Diabetic Retinopathy Clinical Research Network A Phase II ...publicfiles.jaeb.org/drcrnet/protocol/DRCRnet_Protocol_R_V2_8_2_11… · Diabetic Retinopathy Clinical Research Network

DRCRnet Protocol R V2.0 8-2-11

Diabetic Retinopathy Clinical Research

Network

A Phase II Evaluation of Topical NSAIDs

in Eyes with Non Central Involved DME

Version 2.0

August 2, 2011

DRCRnet Protocol R V2.0 8-2-11

Table of Contents 1 2

Chapter 1 - Introduction ................................................................................................................. 1-3 3 1.1 Background and Rationale ................................................................................................. 1-3 4

1.1.1 Impact of Vision Loss from Diabetic Macular Edema Not Involving the Central 5

Subfield of the Macula ......................................................................................................... 1-3 6

1.1.2 Frequency of Non-central Involved Diabetic Macular Edema Progression to Central 7

Involved Edema ................................................................................................................... 1-4 8

1.1.3 Prevalence of Non-central Involved Diabetic Macular Edema .................................. 1-5 9

1.1.4 Current Treatment of Non-central Involved Diabetic Macular Edema ...................... 1-5 10

1.1.5 Role of Inflammation in Edema, Macular Edema, and Diabetic Retinopathy ........... 1-5 11

1.1.6 Rationale for Topical Non-steroidal Anti-Inflammatory Drugs for Non-central 12

Involved Diabetic Macular Edema ...................................................................................... 1-6 13

1.1.7 Nepafenac ................................................................................................................... 1-7 14

1.1.8 Change in Retinal Volume as a Primary Outcome Measure ...................................... 1-7 15

1.1.9 Correlation of OCT Images with Fundus Photographs in Documenting Progression of 16

Non-central-Involved DME to Central-Involved DME ....................................................... 1-8 17

1.1.10 Summary of Rationale for the Study ........................................................................ 1-8 18

1.2 Study Objectives: ............................................................................................................... 1-9 19

1.3 Synopsis of Protocol .......................................................................................................... 1-9 20

1.4 General Considerations .................................................................................................... 1-11 21

CHAPTER 2 STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT........................ 2-1 22 2.1 Identifying Eligible Study Participants and Obtaining Informed Consent ........................ 2-1 23

2.2 Subject Eligibility Criteria ................................................................................................. 2-1 24

2.2.1 Subject-level Criteria .................................................................................................. 2-1 25

2.2.2 Study Eye Criteria ....................................................................................................... 2-2 26

2.2.3 Non-study Eye ............................................................................................................ 2-4 27

2.3 Screening Evaluation and Baseline Testing ....................................................................... 2-4 28

2.3.1 Historical Information ................................................................................................. 2-4 29

2.3.2 Baseline Testing Procedures ....................................................................................... 2-5 30

2.4 Run-in Phase ...................................................................................................................... 2-6 31

2.5 Randomization of Eligible Subjects................................................................................... 2-6 32

CHAPTER 3 -TREATMENT REGIMENS .................................................................................. 3-1 33 3.1 Introduction ........................................................................................................................ 3-1 34

3.1.1 Run-in Phase ............................................................................................................... 3-1 35

3.1.2 Randomized Trial........................................................................................................ 3-1 36

3.2 NSAID ............................................................................................................................... 3-1 37

3.3 Placebo ............................................................................................................................... 3-1 38

3.4 Artificial Tears ................................................................................................................... 3-1 39

3.5 Eye Drops Usage................................................................................................................ 3-1 40

3.6 Assessment of Compliance ................................................................................................ 3-2 41

3.6.1 Run-in Phase ............................................................................................................... 3-2 42

3.6.2 During Follow-up........................................................................................................ 3-2 43

CHAPTER 4 FOLLOW-UP VISITS AND TREATMENT ......................................................... 4-1 44 4.1 Visit Schedule .................................................................................................................... 4-1 45

4.2 Testing Procedures ............................................................................................................. 4-1 46

4.3 Treatment for Diabetic Macular Edema ............................................................................ 4-2 47

CHAPTER 5 - MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP .......................... 5-1 48

DRCRnet Protocol R V2.0 8-2-11DRCRnet Protocol R V2.0 8-2-11 1-2

5.1 Treatment of Diabetic Retinopathy in the Study Eye ........................................................ 5-1 49

5.2 Treatment after Cataract Surgery ....................................................................................... 5-1 50

5.3 Treatment of Diabetic Retinopathy in Non-study Eye ...................................................... 5-1 51

5.4 Diabetes Management ........................................................................................................ 5-1 52

5.5 Study participant Withdrawal and Losses to Follow-up .................................................... 5-1 53

5.6 Discontinuation of Study ................................................................................................... 5-1 54

5.7 Contact Information Provided to the Coordinating Center ................................................ 5-1 55

5.8 Study Participant Reimbursement...................................................................................... 5-2 56

CHAPTER 6 ADVERSE EVENTS ................................................................................................ 6-1 57 6.1 Definition ........................................................................................................................... 6-1 58

6.2 Recording of Adverse Events ............................................................................................ 6-1 59

6.3 Reporting Serious or Unexpected Adverse Events ............................................................ 6-1 60

6.4 Data and Safety Monitoring Committee Review of Adverse Events ................................ 6-2 61

6.5 Risks ................................................................................................................................... 6-2 62

6.5.1 Potential Adverse Effects of Topical NSAIDs ........................................................... 6-2 63

6.5.2 Corneal Complications................................................................................................ 6-3 64

6.5.3 Risk of Artificial Tears (Tears Naturale Forte®)........................................................ 6-3 65

6.5.4 Risks of Eye Examination and Tests .......................................................................... 6-3 66

CHAPTER 7 STATISTICAL METHODS .................................................................................... 7-1 67 7.1 Sample Size ........................................................................................................................ 7-1 68

7.2 Sample Size Estimation ..................................................................................................... 7-1 69

7.3 Efficacy Analysis Plan ....................................................................................................... 7-2 70

7.3.1 Primary Outcome Analysis ......................................................................................... 7-2 71

7.3.2 Secondary and Tertiary Outcomes .............................................................................. 7-3 72

7.4 Assessment of Compliance ................................................................................................ 7-3 73

7.5 Safety Analysis Plan .......................................................................................................... 7-4 74

7.6 Additional Tabulations and Analyses ................................................................................ 7-4 75

REFERENCES ................................................................................................................................. 8-1 76

77


Chapter 1 - Introduction 78

79

1.1 Background and Rationale 80

1.1.1 Impact of Vision Loss from Diabetic Macular Edema Not Involving the Central 81

Subfield of the Macula 82 Data from the Early Treatment Diabetic Retinopathy Study (ETDRS)

1 evaluating eyes with 83

diabetic macular edema (DME) have shown that the presence or absence of thickening involving 84

the center point of the macula (center-involved DME) was an important factor in determining 85

short and long term visual acuity outcomes (Figures 1 and 2). By one year of follow up, 86

approximately 10% of eyes with center-involved edema that were assigned to deferral of 87

photocoagulation had three or more line visual acuity loss, almost tenfold greater than eyes with 88

DME but without center involvement. Moreover, for eyes assigned to deferral of 89

photocoagulation, more than 35% of eyes with center-involved DME at baseline lost three or 90

more lines, while only 10% of the eyes with DME but without center involvement developed the 91

same outcome by five years. Furthermore, eyes which developed center-involved DME during 92

follow up that were assigned to deferral of photocoagulation at baseline, showed trends similar to 93

those which were affected at baseline with center-involved DME. Specifically, over 30% of 94

these eyes lost three or more lines of visual acuity by five years. Therefore, identifying ways to 95

prevent or delay involvement of the central subfield of the macula (central-involved DME, or 96

thickening within the central macular circle that is 1mm in diameter) may be of value to patients 97

who have DME without current central subfield involvement since there are data to suggest that 98

progression to the center of the macula is a reasonable surrogate for visual acuity loss. 99

100

Years

Center Thickening

at Baseline

CSME but No Center

Thickening at Baseline

Macular Edema

Not Clinically Significant10

20

30

40

0

0 1 2 3 4 5

Three Line Visual Acuity Loss

Macular Edema & Mild to Moderate Diabetic Retinopathy

ETDRS Eyes Assigned to Deferral of Photocoagulation% With

Event

101 Figure 1: ETDRS, Ferris III F., Rational for CI DME as a surrogate outcome for VA (ETDRS). In; Sept 15, 2009 102


Years

Three Line Visual Acuity Loss

Macular Edema & Mild to Moderate Diabetic Retinopathy

ETDRS Eyes Assigned to Deferral of Photocoagulation

0 1 2 3 4 5

10

20

30

40

0

% With

Event

Center Definitely

Involved at Baseline

Center Involved

During Follow-up

Center Never Involved

103 Figure 2: ETDRS, Ferris III F., Rational for CI DME as a surrogate outcome for VA (ETDRS). In; Sept 15, 2009 104 105 Gardner et al, 2009, assessed the relationship between visual acuity and DME in relation to the 106

location of retinal thickening and reported a strong relationship between DME center 107

involvement and mean visual acuity. Mean visual acuity was lower when DME involved the 108

foveal center than when the distance of DME was greater than 1500 µm from the fovea. These 109

results also support the notion that progression of macular edema into the center is a reasonable 110

surrogate for vision loss.2 111

112

There is little comparable data for eyes with non-central involved DME that have had prior laser 113

photocoagulation. However, the DRCR.net showed that the treatment effects of focal/grid 114

photocoagulation on DME with regard to vision and retinal thickening were similar in eyes with 115

and without prior macular laser, suggesting that many eyes with a prior history of macular laser 116

may behave similarly to eyes that are treatment naïve.3 117

118

1.1.2 Frequency of Non-central Involved Diabetic Macular Edema Progression to Central 119

Involved Edema 120 The ETDRS showed that in approximately 22% of subjects assigned to deferral of laser 121

photocoagulation for DME that did not involve the center of the macula based on color fundus 122

photographs, the edema progressed to the center of the macula by 12 months.4 With immediate 123

laser photocoagulation, only 15% of subjects had progression to the center. More recently, a 124

study evaluating protein kinase C inhibitors for diabetic retinopathy reported that approximately 125

one-third of the control group subjects with DME not involving the central subfield on color 126

fundus photographs subsequently involved the central subfield within 1 year.5 127

