Diabetic Retinopathy Clinical Research Network A …publicfiles.jaeb.org/.../DRCRnet_Protocol_R_V1_1_18_11.pdfDRCRnet Protocol R V1.0 1-18-11DRCRnet Protocol R V1.0 1-18-11 1-4 Years

DRCRnet Protocol R V1.0 1-18-11

Diabetic Retinopathy Clinical Research

Network

A Phase II Evaluation of Topical NSAIDs

in Eyes with Non Central Involved DME

Version 1.0

January 18, 2011

DRCRnet Protocol R V1.0 1-18-11

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 V1.0 1-18-11DRCRnet Protocol R V1.0 1-18-11 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 (Central subfield retinal thickness 363

increases to 310 μm or more in spectral domain OCT machine from baseline). 364

365 366

D. Run-In Phase 367 All potential study participants will be required to participate in a 30 day run-in phase. In order 368

to enter the run-in phase, all eligibility criteria must be assessed and met. During this phase, the 369

study participant will be required to use artificial tear drops 3 times per day. 370

371

At the end of the 30 day run-in phase (within an additional 30-day window after the 30 day 372

target), compliance with the study regimen will be assessed (see section 3.6), eligibility will be 373

reconfirmed, and the participant‘s willingness to proceed into the randomized trial will be 374

confirmed. 375

376

E. Treatment Groups 377 Study eyes of participants entering the randomized trial will be randomly assigned to receive 378

either topical medication nepafenac 0.1% drops or placebo 3 times per day for 1 year. 379

Randomization will be stratified by site. 380

381

Study participants will receive study drops with no treatment other than the study intervention 382

for DME through 12 months unless criteria for treatment of DME are met (see section 4.3.1). 383

All study participants will continue randomized drops and visits in follow up through 12 months 384

regardless of whether other treatment for DME is received. 385

386

F. Follow-up Schedule 387

Randomized subjects will return for follow-up visits every 4 months (±1 month) for 1 year. 388

Testing required at each visit is summarized below. 389

390

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 391 Testing is only required for the study eye unless otherwise specified below. 392 a = Visual acuity performed on both eyes at each visit, including protocol refraction on both eyes at baseline (time 0 393 above) and month 12, and on the study eye only, at all other protocol visits. E-ETDRS refers to electronic ETDRS 394 testing using the Electronic Visual Acuity Tester that has been validated against 4-meter chart ETDRS testing. 395 Protocol refraction and visual acuity in the study eye also performed prior to initiating treatment for DME at study 396 visit or non-study visit. 397 b = OCT also obtained prior to initiating non-study treatment for DME at a study or non-study visit. OCT may be 398 obtained with, Zeiss Cirrus, Heidelberg Spectralis, or Optovue RTVue OCT machines only. 399 c = Seven field or 4 wide-field digital stereoscopic photos; obtained at baseline (time 0), 12-month visit or prior to 400 initiating treatment for DME at a study or non-study visit. 401

d = Both eyes at enrollment and baseline (time 0) visits study eye only at each follow up-visit including slit lamp 402 exam, corneal and lens assessment, measurement of intraocular pressure, and dilated ophthalmoscopy. 403

e = Does not need to be repeated if HbA1c available from within the prior 3 months; if not available, can be 404 performed within 3 weeks after randomization. 405

406

407

G. Sample Size: 408 A minimum of 60 eyes per group for a minimum of 120 total eyes will be randomized. The total 409

number of subjects randomized may exceed 120 to achieve 120 randomized eyes with accurate 410

retinal volume measurements (See section 2.3.2). 411

412

H. Primary Efficacy Outcome 413

Mean change in OCT measured retinal volume between baseline and 12 months 414

415

416

I. Main Safety Outcomes 417

Corneal ulceration and melting 418

Irritation 419

420

421

1.4 General Considerations 422

The study is being conducted in compliance with the policies described in the DRCR.net Policies 423

document, with the ethical principles that have their origin in the Declaration of Helsinki, with 424

the protocol described herein, and with the standards of Good Clinical Practice. 425

426

The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 427

Testing Procedures Manual, Study Procedures Manual, and photography procedure manuals) 428

provide details of the examination procedures. 429

430


Data will be directly collected in electronic case report forms, which will be considered the 431

source data.432

DRCRnet Protocol R V1.0 1-18-11 2-1

CHAPTER 2 STUDY PARTICIPANT ELIGIBILITY AND 433

ENROLLMENT 434

435

2.1 Identifying Eligible Study Participants and Obtaining Informed Consent 436 A minimum of 120 eyes from 120 study participants are expected to be enrolled into the 437

randomization phase with a goal to enroll an appropriate representation of minorities. As the 438

enrollment goal approaches, sites will be notified of the end date for recruitment. Study 439

participants who have signed an informed consent form can be randomized up until the end date, 440

which means the recruitment goal might be exceeded. In addition, the total number of study 441

participants randomized may exceed 120 to achieve 120 randomized eyes with accurate retinal 442

volume measurements. 443

444

Potential eligibility will be assessed as part of a routine-care examination. Prior to completing 445

any procedures or collecting any data that are not part of usual care, written informed consent 446

will be obtained. For study participants who are considered potentially eligible for the study 447

based on a routine-care exam, the study protocol will be discussed with the study participant by a 448

study investigator and clinic coordinator. The study participant will be given the Informed 449

