NSAID Phase II for Non-central Involved Diabetic Macular Edema (DME)

There is strong evidence to indicate that prevention of non-central involved DME from
progression into the central subfield of the macula is a good anatomic surrogate for
preventing visual acuity loss. Furthermore, the prevalence of macular edema is estimated to
be high among patients with diabetes, and it is likely that approximately 25% of non-central
involved cases of DME extend into the central subfield of the macula within one year. Thus,
if a relatively safe and economical treatment could be identified that reduced the
progression of non-central involved edema to central-involved edema by at least 50%, this
treatment could have a major public health impact.

There is also evidence that inflammation has a role in DME, and that a topical NSAID might
have an effect on retinal edema. Topical NSAIDs are in current widespread clinical use and
appear to be well tolerated and safe when administered chronically, making them a potentially
attractive alternative treatment for DME in patients who would like to delay or avoid laser
photocoagulation or intravitreal injections (for example, patients who are willing to use
daily eye drops to avoid ocular procedures or patients for whom access to experienced retinal
specialists to apply laser photocoagulation or other treatments is limited).

This phase II trial may provide proof of concept evidence that topical NSAID treatment can
have a beneficial effect on DME and possibly prevent increases in retinal volume or
progression of non central-involved DME into the central subfield of the macula. Furthermore,
it could determine the correlation between OCT and fundus photographic documentation of
progression of DME into the central subfield in this clinical trial setting. Since effective
treatments, including laser photocoagulation and intravitreal injections, already exist for
DME treatment, topical NSAIDs would have to demonstrate a substantial effect on DME
progression in order to be of sufficient clinical interest for further investigation. If a
beneficial effect is apparent in this trial, which utilizes a relatively small sample size
and short follow-up period, results from this phase II study might be utilized in planning
future phase III trials. These future phase III trials could definitively answer whether or
not NSAIDs are an efficacious novel therapeutic approach to the treatment of DME or
preventing the progression of DME from extending into the central subfield of the macula.

Inclusion Criteria:

- Age >18 years

- Type 1 or type 2 diabetes

- Only one study eye per subject may be enrolled. The study eye must meet the following:

- Best corrected E-ETDRS visual acuity letter score ≥ 74 (i.e., 20/32 or better)
within 8 days of enrollment.

- On clinical exam, definite retinal thickening due to DME within 3000 μm of the
center of the macula but not involving the central subfield.

- Thickened non-central macular subfields on DRCR.net approved spectral domain OCT
macular map.

- Central subfield thickness within threshold definition for normal central
subfield thickness on DRCR.net approved spectral domain OCT machine.

- No focal/grid laser within the last 6 months or other treatment for DME within
the last 4 months.

- No anticipated need to treat DME during the course of the study, unless the eye
meets the criteria for treatment (Central subfield retinal thickness increases to
310 μm or more in spectral domain OCT machine from baseline).

- Diagnosis of diabetes mellitus (type 1 or type 2). Any one of the following will be
considered to be sufficient evidence that diabetes is present:

- Current regular use of insulin for the treatment of diabetes.

- Current regular use of oral anti-hyperglycemia agents for the treatment of
diabetes.

- Documented diabetes by American Diabetes Association and/or the World Health
Organization criteria.

- At least one eye meets the study eye criteria.

- Able and willing to provide informed consent.

- Successful completion of the run-in phase during which level of compliance is more
than 80%

Study Eye Inclusion Criteria

- Best corrected E-ETDRS visual acuity letter score ≥74 (i.e.20/32 or better) within 8
days of randomization.

- On clinical exam, definite retinal thickening due to DME within 3000 μm of the center
of the macula but not involving the central subfield.

- Thickened non-central macular subfields on spectral domain OCT macular map that meet
either of the following criteria:

- At least two non-central macular subfields with OCT thickness above threshold
(average normal + 2 SD) from DRCR.net approved spectral domain OCT machines- see
below.

- At least one non-central macular subfield with OCT thickness at least 15 μm above
threshold (average normal + 2 SD) from DRCR.net approved spectral domain OCT
machines—see DRCR.net procedures manual for threshold details.

- Central subfield thickness <250 microns obtained by one of the following DRCR.net
approved spectral domain OCT machines:

- Zeiss Cirrus

- Heidelberg Spectralis

- Optovue RTVue

- Media clarity, pupillary dilation, and study participant cooperation sufficient for
adequate OCT and fundus photographs.

- If the study participant is on multiple ocular drops, investigator believes that study
participant can be compliant with a multi-drop regimen.

Exclusion Criteria:

A study participant is not eligible for the run-in phase or the randomized trial if any of
the following exclusion criteria are present:

- A condition that, in the opinion of the investigator, would preclude participation in
the study (e.g., unstable medical status including blood pressure, cardiovascular
disease, and glycemic control).

- Subjects in poor glycemic control who, within the last 4 months, initiated intensive
insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4
months should not be enrolled.

- Use of systemic corticosteroids or anti-VEGF therapy.

- Current use of prescription systemic NSAIDs.

- History of auto-immune diseases such as rheumatoid arthritis.

- Participation in an investigational trial that involved treatment with any drug within
30 days of randomization that has not received regulatory approval at the time of
study entry.

- Note: study participants cannot receive another investigational drug while
participating in the study.

- Known allergy to any component of the study drug.

- Blood pressure > 180/110 mmHg (systolic above 180 or diastolic above 110 mmHg)

- If blood pressure is brought below 180/110 by anti-hypertensive treatment, study
participant can become eligible.

- Participant is expecting to move out of the area of the clinical center to an area not
covered by another clinical center during the 12 months of the study.

- For women of child-bearing potential: pregnant or lactating or intending to become
pregnant within the next 12 months.

- Women who are potential study participants should be questioned about the potential
for pregnancy. Investigator judgment is used to determine when a pregnancy test is
needed.

Study Eye Exclusion Criteria

- History of focal/grid laser within the last 6 months or other treatment for DME within
the last 4 months

-Note: Throughout the study, the distribution of subjects with prior treatment for DME
will be evaluated, and eligibility criteria may be tailored to add balance between
subjects with prior treatment and subjects without prior treatment for DME.

- Anticipated need to treat DME during the course of the study (Any DME treatment during
the study should follow criteria in section 4.3).

- History of use of NSAID eye drops within the last 30 days or anticipated need for such
drops during the study due to other ocular condition

- History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to
randomization

- Anticipated need for PRP in the 6 months following randomization

- Anticipated need for cataract extraction surgery in the study eye during the study
period

- Lipid in the fovea (center of the macula)

- History of major ocular surgery (including scleral buckle, any intraocular surgery,
etc.) within prior 4 months or major ocular surgery anticipated within the next 6
months following randomization

- An ocular condition, other than diabetic macular edema, is present such that, in the
opinion of the investigator, visual acuity might be affected now (e.g., foveal
atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition,
epiretinal membrane or vitreo-macular traction) or during the course of the study
(e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular
glaucoma, etc.)

- History of YAG capsulotomy performed within 2 months prior to randomization

- Exam evidence of severe external ocular infection, including conjunctivitis,
chalazion, or substantial blepharitis

- Aphakia

- History of vitrectomy for any reason

- History of cataract surgery within the prior 1 year

- Uncontrolled glaucoma