128


1.1.3 Prevalence of Non-central Involved Diabetic Macular Edema 129 The prevalence of macular edema, defined as retinal thickening within one disc diameter of the 130

macular center on stereoscopic retinal photographs, was reported as 11.1% among patients with 131

type I diabetes and 8.4% among patients with type II diabetes in Southern Wisconsin in the early 132

1980s.6 Among those patients with macula edema, approximately 38% of patients with type I 133

diabetes and 44% of patients with type II diabetes were described as having clinically significant 134

macular edema, where the center of the retina was involved or threatened to be involved.6 This 135

information may overestimate the current number of cases with non-central involved DME, since 136

trends towards improved care and implementation of focal/grid photocoagulation for DME may 137

have reduced the number of center-involved cases over time. For example, 42% of participants in 138

the ETDRS had a Hemoglobin A1c (HbA1c) of 10 or higher whereas only 10% of participants in 139

a recent DRCR Network study had a HbA1c of 10 or higher.7,8

On the other hand, this 140

information may underestimate the number of cases with non-central involved DME since the 141

prevalence of diabetes has been increasing dramatically since the 1980s.9 In addition, since the 142

cases described above are based on grading of retinal photographs; it is possible that many more 143

cases of central and non-central involved DME would be identified by optical coherence 144

tomography (OCT), which has been shown to be more sensitive at detecting DME.10

145

146

1.1.4 Current Treatment of Non-central Involved Diabetic Macular Edema 147 Currently, when DME does not involve the central subfield of the macula, the Preferred Practice 148

Pattern of the American Academy of Ophthalmology recommends observation until either the 149

center of the macula becomes thickened, or until it is perceived that the central subfield of the 150

macula is imminently threatened to become abnormal, either because lipid associated with the 151

edema is accumulating in the center of the macula, or the edema is documented to be progressing 152

rapidly towards the center of the retina.11

In a survey of DRCR.net investigators regarding 153

diabetic patients with non-central involved macular thickening, 70% and 50% would only 154

observe patients for signs of progression, while 30% and 50% would intervene with laser or 155

other treatment modalities in patients without and with prior history of treatment for DME 156

respectively. When the central subfield of the macula becomes thickened or is judged to be 157

threatened to be thickened, standard treatment for DME is provided, usually intravitreal 158

injections with anti-vascular endothelial growth factor (VEGF) agents, steroids and focal/grid 159

photocoagulation, focal/grid photocoagulation alone, or vitrectomy. 3, 4, 11, 12

160

161

1.1.5 Role of Inflammation in Edema, Macular Edema, and Diabetic Retinopathy 162 Although the full role of inflammation in diabetic maculopathy is not fully elucidated, there is 163

accumulating evidence pointing to the role of inflammatory markers in DME. Macular edema is 164

an end outcome to many diseases in which different combinations of pathophysiologic processes 165

take place such as ischemia, inflammation, and hydrostatic and mechanical forces. Retinas from 166

diabetic animals exhibit biochemical and physiological abnormalities which, in composite, have 167

features that include inflammatory processes.13

DME results from abnormal leakage of fluid and 168

macromolecules, such as lipoproteins, from retinal capillaries into the extravascular space. This 169

is followed by an influx of water into the extravascular space due to increased oncotic pressure.14

170

Laboratory evidence indicates cellular-molecular interactions at the level of retinal blood barrier 171

lead to increased vascular permeability. These processes are mediated by a variety of 172

inflammatory molecules that cause leakage of fluid into the surrounding tissues, resulting in 173

swelling or edema. Limb, et al. have shown elevated levels of intercellular adhesion molecule-1 174


(ICAM-1), an important adhesive molecule for circulating leukocytes in patients with diabetic 175

retinopathy.15

Furthermore, Funatsu et al reported elevated levels of ICAM-1 in patients with 176

DME16

and also demonstrated that other inflammatory markers are associated with the retinal 177

vascular permeability and severity of DME.17

Promising therapeutic efficacy of anti-178

inflammatory drugs to improve both anatomical and functional parameters in DME or cystoid 179

macular edema (CME), points to the active role that the inflammatory process plays in those 180

diseases. Vascular endothelial growth factor (VEGF) was suggested to be an up regulator of 181

ICAM-1 expression.18

Tumor necrosis factor α (TNF-α) is a pro-inflammatory cytokine that has 182

been implicated in the pathogenesis of diabetic retinopathy, and has been associated with the 183

induction of adhesion molecules on endothelial cells.19

Several investigators have provided 184

additional evidence to support the potential role of inflammation with the development of 185

diabetic retinopathy.20

186

187

1.1.6 Rationale for Topical Non-steroidal Anti-Inflammatory Drugs for Non-central 188

Involved Diabetic Macular Edema 189 Because elevated inflammatory markers have been found in patients with diabetic retinopathy, 190

previous investigators have hypothesized that inflammation may have a role in at least some 191

cases of DME. Animal models have shown that topical non-steroidal anti-inflammatory drops 192

(NSAIDs) have the capability of reaching the posterior segment, including nepafenac (Nevanac, 193

Alcon, Fort Worth, TX, data on file with Alcon), ketorolac (Acular, Allergan, Irvine, CA, data 194

on file with Allergan), and bromfenac (Xibrom, ISTA, Irvine, CA, data on file with ISTA). In a 195

randomized investigator-masked multicenter study, Heier et al, randomized thirty one patients 196

undergoing vitrectomy to ketorolac 0.4%, bromfenac 0.09%, nepafenac 0.1%, or to no NSAID 197

beginning three days pre-operatively, and subsequently collected drug and prostaglandin E2 198

levels at time of surgery.21

The investigators showed that all three NSAIDs penetrated into the 199

vitreous cavity, and that those treated with ketorolac 0.4% had significantly lower levels of 200

prostaglandin E2 than those treated with no NSAID (p=0.047) or nepafenac 0.1% (p=0.03). The 201

mean (standard deviation(SD)) vitreous prostaglandin E2 levels of the control patients and those 202

treated with ketorolac 0.4%, bromfenac 0.09%, or nepafenac 0.1% were 270.6 (91.7) pg/mL, 203

189.6 (50.2) pg/mL, 247.2 (38.3) pg/mL, and 267.7 (99.7) pg/mL, respectively.21

If an NSAID 204

drug can reach retinal tissue, it possibly could also reduce vascular permeability by inhibiting the 205

inflammatory cascade. Based on this hypothesis, Callanan and Williams treated cases of DME 206

with the topical NSAID nepafanec.22

Nepafenac is a prodrug that is hydrolyzed into amfenac by 207

uveal tissue and retina.23

Callanan and Williams gave six eyes of five patients with DME topical 208

nepafenac 0.1% bid in an attempt to reduce the edema and improve vision.22

All six eyes had 209

partial or complete resolution of edema on OCT, while three out of six had some improvement in 210

visual acuity. However, given the fact that three of those eyes were pseudophakic, and that 211

cataract surgery had been performed five years prior to the study period, it is unclear whether 212

any of these eyes had a component of post-surgical cystoid macular edema which resolved with 213

the topical NSAID. 214

215

Additional laboratory studies have confirmed the ability of topical nepafenac to cause resolution 216

of edema due to inflammation, 24, 25

confirming the ability of topical application to affect edema 217

in the retina, while a variety of other studies also have suggested that other topical NSAIDs, such 218

as ketorolac (Allergan, Irvine, CA) can affect retinal edema.26-30

However, these clinical cases 219

were in the setting of post-surgical CME and not DME.26-30

220


221

Nevertheless, these studies support the rationale that NSAIDs have the capacity to have a 222

biologic effect on retinal edema, either by reaching the posterior segment of the eye directly, as 223

is suggested by Heier‘s vitrectomy study, or alternatively by influencing anterior segment-224

generated inflammatory mediators that might in turn affect posterior segment edema. Although 225

there is no evidence to date to indicate that one topical NSAID is superior to another with respect 226

to the ability to reach retinal tissue or to affect macular edema, if one or more topical NSAIDs 227

over 1 year were found to reduce the progression of non-central involved DME to the central 228

subfield of the macula from 30% to 15%, these findings could potentially justify the use of this 229

treatment in patients who would like to delay or avoid laser photocoagulation or intravitreal 230

injections (for example, patients who are willing to use daily eye drops to avoid ocular 231

procedures or patients for whom access to experienced retinal specialists to apply laser 232

photocoagulation or other treatments is limited). 233

234

1.1.7 Nepafenac 235 Nepafenac is the member of the NSAID class that will be evaluated in this trial. It is approved 236

for use in the United States and Europe for the treatment of postoperative pain and inflammation 237

associated with cataract surgery. Nepafenac rapidly penetrates the cornea and is deaminated by 238

intraocular hydrolases to form the active metabolite amfenac. Nepafenac and amfenac inhibit 239

activity from both cyclooxygenase isoforms (COX-1 and COX-2) responsible for prostaglandin 240

syntheses. Because the highest concentrations of hydrolases responsible for bioconversion of 241

nepafenac to amfenac are present in the retina and choroid, nepafenac and amfenac may reduce 242

the incidence and severity of macular edema. 243

244

1.1.8 Change in Retinal Volume as a Primary Outcome Measure 245 A majority of previous DME studies have utilized central subfield thickness as a primary 246

outcome measure, primarily because retinal thickening that involves the central subfield of the 247

macula is more likely to impact visual acuity than non-central involved DME. However, retinal 248

volume (the average of the central subfield, 4 inner subfields, and 4 outer subfields weighted by 249

the area of the subfields and converted to cubic millimeters) is a more global measure of DME, 250

and has been shown to be highly correlated with central subfield mean thickness (correlation 251

coefficients 0.75 and 0.77).31

Retinal volume has also been demonstrated to be a highly 252

reproducible measure.32

In the DRCR.net Protocol G, the ―Subclinical Diabetic Macular Edema 253

Study‖, the standard deviation for change in retinal volume from baseline to one year was 0.37 254

mm for N=16 eyes with subclinical DME and gradable volume measurements [Unpublished 255

data, DRCR.net]. 256

257

Because it encompasses a wider retinal area than central subfield thickness, retinal volume may 258

be a more sensitive measure than central subfield thickness for overall changes in DME status. 259