Consent Form to read. Study participants will be encouraged to discuss the study with family 450

members and their personal physician(s) before deciding whether to participate in the study. 451

452

Consent may be given in two stages (if approved by the IRB). The initial stage will provide 453

consent to complete any of the screening procedures needed to assess eligibility, that have not 454

already been performed as part of a usual-care exam. The second stage will be obtained prior to 455

enrollment into the run-in phase and will be for participation in the study. A single consent form 456

will have two signature and date lines for the study participant: one for the study participant to 457

give consent for the completion of the screening procedures and one for the study participant to 458

give consent for the randomized trial. Study participants will be provided with a copy of the 459

signed Informed Consent Form. After the run-in phase, participants will have the opportunity to 460

decline continuation into the randomized trial. 461

462

2.2 Subject Eligibility Criteria 463

2.2.1 Subject-level Criteria 464 465

Inclusion 466

To be eligible for the randomized trial, the following inclusion criteria (1-5) must be met: 467 1. Age ≥ 18 years 468

Subjects <18 years old are not being included because DME is so rare in this age group 469

that the diagnosis may be questionable. 470

2. Diagnosis of diabetes mellitus (type 1 or type 2) 471

Any one of the following will be considered to be sufficient evidence that diabetes is 472

present: 473

Current regular use of insulin for the treatment of diabetes. 474

Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes. 475

Documented diabetes by American Diabetes Association and/or the World Health 476

Organization criteria (see Procedures Manual for definitions). 477

3. At least one eye meets the study eye criteria listed in section 2.2.2. 478


4. Able and willing to provide informed consent. 479

5. Successful completion of the run-in phase during which level of compliance is more than 480

80% (see section 3.6 for details of compliance assessment). 481

482

483

Exclusion 484

A study participant is not eligible for the run-in phase or the randomized trial if any of the 485

following exclusion criteria (6-14) are present: 486 6. A condition that, in the opinion of the investigator, would preclude participation in the study 487

(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 488

control). 489

Subjects in poor glycemic control who, within the last 4 months, initiated intensive 490

insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 491

months should not be enrolled. 492

493

7. Use of systemic corticosteroids or anti-VEGF therapy. 494

495

8. Current use of prescription systemic NSAIDs. 496

497

9. History of auto-immune diseases such as rheumatoid arthritis. 498

499

10. Participation in an investigational trial that involved treatment with any drug within 30 days 500

of randomization that has not received regulatory approval at the time of study entry. 501

Note: study participants cannot receive another investigational drug while participating 502

in the study. 503

504

11. Known allergy to any component of the study drug. 505

506

12. Blood pressure > 180/110 mmHg (systolic above 180 or diastolic above 110 mmHg) 507

If blood pressure is brought below 180/110 by anti-hypertensive treatment, study 508

participant can become eligible. 509

510

13. Participant is expecting to move out of the area of the clinical center to an area not covered 511

by another clinical center during the 12 months of the study. 512

513

14. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 514

within the next 12 months. 515

Women who are potential study participants should be questioned about the potential for 516

pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. 517

518

2.2.2 Study Eye Criteria 519 The study participant must have at least one eye meeting all of the inclusion criteria (a-f), and 520

none of the exclusion criteria (g-u) listed below. 521

A study participant can have only one study eye. If both eyes are eligible at the time of 522

enrollment, the study eye will be selected by the investigator and study participant before 523

enrollment into the run-in phase. 524


525

1. The eligibility criteria for a study eye are as follows: 526

527

Inclusion 528

To be eligible for the run-in phase and the randomized trial, the following inclusion criteria for 529

the study eye must be met at the screening and baseline (randomization) visits: 530

531

a. Best corrected E-ETDRS visual acuity letter score ≥74 (i.e.20/32 or better) within 8 days of 532

randomization. 533

534

b. On clinical exam, definite retinal thickening due to DME within 3000 μm of the center of the 535

macula but not involving the central subfield. 536

537

c. Thickened non-central macular subfields on spectral domain OCT macular map that meet 538

either of the following criteria: 539

At least two non-central macular subfields with OCT thickness above threshold 540

(average normal + 2 SD) from DRCR.net approved spectral domain OCT machines- 541

see below. 542

At least one non-central macular subfield with OCT thickness at least 15 μm above 543

threshold (average normal + 2 SD) from DRCR.net approved spectral domain OCT 544

machines—see DRCR.net procedures manual for threshold details. 545

546

d. Central subfield thickness <250 microns obtained by one of the following DRCR.net 547

approved spectral domain OCT machines: 548

Zeiss Cirrus 549

Heidelberg Spectralis 550

Optovue RTVue 551

552

e. Media clarity, pupillary dilation, and study participant cooperation sufficient for adequate 553

OCT and fundus photographs. 554

555

f. If the study participant is on multiple ocular drops, investigator believes that study participant 556

can be compliant with a multi-drop regimen. 557

558

Exclusion 559

The following exclusions apply to the study eye: 560

g. History of focal/grid laser within the last 6 months or other treatment for DME within the last 561

