The Diabetic Retinopathy Clinical The Diabetic Retinopathy Clinical Research NetworkResearch Network

The Diabetic Retinopathy Clinical The Diabetic Retinopathy Clinical Research NetworkResearch Network

A Phase II Evaluation of Topical NSAIDs in Eyes with Non-Central Involved DME (Protocol R)

Scott Friedman MDProtocol Chair

Sponsored by the National Eye Institute,

National Institutes of Health, U.S. Department of Health and Human Services.

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Do topical non-steroidal anti-inflammatory drugs (NSAIDs) have biological effects on non-central involved DME? Is macular volume influenced by using NSAID drops

in these eyes? Do NSAIDs reduce the risk of progression to central-

involved DME? Do NSAIDs reduce the risk of progression of current

non-central DME? Do NSAIDs increase the chance of resolution of non-

central DME?

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Study QuestionStudy Question

Non-central DME Non-central DME

Clinical Definition - Retinal thickening due to DME within 3000µm of, but not involving, the center of macula

OCT definition - Retinal thickening due to DME >2 SD beyond the normal value outside the central subfield BUT <mean+2 SD in spectral domain OCT machines within the central subfield

Typical Management – observation until center becomes thickened or until imminent involvement of center is perceived

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Progression of Non-center Involved DME

Progression of Non-center Involved DME

ETDRS 22% of study participants with non-center involved

(DME) by color fundus photographs assigned to deferral of laser progressed to the center of the macula by 1 year

Protein Kinase C-β DME Study Group 1/3 of eyes with non-central DME in the control

group progressed to the central subfield within 1 year

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Rationale for Use of NSAIDs on Rationale for Use of NSAIDs on Non-central DMENon-central DME

Rationale for Use of NSAIDs on Rationale for Use of NSAIDs on Non-central DMENon-central DME

Possible role of inflammatory markers in DME Some topical NSAID medicines reach

posterior segment of the eye Observational studies showed some beneficial

effects of topical NSAID eye drops on DME

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Study ObjectivesStudy Objectives Primary Objective: Assess effect of topical

NSAIDs on retinal volume compared with placebo in eyes with non-central DME

Secondary Objective: Assess effect of topical NSAIDs on central subfield thickness, and to compare the progression of non-central to central DME as determined by spectral domain OCT, and as determined by color fundus photographs

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Nepafenac 0.1%(Nevanac®)Nepafenac 0.1%(Nevanac®)

Converted to active metabolite, amfenac, in ocular tissues

Nepafenac and amfenac inhibit both cyclooxygenase (COX) I and II which catalyze the formation of pro-inflammatory prostaglandins that contribute to edema

FDA approved to treat pain and inflammation associated with cataract surgery

Dosage: 1 drop, 3 times per day (TID)

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Study DesignStudy Design

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Phase IIMulti-centerRandomized

Double-maskedClinical Trial

Study DesignStudy Design

99Primary outcome analysis at 1 year

Run-In Phase/Enrollment Visit

Eligibility Criteria Met/Informed Consent

Placebo (TID)

Randomization Visit/Baseline

Nepafenac (TID)

4 Months

8 Months

4 Months

8 Months

30-60 days

Subject Eligibility CriteriaSubject Eligibility CriteriaInclusion

• Age ≥ 18 years • Diabetes mellitus (type 1 or type 2) • Successful completion of the run-in

phase during which level of compliance is more than 80%

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Subject Eligibility Criteria (cont.)Subject Eligibility Criteria (cont.)

Exclusion• Use of systemic corticosteroids or anti-VEGF

therapy• Current use of prescription systemic NSAIDs.• Auto-immune diseases judged to result in a

higher risk for corneal complications• Known allergy to any component of the study

drug• Blood pressure > 180/110 mmHg• For women of child-bearing potential:

pregnant or lactating or intending to become pregnant within the next 12 months

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Ocular Eligibility CriteriaOcular Eligibility CriteriaOcular Eligibility CriteriaOcular Eligibility Criteria

Inclusion• BCVA letter score ≥ 74 E-ETDRS (20/32 or better)

• By Clinical exam: Retinal thickening due to DME within 3000 µm of but not involving the macular center

• By OCT: Thickened non-central macular subfields

• Media clarity

• If patient on other drop(s), willingness to comply with a multi-drop regimen

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Ocular Eligibility Criteria (cont.)Ocular Eligibility Criteria (cont.)

CSF less than the gender-specific mean thickness from a normal cohort + 2 SD, from one of the following SD OCT machines:

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Machine Women Men

Zeiss Cirrus <290 <305

Optovue RTVue <290 <305

Heidelberg Spectralis <305 <320

Ocular Eligibility Criteria (cont.)Ocular Eligibility Criteria (cont.)