Its use as a primary outcome variable may thus allow observation of an anatomical effect of 260

NSAID therapy on DME to be determined within a relatively short period of time and with 261

relatively few study participants. For this reason, retinal volume rather than central subfield 262

thickness will be used as a primary outcome in this short term pilot study, although change in 263

central subfield thickness over time will also be considered a crucial endpoint from a scientific 264

standpoint. 265

266


267

1.1.9 Correlation of OCT Images with Fundus Photographs in Documenting Progression of 268

Non-central-Involved DME to Central-Involved DME 269

As mentioned in Section 1.1.1., analyses from the ETDRS have shown that eyes with DME but 270

without central involvement of the macula assigned to deferral of photocoagulation at baseline 271

were afflicted over time with central-involved DME and showed trends similar to those that were 272

affected at baseline with central-involved DME. These outcomes were based on stereoscopic 273

fundus photographs. Specifically, only 10% eyes without center involved DME for the duration 274

of the study lost three or more lines of visual acuity over 5 years compared with over 30% of 275

eyes that developed center involved DME over the same time period. Therefore, the goal of a 276

subsequent Phase III study that potentially would follow this phase II study would be to evaluate 277

treatments to prevent or delay involvement of the central subfield of the macula for patients who 278

have DME but without central subfield involvement, since there is rationale to suggest that 279

progression to the central subfield of the macula is a reasonable surrogate for visual acuity loss. 280

While OCT may be a more reliable, objective, and reproducible means of documenting the 281

progression of non-central-involved DME to central-involved DME, it is unknown how these 282

findings compare with presumably less sensitive evaluations on stereoscopic fundus 283

photographs. Thus, the phase II study described in this protocol will include the acquisition of 284

OCT and stereoscopic fundus photographs at specific times to provide information on the 285

correlation of progression to central involved DME on OCT and fundus photographs in this 286

study design. 287

288

1.1.10 Summary of Rationale for the Study 289 In summary, there is strong evidence to indicate that prevention of non-central involved DME 290

from progression into the central subfield of the macula is a good anatomic surrogate for 291

preventing visual acuity loss. Furthermore, the prevalence of macular edema is estimated to be 292

high among patients with diabetes, and it is likely that approximately 25% of non-central 293

involved cases of DME extend into the central subfield of the macula within one year. Thus, if a 294

relatively safe and economical treatment could be identified that reduced the progression of non-295

central involved edema to central-involved edema by at least 50%, this treatment could have a 296

major public health impact. 297

298

There is also evidence that inflammation has a role in DME, and that a topical NSAID might 299

have an effect on retinal edema. Topical NSAIDs are in current widespread clinical use and 300

appear to be well tolerated and safe when administered chronically, making them a potentially 301

attractive alternative treatment for DME in patients who would like to delay or avoid laser 302

photocoagulation or intravitreal injections (for example, patients who are willing to use daily eye 303

drops to avoid ocular procedures or patients for whom access to experienced retinal specialists to 304

apply laser photocoagulation or other treatments is limited). 305

306

This phase II trial may provide proof of concept evidence that topical NSAID treatment can have 307

a beneficial effect on DME and possibly prevent increases in retinal volume or progression of 308

non central-involved DME into the central subfield of the macula. Furthermore, it could 309

determine the correlation between OCT and fundus photographic documentation of progression 310

of DME into the central subfield in this clinical trial setting. Since effective treatments, 311


including laser photocoagulation and intravitreal injections, already exist for DME treatment, 312

topical NSAIDs would have to demonstrate a substantial effect on DME progression in order to 313

be of sufficient clinical interest for further investigation. If a beneficial effect is apparent in this 314

trial, which utilizes a relatively small sample size and short follow-up period, results from this 315

phase II study might be utilized in planning future phase III trials. These future phase III trials 316

could definitively answer whether or not NSAIDs are an efficacious novel therapeutic approach 317

to the treatment of DME or preventing the progression of DME from extending into the central 318

subfield of the macula. 319

320 321

1.2 Study Objectives: 322 Primary Objective: This study is being conducted to assess the effects of topical NSAIDs on 323

macular retinal volume compared with placebo in eyes with non-central DME. 324

325

Secondary Objective: A secondary objective of this study is to assess the effects of topical 326

NSAIDs on central subfield thickness and to compare the progression of non-central DME to 327

central DME as determined by OCT and stereoscopic fundus photographs. 328

329

Furthermore, this phase II study is being conducted (1) to determine whether the conduct of a 330

phase III trial has merit based on an anatomic outcome, (2) to estimate recruitment potential of a 331

phase III investigation, and (3) to provide information on outcome measures needed to design a 332

phase III trial. The study is not designed to establish the efficacy of NSAIDs in the treatment of 333

non- central DME. 334

335

1.3 Synopsis of Protocol 336

A. Definitions 337

Central-involved DME: Macular edema that involves the central circular subfield of the 338

macula that is 1 mm in diameter. 339

Center-involved DME: Macular edema that involves the anatomic center of the macula, 340

or foveal point. 341

342

B. Study Design 343

Phase II, Multi-center double-masked randomized clinical trial. 344

345

C. Major Eligibility Criteria 346

Age >18 years 347

Type 1 or type 2 diabetes 348

Only one study eye per subject may be enrolled. The study eye must meet the 349

following: 350

Best corrected E-ETDRS visual acuity letter score ≥ 74 (i.e., 20/32 or better) 351

within 8 days of enrollment. 352

On clinical exam, definite retinal thickening due to DME within 3000 μm of 353

the center of the macula but not involving the central subfield. 354

Thickened non-central macular subfields on DRCR.net approved spectral 355

domain OCT macular map— See section 2.2 for details. 356


Central subfield thickness within threshold definition for normal central 357

subfield thickness on DRCR.net approved spectral domain OCT machine – 358

See section 2.2 for details. 359

No focal/grid laser within the last 6 months or other treatment for DME within 360

the last 4 months. 361

No anticipated need to treat DME during the course of the study, unless the 362

eye meets the criteria for treatment (See section 4.3 for treatment criteria). 363

364 365

D. Run-In Phase 366 All potential study participants will be required to participate in a 30 day run-in phase. In order 367

to enter the run-in phase, all eligibility criteria must be assessed and met. During this phase, the 368

study participant will be required to use artificial tear drops 3 times per day. 369

370

At the end of the 30 day run-in phase (within an additional 30-day window after the 30 day 371

target), compliance with the study regimen will be assessed (see section 3.6), all eligibility 372

criteria will be reconfirmed except that of OCT and visual acuity, and the participant‘s 373

willingness to proceed into the randomized trial will be confirmed. 374

375

E. Treatment Groups 376 Study eyes of participants entering the randomized trial will be randomly assigned to receive 377

either topical medication nepafenac 0.1% drops or placebo 3 times per day for 1 year. 378

Randomization will be stratified by site. 379

380

Study participants will receive study drops with no treatment other than the study intervention 381

for DME through 12 months unless criteria for treatment of DME are met (see section 4.3.1). 382

All study participants will continue randomized drops and visits in follow up through 12 months 383

regardless of whether other treatment for DME is received. 384

385

F. Follow-up Schedule 386

Randomized subjects will return for follow-up visits every 4 months (±1 month) for 1 year. 387

Testing required at each visit is summarized below. 388

389

Run-in

Phase 0 4M 8M 12M

Visit Window 30-60

days ±1M ±1M ±1M

Artificial tears drops provided X

Randomization X

DME treatment assessment X X X

E-ETDRS best corrected visual acuitya X X X X X

Spectral Domain OCT b X X X X X

Fundus Photosc X X


Eye Examd

X X X X X

Blood pressure X X

HbA1ce

X

Compliance Assessment X X X X

Notes 390 Testing is only required for the study eye unless otherwise specified below. 391 a = Visual acuity performed on both eyes at each visit, including protocol refraction on both eyes at baseline (time 0 392 above) and month 12, and on the study eye only, at all other protocol visits. E-ETDRS refers to electronic ETDRS 393 testing using the Electronic Visual Acuity Tester that has been validated against 4-meter chart ETDRS testing. 394 Protocol refraction and visual acuity in the study eye also performed prior to initiating treatment for DME at study 395 visit or non-study visit. 396 b = OCT also obtained prior to initiating non-study treatment for DME at a study or non-study visit. OCT may be 397 obtained with, Zeiss Cirrus, Heidelberg Spectralis, or Optovue RTVue OCT machines only. 398 c = Seven field or 4 wide-field digital stereoscopic photos; obtained at baseline (time 0), 12-month visit or prior to 399 initiating treatment for DME at a study or non-study visit. 400

d = Both eyes at enrollment and baseline (time 0) visits study eye only at each follow up-visit including slit lamp 401 exam, corneal and lens assessment, measurement of intraocular pressure, and dilated ophthalmoscopy. 402

e = Does not need to be repeated if HbA1c available from within the prior 3 months; if not available, can be 403 performed within 3 weeks after randomization. 404