4 months 562

Note: Throughout the study, the distribution of subjects with prior treatment for DME 563

will be evaluated, and eligibility criteria may be tailored to add balance between 564

subjects with prior treatment and subjects without prior treatment for DME. 565

566

h. Anticipated need to treat DME during the course of the study (Any DME treatment during 567

the study should follow criteria in section 4.3). 568

569


i. History of use of NSAID eye drops within the last 30 days or anticipated need for such drops 570

during the study due to other ocular condition 571

572

j. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to 573

randomization 574

575

k. Anticipated need for PRP in the 6 months following randomization 576

577

l. Anticipated need for cataract extraction surgery in the study eye during the study period 578

579

m. Lipid in the fovea (center of the macula) 580

581

n. History of major ocular surgery (including scleral buckle, any intraocular surgery, etc.) 582

within prior 4 months or major ocular surgery anticipated within the next 6 months following 583

randomization 584

585

o. An ocular condition, other than diabetic macular edema, is present such that, in the opinion 586

of the investigator, visual acuity might be affected now (e.g., foveal atrophy, pigment 587

abnormalities, dense subfoveal hard exudates, non-retinal condition, epiretinal membrane or 588

vitreo-macular traction) or during the course of the study (e.g., vein occlusion, uveitis or 589

other ocular inflammatory disease, neovascular glaucoma, etc.) 590

591

p. History of YAG capsulotomy performed within 2 months prior to randomization 592

593

q. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 594

substantial blepharitis 595

596

r. Aphakia 597

598

s. History of vitrectomy for any reason 599

600

t. History of cataract surgery within the prior 1 year 601

602

u. Uncontrolled glaucoma 603

604

2.2.3 Non-study Eye 605 Subjects can have only one study eye. There are no eligibility or exclusion criteria with respect 606

to the non-study eye. 607

608

2.3 Screening Evaluation and Baseline Testing 609

2.3.1 Historical Information 610 A history will be elicited from the study participant and extracted from available medical 611

records. Data to be collected will include: age, gender, ethnicity and race, diabetes history and 612

current management, other medical conditions, medications being used, as well as ocular 613

diseases, surgeries, and treatment. 614


615

2.3.2 Baseline Testing Procedures 616 The following procedures are needed to assess eligibility and/or to serve as baseline measures for 617

the study. 618

If a procedure has been performed (using the study technique and by study certified 619

personnel) as part of usual care, it does not need to be repeated specifically for the study 620

if it was performed within the defined time windows specified below. 621

The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual Acuity-622

Refraction Testing Procedures Manual and Study Procedures Manual, OCT testing 623

procedure manual, digital color photo procedures manual). Visual acuity testing, OCT, 624

color fundus photographs, and ocular exam will be performed by DRCR.net certified 625

personnel. 626

For the run-in phase (see section 2.4), only Electronic-ETDRS visual acuity test© (E-627

ETDRS), OCT, ocular exam, and blood pressure as described below, are needed to 628

determine patient‘s eligibility for this phase. These procedures should be performed 629

within 8 days of the start of the run-in phase. At the end of the run-in phase, provided 630

study participant remains eligible, these procedures will be repeated in addition to the 631

other procedures below and be considered the baseline measurements. 632

OCT obtained for the run-in phase of the study eye will be sent to a centralized reading 633

center for grading, although study participant eligibility is determined by the site at the 634

time of enrollment (i.e., study participants deemed eligible by the investigator). 635

Subsequently, if the reading center grading indicates faulty OCT measurements that make 636

eye ineligible, then the corresponding eye will not be eligible for randomization. If the 637

automated volume reading by the OCT machine is determined to be inaccurate by the 638

reading center and cannot be adjusted, the study participant will not be included in the 639

primary analysis and an additional study participant will be recruited for each occurrence. 640

OCTs at randomization and throughout follow-up may be sent to a centralized reading 641

center for grading. Fundus photographs may also be sent to a centralized reading center 642

for grading, although this will not be done for eligibility purposes either. 643

644

1. E-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 645

(including protocol refraction) in each eye. (Within 8 days prior to randomization). 646

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

647

648

2. OCT on study eye (within 8 days prior to randomization) 649

650

3. Ocular examination of each eye including slit lamp, measurement of intraocular pressure, 651

lens assessment, and dilated ophthalmoscopy (within 8 days prior to randomization; 652

eligibility must be confirmed on day of randomization via slit lamp biomicroscopy) 653

654

4. ETDRS protocol 7-standard field or 4 wide-field digital stereoscopic fundus photographs in 655

study eye (within 21 days prior to randomization) 656

657

5. Measurement of blood pressure 658

659

6. Laboratory testing- HbA1c. 660


HbA1c does not need to be repeated if available in the prior 3 months. If not available 661

at the time of randomization, the study participant may be enrolled but the test must 662

be obtained within 3 weeks after randomization 663

664

2.4 Run-in Phase 665 All potential study participants will be required to complete a 30-60 day run-in phase. In order to 666

enter the run-in phase, electronic-ETDRS visual acuity, OCT, ocular exam, and blood pressure 667

measurements as described in section 2.3.2 must be completed, and all eligibility criteria listed in 668

section 2.2.1-2.2.2 must be met. During this phase, the study participant will be required to use 669

artificial tears drops 3 times per day. At the end of the 30-day preliminary phase (within an 670

additional 30 day window after the 30 day target), compliance with the study regimen will be 671

assessed, eligibility will be reconfirmed, and the study participant will be randomized if still 672

eligible and willing to continue. Compliance assessment is detailed in section 3.6. 673