Thickened non-central macular subfields on OCT map must meet either one of the following criteria:

* Threshold= average normal + 2 standard deviations (SD)1414

• At least two subfields with thickness above threshold* in spectral domain OCT machines

• At least one subfield with thickness of at least 15μm above threshold in spectral domain OCT machines

Ocular Eligibility Criteria (cont.)Ocular Eligibility Criteria (cont.) Exclusion

• Focal/grid laser within the last 6 months or other treatment for DME within the last 4 months

• Anticipated need to treat DME during the study

• NSAID eye drops use within the last 30 days or anticipated need for such drops during the study

• History of PRP within 4 months prior to randomization

• Need for PRP in the 6 months following randomization

• Need for cataract surgery of study eye during the study

•  Lipid in the fovea 

• History of major ocular surgery within prior 4 months or anticipated within the next 6 months

• An ocular condition, other than DME, that may affect VA

• YAG capsulotomy within 2 months of randomization

• Severe external ocular infection  

• Aphakia

• Vitrectomy for any reason

• Cataract surgery within the prior 1 year

• Uncontrolled glaucoma

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How can investigators know if an eye meets the protocol definition of

non-central DME?

How can investigators know if an eye meets the protocol definition of

non-central DME? OCT threshold grids provided by the

coordinating center for reference Site personnel enter each subfield thickness

value directly into the study website Computer algorithm determines if an eye meets

protocol criteria for non-central DME

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Study EyeStudy EyeStudy EyeStudy EyeBoth eyes may be evaluated for

eligibility, but only ONE eye will be enrolled

If both eyes are eligible at the time of enrollment, study eye will be selected by investigator and study participant

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Run-in PhaseRun-in PhaseRun-in PhaseRun-in PhasePurpose

Filtering participants with poor compliance

Protocol All eligibility criteria must be met before

enrollment Artificial tears (Tears Naturale Forte®)-1

drop, 3 times per day At least 30 days (30-60 days) Compliance assessed at end of run-in

phase before randomization1919

RandomizationRandomization All eligibility criteria, except VA and OCT,

will be reconfirmed again after run-in phase

OCT and VA will not be reconfirmed at randomization, provided investigator is not planning on DME treatment

Randomization data will be the baseline Study participants must show good

compliance with drops during the run-in period

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Compliance Assessment and Randomization Eligibility

Compliance Assessment and Randomization Eligibility

Compliance will be assessed by weighing bottles and comparing to an expected weight

Study participants will be eligible for randomization if compliance was 80% or more of expected

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Compliance AssessmentCompliance Assessment

Digital scales are provided by the Coordinating Center

Each bottle will be weighed prior to dispending to study participant

Each bottle will be re-weighed at the next visit One artificial tears bottle for run-in phase Six drug/placebo bottles at randomization and

each follow-up visit

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Study Testing ProceduresStudy Testing Procedures

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Enrollment Randomization 4M 8M 12M

Run-in (30-60 days)

Baseline ±1M ±1M ±1M

E-ETDRS BCVA/Eye Exam/OCT

X X X X X

Fundus Photo X X

Blood Pressure X X

HbA1c X

Weighing Bottles X X X X X

Guidelines for DME TreatmentGuidelines for DME Treatment

Primary outcome analysis at 1 year

Randomized eye drops

OCT CSF increases to more than gender and machine specific mean+2 SD value, provided at least 10% increase from baseline. Computer algorithm will calculate and give appropriate alert.

Extenuating circumstances after protocol chair discussion e.g. rapidly-developing cataract prior to cataract surgery

Study participants will continue their study treatment through 12 months regardless of whether treatment for

DME is received

No treatment for DME is given unless

Secondary OutcomesSecondary OutcomesSecondary OutcomesSecondary Outcomes

Mean change in macular retinal volume (mm3) between baseline and 12 months

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Outcome MeasuresOutcome MeasuresOutcome MeasuresOutcome MeasuresPrimary OutcomePrimary OutcomePrimary OutcomePrimary Outcome

Progression of non-central involved DME Correlation of progression of DME in OCT

and fundus photographs Visual Acuity Safety Outcomes

Safety OutcomeSafety OutcomeCornea

• Irritation/burning sensation• Corneal edema• Superficial keratitis• Ulceration• Melting• Note: Corneal complications will be expeditiously

sent for review by the DSMC

Cataract/cataract surgeryOcular infection/inflammation

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Sample SizeSample SizeSample SizeSample Size

60 study participants per group convenience sample size will be recruited

Total number of eyes is 120 in 120 study participants

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Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)

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Dedicated to multicenter clinical research of diabeticretinopathy, macular edema and associated disorders.