Diabetic Retinopathy Clinical Research

Network

Protocol #1A

A Pilot Study of Laser Photocoagulation

for
Diabetic Macular Edema

Version 1.1

April 16, 2003

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 Table of Contents
1. Chapter 1: Introduction ...............................................................................................................1-1
1.1 General Overview .................................................................................................................1-1
1.2 Protocol Goals & Questions..................................................................................................1-1
1.3 Background Information on Diabetic Macular Edema .........................................................1-2
1.4 Rationale for modified-ETDRS Treatment ...........................................................................1-3
1.5 Rationale for Mild Macular Grid (MMG) ............................................................................1-3
1. 6 Current Study Overview .....................................................................................................1-4
2. Chapter 2: Subject Eligibility and Enrollment ..........................................................................2-1
2.1 Identification of Eligible Subjects and Obtaining Informed Consent ...................................2-1
2.2 Eligibility Criteria .................................................................................................................2-1
2.3 Screening Evaluation and Baseline Testing ..........................................................................2-2
2.3.1 Historical Information .............................................................................................2-2
2.3.2 Examination Procedures..........................................................................................2-2
2.3.3 Laboratory Test .......................................................................................................2-3
2.4 Enrollment/Randomization of Eligible Patients....................................................................2-4
2.5 Baseline Photocoagulation ....................................................................................................2-4
2.6 Post-photocoagulation Photographs......................................................................................2-4
3. Chapter 3: Follow-up Visit Schedule and Procedures...............................................................3-1
3.1 Follow-up Visit Schedule......................................................................................................3-1
3.2 Follow-up Visit Testing and Procedures...............................................................................3-1
3.3 Assessment of Need for Additional Photocoagulation for DME..........................................3-2
3.4 Nonprotocol Visits ................................................................................................................3-2
4. Chapter 4: Miscellaneous Considerations in Follow-up............................................................4-1
4.1 Non protocol Treatment of DME ..........................................................................................4-1
4.2 Panretinal Photocoagulation..................................................................................................4-1
4.3 Diabetes Management...........................................................................................................4-1
4.4 Patient Withdrawal and Losses to Follow up .......................................................................4-1
4.5 Discontinuation of Study.......................................................................................................4-1
4.6 Participation in Other Studies Prior to the End of Three-year Follow up.............................4-1
4.7 Contact Information Provided to the Coordinating Center ...................................................4-1
4.8 Patient Reimbursement .........................................................................................................4-2
5. Chapter 5: Photocoagulation Treatment ....................................................................................5-1
5.1 DME Laser Treatment Techniques .......................................................................................5-1
5.1.1 Retreatment of DME ...............................................................................................5-2
5.2 Laser Scatter (Panretinal) Photocoagulation (PRP) ..............................................................5-3
5.2.1 Burn Characteristics ................................................................................................5-3
6. Chapter 6: Adverse Events ..........................................................................................................6-1
6.1 Events to be Reported ...........................................................................................................6-1
6.2 Definitions.............................................................................................................................6-1
6.3 Reporting Requirements for Adverse Events........................................................................6-1
6.4 Data and Safety Monitoring Board ........................................................................................6-1
6.5 Risk and Discomforts............................................................................................................6-1
6.5.1 Photocoagulation.....................................................................................................6-1
6.5.2 Examination Procedures..........................................................................................6-2
6.5.3 Fundus Photography................................................................................................6-2
6.5.4 Fluorescein Angiography ........................................................................................6-2
6.5.5 Optical Coherence Tomography .............................................................................6-2
7. Chapter 7:Statistical Considerations .........................................................................................7-1
7.1 Sample Size and Power Considerations ................................................................................7-1
7.2 Statistical Analysis ................................................................................................................7-1
8. References…………………………………………………………………………………………8-1