674

This phase II study is designed to assess if NSAIDs have an effect on macular edema. The run-675

in phase will identify study participants who are unwilling or unable to use eye drops. 676

Identifying these individuals prior to randomization and not enrolling them in the study will 677

allow a better assessment of the effect of topical NSAIDs on macular edema. 678

679

2.5 Randomization of Eligible Subjects 680 681

1. Prior to randomization, the study participant‘s understanding of the trial, compliance with 682

medication use, willingness to accept the assigned treatment group, and commitment to the 683

follow-up schedule will be reconfirmed. 684

2. Drops must be initiated on the day of randomization; therefore, a study participant should not 685

be randomized until this is possible. 686

3. Randomization is completed on the DRCR.net website. 687

Study participants will be assigned randomly (stratified by site) with equal probability to 688

one of two treatment groups: 689

o Nepafenac 0.1% eye drops 3 times per day in the study eye 690

o Placebo eye drops 3 times per day in the study eye 691


CHAPTER 3 -TREATMENT REGIMENS 692

3.1 Introduction 693

3.1.1 Run-in Phase 694 All study participants will receive artificial tear drops during the study‘s preliminary run-in 695

phase. The drops should be taken 3 times per day consistent with the regimen in the follow-up 696

phase. 697

698

3.1.2 Randomized Trial 699 All study eyes will be randomly assigned to one of the following two treatment groups: 700

Nepafenac 0.1% eye drops 3 times per day in the study eye 701

Placebo eye drops 3 times per day in the study eye 702

703

Each group must start the drops on the day of randomization. 704

705

The nepafenac drops and placebo drops will be provided in masked bottles by the Coordinating 706

Center to the clinical sites for distribution to the study participants. 707

708

3.2 NSAID 709 Nepafenac ophthalmic solution 0.1% (Nevanac®), made by Alcon Research Ltd., will be used as 710

the NSAID study drug. 711

712

Study eyes assigned to nepafenac drops will receive 1 drop, 3 times per day. Each 1 mL of 713

nevanac suspension contains 1 mg of nepafenac. The physical, chemical, and pharmaceutical 714

properties and formulation of nepafenac are provided in the Clinical Investigator‘s Brochure. 715

716

3.3 Placebo 717 Study eyes assigned to receive placebo drops will receive the vehicle contained in the nepafenac 718

drops, provided by Alcon Research Ltd. These drops will be administered 3 times per day using 719

bottles identical to that of nepafenac. 720

721

3.4 Artificial Tears 722 During the run-in phase, study participants will apply artificial tears 3 times per day to assess 723

compliance. 724

725

Tears Naturale Forte®, made by Alcon Research Ltd, will be the artificial tears used in the run-in 726

phase of this study. 727

728

3.5 Eye Drops Usage 729 Before start of the run-in phase, clinical site coordinators will instruct study participants 730

regarding the proper use and storage of eye drops. The study participant will be asked to 731

demonstrate proper application of the drops into the study eye. The eyelid will be lightly closed 732

for 1 minute after each application. Following dispensing of study drug, the coordinating center 733

staff will call study participants within the first week to confirm adherence with eye drop 734

protocol. 735


736

3.6 Assessment of Compliance 737

3.6.1 Run-in Phase 738

Prior to dispensing to a study participant, site personnel will weigh each bottle of study 739

medication using a calibrated scale. Upon return of the bottles to the site by end of the run-in 740

phase, the bottle will be weighed. Bottle weight will be recorded in grams (to the hundredth 741

decimal place). Site personnel will be responsible for scale calibration (according to the 742

manufacturer‘s instructions). A study participant will be considered below the compliance 743

threshold and will not be allowed to enroll into the randomized trial if her/his compliance level at 744

end of the run-in phase is less than 80% of the target level. Level of compliance will be 745

determined as follows: 746

747

Where EI =Expected initial bottle weight; EFU = Expected follow-up weight; OI= observed initial 748

bottle weight; OFU=observed follow-up bottle weight. 749

750

3.6.2 During Follow-up 751

Assessment of compliance will also be performed by site personnel at each follow-up study visit 752

as described above. 753


CHAPTER 4 FOLLOW-UP VISITS AND TREATMENT 754

755

4.1 Visit Schedule 756

Scheduled follow-up visits will occur at: 757

4 months ± 1 month 758



761

A phone call is completed by coordinating center within approximately one week of initiating 762

drops and then at approximately 2, 6, and 10 months to emphasize compliance with drop 763

dispensing. 764

765

4.2 Testing Procedures 766 The following procedures will be performed at each protocol visit on the study eye only unless 767

otherwise specified. 768

769

In addition, the first time non-topical treatment for DME will be administered, whether at a study 770

visit or non-study visit, an E-ETDRS visual acuity with refraction, OCT, and color fundus 771

photographs should be performed on the study eye prior to initiation of the treatment. 772

773

A grid in section 1.3D summarizes the testing performed at each visit. 774

775

1. E- ETDRS visual acuity testing (best corrected). 776

Testing is performed on each eye prior to dilation at each required follow-up visit. 777