405

406

G. Sample Size: 407 A minimum of 60 eyes per group for a minimum of 120 total eyes will be randomized. The total 408

number of subjects randomized may exceed 120 to achieve 120 randomized eyes with accurate 409

retinal volume measurements (See section 2.3.2). 410

411

H. Primary Efficacy Outcome 412

Mean change in OCT measured retinal volume between baseline and 12 months 413

414

415

I. Main Safety Outcomes 416

Corneal ulceration and melting 417

Irritation 418

419

420

1.4 General Considerations 421

The study is being conducted in compliance with the policies described in the DRCR.net Policies 422

document, with the ethical principles that have their origin in the Declaration of Helsinki, with 423

the protocol described herein, and with the standards of Good Clinical Practice. 424

425

The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 426

Testing Procedures Manual, Study Procedures Manual, and photography procedure manuals) 427

provide details of the examination procedures. 428

429


Data will be directly collected in electronic case report forms, which will be considered the 430

source data.431

DRCRnet Protocol R V2.0 8-2-11 2-1

CHAPTER 2 STUDY PARTICIPANT ELIGIBILITY AND 432

ENROLLMENT 433

434

2.1 Identifying Eligible Study Participants and Obtaining Informed Consent 435 A minimum of 120 eyes from 120 study participants are expected to be enrolled into the 436

randomization phase with a goal to enroll an appropriate representation of minorities. As the 437

enrollment goal approaches, sites will be notified of the end date for recruitment. Study 438

participants who have signed an informed consent form can be randomized up until the end date, 439

which means the recruitment goal might be exceeded. In addition, the total number of study 440

participants randomized may exceed 120 to achieve 120 randomized eyes with accurate retinal 441

volume measurements. 442

443

Potential eligibility will be assessed as part of a routine-care examination. Prior to completing 444

any procedures or collecting any data that are not part of usual care, written informed consent 445

will be obtained. For study participants who are considered potentially eligible for the study 446

based on a routine-care exam, the study protocol will be discussed with the study participant by a 447

study investigator and clinic coordinator. The study participant will be given the Informed 448

Consent Form to read. Study participants will be encouraged to discuss the study with family 449

members and their personal physician(s) before deciding whether to participate in the study. 450

451

Consent may be given in two stages (if approved by the IRB). The initial stage will provide 452

consent to complete any of the screening procedures needed to assess eligibility, that have not 453

already been performed as part of a usual-care exam. The second stage will be obtained prior to 454

enrollment into the run-in phase and will be for participation in the study. A single consent form 455

will have two signature and date lines for the study participant: one for the study participant to 456

give consent for the completion of the screening procedures and one for the study participant to 457

give consent for the randomized trial. Study participants will be provided with a copy of the 458

signed Informed Consent Form. After the run-in phase, participants will have the opportunity to 459

decline continuation into the randomized trial. 460

461

2.2 Subject Eligibility Criteria 462

2.2.1 Subject-level Criteria 463 464

Inclusion 465

To be eligible for the randomized trial, the following inclusion criteria (1-5) must be met: 466 1. Age ≥ 18 years 467

Subjects <18 years old are not being included because DME is so rare in this age group 468

that the diagnosis may be questionable. 469

2. Diagnosis of diabetes mellitus (type 1 or type 2) 470

Any one of the following will be considered to be sufficient evidence that diabetes is 471

present: 472

Current regular use of insulin for the treatment of diabetes. 473

Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes. 474

Documented diabetes by American Diabetes Association and/or the World Health 475

Organization criteria (see Procedures Manual for definitions). 476

3. At least one eye meets the study eye criteria listed in section 2.2.2. 477


4. Able and willing to provide informed consent. 478

5. Successful completion of the run-in phase during which level of compliance is more than 479

80% (see section 3.6 for details of compliance assessment). 480

481

482

Exclusion 483

A study participant is not eligible for the run-in phase or the randomized trial if any of the 484

following exclusion criteria (6-14) are present: 485 6. A condition that, in the opinion of the investigator, would preclude participation in the study 486

(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 487

control). 488

Subjects in poor glycemic control who, within the last 4 months, initiated intensive 489

insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 490

months should not be enrolled. 491

492

7. Use of systemic corticosteroids or anti-VEGF therapy. 493

494

8. Current use of prescription systemic NSAIDs. 495

496

9. Auto-immune diseases judged to result in a higher risk for corneal complications. 497

498

10. Participation in an investigational trial that involved treatment with any drug within 30 days 499

of randomization that has not received regulatory approval at the time of study entry. 500

Note: study participants cannot receive another investigational drug while participating 501

in the study. 502

503

11. Known allergy to any component of the study drug. 504

505

12. Blood pressure > 180/110 mmHg (systolic above 180 or diastolic above 110 mmHg) 506

If blood pressure is brought below 180/110 by anti-hypertensive treatment, study 507

participant can become eligible. 508

509

13. Participant is expecting to move out of the area of the clinical center to an area not covered 510

by another clinical center during the 12 months of the study. 511

512

14. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 513

within the next 12 months. 514

Women who are potential study participants should be questioned about the potential for 515

pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. 516

517

2.2.2 Study Eye Criteria 518 To be eligible for the run-in phase, the study participant must have at least one eye meeting all of 519

the inclusion criteria (a-f), and none of the exclusion criteria (g-u) listed below. At the 520

randomization visit, all of the inclusion and none of the exclusion criteria must be reconfirmed 521

for randomized trial eligibility except for the visual acuity and OCT criteria. 522

523


A study participant can have only one study eye. If both eyes are eligible at the time of 524

enrollment, the study eye will be selected by the investigator and study participant before 525

enrollment into the run-in phase. 526

527

The eligibility criteria for a study eye are as follows: 528

529

Inclusion 530

The following inclusions apply to the study eye: 531

532

533

a. Best corrected E-ETDRS visual acuity letter score ≥74 (i.e.20/32 or better) within 8 days of 534

screening. 535

536

b. On clinical exam, definite retinal thickening due to DME within 3000 μm of the center of the 537

macula but not involving the central subfield. 538

539

c. Thickened non-central macular subfields on spectral domain OCT macular map that meet 540

either of the following criteria: 541

At least two non-central macular subfields with OCT thickness above threshold 542

(average normal + 2 SD) from DRCR.net approved spectral domain OCT machines- 543

see below. 544

At least one non-central macular subfield with OCT thickness at least 15 μm above 545

threshold (average normal + 2 SD) from DRCR.net approved spectral domain OCT 546

machines—see DRCR.net procedures manual for threshold details. 547

548

d. Central subfield thickness less than the gender-specific mean thickness from a normal cohort 549

+ 2 standard deviations (SD), obtained by and specific to one of the following DRCR.net 550

approved spectral domain OCT machines: 551

Zeiss Cirrus: <290 in women, and <305 in men 552

Heidelberg Spectralis: <305 in women, and <320 in men 553

Optovue RTVue: <290 in women, and <305 in men 554

555

e. Media clarity, pupillary dilation, and study participant cooperation sufficient for adequate 556

OCT and fundus photographs. 557

558

f. If the study participant is on multiple ocular drops, investigator believes that study participant 559

can be compliant with a multi-drop regimen. 560

561

Exclusion 562

The following exclusions apply to the study eye: 563

g. History of focal/grid laser within the last 6 months or other treatment for DME within the last 564

4 months 565

Note: Throughout the study, the distribution of subjects with prior treatment for DME 566

will be evaluated, and eligibility criteria may be tailored to add balance between 567

subjects with prior treatment and subjects without prior treatment for DME. 568

569


h. Anticipated need to treat DME during the course of the study (Any DME treatment during 570

the study should follow criteria in section 4.3). 571

572

i. History of use of NSAID eye drops within the last 30 days or anticipated need for such drops 573

during the study due to other ocular condition 574

575

j. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to 576

randomization 577

578

k. Anticipated need for PRP in the 6 months following randomization 579

580

l. Anticipated need for cataract extraction surgery in the study eye during the study period 581

582

m. Lipid in the fovea (center of the macula) 583

584

n. History of major ocular surgery (including scleral buckle, any intraocular surgery, etc.) 585

within prior 4 months or major ocular surgery anticipated within the next 6 months following 586

randomization 587

588

o. An ocular condition, other than diabetic macular edema, is present such that, in the opinion 589

of the investigator, visual acuity might be affected now (e.g., foveal atrophy, pigment 590

abnormalities, dense subfoveal hard exudates, non-retinal condition, epiretinal membrane or 591

vitreo-macular traction) or during the course of the study (e.g., vein occlusion, uveitis or 592

other ocular inflammatory disease, neovascular glaucoma, etc.) 593

594

p. History of YAG capsulotomy performed within 2 months prior to randomization 595