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 1 CHAPTER 1
2 INTRODUCTION
3
4
5 1.1 General Overview
6 The Diabetic Retinopathy Clinical Research Network (DRCRnet) was formed to conduct clinical
7 trials and epidemiological studies for diabetic retinopathy.
8
9 As part of the establishment of the network, it is necessary to standardize data collection methods,
10 testing procedures, and treatment techniques for use in the anticipated multiple protocols to be
11 conducted by the network. One of the treatment techniques requiring standardization is laser
12 photocoagulation treatment of diabetic macular edema. To accomplish this goal, a protocol has
13 been developed to enroll patients with diabetic macular edema who require laser treatment.
14 Procedures to be conducted by standardized protocols include refraction,1 visual acuity testing,2
15 fundus photography,3 fluorescein angiography,4 optical coherence tomography (OCT) and laser
16 photocoagulation5 One of the benefits from having a structured protocol will be that the outcome
17 data using the standardized techniques can be used for sample size estimations in future protocols.
18 This is particularly true for OCT for which we need to develop standard methods to assess changes
19 in groups of patients and for which there are limited longitudinal data, especially in groups of
20 patients.6
21
22 The conduct of this study provides the opportunity not only to collect data on a standardized laser
23 protocol commonly used in current clinical practice but also to collect pilot data evaluating a new
24 laser technique. The ‘current practice’ laser protocol, modified from the ETDRS treatment
25 protocol,5, 7-9 involves focal/grid photocoagulation to areas of macular thickening with leaking MA,
26 diffuse leakage or nonperfusion (modified-ETDRS technique). There is extensive evidence
27 supporting the efficacy of ETDRS laser photocoagulation technique for the treatment of macular
28 edema. The alternative technique, called mild macular grid (MMG) photocoagulation, provides
29 mild grid treatment using small, widely separated burns to the retina from 500 to 3000 microns
30 (3500 microns temporally) from the macular center. This technique may potentially have fewer
31 side effects, different edema resolution rate or prevention of future development of macular edema
32 as discussed below. The study will use randomization to assign each patient to receive one of the
33 two treatment methods.
34
35 For this protocol, participation will be open to all clinical sites that have the requisite equipment
36 needed for the study and to all ophthalmologists who meet criteria to be a DRCR.net investigator.
37 The sample size for the study will be dictated by the number of participating sites, with each site
38 limited to the enrollment of a maximum of four patients or one patient per certified investigator,
39 whichever is greater.
40
41 1.2 Protocol Goals & Questions
42 This pilot study is not designed for hypothesis testing, but rather for hypothesis generation, for
43 gathering outcome data, and for standardization of network protocols as discussed above.
44
45 With regard to hypothesis generation, some of the important issues that the protocol can address in
46 terms of the modified-ETDRS macular photocoagulation technique include:
47
48

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49 1) Evaluate the risk of moderate visual loss in patients treated with the modified-ETDRS
50 technique which incorporates the lighter treatment approach in common clinical practice
51 today.
52 2) Evaluate outcome rates in today’s patient populations with improved glycemic control as
53 compared with the outcomes derived from the classic reference studies such as DRS and
54 ETDRS, which were performed when glycemic control was generally less stringent.
55 3) Gain experience and evaluate usefulness of objective retinal thickness measurements
56 (e.g. OCT and modified photographic methods) in prospective, longer duration, diabetic
57 macular edema studies.
58 4) Evaluate improved photographic grading methods compared with classic reference
59 studies.
60
61 With regard to hypothesis generation, some of the important issues that data from the group of
62 patients randomized to mild macular grid (MMG) treatment can address include:
63 1) Evaluate risk of moderate visual loss and side effects from a treatment approach that
64 incorporates:
65 lighter treatment of areas of retinal thickening (i.e. without focal microaneurysm
66 treatment) and
67 potential distant effects of additional light grid treatment (i.e. treatment to
68 macular areas without thickening)
69 2) Evaluate potential for prevention of macular edema onset in areas of initially
70 unthickened retina that were treated with light grid treatment
71 3) Evaluate number of treatments required to resolve macular edema as compared with the
72 modified-ETDRS technique
73
74 1.3 Background Information on Diabetic Macular Edema
75 Diabetic retinopathy is a disorder of major public health importance, accounting for the majority of
76 visual loss among working age Americans. Diabetic macular edema (DME) is a manifestation of
77 diabetic retinopathy that produces loss of central vision. Data from the Wisconsin Epidemiologic
78 Study of Diabetic Retinopathy (WESDR) estimate that after 15 years of known diabetes, the
79 prevalence of diabetic macular edema is approximately 20% in patients with type 1 diabetes
80 mellitus (DM), 25% in patients with type 2 DM who are taking insulin, and 14% in patients with
81 type 2 DM who do not take insulin10 The Early Treatment Diabetic Retinopathy Study (ETDRS)
82 showed that moderate vision loss, defined as a doubling of the visual angle (e.g., 20/20 reduced to
83 20/40), can be reduced by 50% or more by focal/grid laser photocoagulation according to ETDRS
84 protocol.5 Although several treatment modalities are currently under investigation, the only
85 demonstrated means to reduce the risk of vision loss from diabetic macular edema are ETDRS laser
86 photocoagulation, as demonstrated by the ETDRS, and intensive glycemic control, as demonstrated
87 by the Diabetes Control and Complications Trial (DCCT) 11 and the United Kingdom Prospective
88 Diabetes Study (UKPDS).12 In the DCCT, intensive glucose control reduced the risk of onset of
89 diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of
90 patients in the DCCT show a sustained effect of intensive glucose control, with a 58% risk
91 reduction in the development of diabetic macular edema for the DCCT patients followed in the
92 Epidemiology of Diabetes Interventions and Complications Study.13
93
94 1.4 Rationale for modified-ETDRS Treatment
95 ETDRS treatment for diabetic macular edema involved direct focal treatment to discrete lesions
96 between 500 microns and 3000 microns from the center of the macula that were thought to be

