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

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT01331005
• Collaborator: National Eye Institute (NEI) (NIH)
• Enrollment: 125
• Locations: 32
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: nepafenac 0.1% drops; Other: Nepafenac Vehicle	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Mean Change in Optical Coherence Tomography Measure Retinal Volume, mm3 [From Baseline to 12 months]

Secondary Outcome Measures

1. Mean Change in Visual Acuity [baseline to 12 months]

   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.

2. Change in OCT Central Subfield Thickness [baseline to 12 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California	United States	92354
2	Southern California Desert Retina Consultants, MC	Palm Springs	California	United States	92262
3	California Retina Consultants	Santa Barbara	California	United States	93103
4	Bay Area Retina Associates	Walnut Creek	California	United States	94598
5	Retinal Consultants of Southern California Medical Group, Inc.	Westlake Village	California	United States	91361
6	Retina Consultants of Southwest Florida	Fort Myers	Florida	United States	33912
7	Central Florida Retina Institute	Lakeland	Florida	United States	33805
8	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
9	Retina Associates of Hawaii, Inc.	Honolulu	Hawaii	United States	96813
10	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46290
11	American Eye Institute	New Albany	Indiana	United States	47150
12	Wolfe Eye Clinic	West Des Moines	Iowa	United States	50266
13	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky	United States	40509-1802
14	Paducah Retinal Center	Paducah	Kentucky	United States	42001
15	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
16	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
17	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan	United States	48202
18	Vitreo-Retinal Associates	Grand Rapids	Michigan	United States	49525
19	University of Minnesota	Minneapolis	Minnesota	United States	55455
20	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire	United States	03801
21	Eye Care for the Adirondacks	Plattsburgh	New York	United States	12901
22	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York	United States	13224
23	Charlotte Eye Ear Nose and Throat Assoc, PA	Charlotte	North Carolina	United States	28210
24	Retina Associates of Cleveland, Inc.	Beachwood	Ohio	United States	44122
25	Retina Northwest, PC	Portland	Oregon	United States	97210
26	Family Eye Group	Lancaster	Pennsylvania	United States	17601-2644
27	Southeastern Retina Associates, PC	Kingsport	Tennessee	United States	37660
28	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
29	Texas Retina Associates	Lubbock	Texas	United States	79424
30	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
31	University of Washington Medical Center	Seattle	Washington	United States	98195
32	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Jaeb Center for Health Research
• National Eye Institute (NEI)

Investigators

• Principal Investigator: Scott M Friedman, MD, Florida Retina Consultants

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT01331005
• Other Study ID Numbers: DRCR.net Protocol R; U10EY018817-03; U10EY014231-09
• First Posted: Apr 7, 2011
• Last Update Posted: Sep 21, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Jaeb Center for Health Research: Macular Edema; Non steroidal anti-inflammatories
• Additional relevant MeSH terms: Macular Edema; Edema; Nepafenac

Study Results

Participant Flow

Arm/Group Title	Placebo	Nepafenac 0.1% Drops
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo	Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year
Period Title: Overall Study
STARTED	64	61
COMPLETED	60	57
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Placebo	Nepafenac 0.1% Drops	Total
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo	Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year	Total of all reporting groups
Overall Participants	64	61	125
Age, Customized (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	59	60	60
Sex: Female, Male (Count of Participants)
Female	28 43.8%	23 37.7%	51 40.8%
Male	36 56.3%	38 62.3%	74 59.2%
Race/Ethnicity, Customized (participants) [Number]
White	38 59.4%	44 72.1%	82 65.6%
African American	13 20.3%	7 11.5%	20 16%
Hispanic or Latino	12 18.8%	5 8.2%	17 13.6%
American Indian/Alaskan Native	1 1.6%	0 0%	1 0.8%
Native Hawaiian/Other Pacific Islander	0 0%	2 3.3%	2 1.6%
Asian	0 0%	2 3.3%	2 1.6%
More than one race	0 0%	1 1.6%	1 0.8%
Type of Diabetes (participants) [Number]
Type 1	5 7.8%	5 8.2%	10 8%
Type 2	56 87.5%	53 86.9%	109 87.2%
Uncertain	3 4.7%	3 4.9%	6 4.8%
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17 (11)	19 (11)	18 (11)
Hemoglobin A1c (Percent HbA1c) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Percent HbA1c]	7.9	8.1	7.9
Electronic-Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	83 (7)	82 (6)	83 (7)
History of Diabetic Macular Edema Treatment (participants) [Number]
yes	28 43.8%	30 49.2%	58 46.4%
no	36 56.3%	31 50.8%	67 53.6%
History of Panretinal Photocoagulation (participants) [Number]
yes	11 17.2%	13 21.3%	24 19.2%
no	53 82.8%	48 78.7%	101 80.8%
Optical Coherence Tomography Machine (participants) [Number]
Zeiss Cirrus	41 64.1%	37 60.7%	78 62.4%
Heidelberg Spectralis	23 35.9%	24 39.3%	47 37.6%
Optical Coherence Tomography Central Subfield Thickness (Microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Microns]	218 (25)	227 (29)	223 (27)
Optical Coherence Tomography Retinal Volume (mm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm^3]	7.7 (0.4)	7.9 (0.6)	7.8 (0.5)

Outcome Measures

1. Primary Outcome

Title	Mean Change in Optical Coherence Tomography Measure Retinal Volume, mm3
Time Frame	From Baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nepafenac 0.1% Drops
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo	Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year
Measure Participants	64	61
Mean (95% Confidence Interval) [mm3]	0.02	-0.03

2. Secondary Outcome

Title	Mean Change in Visual Acuity
Description	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.
Time Frame	baseline to 12 months

Outcome Measure Data

Analysis Population Description

Original 12-month values are not available in 4 eyes of each of nepafenac and placebo groups because 12-month visit was not completed and were imputed from the last available measurement; values at or before first diabetic macular edema treatment were carried forward in 5 and 3 eyes of nepafenac and placebo groups respectively.