Protocol refraction is required in the study eye at each protocol visit. When a 778

refraction is not performed (e.g. non protocol visit), the most-recently performed 779

refraction is used for the testing. 780

If the E-ETDRS visual acuity letter score is 0, then counting fingers, hand motion, 781

and light perception are assessed. 782

Also obtained at a non-study visit if treatment for DME is to be initiated. 783

2. OCT on the study eye 784

The same type of OCT machine used at baseline should be used for all subsequent 785

follow-up visits. 786

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

3. Ocular exam including slit lamp examination (including corneal and lens assessment), 788

measurement of intraocular pressure, and dilated ophthalmoscopy on the study eye. 789

4. ETDRS protocol 7-standard field or 4 wide-field digital stereoscopic fundus photographs in 790

study eye (Baseline and 1 year visits only). 791

Also obtained at a non-study visit if treatment other than the study intervention for 792

DME is to be initiated. 793

794

All of the testing procedures do not need to be performed on the same day, provided that they are 795

completed within the time window of a specific visit and prior to initiating any treatment for 796

DME other than the study related intervention. 797

798


Testing procedures at non-protocol visits are at investigator discretion. However, it is 799

recommended that procedures that are performed should follow the standard DRCR.net protocol 800

for each procedure. 801

802

4.3 Treatment for Diabetic Macular Edema 803 Study participants will receive the randomly assigned topical medication with no other treatment 804

for DME unless at least one of the criteria below is met. All study participants will continue 805

their study assigned topical medication through 12 months and complete all protocol visits 806

through 12 months regardless of whether other treatment for DME is received. 807

808

Treatment for DME should not be given unless one of the following criteria is met: 809

1. Central subfield retinal thickness increases to 310 μm or more by spectral domain OCT 810

machine measurement. 811

812

2. In any other circumstance where the investigator believes it is in the study participant‘s 813

best interest to receive treatment for non-central involved DME (for example, rapidly 814

progressing cataract prior to cataract surgery or new PDR) after review with the Protocol 815

Chair or Protocol Chair designate. 816


817

CHAPTER 5 - MISCELLANEOUS CONSIDERATIONS IN 818

FOLLOW-UP 819

820

5.1 Treatment of Diabetic Retinopathy in the Study Eye 821 Treatment of diabetic retinopathy in the study eye with PRP is at investigator discretion. Due to 822

the effect on macular edema, treatment of diabetic retinopathy with intravitreal injections is 823

discouraged. In any circumstance where the investigator believes it is in the study participant‘s 824

best interest to receive intravitreal injections for the treatment of diabetic retinopathy the 825

Protocol Chair or Protocol Chair designee must be contacted for approval. 826

827

5.2 Treatment after Cataract Surgery 828 Post-operative treatment with NSAIDs (including non protocol drops) after cataract surgery is at 829

investigator discretion; however, it should not affect the use of protocol assigned treatment. 830

831

5.3 Treatment of Diabetic Retinopathy in Non-study Eye 832 Treatment of proliferative diabetic retinopathy and DME in the non-study eye is at investigator 833

discretion. 834

835

5.4 Diabetes Management 836

Diabetes management is left to the study participant‘s medical care provider. 837

838

5.5 Study participant Withdrawal and Losses to Follow-up 839 A study participant has the right to withdraw from the study at any time. If a study participant is 840

considering withdrawal from the study, the principal investigator should personally speak to the 841

participant about the reasons, and every effort should be made to accommodate the study 842

participant. 843

844

The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 845

will assist in the tracking of study participants who cannot be contacted by the site. The 846

Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 847

848

Study participants who withdraw will be asked to have a final closeout visit at which the testing 849

described for the protocol visits will be performed. Study participants who have an adverse 850

effect attributable to a study treatment or procedure will be asked to continue in follow-up until 851

the adverse event has resolved or stabilized. Study participants who withdraw or are determined 852

to have been ineligible post-randomization will not be replaced (note: study participants with 853

poor quality scans which the reading center cannot manually adjust may be replaced). 854

855

5.6 Discontinuation of Study 856 The study may be discontinued by the Executive Committee (with approval of the Data and 857

Safety Monitoring Committee (DSMC)) prior to the preplanned completion of follow-up for all 858

subjects. 859

860

5.7 Contact Information Provided to the Coordinating Center 861 The Coordinating Center will be provided with contact information for each study participant. 862


Permission to obtain such information will be included in the Informed Consent Form. The 863

contact information may be maintained in a secure database and will be maintained separately 864

from the study data. 865

866

Phone contact from the Coordinating Center may be made with each study participant in the first 867

month after enrollment. Additional phone contacts from the Coordinating Center will be made if 868

necessary to facilitate the scheduling of the study participant for follow-up visits or as part of the 869

protocol to assess compliance with the drop regimen. A study participant-oriented newsletter 870

will be sent at least twice a year. A study logo item may be sent once a year. 871