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 97 causing retinal thickening or hard exudates with or without “grid” treatment to other macular areas
98 of retinal thickening.7 or non-perfusion. The lesions treated focally included microaneurysms,
99 identified on fluorescein angiography, that either filled or leaked, intraretinal microvascular
100 abnormalities (IRMA), or pruned capillaries that leaked fluorescein. Grid treatment was applied in
101 the ETDRS to areas of thickened retina that showed diffuse fluorescein leakage or capillary
102 dropout. Areas of non-perfusion in the macula could be treated with grid at the discretion of the
103 treating ophthalmologist. Areas that had both discrete lesions and diffuse leakage or capillary
104 dropout would receive a combination of direct focal and grid treatment. A full description of
105 ETDRS treatment for diabetic macular edema is detailed in ETDRS report #4. In the ETDRS,
106 focal/grid treatment resulted in a decrease in retinal thickening, a decreased risk of moderate vision
107 loss, and, in some cases, an increased likelihood of moderate vision gain.
108
109 The mechanism of action of focal/grid laser photocoagulation in the ETDRS is not fully understood;
110 however, it is clear that the retinal pigment epithelium (RPE) absorbs the majority of the laser
111 energy and thermal injury occurs at the level of the RPE.14, 15 Studies have shown that
112 photocoagulation eventually results in retinal and apparent RPE atrophy 200-300% larger than the
113 original laser spot size.16, 17 These areas of expanded atrophy can lead to loss of central vision,
114 central scotomata, and decreased color vision. Consequently, many retinal specialists today tend to
115 treat with lighter, less intense laser burns than originally specified in the ETDRS.18-21
116
117 In addition to the concern regarding the spread of intense laser burns, there are a number of other
118 reasons that retinal specialists today have modified the treatment procedures originally specified in
119 the ETDRS protocol. These reasons include the advent of new lasers, a desire to develop an easier
120 method to deliver macular treatment, and the clinical observation that different techniques, such as
121 focal or grid treatment alone, are apparently similar in beneficial effect as the original ETDRS
122 treatment protocol.19, 22
123
124 There is a need, therefore, to evaluate the efficacy of treatments that have come into common
125 clinical use. In addition to evaluating the efficacy of these modified treatment protocols, it is
126 important that we develop a common treatment protocol for the DRCR.net upon which all
127 investigators can agree.
128
129 1.5 Rationale for Mild Macular Grid (MMG)
130 There are several reasons for evaluating the MMG treatment approach. Lighter treatment
131 techniques hold theoretical benefits such as reduced scotomata, less burn spread, decreased
132 epiretinal membrane formation, less likelihood to rupture Bruchs’ membrane, etc.23-27 To date such
133 therapeutic approaches have not been rigorously evaluated in large clinical trials. MMG does not
134 focally treat microaneurysms.
135
136 Beneficial effects of photocoagulation may be expected even without treatment of focal
137 microaneurysms. Grid treatments alone have been evaluated in limited trials with evidence of
138 reduced macular edema. Indeed, in patients with diffuse macular edema and few or no
139 microaneurysms, the well-proven ETDRS treatment approach employs only a grid.22, 25-27
140
141 It is also clear that laser treatments alter biochemical processes within the retinal pigment
142 epithelium and studies have suggested that such stimulation may account for some of the
143 therapeutic effect.28-32
144
145 Thus, resolution of macular edema following laser photocoagulation is not solely dependent on
146 focal treatment of microaneurysms.