596

q. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 597

substantial blepharitis 598

599

r. Aphakia 600

601

s. History of vitrectomy for any reason 602

603

t. History of cataract surgery within the prior 1 year 604

605

u. Uncontrolled glaucoma 606

607

2.2.3 Non-study Eye 608 Subjects can have only one study eye. There are no eligibility or exclusion criteria with respect 609

to the non-study eye. 610

611

2.3 Screening Evaluation and Baseline Testing 612

2.3.1 Historical Information 613 A history will be elicited from the study participant and extracted from available medical 614

records. Data to be collected will include: age, gender, ethnicity and race, diabetes history and 615


current management, other medical conditions, medications being used, as well as ocular 616

diseases, surgeries, and treatment. 617

618

2.3.2 Baseline Testing Procedures 619 The following procedures are needed to assess eligibility and/or to serve as baseline measures for 620

the study. 621

If a procedure has been performed (using the study technique and by study certified 622

personnel) as part of usual care, it does not need to be repeated specifically for the study 623

if it was performed within the defined time windows specified below. 624

The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual Acuity-625

Refraction Testing Procedures Manual and Study Procedures Manual, OCT testing 626

procedure manual, digital color photo procedures manual). Visual acuity testing, OCT, 627

color fundus photographs, and ocular exam will be performed by DRCR.net certified 628

personnel. 629

For the run-in phase (see section 2.4), only Electronic-ETDRS visual acuity test© (E-630

ETDRS), OCT, ocular exam, and blood pressure as described below, are needed to 631

determine patient‘s eligibility for this phase. These procedures should be performed 632

within 8 days of the start of the run-in phase. At the end of the run-in phase, provided 633

study participant shows good compliance (See 3.6.1), these procedures will be repeated in 634

addition to the other procedures below and be considered the baseline measurements. 635

OCT obtained for the run-in phase of the study eye will be sent to a centralized reading 636

center for grading, although study participant eligibility is determined by the site at the 637

time of enrollment (i.e., study participants deemed eligible by the investigator). 638

Subsequently, if the reading center grading indicates faulty OCT measurements that make 639

eye ineligible, then the corresponding eye will not be eligible for randomization. If the 640

automated volume reading by the OCT machine is determined to be inaccurate by the 641

reading center and cannot be adjusted, the study participant will not be included in the 642

primary analysis and an additional study participant will be recruited for each occurrence. 643

OCTs at randomization and throughout follow-up may be sent to a centralized reading 644

center for grading. Fundus photographs may also be sent to a centralized reading center 645

for grading, although this will not be done for eligibility purposes either. 646

647

1. E-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 648

(including protocol refraction) in each eye. (Within 8 days prior to randomization). 649

This testing procedure has been validated against 4-meter ETDRS chart testing.33

650

651

2. OCT on study eye (within 8 days prior to randomization) 652

653

3. Ocular examination of each eye including slit lamp, measurement of intraocular pressure, 654

lens assessment, and dilated ophthalmoscopy (within 8 days prior to randomization; 655

eligibility must be confirmed on day of randomization via slit lamp biomicroscopy) 656

657

4. ETDRS protocol 7-standard field or 4 wide-field digital stereoscopic fundus photographs in 658

study eye (within 21 days prior to randomization) 659

660

5. Measurement of blood pressure 661


662

6. Laboratory testing- HbA1c. 663

HbA1c does not need to be repeated if available in the prior 3 months. If not available 664

at the time of randomization, the study participant may be enrolled but the test must 665

be obtained within 3 weeks after randomization 666

667

2.4 Run-in Phase 668 All potential study participants will be required to complete a 30-60 day run-in phase. In order to 669

enter the run-in phase, electronic-ETDRS visual acuity, OCT, ocular exam, and blood pressure 670

measurements as described in section 2.3.2 must be completed, and all eligibility criteria listed in 671

section 2.2.1-2.2.2 must be met. During this phase, the study participant will be required to use 672

artificial tears drops 3 times per day. At the end of the 30-day preliminary phase (within an 673

additional 30 day window after the 30 day target), compliance with the study regimen will be 674

assessed, eligibility will be reconfirmed, and the study participant will be randomized if still 675

eligible and willing to continue. Compliance assessment is detailed in section 3.6. 676

677

This phase II study is designed to assess if NSAIDs have an effect on macular edema. The run-678

in phase will identify study participants who are unwilling or unable to use eye drops. 679

Identifying these individuals prior to randomization and not enrolling them in the study will 680

allow a better assessment of the effect of topical NSAIDs on macular edema. 681

682

2.5 Randomization of Eligible Subjects 683 684

1. Prior to randomization, the study participant‘s understanding of the trial, compliance with 685

medication use, willingness to accept the assigned treatment group, and commitment to the 686

follow-up schedule will be reconfirmed. 687

2. Drops must be initiated on the day of randomization; therefore, a study participant should not 688

be randomized until this is possible. 689

3. Randomization is completed on the DRCR.net website. 690

Study participants will be assigned randomly (stratified by site) with equal probability to 691

one of two treatment groups: 692

o Nepafenac 0.1% eye drops 3 times per day in the study eye 693

o Placebo eye drops 3 times per day in the study eye 694


CHAPTER 3 -TREATMENT REGIMENS 695

3.1 Introduction 696

3.1.1 Run-in Phase 697 All study participants will receive artificial tear drops during the study‘s preliminary run-in 698

phase. The drops should be taken 3 times per day consistent with the regimen in the follow-up 699

phase. 700

701

3.1.2 Randomized Trial 702 All study eyes will be randomly assigned to one of the following two treatment groups: 703

Nepafenac 0.1% eye drops 3 times per day in the study eye 704

Placebo eye drops 3 times per day in the study eye 705

706

Each group must start the drops on the day of randomization. 707

708

The nepafenac drops and placebo drops will be provided in masked bottles by the Coordinating 709

Center to the clinical sites for distribution to the study participants. 710

711

3.2 NSAID 712 Nepafenac ophthalmic solution 0.1% (Nevanac®), made by Alcon Research Ltd., will be used as 713

the NSAID study drug. 714

715

Study eyes assigned to nepafenac drops will receive 1 drop, 3 times per day. Each 1 mL of 716

nevanac suspension contains 1 mg of nepafenac. The physical, chemical, and pharmaceutical 717

properties and formulation of nepafenac are provided in the Clinical Investigator‘s Brochure. 718

719

3.3 Placebo 720 Study eyes assigned to receive placebo drops will receive the vehicle contained in the nepafenac 721

drops, provided by Alcon Research Ltd. These drops will be administered 3 times per day using 722

bottles identical to that of nepafenac. 723

724

3.4 Artificial Tears 725 During the run-in phase, study participants will apply artificial tears 3 times per day to assess 726

compliance. 727

728

Tears Naturale Forte®, made by Alcon Research Ltd, will be the artificial tears used in the run-in 729

phase of this study. 730

731

3.5 Eye Drops Usage 732 Before start of the run-in phase, clinical site coordinators will instruct study participants 733

regarding the proper use and storage of eye drops. The study participant will be asked to 734

demonstrate proper application of the drops into the study eye. The eyelid will be lightly closed 735

for 1 minute after each application. Following dispensing of study drug, the coordinating center 736

staff will call study participants within the first week to confirm adherence with eye drop 737

protocol. 738


739

3.6 Assessment of Compliance 740

3.6.1 Run-in Phase 741

Prior to dispensing to a study participant, site personnel will weigh each bottle of study 742

medication using a calibrated scale. Upon return of the bottles to the site by end of the run-in 743

phase, the bottle will be weighed. Bottle weight will be recorded in grams (to the hundredth 744

decimal place). Site personnel will be responsible for scale calibration (according to the 745

manufacturer‘s instructions). A study participant will be considered below the compliance 746

threshold and will not be allowed to enroll into the randomized trial if her/his compliance level at 747

end of the run-in phase is less than 80% of the target level. Level of compliance will be 748

determined as follows: 749

750

751

Where EI =Expected initial bottle weight; EFU = Expected follow-up weight; OI= observed initial 752

bottle weight; OFU=observed follow-up bottle weight. 753

754

3.6.2 During Follow-up 755

Assessment of compliance will also be performed by site personnel at each follow-up study visit 756

as described above. 757


CHAPTER 4 FOLLOW-UP VISITS AND TREATMENT 758

759

4.1 Visit Schedule 760

Scheduled follow-up visits will occur at: 761

4 months ± 1 month 762



765

A phone call is completed by coordinating center within approximately one week of initiating 766

drops and then at approximately 2, 6, and 10 months to emphasize compliance with drop 767

dispensing. 768

769

4.2 Testing Procedures 770 The following procedures will be performed at each protocol visit on the study eye only unless 771

otherwise specified. 772

773

In addition, the first time non-topical treatment for DME will be administered, whether at a study 774

visit or non-study visit, an E-ETDRS visual acuity with refraction, OCT, and color fundus 775

photographs should be performed on the study eye prior to initiation of the treatment. 776

777

A grid in section 1.3F summarizes the testing performed at each visit. 778

779

1. E- ETDRS visual acuity testing (best corrected). 780

Testing is performed on each eye prior to dilation at each required follow-up visit. 781

Protocol refraction is required in the study eye at each protocol visit. When a 782

refraction is not performed (e.g. non protocol visit), the most-recently performed 783

refraction is used for the testing. 784

If the E-ETDRS visual acuity letter score is 0, then counting fingers, hand motion, 785

and light perception are assessed. 786

Also obtained at a non-study visit if treatment for DME is to be initiated. 787

2. OCT on the study eye 788

The same type of OCT machine used at baseline should be used for all subsequent 789

follow-up visits. 790

Also obtained at a non-study visit if treatment for DME is to be initiated. 791

3. Ocular exam including slit lamp examination (including corneal and lens assessment), 792

measurement of intraocular pressure, and dilated ophthalmoscopy on the study eye. 793