872

Study participants will be provided with a summary of the study results in a newsletter format 873

after completion of the study by all subjects. 874

875

5.8 Study Participant Reimbursement 876 The study will be providing study participants $25 per completed protocol visit ($125 maximum 877

if all 4 visits are completed) to cover travel and other visit-related expenses. Payment will be 878

made directly from the Coordinating Center to the participant. Additional travel expenses may 879

be paid in cases for subjects with higher expenses if approved by the IRB. 880


CHAPTER 6 ADVERSE EVENTS 881

882

6.1 Definition 883 An adverse event is any untoward medical occurrence in a study participant, irrespective of 884

whether or not the event is considered treatment-related. 885

886

6.2 Recording of Adverse Events 887

Throughout the course of the study, all efforts will be made to remain alert to possible adverse 888

events or untoward findings. The first concern will be the safety of the study participant, and 889

appropriate medical intervention will be made. 890

891

The investigator will elicit reports of adverse events from the study participant at each visit and 892

complete all adverse event forms online. Each adverse event form is reviewed by the 893

Coordinating Center to verify the coding and the reporting that is required. 894

895

The study investigator will assess the relationship of any adverse event to be related or unrelated 896

by determining if there is a reasonable possibility that the adverse event may have been caused 897

by the treatment. 898

899

The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 900

severe. It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 901

event is not necessarily serious. For example, itching for several days may be rated as severe, 902

but may not be clinically serious. 903

904

Adverse events will be coded using the MedDRA dictionary. 905

906

Definitions of relationship and intensity are listed on the DRCR.net website data entry form. 907

908

Adverse events that continue after the study participants‘ discontinuation or completion of the 909

study will be followed until their medical outcome is determined or until no further change in the 910

condition is expected. 911

912

6.3 Reporting Serious or Unexpected Adverse Events 913 A serious adverse event is any untoward occurrence that: 914

Results in death. 915

Is life-threatening; (a non life-threatening event which, had it been more severe, might have 916

become life-threatening, is not necessarily considered a serious adverse event). 917

Requires inpatient hospitalization or prolongation of existing hospitalization. 918

Results in significant disability/incapacity (sight threatening). 919

Is a congenital anomaly/birth defect. 920

921

Unexpected adverse events are those that are not identified in nature, severity, or frequency in 922

the current nepafenac Clinical Investigator‘s Brochure. Serious or unexpected adverse events 923

must be reported to the Coordinating Center immediately via completion of the online serious 924

adverse event form. 925


926

The Coordinating Center will notify all participating investigators of any adverse event that is 927

both serious and unexpected. Notification will be made within 10 days after the Coordinating 928

Center becomes aware of the event. 929

930

Each principal investigator is responsible for informing his or her Internal Review Board (IRB) 931

of serious study-related adverse events and abiding by any other reporting requirements specific 932

to their IRB. 933

934

6.4 Data and Safety Monitoring Committee Review of Adverse Events 935 A DSMC will approve the protocol, template informed consent form, and substantive 936

amendments and provide independent monitoring of adverse events. Cumulative adverse event 937

data are semi-annually tabulated for review by the DSMC. Following each DSMC data review, 938

a summary will be provided to IRBs. A list of specific adverse events to be reported to the 939

DSMC expeditiously, if applicable, will be compiled and included as part of the DSMC Standard 940

Operating Procedures document. 941

942

6.5 Risks 943

6.5.1 Potential Adverse Effects of Topical NSAIDs 944

NSAIDs have been mainly approved to treat pain and inflammation associated with cataract 945

surgery (Nevanac and Xibrom)34, 35

or pain and burning associated with refractive surgery 946

(Acular).36

Allergic reactions to the drug or to the preservative ingredient in the bottle have been 947

reported. In severe cases, allergic reactions can lead to difficulty of breathing due to swelling in 948

the face, tongue or throat, which might necessitate medical intervention. Other non-ocular 949

adverse reactions reported at an incidence of 1 to 4% include headache, hypertension, nausea, 950

vomiting, and sinusitis. 951

952

Topical NSAIDs may result in keratitis. Severe cases can lead to corneal epithelial breakdown, 953

corneal thinning, corneal erosion and corneal ulceration.37

However, the incidence of corneal 954

melting appears to be relatively low. Singer and colleagues presented data on long term safety of 955

NSAIDs in 501 patients who were treated with topical NSAIDS for an average of 26 months 956

(range 3 -120 months). A variety of NSAIDs were used, including nepafenac, ketorolac, and 957

bromfenac with the most frequent dosing regimen being four times a day. Only 31 % of the study 958

cohort was diabetic. However, no corneal melting was observed in any patient in this study. A 959

further review of the literature identified 28 cases of corneal melting associated with topical 960