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147 Since laser treatments alter biochemical processes within the retinal pigment epithelium and studies
148 have suggested that such stimulation may have therapeutic benefit, MMG may stimulate more RPE
149 or RPE that is healthier than would be treated by standard focal treatment. This might increase the
150 beneficial biochemical changes or release of helpful factors.
151
152 Macular treatment in areas without retinal thickening has been used in preliminary light intensity
153 diode laser studies with reported effectiveness.19, 22 The burns in the MMG protocol are well-
154 separated and light in intensity. This should have little effect on visual function. It is well
155 established that panretinal (scatter) photocoagulation can have marked therapeutic effect in areas
156 distant to the laser burns themselves.33
157
158 It is possible that the light MMG burns throughout the macula may have a similar effect on distant
159 areas of retinal thickening in the macula, thus possibly increasing the therapeutic effect. It is also
160 possible that increased RPE stimulation or improved retinal oxygenation provided by the use of the
161 MMG approach, which treats areas of the macula that are not treated by the standard ETDRS
162 approach, may help prevent subsequent onset of macular edema in these areas.
163
164 There is also clear evidence that macular edema may exist that is not appreciated clinically. These
165 subclinical areas are classically not treated. The MMG approach would result in treatment of these
166 areas and thus may have added benefit.
167
168 1.6 Current Study Overview
169 In brief, the study protocol involves the enrollment of patients >18 years of age who have DME
170 involving or threatening the center of the macula and who have not had prior focal/grid laser
171 photocoagulation for DME. These are patients for whom the standard of care would be to treat with
172 laser photocoagulation. Eligible eyes will be randomly assigned to receive either the modified-
173 ETDRS technique or the MMG technique. The initial laser treatment protocol for each technique is
174 described in section 5.1. The criteria for and protocol for retreatments are described in section
175 5.1.1. Outcome assessments will include Optical Coherence Tomography (OCT), fundus
176 photography, fluorescein angiography and standardized best-corrected visual acuity.
177
178 The study consists of two phases: Phase 1 (the primary study), which consists of the first 12 months
179 of follow up, during which a structured protocol is followed; and Phase 2, which consists of the
180 second and third years of follow up, during which the management of DME can include techniques
181 other than laser photocoagulation, at discretion of the investigator.
182
183 During Phase 1, follow-up visits will occur at 15 weeks (3.5 months) +14 days, 34 weeks (8
184 months) + 28 days, and 52 weeks (12 months) + 28 days. The primary outcome for phase 1 is at 12
185 months. The primary study objectives of Phase 1 include:
186 Develop standardized study procedures for future DME studies
187 Obtain outcome data (e.g. changes in retinal thickness, area of retinal thickening, area of
188 hard exudate, need for retreatment, onset of new areas of DME and changes in visual
189 acuity) following use of the modified-ETDRS photocoagulation technique for patients
190 with DME and various levels of retinopathy severity.
191 Collect pilot data using the MMG technique to determine whether a subsequent large
192 scale definitive trial should be conducted

193

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194 Phase 2 (2nd and 3rd years of follow up) is being conducted to collect data on, and generate
195 hypotheses from, the long-term outcome of DME, irrespective of treatment received.
196 Protocol visits will occur at 2 years + 8 weeks and 3 years + 8 weeks.
197 During this phase of the study, therapies other than laser photocoagulation may be used to treat
198 DME at the investigator’s discretion. Because treatment other than photocoagulation will be
199 allowed after one year, ‘pure’ results regarding outcomes with each laser technique cannot be
200 obtained in all groups, but will be available in a subset of patients. The data are being collected at
201 relatively low cost and no risk over and above usual care. Therefore, the collection of potentially
202 hypothesis-generating data from exploratory analysis is justified and could be important in
203 designing future studies. Interpretation of the results of the above analyses will be complicated by
204 the lack of a standardized protocol with regard to which patients receive treatment and what
205 treatment is provided. Therefore, the results will be interpreted with caution. The phase 2 data
206 collection may be useful for the following:
207 1) Evaluation of retreatment rates in patients who responded to laser such that no additional
208 treatment was required at 12 months. This is a long term analysis on a “pure” group of patients
209 and will provide important information on the DME recurrence rate and need for retreatment in
210 study eyes of those patients whose DME improved with either of the two protocol-specified
211 treatments received in Phase 1 such that further treatment was not necessary at the 12-month
212 visit.
213 2) Provide long-term safety data for MMG. This is important due to the less well studied nature of
214 MMG, especially over the long term.
215 3) Provide long-term outcome data on current standard treatment (modified ETDRS laser) in
216 today’s patient populations to assist in powering future studies that will require at least 3 years
217 of follow up.
218 4) Provide data on outcome of intravitreal steroids in patients in whom laser treatment is not
219 successful. For many patients who still have DME at 12 months, it is anticipated that
220 intravitreal steroids will be administered. The continued follow up of these patients will provide
221 an opportunity to explore the effect of the steroids on retinal thickness and visual acuity.
222
223
224
225

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225 Schedule of Study Visits and Examination Procedures
226
Follow-up Visits
(timed from randomization, months)
Phase 1 Phase 2
Baseline 3.5 8 12 24 36
ETDRS refraction and visual acuity OU x x x x x x
a a a a a a
Fundus photos OU 7F 3F 3F 7F 7F 7F

ETDRS fluorescein angiography OU x x

OCT OU x x x x x x

Eye Examb x x x x x x

Blood pressure x x x x

HbA1cc x x x x

BUN, creatnine, microalbuminc x

Fasting lipid profiled x

227 a= post-laser photos (only field 2 stereo) to be done in addition after any laser treatment.
228 b=exam performed according to investigator’s usual routine
229 c=does not need to be repeated if HbA1c, BUN, creatnine, microalbumin result and lab normal values are available
230 from within the prior 3 months (at baseline, can be performed within 3 weeks after randomization)
231 d=performed after overnight fast; does not need to be repeated if LDL and triglyceride results are available in prior 6
232 months (at baseline, can be performed within 3 weeks after randomization)
233