Arm/Group Title	Placebo	Nepafenac 0.1% Drops
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo	Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year
Measure Participants	64	61
Mean (Standard Deviation) [Letter Score]	-0.3 (6.2)	0.2 (5.7)

3. Secondary Outcome

Title	Change in OCT Central Subfield Thickness
Description	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.
Time Frame	baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nepafenac 0.1% Drops
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo	Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year
Measure Participants	64	61
Mean (Standard Deviation) [microns]	7 (35)	9 (45)

Adverse Events

Arm/Group Title	Placebo		Nepafenac 0.1% Drops
Arm/Group Description	Placebo will be given three times per day for one year Nepafenac Vehicle: Placebo		Nepafenac drops will be given three times per day for one year nepafenac 0.1% drops: One drop three times per day for one year
All Cause Mortality
	Placebo		Nepafenac 0.1% Drops
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Nepafenac 0.1% Drops
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/64 (18.8%)		16/61 (26.2%)
Blood and lymphatic system disorders
Hyperglycemia	1/64 (1.6%)	1	1/61 (1.6%)	1
Cardiac disorders
Atrial Fibrillation	1/64 (1.6%)	1	0/61 (0%)	0
Chest Pain	2/64 (3.1%)	2	1/61 (1.6%)	1
Eye disorders
Burning Eyes	0/64 (0%)	0	1/61 (1.6%)	1
Chemical Conjunctivitis	1/64 (1.6%)	1	0/61 (0%)	0
Corneal Melt	0/64 (0%)	0	1/61 (1.6%)	1
Vision Decreased	0/64 (0%)	0	1/61 (1.6%)	1
Gastrointestinal disorders
Bowl Obstruction	0/64 (0%)	0	1/61 (1.6%)	1
Rectal Bleeding	0/64 (0%)	0	1/61 (1.6%)	1
Gallbladder Stones	1/64 (1.6%)	1	1/61 (1.6%)	1
Musculoskeletal and connective tissue disorders
Hip Fracture	0/64 (0%)	0	1/61 (1.6%)	1
Shoulder Fracture	1/64 (1.6%)	1	0/61 (0%)	0
Tendon disorder	0/64 (0%)	0	1/61 (1.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	0/64 (0%)	0	1/61 (1.6%)	1
Kidney Cancer	1/64 (1.6%)	1	0/61 (0%)	0
Nervous system disorders
Seizures	1/64 (1.6%)	1	0/61 (0%)	0
Spinal stenosis of unspecified region	1/64 (1.6%)	1	0/61 (0%)	0
Stroke (cerebrovascular accident)	0/64 (0%)	0	1/61 (1.6%)	1
Renal and urinary disorders
Chronic kidney disease	0/64 (0%)	0	1/61 (1.6%)	1
Surgical and medical procedures
Gastric bypass surgery	1/64 (1.6%)	1	0/61 (0%)	0
Removal of foreign body from throat	0/64 (0%)	0	1/61 (1.6%)	1
Vascular disorders
Aortic stenosis	1/64 (1.6%)	1	0/61 (0%)	0
Arteriovenous fistula	0/64 (0%)	0	1/61 (1.6%)	1
Caratoid artery disease	0/64 (0%)	0	1/61 (1.6%)	1
Hypotension	0/64 (0%)	0	1/61 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Nepafenac 0.1% Drops
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/64 (57.8%)		30/61 (49.2%)
Cardiac disorders
Chest Pain	3/64 (4.7%)	3	2/61 (3.3%)	2
Eye disorders
Eye Pain	5/64 (7.8%)	5	1/61 (1.6%)	1
Blurred Vision	6/64 (9.4%)	6	6/61 (9.8%)	6
Floaters	4/64 (6.3%)	4	4/61 (6.6%)	4
Vitreous Hemorrhage	1/64 (1.6%)	1	4/61 (6.6%)	4
Cataract	3/64 (4.7%)	3	3/61 (4.9%)	3
Eye Itching	3/64 (4.7%)	3	0/61 (0%)	0
Proliferative Diabetic Retinopathy	3/64 (4.7%)	3	0/61 (0%)	0
Vision Decreased	3/64 (4.7%)	3	3/61 (4.9%)	3
Visual Acuity Decreased	1/64 (1.6%)	1	3/61 (4.9%)	3
Gastrointestinal disorders
Stomach Virus	2/64 (3.1%)	2	3/61 (4.9%)	3
General disorders
Fall	3/64 (4.7%)	3	1/61 (1.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Members of the Network can not discuss the trial results until the primary outcome has been made publicly available.