1. The Diabetic Retinopathy Clinical Research Network
A Phase II Evaluation of Topical NSAIDs in Eyes with Non-Central Involved DME (Protocol R)
Scott Friedman MD
Protocol Chair
Sponsored by the National Eye Institute,
National Institutes of Health, U.S. Department of Health and Human Services.

2. Study Question
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? 2

3. 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

4. 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

5. Rationale for Use of NSAIDs on Non-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

6. Study 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

7. 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)

8. Study Design Phase II Multi-center Randomized Double-masked
Clinical Trial

9. Study Design Primary outcome analysis at 1 year
Eligibility Criteria Met/Informed Consent
Run-In Phase/Enrollment Visit
30-60 days
Randomization Visit/Baseline
Nepafenac (TID)
Placebo (TID)
4 Months
4 Months
8 Months
8 Months
Primary outcome analysis at 1 year

10. Subject Eligibility Criteria
Inclusion
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%

11. 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

12. Ocular 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

13. 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:
Machine
Women
Men
Zeiss Cirrus
<290
<305
Optovue RTVue
Heidelberg Spectralis
<320

14. 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)
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

15. 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

16. 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

18. Study Eye
Both 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

19. Run-in Phase Purpose Protocol
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 randomization

20. Randomization
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

21. 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

22. Compliance 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

23. Study Testing Procedures
Enrollment
Randomization 4M 8M
12M
Run-in (30-60 days)
Baseline
±1M
E-ETDRS BCVA/
Eye Exam/
OCT X
Fundus Photo
Blood Pressure
HbA1c
Weighing Bottles

24. Guidelines for DME Treatment
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
No treatment for DME is given unless
Study participants will continue their study treatment through 12 months regardless of whether treatment for DME is received
Primary outcome analysis at 1 year

25. Outcome Measures Primary Outcome Secondary Outcomes
Mean change in macular retinal volume (mm3) between baseline and 12 months
Secondary Outcomes
Progression of non-central involved DME
Correlation of progression of DME in OCT and fundus photographs
Visual Acuity
Safety Outcomes

26. Safety Outcome Cornea Cataract/cataract surgery
Irritation/burning sensation
Corneal edema
Superficial keratitis
Ulceration
Melting
Note: Corneal complications will be expeditiously sent for review by the DSMC
Cataract/cataract surgery
Ocular infection/inflammation

27. Sample Size
60 study participants per group convenience sample size will be recruited
Total number of eyes is 120 in 120 study participants

28. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Dedicated to multicenter clinical research of diabetic
retinopathy, macular edema and associated disorders. 28