NSAID Phase II for Non-central Involved Diabetic Macular Edema (DME)
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: nepafenac 0.1% drops; Nepafenac Vehicle
Intervention description: One drop three times per day for one year; Placebo
Intervention MeSH terms: Nepafenac
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 125.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Macular Edema; Non steroidal anti-inflammatories

Summary:

      This study is being conducted to assess the effects of topical nonsteroidal
      anti-inflammatories (NSAIDs) on macular retinal volume compared with placebo in eyes with
      non-central diabetic macular edema (DME). A secondary objective of this study is to assess
      the effects of topical NSAIDs on central subfield thickness and to compare the progression of
      non-central DME to central DME as determined by optical coherence tomography (OCT) and
      stereoscopic fundus photographs. Furthermore, this phase II study is being conducted (1) to
      determine whether the conduct of a phase III trial has merit based on an anatomic outcome,
      (2) to estimate recruitment potential of a phase III investigation, and (3) to provide
      information on outcome measures needed to design a phase III trial. The study is not designed
      to establish the efficacy of NSAIDs in the treatment of non- central DME.
    

Eligibility criteria:

        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