4. ETDRS protocol 7-standard field or 4 wide-field digital stereoscopic fundus photographs in 794

study eye (Baseline and 1 year visits only). 795

Also obtained at a non-study visit if treatment other than the study intervention for 796

DME is to be initiated. 797

798

All of the testing procedures do not need to be performed on the same day, provided that they are 799

completed within the time window of a specific visit and prior to initiating any treatment for 800

DME other than the study related intervention. 801

802


Testing procedures at non-protocol visits are at investigator discretion. However, it is 803

recommended that procedures that are performed should follow the standard DRCR.net protocol 804

for each procedure. 805

806

4.3 Treatment for Diabetic Macular Edema 807 Study participants will receive the randomly assigned topical medication with no other treatment 808

for DME unless at least one of the criteria below is met. All study participants will continue 809

their study assigned topical medication through 12 months and complete all protocol visits 810

through 12 months regardless of whether other treatment for DME is received. 811

812

Treatment for DME should not be given unless one of the following criteria is met: 813

1. Central subfield retinal thickness is at or above the gender and OCT machine-specific 814

threshold value listed below and there was at least a 10% increase in central subfield 815

thickness from baseline: 816

Zeiss Cirrus: Women, ≥290; Men, ≥305 817

Heidelberg Spectralis: Women, ≥305; Men, ≥320. 818

Optovue RTVue: Women, ≥290; Men, ≥305 819

820

2. In any other circumstance where the investigator believes it is in the study participant‘s 821

best interest to receive treatment for non-central involved DME (for example, rapidly 822

progressing cataract prior to cataract surgery or new PDR) after review with the Protocol 823

Chair or Protocol Chair designate. 824


825

CHAPTER 5 - MISCELLANEOUS CONSIDERATIONS IN 826

FOLLOW-UP 827

828

5.1 Treatment of Diabetic Retinopathy in the Study Eye 829 Treatment of diabetic retinopathy in the study eye with PRP is at investigator discretion. Due to 830

the effect on macular edema, treatment of diabetic retinopathy with intravitreal injections is 831

discouraged. In any circumstance where the investigator believes it is in the study participant‘s 832

best interest to receive intravitreal injections for the treatment of diabetic retinopathy the 833

Protocol Chair or Protocol Chair designee must be contacted for approval. 834

835

5.2 Treatment after Cataract Surgery 836 Post-operative treatment with NSAIDs (including non protocol drops) after cataract surgery is at 837

investigator discretion; however, it should not affect the use of protocol assigned treatment. 838

839

5.3 Treatment of Diabetic Retinopathy in Non-study Eye 840 Treatment of proliferative diabetic retinopathy and DME in the non-study eye is at investigator 841

discretion. 842

843

5.4 Diabetes Management 844

Diabetes management is left to the study participant‘s medical care provider. 845

846

5.5 Study participant Withdrawal and Losses to Follow-up 847 A study participant has the right to withdraw from the study at any time. If a study participant is 848

considering withdrawal from the study, the principal investigator should personally speak to the 849

participant about the reasons, and every effort should be made to accommodate the study 850

participant. 851

852

The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 853

will assist in the tracking of study participants who cannot be contacted by the site. The 854

Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 855

856

Study participants who withdraw will be asked to have a final closeout visit at which the testing 857

described for the protocol visits will be performed. Study participants who have an adverse 858

effect attributable to a study treatment or procedure will be asked to continue in follow-up until 859

the adverse event has resolved or stabilized. Study participants who withdraw or are determined 860

to have been ineligible post-randomization will not be replaced (note: study participants with 861

poor quality scans which the reading center cannot manually adjust may be replaced). 862

863

5.6 Discontinuation of Study 864 The study may be discontinued by the Executive Committee (with approval of the Data and 865

Safety Monitoring Committee (DSMC)) prior to the preplanned completion of follow-up for all 866

subjects. 867

868

5.7 Contact Information Provided to the Coordinating Center 869 The Coordinating Center will be provided with contact information for each study participant. 870


Permission to obtain such information will be included in the Informed Consent Form. The 871

contact information may be maintained in a secure database and will be maintained separately 872

from the study data. 873

874

Phone contact from the Coordinating Center may be made with each study participant in the first 875

month after enrollment. Additional phone contacts from the Coordinating Center will be made if 876

necessary to facilitate the scheduling of the study participant for follow-up visits or as part of the 877

protocol to assess compliance with the drop regimen. A study participant-oriented newsletter 878

will be sent at least twice a year. A study logo item may be sent once a year. 879

880

Study participants will be provided with a summary of the study results in a newsletter format 881

after completion of the study by all subjects. 882

883

5.8 Study Participant Reimbursement 884 The study will be providing study participants $25 per completed protocol visit ($125 maximum 885

if all 4 visits are completed) to cover travel and other visit-related expenses. Payment will be 886

made directly from the Coordinating Center to the participant. Additional travel expenses may 887

be paid in cases for subjects with higher expenses if approved by the IRB. 888


CHAPTER 6 ADVERSE EVENTS 889

890

6.1 Definition 891 An adverse event is any untoward medical occurrence in a study participant, irrespective of 892

whether or not the event is considered treatment-related. 893

894

6.2 Recording of Adverse Events 895

Throughout the course of the study, all efforts will be made to remain alert to possible adverse 896

events or untoward findings. The first concern will be the safety of the study participant, and 897

appropriate medical intervention will be made. 898

899

The investigator will elicit reports of adverse events from the study participant at each visit and 900

complete all adverse event forms online. Each adverse event form is reviewed by the 901

Coordinating Center to verify the coding and the reporting that is required. 902

903

The study investigator will assess the relationship of any adverse event to be related or unrelated 904

by determining if there is a reasonable possibility that the adverse event may have been caused 905

by the treatment. 906

907

The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 908

severe. It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 909

event is not necessarily serious. For example, itching for several days may be rated as severe, 910

but may not be clinically serious. 911

912

Adverse events will be coded using the MedDRA dictionary. 913

914

Definitions of relationship and intensity are listed on the DRCR.net website data entry form. 915

916

Adverse events that continue after the study participants‘ discontinuation or completion of the 917

study will be followed until their medical outcome is determined or until no further change in the 918

condition is expected. 919

920

6.3 Reporting Serious or Unexpected Adverse Events 921 A serious adverse event is any untoward occurrence that: 922

Results in death. 923

Is life-threatening; (a non life-threatening event which, had it been more severe, might have 924

become life-threatening, is not necessarily considered a serious adverse event). 925

Requires inpatient hospitalization or prolongation of existing hospitalization. 926

Results in significant disability/incapacity (sight threatening). 927

Is a congenital anomaly/birth defect. 928

929

Unexpected adverse events are those that are not identified in nature, severity, or frequency in 930

the current nepafenac Clinical Investigator‘s Brochure. Serious or unexpected adverse events 931

must be reported to the Coordinating Center immediately via completion of the online serious 932

adverse event form. 933


934

The Coordinating Center will notify all participating investigators of any adverse event that is 935

both serious and unexpected. Notification will be made within 10 days after the Coordinating 936

Center becomes aware of the event. 937

938

Each principal investigator is responsible for informing his or her Internal Review Board (IRB) 939

of serious study-related adverse events and abiding by any other reporting requirements specific 940

to their IRB. 941

942

6.4 Data and Safety Monitoring Committee Review of Adverse Events 943 A DSMC will approve the protocol, template informed consent form, and substantive 944

amendments and provide independent monitoring of adverse events. Cumulative adverse event 945

data are semi-annually tabulated for review by the DSMC. Following each DSMC data review, 946

a summary will be provided to IRBs. A list of specific adverse events to be reported to the 947

DSMC expeditiously, if applicable, will be compiled and included as part of the DSMC Standard 948

Operating Procedures document. 949

950

6.5 Risks 951

6.5.1 Potential Adverse Effects of Topical NSAIDs 952

NSAIDs have been mainly approved to treat pain and inflammation associated with cataract 953

surgery (Nevanac and Xibrom)34, 35

or pain and burning associated with refractive surgery 954

(Acular).36

Allergic reactions to the drug or to the preservative ingredient in the bottle have been 955

reported. In severe cases, allergic reactions can lead to difficulty of breathing due to swelling in 956

the face, tongue or throat, which might necessitate medical intervention. Other non-ocular 957

adverse reactions reported at an incidence of 1 to 4% include headache, hypertension, nausea, 958

vomiting, and sinusitis. 959

960

Topical NSAIDs may result in keratitis. Severe cases can lead to corneal epithelial breakdown, 961

corneal thinning, corneal erosion and corneal ulceration.37

However, the incidence of corneal 962

melting appears to be relatively low. Singer and colleagues presented data on long term safety of 963

NSAIDs in 501 patients who were treated with topical NSAIDS for an average of 26 months 964

(range 3 -120 months). A variety of NSAIDs were used, including nepafenac, ketorolac, and 965

bromfenac with the most frequent dosing regimen being four times a day. Only 31 % of the study 966

cohort was diabetic. However, no corneal melting was observed in any patient in this study. A 967

further review of the literature identified 28 cases of corneal melting associated with topical 968