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234 CHAPTER 2
235 SUBJECT ELIGIBILITY AND ENROLLMENT
236
237 2.1 Identification of Eligible Subjects and Obtaining Informed Consent
238 A minimum of 200 subjects are expected to be enrolled with a goal to enroll an appropriate
239 representation of minorities. Potential eligibility will be assessed as part of a routine-care
240 examination. Prior to completing any procedures or collecting any data that are not part of usual
241 care, informed consent will be obtained. For subjects who are considered potentially eligible for the
242 study based on a routine-care exam, the study protocol will be discussed with the patient by a study
243 investigator and clinic coordinator. The patient will be given the Informed Consent Form to read.
244
245 Consent will be given in two stages. The initial stage will provide consent to complete any of the
246 screening procedures needed to assess eligibility that have not already been performed as part of a
247 usual-care exam. The second stage will be obtained prior to randomization and will be for
248 participation in the study. A single consent form will have two signature lines for the patient: one
249 for the patient to give consent to the completion of the screening procedures and one for the patient
250 to give consent for the randomized trial.
251
252 Patients who are found to be eligible will be encouraged to discuss the study with family members,
253 friends, or their personal physician before deciding whether to participate in the study. Patients who
254 decide to participate will have signed both stages of the consent form prior to randomization for
255 participation in the study. Patients will be provided with a signed copy of the Informed Consent
256 Form.
257
258 Once a patient is randomized, that patient will be counted regardless of whether the assigned
259 treatment is received or not. Thus, the investigator must not proceed to randomize a patient until
260 he/she is convinced that the patient will accept either treatment group assignment.
261
262
263 2.2 Eligibility Criteria
264 2.2.1 Subject-level Criteria
265 1. Age >= 18 years
266 o Patients <18 years old are not being included because DME is so rare in this age group
267 that the diagnosis of DME may be questionable.
268 2. Diagnosis of diabetes mellitus (type 1 or type 2)
269 o Any one of the following will be considered to be sufficient evidence that diabetes is
270 present:
271 a. Current regular use of insulin for the treatment of diabetes
272 b. Current regular use of oral antihyperglycemia agents for the treatment of diabetes
273 c. Documented diabetes by ADA guidelines (see DRCR.net Procedures Manual)
274 3. No history of renal failure requiring dialysis or renal transplant.
275 4. No condition that in the opinion of the investigator would preclude participation in the study
276 (e.g., unstable medical status including blood pressure and glycemic control;
277 o Patients in poor glycemic control who recently initiated intensive insulin treatment (a
278 pump or multiple daily injections) or plan to do so in the next 3 months should not be
279 enrolled.
280

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281 5. Ability and willingness to provide informed consent.
282 6. No expectation that subject will be moving out of the area of the clinical center to an area not
283 covered by another clinical center during the next 12 months.
284
285 2.2.2 Study Eye Criteria
286 At least one eye must meet all of the following criteria:
287 1. Best corrected ETDRS visual acuity score >= 19 letters (approximately 20/400 or better).
288 2. Definite retinal thickening due to diabetic macular edema based on clinical exam at or within
289 500 microns of the macular center for which the investigator believes laser photocoagulation is
290 indicated.
291 3. A thickness of 250 microns or more in the central subfield OR a thickness of 300 microns or
292 more in any one of the four subfields directly adjacent to the central subfield on OCT.
293 4. No prior focal/grid laser photocoagulation in the macula.
294 5. No prior medical treatment for DME (e.g., intravitreal/peribulbar steroids).
295 6. No panretinal scatter photocoagulation (PRP) within prior 4 months.
296 7. No anticipated need for PRP within next 4 months.
297 8. No major ocular surgery (including cataract extraction, any other intraocular surgery, scleral
298 buckle, glaucoma filter, cornea transplant, etc.) within prior 6 months.
299 9. No Nd:YAG laser capsulotomy within prior 2 months.
300 10. Macular edema is not considered to be due to a cause other than diabetic macular edema
301 o An eye should not be considered eligible (1) if the macular edema is considered to be
302 related to cataract extraction or (2) clinical exam and/or OCT suggests that vitreoretinal
303 interface disease (eg. vitreo-retinal traction or epriretinal membrane) is the primary
304 cause of the macular edema.
305 11. Media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus photos.
306 12. No ocular condition (other than diabetes) that, in the opinion of the investigator, might affect
307 macular edema or alter visual acuity during the first 12 months of the study (e.g., vein
308 occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass
309 Syndrome).
310 o Glaucoma per se is not an exclusion.
311
312 A patient may have two “study eyes” only if both are eligible at the time of randomization. An eye
313 that becomes eligible after randomization will not be considered a study eye for purposes of data
314 analyses or treatment decisions although information is being gathered on all eyes)
315
316 2.3 Screening Evaluation and Baseline Testing
317 2.3.1 Historical Information
318 A history will be elicited from the patient and extracted from available medical records. Data to be
319 collected will include: age, gender, ethnicity and race, diabetes history and current management,
320 other medical conditions, medications being used, and ocular diseases, surgeries, and treatment.
321
322

