 >20/20 >20/25 >20/32 >20/40 >20/50 >20/63 >20/80 >20/100 >20/125 >20/160

N=89

N=84

>20/200


• Atropine and patching improve the vision of older children (7 to <13 years) similarly

• Less effective than in younger children

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Residual Amblyopia Older Kids

• Patching and atropine not universally successful

• Research suggests benefit in using oral levodopa-carbidopa as adjunct to patching

• PEDIG pilot Study (ATS 14) established dosage

• PEDIG RCT to answer question (ATS 17)

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ATS17 Objectives

• Compare efficacy and safety of oral levodopa with patching vs. placebo with patching• 139 subjects randomized to levodopa or

placebo in a 2:1 allocation• Manuscript to be submitted to shortly

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Residual Amblyopia Younger Kids

• When stable does increasing the treatment improve the outcome?– ATS15 - at 2 hours per day, does increased

patching help?– ATS16 – does adding plano to twice weekly

atropine help?

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ATS15 - Amblyopic Eye Visual Acuity Improvement

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Proportion with ≥ 2 logMAR line improvement since baseline


• When amblyopic eye stops improving with 2hrs daily patching, increasing dosage to 6hrs results in more improvement after 10wks compared with continuing 2 hours daily

53Ophthalmology 2013;120:2270-77

ATS16

• Manuscript submitted to JAAPOS• When stable does increasing the treatment

improve the outcome?– Adding plano to twice weekly atropine

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What’s Next for Amblyopia?

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Amblyopia Treatment Study 18

A Study of Binocular Computer Activities for Treatment of Amblyopia

September 2014

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iPad Binocular Tetris Game

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ATS18 Study Questions

1. Is Binocular Treatment non-inferior to Patching in 5 to <13y olds with amblyopia ? (if not inferior, subsequent test of superiority)

2. Is Binocular Treatment superior to Patching in 13 to <17y olds with amblyopia ?

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ATS18 Study Design

Children 5-<17 years with Aniso/Strab/Combined Amblyopia

Binocular iPad game 1h/d Patching 2h/d

Assessment of VA, Stereo at 4, 8, 12 weeks

Final masked exam at 16 weeks

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Other Pedig Studies

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Current and Future Studies

Questions?

Public Website list of PEDIG studies and more

information

http://www.pedig.netEmail: [email protected]

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Documents

PEDIG Update