NSAIDs, 96% of which were associated with perioperative NSAID use. Furthermore, 20% of 961

the patients who experienced corneal melting had an underlying rheumatologic or autoimmune 962

disease. The average time to corneal melt was 1 month after initiation of NSAID treatment, 963

suggesting that patients who are prone to melting might be able to be identified shortly after they 964

begin using topical NSAIDs.38

965

966

Less serious but more frequently reported adverse effects are also ocular ones. Itching or 967

watering of the eye is a common complaint among patients who use topical NSAIDs. Because 968

post cataract or refractive surgery is the usual setting where topical NSAIDs are used, many of 969

the ocular side effects commonly listed (including a dry or sticky feeling in the eye and eye 970

redness) might be attributed to the ocular surgery itself. Decrease in visual acuity, capsular 971


opacity, and an increase in intra-ocular pressure have been reported in 5-10% of patients using 972

topical nepafenac post cataract surgery.34

Other ocular adverse reactions occurring at an 973

incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid 974

margin crusting, ocular pain, and vitreous detachment.34

975

976

In clinical studies the most frequent adverse reactions reported in the post-cataract or post-ocular 977

surgery studies for patients exposed to nepafenac 0.1% were eyelid margin crusting (0.3%), 978

foreign body sensation in eyes (0.3%), allergic conjunctivitis (0.2%),eye discharge (0.2%), eye 979

pain (0.2%), and keratitis (0.2%). Other less frequent adverse reactions included blepharitis, 980

choroidal effusion, conjunctival hyperaemia, conjunctivitis, corneal deposits, corneal disorder, 981

cutis laxa, eye pruritis, hypersensitivity, increased, lacrimation, iritis, nausea, and ocular 982

discomfort. 983

984

There may be side effects and discomforts that are not yet known. Long term adverse effects are 985

not well documented; furthermore, topical NSAIDs have not been evaluated in long-term 986

carcinogenicity studies. Animal chromosomal aberration studies indicate a safe profile. 987

988

6.5.2 Corneal Complications 989 At each study visit, a thorough corneal examination will be conducted as part of the ocular exam 990

to assess the cornea for any potential adverse effect that may take place as a result of using the 991

study drugs. 992

993

6.5.3 Risk of Artificial Tears (Tears Naturale Forte®) 994 Preservatives in Tears Naturale Forte solution can rarely be associated with ocular irritation, 995

redness or blurred vision. These side effects are uncommon when tears are used less often than 4 996

times per day and are generally alleviated when the drops are stopped. 997

998

6.5.4 Risks of Eye Examination and Tests 999 There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 1000

or dilate the pupil. Dilating drops rarely could cause an acute angle closure glaucoma attack, but 1001

this is highly unlikely since the subjects in the study will have had their pupils dilated many 1002

times previously. 1003


CHAPTER 7 STATISTICAL METHODS 1004

1005

The approach to sample size and statistical analyses are summarized below. A detailed statistical 1006

analysis plan will be written and finalized prior to the completion of the study. The analysis plan 1007

synopsis in this chapter contains the framework of the anticipated final analysis plan. 1008

1009

This study is a phase II clinical trial conducted to establish whether topical NSAIDs have 1010

sufficient biological activity in reducing DME to warrant further investigation. The primary 1011

outcome of the study will be mean change in retinal volume at the 12 month visit in eyes with 1012

non-central subfield involved DME. 1013

1014

7.1 Sample Size 1015 The primary analysis consists of a statistical comparison of the mean change in retinal volume 1016

from baseline to 1 year in the control group compared with the NSAID group. 1017

1018

7.2 Sample Size Estimation 1019 DRCR.net non-published protocol G (―Subclinical Diabetic Macular Edema Study‖) data were 1020

used to estimate the standard deviation of mean retinal volume changes. From this study, based 1021

on N=16 eyes with gradable volume measurements the standard deviation for change in retinal 1022

volume from baseline to 1 year was 0.37 mm3 (95% confidence interval (CI) 0.28 to 0.56). If a 1023

convenience sample of N=50 subjects per group is selected, this study will have 90% power to 1024

detect a difference if the true difference is 0.40 and the SD is 0.60 (the approximate upper end of 1025

the 95% CI for change in volume). 1026

1027

Effect sizes (μ1-μ2 change) for different sample sizes and standard deviations for retinal 1028

volume change, power 90%, α 0.05 1029

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 1030

Sample size will be increased by 10% to account for participants lost to follow up, and another 1031

10% to account for poor quality scans which the reading center cannot manually adjust the 1032

volume measurement up to a total sample size of 120. 1033


1034

From DRCR.net subclinical DME protocol (Protocol G), non-gradable retinal volume scans, as 1035

identified by a reading center, at baseline and at 1 year were estimated to be 15%. Since only 1036

spectral domain OCTs are used in this study and software is available to potentially manually 1037

adjust the retinal volume measurement of spectral domain OCTs, an estimate of approximately 1038

10% for poor scan quality will be used. 1039

1040

7.3 Efficacy Analysis Plan 1041

7.3.1 Primary Outcome Analysis 1042 The primary analysis will involve comparison of the mean change in retinal volume in eyes with 1043

non-central involved DME at baseline through 1 year in eyes receiving NSAIDs versus those 1044

receiving placebo. 1045

1046

Retinal volume change will be calculated by subtracting retinal volume measurements at 12-1047

month visit from that at baseline. 1048

1049

The treatment group comparison will be performed using an ANCOVA model, with change in 1050

retinal volume measurements at 12 months fitted as the dependent variable, and the treatment 1051

group as the independent variable, adjusting for baseline retinal volume measurement. Eyes 1052

treated for DME prior to the 1 year visit will have the last volume measurement prior to the 1053

treatment imputed into the final analysis. Eyes with inaccurate automated retinal volume 1054

measurement at baseline, which cannot be adjusted by a central reading center, will be excluded 1055

from the primary analysis. The significance level used for the final primary analysis will be 1056