NSAIDs, 96% of which were associated with perioperative NSAID use. Furthermore, 20% of 969

the patients who experienced corneal melting had an underlying rheumatologic or autoimmune 970

disease. The average time to corneal melt was 1 month after initiation of NSAID treatment, 971

suggesting that patients who are prone to melting might be able to be identified shortly after they 972

begin using topical NSAIDs.38

973

974

Less serious but more frequently reported adverse effects are also ocular ones. Itching or 975

watering of the eye is a common complaint among patients who use topical NSAIDs. Because 976

post cataract or refractive surgery is the usual setting where topical NSAIDs are used, many of 977

the ocular side effects commonly listed (including a dry or sticky feeling in the eye and eye 978

redness) might be attributed to the ocular surgery itself. Decrease in visual acuity, capsular 979


opacity, and an increase in intra-ocular pressure have been reported in 5-10% of patients using 980

topical nepafenac post cataract surgery.34

Other ocular adverse reactions occurring at an 981

incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid 982

margin crusting, ocular pain, and vitreous detachment.34

983

984

In clinical studies the most frequent adverse reactions reported in the post-cataract or post-ocular 985

surgery studies for patients exposed to nepafenac 0.1% were eyelid margin crusting (0.3%), 986

foreign body sensation in eyes (0.3%), allergic conjunctivitis (0.2%),eye discharge (0.2%), eye 987

pain (0.2%), and keratitis (0.2%). Other less frequent adverse reactions included blepharitis, 988

choroidal effusion, conjunctival hyperaemia, conjunctivitis, corneal deposits, corneal disorder, 989

cutis laxa, eye pruritis, hypersensitivity, increased, lacrimation, iritis, nausea, and ocular 990

discomfort. 991

992

There may be side effects and discomforts that are not yet known. Long term adverse effects are 993

not well documented; furthermore, topical NSAIDs have not been evaluated in long-term 994

carcinogenicity studies. Animal chromosomal aberration studies indicate a safe profile. 995

996

6.5.2 Corneal Complications 997 At each study visit, a thorough corneal examination will be conducted as part of the ocular exam 998

to assess the cornea for any potential adverse effect that may take place as a result of using the 999

study drugs. 1000

1001

6.5.3 Risk of Artificial Tears (Tears Naturale Forte®) 1002 Preservatives in Tears Naturale Forte solution can rarely be associated with ocular irritation, 1003

redness or blurred vision. These side effects are uncommon when tears are used less often than 4 1004

times per day and are generally alleviated when the drops are stopped. 1005

1006

6.5.4 Risks of Eye Examination and Tests 1007 There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 1008

or dilate the pupil. Dilating drops rarely could cause an acute angle closure glaucoma attack, but 1009

this is highly unlikely since the subjects in the study will have had their pupils dilated many 1010

times previously. 1011


CHAPTER 7 STATISTICAL METHODS 1012

1013

The approach to sample size and statistical analyses are summarized below. A detailed statistical 1014

analysis plan will be written and finalized prior to the completion of the study. The analysis plan 1015

synopsis in this chapter contains the framework of the anticipated final analysis plan. 1016

1017

This study is a phase II clinical trial conducted to establish whether topical NSAIDs have 1018

sufficient biological activity in reducing DME to warrant further investigation. The primary 1019

outcome of the study will be mean change in retinal volume at the 12 month visit in eyes with 1020

non-central subfield involved DME. 1021

1022

7.1 Sample Size 1023 The primary analysis consists of a statistical comparison of the mean change in retinal volume 1024

from baseline to 1 year in the control group compared with the NSAID group. 1025

1026

7.2 Sample Size Estimation 1027 DRCR.net non-published protocol G (―Subclinical Diabetic Macular Edema Study‖) data were 1028

used to estimate the standard deviation of mean retinal volume changes. From this study, based 1029

on N=16 eyes with gradable volume measurements the standard deviation for change in retinal 1030

volume from baseline to 1 year was 0.37 mm3 (95% confidence interval (CI) 0.28 to 0.56). If a 1031

convenience sample of N=50 subjects per group is selected, this study will have 90% power to 1032

detect a difference if the true difference is 0.40 and the SD is 0.60 (the approximate upper end of 1033

the 95% CI for change in volume). 1034

1035

Effect sizes (μ1-μ2 change) for different sample sizes and standard deviations for retinal 1036

volume change, power 90%, α 0.05 1037

SD† Sample Size Per Group

25 50 75 100 125

0.20 0.19 0.13 0.11 0.09 0.08

0.30 0.28 0.20 0.16 0.14 0.12

0.40 0.37 0.26 0.21 0.18 0.16

0.60 0.56 0.40 0.32 0.28 0.25

0.80 0.75 0.52 0.43 0.37 0.33

1.00 0.94 0.65 0.53 0.46 0.41

1.20 1.23 0.79 0.64 0.55 0.49

† Represents the standard deviation of retinal volume change from baseline 1038

Sample size will be increased by 10% to account for participants lost to follow up, and another 1039

10% to account for poor quality scans which the reading center cannot manually adjust the 1040

volume measurement up to a total sample size of 120. 1041


1042

From DRCR.net subclinical DME protocol (Protocol G), non-gradable retinal volume scans, as 1043

identified by a reading center, at baseline and at 1 year were estimated to be 15%. Since only 1044

spectral domain OCTs are used in this study and software is available to potentially manually 1045

adjust the retinal volume measurement of spectral domain OCTs, an estimate of approximately 1046

10% for poor scan quality will be used. 1047

1048

7.3 Efficacy Analysis Plan 1049

7.3.1 Primary Outcome Analysis 1050 The primary analysis will involve comparison of the mean change in retinal volume in eyes with 1051

non-central involved DME at baseline through 1 year in eyes receiving NSAIDs versus those 1052

receiving placebo. 1053

1054

Retinal volume change will be calculated by subtracting retinal volume measurements at 12-1055

month visit from that at baseline. 1056

1057

The treatment group comparison will be performed using an ANCOVA model, with change in 1058

retinal volume measurements at 12 months fitted as the dependent variable, and the treatment 1059

group as the independent variable, adjusting for baseline retinal volume measurement. Eyes 1060

treated for DME prior to the 1 year visit will have the last volume measurement prior to the 1061

treatment imputed into the final analysis. Eyes with inaccurate automated retinal volume 1062

measurement at baseline, which cannot be adjusted by a central reading center, will be excluded 1063

from the primary analysis. The significance level used for the final primary analysis will be 1064

0.05. Last-observation-carried-forward will be used for participants with incomplete follow up. 1065

A sensitivity analysis will be conducted to compare LOCF results with those using a per-protocol 1066

analysis only including study participants who completed the 1 year visit and with results from 1067

Rubin's multiple imputation technique. 1068

1069

Pre-planned subgroup analyses will be conducted in the same way as the primary analysis and 1070

include stratification by prior DME treatment. Other subgroup analyses will be described in the 1071

detailed Statistical Analysis Plan. 1072

1073

Imbalances between groups in important covariates are not expected to be of sufficient 1074

magnitude to produce confounding; however, a second analysis that adjusts for imbalanced 1075

baseline covariates will be performed. If results are similar to the primary analysis, the primary 1076

analysis will be accepted as the definitive analysis; otherwise, the reasons for the difference will 1077

be explored. 1078

1079

There are no data to suggest that the treatment effect will vary by gender or race and ethnicity. 1080

However, both of these factors will be evaluated in exploratory analyses. 1081

1082

Analogous analyses as described above will be conducted at the 4 and 8 month visits. In 1083

addition, longitudinal analysis over time will be performed using repeated measures analysis 1084

with a fixed time effect including all visits up to and including the primary outcome time point. 1085


1086

7.3.2 Secondary and Tertiary Outcomes 1087

In addition to the primary outcome, the following secondary outcomes will be estimated, and 1088

their 95% CI will be obtained in each treatment group and compared between treatment groups: 1089

Proportion of eyes with 1 or more logOCT step increase in central subfield thickness at 1 1090

year 1091

Proportion of eyes that progress from non-central to central involved DME by fundus 1092

photographs at 1 year 1093

Proportion of eyes receiving treatment for DME other than the study intervention by 1 1094

year 1095

Proportion of eyes reaching central subfield thickness ≥the gender and OCT machine-1096

specific mean + 2SD values listed under section 4.3 at 1 year provided there was at least 1097

10% increase from baselineCorrelation of progression from non-central involved DME to 1098

central involved edema as determined on stereoscopic fundus photographs compared with 1099

OCT 1100

Proportion of eyes with diabetic retinopathy progression or regression of 2 steps between 1101

baseline and 1 year 1102

Change in maximum inner and outer macular subfield thickness 1103

1104

1105

The following tertiary outcomes will be estimated, and their 95% CI will be obtained in each 1106

treatment group and compared between treatment groups at 1 year. For eyes that have received 1107

treatment for DME before 1 year, visual acuity and OCT measurements obtained at time of 1108

failure will be used instead of measurements at 1 year. 1109

Mean change in visual acuity 1110

Change in OCT central subfield thickness 1111

Change in the number of thickened (>mean+2SD) subfields on OCT 1112

Change in level of diabetic retinopathy on stereoscopic fundus photographs 1113

1114

Analyses of the secondary and tertiary outcomes will be conducted as follows: 1115

Binary outcomes will be analyzed using logistic regression to control for baseline level of the 1116

outcome. Continuous outcome comparisons will be performed using ANCOVA with adjustment 1117

for baseline. All linear model assumptions will be verified including linearity, normality of 1118

residuals, and homoscedasticity. If model assumptions are not met, a nonparametric analogue 1119

for ANCOVA will be considered. Last-observation-carried-forward (LOCF) will be 1120

implemented for patients lost to follow up. 1121

1122

7.4 Assessment of Compliance 1123

Level of compliance will be determined as the average level of compliance from each study visit 1124

(excluding the run-in phase compliance assessment visit). A study participant will be considered 1125

below the compliance threshold if her or his compliance level by end of the study was less than 1126