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323 2.3.2 Examination Procedures
324 The following procedures are needed to assess eligibility and/or to serve as a baseline measures for
325 the study.
326
327 If a procedure has been performed (using the study technique) as part of usual care, it does not need
328 to be repeated specifically for the study if it was performed within the defined time windows
329 specified below. The testing procedures are detailed in the DRCR.net Procedures Manual. Visual
330 acuity testing, fundus photography, fluorescein angiography, OCT, and ocular exam will be
331 performed by certified personnel.
332
333 1. ETDRS protocol refraction and visual acuity testing in both eyes (must be done on day of
334 randomization)
335 Acuity testing will be performed using the electronic ETDRS testing procedure. If not
336 available, standard ETDRS charts at 4 meters (plus 1 meter testing for low vision) will
337 be used.
338 2. OCT of both eyes (done within 21 days of randomization).
339 Must be performed using the same OCT machine version used at baseline (eg. OCT1 or
340 OCT2 or OCT3 used throughout the study for a particular patient)
341 3. Ocular examination including dilated ophthalmoscopy in both eyes (done within 21 days of
342 randomization).
343 4. ETDRS protocol 7-standard field stereoscopic fundus photography (fields 1M, 2, 3M, 4, 5, 6, 7)
344 in both eyes (done within 21 days of randomization).
345 5. ETDRS fluorescein angiography (study eye first, then fellow eye) (done within 21 days of
346 randomization)
347 For patients with two study eyes, please refer to the Procedures Manual for sequence
348 instructions.
349 6. Measurement of blood pressure (done within 21 days of randomization)
350 Measured in sitting position after patient has been sitting for at least 5 minutes
351 The fundus photographs, OCT, and fluorescein angiogram will be sent to the Fundus Photograph
352 Reading Center for grading, but patient eligibility is determined by the site (i.e., patients deemed
353 eligible by the investigator will be randomized without need for Reading Center approval).
354 In most cases, assessment of eligibility will require at least two visits. For this reason, maximum
355 time windows from the completion of each procedure above to the day of randomization have been
356 established.
Maximum Time from
Procedure Completion to Randomization
ETDRS Visual Acuity Testing 0 days*
Ophthalmic Exam 21 days
OCT 21 days
ETDRS Fundus Photographs 21 days
ETDRS Fluorescein Angiography 21 days
357
358 * must be done on day of randomization
359

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360 2.3.3 Laboratory Tests
361 1. HbA1c, BUN, creatinine
362 2. Lipids (fasting LDL and triglycerides)
363 3. Microalbumin
364 HbA1c, BUN, creatinine, and microalbumin testing does not need to be repeated if available in the
365 prior 3 months and lipid testing does not need to be repeated if available in the last 6 months.
366
367 If all of the required laboratory test results are not available at the time of randomization, the patient
368 may be enrolled, but the tests will be obtained within 3 weeks after randomization.
369
370 Whenever possible, the HbA1c will be measured using the DCCT method at a laboratory that is
371 certified for the national glycohemoglobin standardization program.
372
373 2.4 Enrollment/Randomization of Eligible Patients
374 1. The Coordinating Center will construct separate master randomization lists for patients with one
375 study eye and for patients with two study eyes
376 For patients with one study eye, the randomization will be stratified according to the
377 presence/absence of unthickened subfields on OCT. Among patients with at least one
378 unthickened subfield (expected to be a majority), the randomization also will be
379 stratified by site.
380 For patients with two study eyes (both eligible at time of enrollment), one eye at random
381 will be selected to receive one treatment technique and the other eye will receive the
382 other treatment technique.
383 2. Prior to randomization, the patient’s understanding of the trial, willingness to accept either
384 treatment assignment, and commitment to the follow-up schedule should be reconfirmed. The
385 patient must then sign the enrollment line on the informed consent document.
386 3. The photocoagulation treatment must commence on the day of randomization; therefore, a
387 patient should not be randomized until the investigator and patient are ready to begin the laser
388 treatment.
389 4. If there is an equipment failure or other reason why the laser cannot be given on the day of
390 randomization, treatment should be given as soon as possible.
391 ETDRS refraction and acuity testing will need to be repeated on the day the laser
392 treatment begins.
393 OCT, fundus photography, and fluorescein angiography will only need to be repeated if
394 the maximum time limits in section 2.4.2 are exceeded.
395
396 2.5 Baseline Photocoagulation
397 Each study eye is randomly assigned to receive either (a) modified-ETDRS photocoagulation or (b)
398 mild macular grid photocoagulation.
399 The initial treatment session for laser photocoagulation may be performed over single or multiple
400 sittings, as long the entire treatment session is completed within 6 weeks of beginning the treatment
401 session. Subsequent retreatment should then be deferred until at least the 3.5 month visit.
402 Chapter 5 describes the photocoagulation treatment techniques.
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403
404 2.6 Post-photocoagulation Photographs
405 During phase 1, a Field 2 stereo pair will be taken following photocoagulation in all patients.
406 Post-treatment photos will be taken at the end of each sitting.

