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

Sponsor:	Diabetic Retinopathy Clinical Research Network
Collaborator:	National Eye Institute (NEI)
Information provided by (Responsible Party):	Diabetic Retinopathy Clinical Research Network
ClinicalTrials.gov Identifier:	NCT01331005

Purpose

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 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 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.

Condition	Intervention	Phase
Diabetic Macular Edema	Drug: nepafenac 0.1% drops Other: Nepafenac Vehicle	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	A Phase II Evaluation of Topical Non-steroidal Anti-inflammatories in Eyes With Non Central Involved Diabetic Macular Edema

Resource links provided by NLM:

Genetics Home Reference related topics: age-related macular degeneration X-linked juvenile retinoschisis

MedlinePlus related topics: Diabetic Eye Problems Edema Retinal Disorders

Drug Information available for: Nepafenac

U.S. FDA Resources

Further study details as provided by Diabetic Retinopathy Clinical Research Network:

Primary Outcome Measures:

Mean change in optical coherence tomography measure retinal volume [ Time Frame: From Baseline to 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Corneal Ulceration [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: Yes ]
Corneal Melting [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: Yes ]
Irritation [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: Yes ]
Mean change in visual acuity [ Time Frame: baseline to 12 months ] [ Designated as safety issue: No ]
The 95% CI will be obtained in each treatment group and compared between treatment groups at 1 year. For eyes that have received treatment for diabetic macular edema(DME) before 1 year, visual acuity and optical coherence tomography (OCT) measurements obtained at time of failure will be used instead of measurements at 1 year.
Change in OCT central subfield thickness [ Time Frame: baseline to 12 months ] [ Designated as safety issue: No ]
95% CI will be obtained in each treatment group and compared between treatment groups at 1 year. For eyes that have received treatment for DME before 1 year, visual acuity and OCT measurements obtained at time of failure will be used instead of measurements at 1 year.
Change in number of thickened subfields on OCT [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
95% CI will be obtained in each treatment group and compared between treatment groups at 1 year. For eyes that have received treatment for DME before 1 year, visual acuity and OCT measurements obtained at time of failure will be used instead of measurements at 1 year.
Change in level of diabetic retinopathy on stereoscopic fundus photographs [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
95% CI will be obtained in each treatment group and compared between treatment groups at 1 year. For eyes that have received treatment for DME before 1 year, visual acuity and OCT measurements obtained at time of failure will be used instead of measurements at 1 year.

Estimated Enrollment:	120
Study Start Date:	May 2011
Estimated Study Completion Date:	May 2012
Estimated Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo Placebo will be given three times per day for one year	Other: Nepafenac Vehicle Placebo
Active Comparator: nepafenac 0.1% drops Nepafenac drops will be given three times per day for one year	Drug: nepafenac 0.1% drops One drop three times per day for one year

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01331005

Contacts

Contact: Adam R Glassman, MS

813-975-8690

aglassman@jaeb.org

Show 32 Study Locations

Sponsors and Collaborators

Diabetic Retinopathy Clinical Research Network

National Eye Institute (NEI)

Investigators

Principal Investigator:

Scott M Friedman, MD

Florida Retina Consultants

More Information

No publications provided

Responsible Party:	Diabetic Retinopathy Clinical Research Network
ClinicalTrials.gov Identifier:	NCT01331005 History of Changes
Other Study ID Numbers:	DRCR.net Protocol R, U10EY018817-03, U10EY014231-09
Study First Received:	April 6, 2011
Last Updated:	November 11, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Diabetic Retinopathy Clinical Research Network:

Macular Edema
Non steroidal anti-inflammatories

Additional relevant MeSH terms:

Edema
Macular Edema
Signs and Symptoms
Macular Degeneration
Retinal Degeneration

Retinal Diseases
Eye Diseases
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2012