0.05. Last-observation-carried-forward will be used for participants with incomplete follow up. 1057

A sensitivity analysis will be conducted to compare LOCF results with those using a per-protocol 1058

analysis only including study participants who completed the 1 year visit and with results from 1059

Rubin's multiple imputation technique. 1060

1061

Pre-planned subgroup analyses will be conducted in the same way as the primary analysis and 1062

include stratification by prior DME treatment. Other subgroup analyses will be described in the 1063

detailed Statistical Analysis Plan. 1064

1065

Imbalances between groups in important covariates are not expected to be of sufficient 1066

magnitude to produce confounding; however, a second analysis that adjusts for imbalanced 1067

baseline covariates will be performed. If results are similar to the primary analysis, the primary 1068

analysis will be accepted as the definitive analysis; otherwise, the reasons for the difference will 1069

be explored. 1070

1071

There are no data to suggest that the treatment effect will vary by gender or race and ethnicity. 1072

However, both of these factors will be evaluated in exploratory analyses. 1073

1074

Analogous analyses as described above will be conducted at the 4 and 8 month visits. In 1075

addition, longitudinal analysis over time will be performed using repeated measures analysis 1076

with a fixed time effect including all visits up to and including the primary outcome time point. 1077


1078

7.3.2 Secondary and Tertiary Outcomes 1079

In addition to the primary outcome, the following secondary outcomes will be estimated, and 1080

their 95% CI will be obtained in each treatment group and compared between treatment groups: 1081

Proportion of eyes with 1 or more logOCT step increase in central subfield thickness at 1 1082

year 1083

Proportion of eyes that progress from non-central to central involved DME by fundus 1084

photographs at 1 year 1085

Proportion of eyes receiving treatment for DME other than the study intervention by 1 1086

year 1087

Proportion of eyes reaching central subfield thickness ≥310 µm at 1 year 1088

Correlation of progression from non-central involved DME to central involved edema as 1089

determined on stereoscopic fundus photographs compared with OCT 1090

Proportion of eyes with diabetic retinopathy progression or regression of 2 steps between 1091

baseline and 1 year 1092

Change in maximum inner and outer macular subfield thickness 1093

1094

1095

The following tertiary outcomes will be estimated, and their 95% CI will be obtained in each 1096

treatment group and compared between treatment groups at 1 year. For eyes that have received 1097

treatment for DME before 1 year, visual acuity and OCT measurements obtained at time of 1098

failure will be used instead of measurements at 1 year. 1099

Mean change in visual acuity 1100

Change in OCT central subfield thickness 1101

Change in the number of thickened (>mean+2SD) subfields on OCT 1102

Change in level of diabetic retinopathy on stereoscopic fundus photographs 1103

1104

Analyses of the secondary and tertiary outcomes will be conducted as follows: 1105

Binary outcomes will be analyzed using logistic regression to control for baseline level of the 1106

outcome. Continuous outcome comparisons will be performed using ANCOVA with adjustment 1107

for baseline. All linear model assumptions will be verified including linearity, normality of 1108

residuals, and homoscedasticity. If model assumptions are not met, a nonparametric analogue 1109

for ANCOVA will be considered. Last-observation-carried-forward (LOCF) will be 1110

implemented for patients lost to follow up. 1111

1112

7.4 Assessment of Compliance 1113

Level of compliance will be determined as the average level of compliance from each study visit 1114

(excluding the run-in phase compliance assessment visit). A study participant will be considered 1115

below the compliance threshold if her or his compliance level by end of the study was less than 1116

80% of the target level. Level of compliance will be determined as follows: 1117


Where EI =Expected initial bottle weight; EFU = Expected follow-up weight; OI= observed initial 1118

bottle weight; OFU=observed follow-up bottle weight. 1119

1120

As an exploratory analysis, an ‗as-treated‘ analysis will be performed limited to participants with 1121

at least 80% compliance. In addition, compliance will be evaluated over time. If compliance 1122

lessens over time, an exploratory analysis will investigate whether there appears to be any 1123

association of compliance versus magnitude of treatment effect over time. 1124

1125

7.5 Safety Analysis Plan 1126 Adverse events will be categorized as study eye, non-study eye, and systemic. The events will 1127

be tabulated and compared between treatment groups. Separate analyses will compare related 1128

adverse events between groups. 1129

Corneal complications: corneal edema, superficial keratitis, corneal erosion, corneal 1130

thinning, corneal ulceration and corneal melting 1131

Elevated intraocular pressure/glaucoma (medication and/or surgery) 1132

Cataract/cataract surgery 1133

Burning/stinging/itching/watering 1134

Ocular inflammation 1135

Ocular infection 1136

1137

Further definitions of the events for analysis and the analytic approach will be provided in the 1138

detailed statistical analysis plan. 1139

1140

7.6 Additional Tabulations and Analyses 1141 The following will be tabulated according to treatment group: 1142

Baseline demographic and clinical characteristics. 1143

Visit completion rate for each visit. 1144

Protocol deviations.1145


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Diabetic Retinopathy Clinical Research Network A …publicfiles.jaeb.org/.../DRCRnet_Protocol_R_V1_1_18_11.pdfDRCRnet Protocol R V1.0 1-18-11DRCRnet Protocol R V1.0 1-18-11 1-4 Years