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407 CHAPTER 3
408 FOLLOW-UP VISIT SCHEDULE AND PROCEDURES
409
410 3.1 Follow-up Visit Schedule
411 Below is the visit schedule and time windows for each phase of the study. A visit is not considered
412 missed until the next visit window opens. All attempts should be made to complete a visit even
413 after the visit window closes.
414
415 Phase 1 (0-12 Months)
416 15 weeks (3.5 months) + 14 days
417 34 weeks (8 months) + 28 days
418 52 weeks (12 months) + 28 days
419
420 Phase 2 (13-36 Months)
421 2 years + 8 weeks
422 3 years + 8 weeks
423
424 3.2 Follow-up Visit Testing and Procedures
425 The following procedures are performed at each protocol visit unless otherwise specified. The
426 procedures are detailed in the DRCR.net Procedures Manual. Visual acuity testing, fundus
427 photography, fluorescein angiography, OCT, and ocular exam will be performed by certified
428 personnel. A table in chapter 1 (section 1.6) summarizes the procedures to be performed at each
429 visit.
430
431 1. ETDRS protocol refraction and visual acuity testing in both eyes.
432 Acuity testing will always be performed by a certified, masked tester
433 If a masked tester is unavailable, testing may be done by an unmasked tester (this will be
434 considered a protocol deviation).
435 2. OCT in both eyes.
436 Must be performed using the same OCT machine version used at baseline (eg. OCT1
437 or OCT2 or OCT3 used throughout the study for a particular patient)
438 3. Ocular examination including dilated ophthalmoscopy in both eyes.
439 4. Stereoscopic fundus photography in both eyes.
440 ETDRS 3-fields (1M, 2, 3M) at the 3.5-month and 8-month visits
441 ETDRS 7-fields (1M, 2, 3M, 4, 5, 6, 7) at 12, 24, and 36 month visit
442 ETDRS field 2 following any DME photocoagulation session
443 5. Measurement of blood pressure (12, 24, and 36 month visits only).
444 Measured in sitting position after patient has been sitting for at least 5 minutes
445 6. HbA1c (12 24, and 36 month visits only).
446 If a HbA1c test result is available from the prior 3 months, it does not need to be
447 repeated at this visit.
448 7. ETDRS fluorescein angiography (12-month visit only, if not medically contraindicated).
449

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450 The fundus photographs, fluorescein angiograms, and OCT will be sent to the Fundus Photograph
451 Reading Center for grading.
452 3. Assessment of Need for Additional Photocoagulation for DME
453 At each visit the investigator will assess whether persistent, recurrent, or new DME is present that
454 warrants additional photocoagulation.
455
456 The criteria for determining whether retreatment is indicated are described in section 5.1.1. Section
457 5.1.1 also provides the retreatment protocol.
458
459 3.4 Non-protocol Visits
460 Additional visits can be performed at any time based on the perceived need for such visits by the
461 study investigator. A data form will be submitted for each non-protocol visit.
462
463