80% of the target level. Level of compliance will be determined as follows: 1127


1128

Where EI =Expected initial bottle weight; EFU = Expected follow-up weight; OI= observed initial 1129

bottle weight; OFU=observed follow-up bottle weight. 1130

1131

As an exploratory analysis, an ‗as-treated‘ analysis will be performed limited to participants with 1132

at least 80% compliance. In addition, compliance will be evaluated over time. If compliance 1133

lessens over time, an exploratory analysis will investigate whether there appears to be any 1134

association of compliance versus magnitude of treatment effect over time. 1135

1136

7.5 Safety Analysis Plan 1137 Adverse events will be categorized as study eye, non-study eye, and systemic. The events will 1138

be tabulated and compared between treatment groups. Separate analyses will compare related 1139

adverse events between groups. 1140

Corneal complications: corneal edema, superficial keratitis, corneal erosion, corneal 1141

thinning, corneal ulceration and corneal melting 1142

Elevated intraocular pressure/glaucoma (medication and/or surgery) 1143

Cataract/cataract surgery 1144

Burning/stinging/itching/watering 1145

Ocular inflammation 1146

Ocular infection 1147

1148

Further definitions of the events for analysis and the analytic approach will be provided in the 1149

detailed statistical analysis plan. 1150

1151

7.6 Additional Tabulations and Analyses 1152 The following will be tabulated according to treatment group: 1153

Baseline demographic and clinical characteristics. 1154

Visit completion rate for each visit. 1155

Protocol deviations.1156


REFERENCES 1157

1. Ferris III F. Personal communication: Rational for CI DME as a surrogate outcome for 1158

VA (ETDRS); Sept 15, 2009. 1159

2. Gardner T, Larsen M, Girach A, Zhi X. Diabetic macular oedema and visual loss: 1160

relationship to location, severity and duration. Acta ophthalmologica. 2009. 1161

3. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing 1162

intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular 1163

edema. Ophthalmology. Sep 2008;115(9):1447-1449, 1449 e1441-1410. 1164

4. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 1165

diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. 1166

Arch Ophthalmol. 1985;103(12):1796-1806. 1167

5. PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular 1168

edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch 1169

Ophthalmol. Mar 2007;125(3):318-324. 1170

6. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic 1171

study of diabetic retinopathy IV. Diabetic macular edema. Ophthalmology. Dec 1172

1984;91(12):1464-1474. 1173

7. Ip MS, Bressler SB, Antoszyk AN, et al. A randomized trial comparing intravitreal 1174

triamcinolone and laser photocoagulation for diabetic macular edema: Baseline features. 1175

Retina. 2008;28(7):919-930. 1176

8. Early Treatment Diabetic Retinopathy Study Research Group. Early treatment diabetic 1177

retinopathy study design and baseline patient characteristics. ETDRS report number 7. 1178

Ophthalmology. 1991;98:741-756. 1179

9. Division of Diabetes Translation, National Center for Chronic Disease Prevention and 1180

Health Promotion, CDC. Crude and Age-Adjusted Percentage of Civilian, 1181

Noninstitutionalized Population with Diagnosed Diabetes, United States, 1980–2006. 1182

http://www.cdc.gov/diabetes/statistics/prev/national/figage.htm. 1183

10. Davis MD, Bressler SB, Aiello LP, et al. Comparison of time-domain OCT and fundus 1184

photographic assessments of retinal thickening in eyes with diabetic macular edema. 1185

Invest Ophthalmol Vis Sci. May 2008;49(5):1745-1752. 1186

11. Ophthalmology AAo. Preferred Practice Patterns: Diabetic Retinopathy. 1187

http://www.guideline.gov/summary/summary.aspx?doc_id=13502 Accessed Accessed 1188

November 9, 2009. 1189

12. The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 1190

ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic 1191

macular edema. Ophthalmology. Jun 2010;117(6):1064-1077 e1035. 1192

13. Carmo A, Cunha-Vaz JG, Carvalho AP, Lopes MC. L-arginine transport in retinas from 1193

streptozotocin diabetic rats: correlation with the level of IL-1 beta and NO synthase 1194

activity. Vision Res. Nov 1999;39(23):3817-3823. 1195

14. Ferris FL, 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv 1196

Ophthalmol. 1984;28 (suppl)(May):452-461. 1197

15. Limb GA, Hickman-Casey J, Hollifield RD, Chignell AH. Vascular adhesion molecules 1198

in vitreous from eyes with proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 1199

Sep 1999;40(10):2453-2457. 1200

16. Funatsu H, Yamashita H, Sakata K, et al. Vitreous levels of vascular endothelial growth 1201

http://www.cdc.gov/diabetes/statistics/prev/national/figage.htm

http://www.guideline.gov/summary/summary.aspx?doc_id=13502


factor and intercellular adhesion molecule 1 are related to diabetic macular edema. 1202

Ophthalmology. May 2005;112(5):806-816. 1203

17. Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of 1204

vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics 1205

with macular edema. Am J Ophthalmol. 2002;133(1):70-77. 1206

18. Usui T, Ishida S, Yamashiro K, et al. VEGF164(165) as the pathological isoform: 1207

differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest 1208

Ophthalmol Vis Sci. Feb 2004;45(2):368-374. 1209

19. Limb GA, Chignell AH, Green W, LeRoy F, Dumonde DC. Distribution of TNF alpha 1210

and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative 1211

diabetic retinopathy. Br J Ophthalmol. Feb 1996;80(2):168-173. 1212

20. Meleth AD, Agron E, Chan CC, et al. Serum inflammatory markers in diabetic 1213

retinopathy. Invest Ophthalmol Vis Sci. Nov 2005;46(11):4295-4301. 1214

21. Heier JS, Awh CC, Busbee BG, et al. Vitreous Nonsteroidal Antiinflammatory Drug 1215

Concentrations and Prostaglandin E2 Levels in Vitrectomy Patients Treated With 1216

Ketorolac 0.4%, Bromfenac 0.09%, and Nepafenac 0.1%. Retina. 2009;29(9):1310-1313. 1217

22. Callanan D, Williams P. Topical nepafenac in the treatment of diabetic macular edema. 1218

Clinical Ophthalmology 2008;2(4):689-692. 1219

23. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with 1220

potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro 1221

bioactivation and permeation of external ocular barriers. Inflammation. Aug 1222

2000;24(4):371-384. 1223

24. Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the 1224

rabbit is inhibited by topical nepafenac. Inflammation. Oct 2003;27(5):281-291. 1225

25. Takahashi K, Saishin Y, Mori K, et al. Topical nepafenac inhibits ocular 1226

neovascularization. Invest Ophthalmol Vis Sci. Jan 2003;44(1):409-415. 1227

26. Almeida DR, Johnson D, Hollands H, et al. Effect of prophylactic nonsteroidal 1228

antiinflammatory drugs on cystoid macular edema assessed using optical coherence 1229

tomography quantification of total macular volume after cataract surgery. J Cataract 1230

Refract Surg. Jan 2008;34(1):64-69. 1231

27. Donnenfeld ED, Perry HD, Wittpenn JR, Solomon R, Nattis A, Chou T. Preoperative 1232

ketorolac tromethamine 0.4% in phacoemulsification outcomes: pharmacokinetic-1233

response curve. J Cataract Refract Surg. Sep 2006;32(9):1474-1482. 1234

28. Heier JS, Topping TM, Baumann W, Dirks MS, Chern S. Ketorolac versus prednisolone 1235

versus combination therapy in the treatment of acute pseudophakic cystoid macular 1236

edema. Ophthalmology. 2000;107(11):2034-2038. 1237

29. Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac versus 1238

ketorolac. J Cataract Refract Surg. Dec 2003;29(12):2378-2384. 1239

30. Weisz JM, Bressler NM, Bressler SB, Schachat AP. Ketorolac treatment of pseudophakic 1240

cystoid macular edema identified more than 24 months after cataract extraction. 1241

Ophthalmology. Sep 1999;106(9):1656-1659. 1242

31. Browning DJ, Glassman AR, Aiello LP, et al. Optical coherence tomography 1243

measurements and analysis methods in optical coherence tomography studies of diabetic 1244

macular edema. Ophthalmology. Aug 2008;115(8):1366-1371, 1371 e1361. 1245

32. Diabetic Retinopathy Clincical Research Network. Reproducibility of macular thickness 1246


and volume using Zeiss optical coherence tomography in patients with diabetic macular 1247

edema. Ophthalmology. Aug 2007;114(8):1520-1525. Epub 2007 Mar 1513. 1248

33. Beck RW, Moke PS, Turpin AH, et al. A computerized method of visual acuity testing: 1249

adaptation of the early treatment of diabetic retinopathy study testing protocol. Am J 1250

Ophthalmol. Feb 2003;135(2):194-205. 1251

34. Alcon. NEVANAC Ophthalmic Suspension Product Insert. 1252

http://www.alcon.com/en/alcon-products/pharmaceutical.asp. 1253

35. ISTA. Xibrom Ophthalmic Solution Product Insert. 1254

http://www.istavision.com/products/products_xibrom.asp. 1255

36. Allergan. Acular LS Product Insert. 1256

http://www.allergan.com/products/eye_care/acular.htm. 1257

37. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with 1258

topical nonsteroidal anti-inflammatory drugs. Ophthalmology. May 2001;108(5):936-1259

944. 1260

38. Singer M. Are non-Steroidal Drops Safe for Long-Term Use? American Academy of 1261

Ophthalmology Annual Meeting. San Francisco, CA; 2009. 1262

http://www.alcon.com/en/alcon-products/pharmaceutical.asp

http://www.istavision.com/products/products_xibrom.asp

http://www.allergan.com/products/eye_care/acular.htm

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