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464 CHAPTER 4
465 MISCELLANEOUS CONSIDERATIONS IN FOLLOW UP
466
467 4.1 Non-protocol Treatment for DME
468 During Phase 1 (prior to the 12 month visit), the patient should receive no treatment in the study eye
469 for DME other than the protocol-defined laser treatment.
470
471 During Phase 2 (after the 12 month visit), non-photocoagulation therapies for DME may be given at
472 the discretion of the investigator. This includes treatment that might be received as part of another
473 research study (see section 4.6). Any additional laser photocoagulation of the study eye will follow
474 the retreatement protocol described in chapter 5.
475
476 4.2 Panretinal Photocoagulation
477 PRP can be given at any time if it is indicated in the judgment of the investigator. As part of the
478 eligibility criteria, at the time of enrollment patients are not expected to need PRP within 4 months.
479 In general, PRP should not be given if the patient has less than severe NPDR. In general, PRP
480 should be given promptly for previously untreated eyes exhibiting PDR with high-risk
481 characteristics.
482
483 4.3 Diabetes Management
484 Diabetes management is left to the patient’s medical care provider.
485
486 4.4 Patient Withdrawal and Losses to Follow up
487 A patient has the right to withdraw from the study at any time. If a patient is considering
488 withdrawal from the study, the principal investigator should personally speak to the patient about
489 the reasons and every effort should be made to accommodate the patient.
490
491 The goal for the study is to have as few losses to follow up as possible. The Coordinating Center
492 will assist in the tracking of patients who cannot be contacted by the site. The Coordinating Center
493 will be responsible for classifying a patient as lost to follow up.
494
495 4.5 Discontinuation of Study
496 The study may be discontinued by the Steering Committee (with approval of the Data and Safety
497 Monitoring Committee) prior to the preplanned completion of three-year follow up for all patients.
498
499 4.6 Participation in Other Studies Prior to the End of Three-year Follow Up
500 The Steering Committee may decide (with concurrence of the Data and Safety Monitoring
501 Committee) to permit patients to participate in a new DRCR.net or other study during Phase 2 of
502 this study. If the patient enters another research study, data will still be collected during Phase 2 of
503 this current study.
504
505 4.7 Contact Information Provided to the Coordinating Center
506 The Coordinating Center will be provided with contact information for each subject. Permission to
507 obtain such information will be included in the Informed Consent Form. The contact information
508 will be maintained in a secure database and will be maintained separately from the study data.
509
510 Phone contact from the Coordinating Center will be made with each patient in the first month after
511 enrollment. Additional phone contacts from the Coordinating Center will be made if necessary to
512 facilitate the scheduling of the patient for follow-up visits. A patient newsletter will be sent at least
513 twice a year. A study logo item may be sent once a year.
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514
515 4.8 Patient Reimbursement
516 The study will be paying $25 per completed visit for the randomization visit and follow up visits at
517 3.5, 8, 12, 24 and 36 months (6 visits = maximum payment of $150) to cover travel and other visit-
518 related expenses. Payment will not be made for missed visits. Payment will be made following each
519 visit from the Coordinating Center.
520

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521 CHAPTER 5
522 PHOTOCOAGULATION TREATMENT
523
524 5.1 DME Laser Treatment Techniques
525 As the initial laser treatment in the study eye, each patient is randomly assigned to receive either (a)
526 modified-ETDRS focal/grid photocoagulation or (b) mild macular grid photocoagulation.
527
528

Burn Characteristic Focal / Grid Photocoagulation Mild Macular Grid

(modified-ETDRS technique) Photocoagulation Technique
Focal Treatment Focally treat all leaking MAs in areas of retinal thickening Not applicable
between 500 and 3000 microns from the center of the
macula (but not within 500 microns of disk)
Change in MA Not required, but at least a mild gray-white burn Not applicable
Color with Focal should be evident beneath all MAs
Treatment
Burn Size for Focal 50 microns Not applicable
Treatment
Burn Duration for 0.05 to 0.1 sec Not applicable
Focal Treatment
Grid Treatment Applied to all areas with diffuse leakage or nonperfusion Applied to entire area described below for treatment
within area described below for treatment (including unthickened retina)
Area Considered 500 to 3000 microns from the center of macula 500 to3000 microns superiorly, nasally and
for Grid Treatment inferiorly from center of macula
500-3500 microns temporally from macular center (or to
posterior edge of PRP temporally if that is less than 3500 500-3500 microns temporally from macular center
microns temporally from macular center) (or to posterior edge of PRP temporally if that is
less than 3500 microns temporally from macular
No burns are placed within 500 microns of disk center)

No burns are placed within 500 microns of the disk

Burn Size for Grid 50 microns 50 microns
Treatment
Burn Duration for 0.05 to 0.1 sec 0.05 to 0.1 sec
Grid Treatment
Burn Intensity for Barely visible (light gray) Barely visible (light gray)
Grid Treatment*

Burn Separation for 2 visible burn widths apart 200-300 total burns evenly distributed
Grid Treatment* over the treatment area outlined above
(approx. 2-3 burn widths apart)
Wavelength Green to yellow wavelengths Green to yellow wavelengths
(Grid and Focal
Treatment)
529
530 * see reference photographs in the Testing Procedures Manual
531 MA = microaneurysm
532
533 NOTES:
534 The investigator may choose any laser wavelength for photocoagulation within the green to yellow
535 spectrum. The wavelength used will be recorded and any retreatment must use the same
536 wavelength.
537

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538 A treatment session can be given in single or multiple sittings at the investigator’s discretion, as
539 long as the entire treatment session is completed within 6 weeks. If treatment is given over more
540 than one sitting, post-treatment photographs (field 2 stereo) will be taken at the end of each sitting.
541
542 5.1.1 Retreatment of DME
543 At each visit the investigator will assess whether persistent, recurrent or new DME is present that
544 warrants additional photocoagulation.
545
546 It is generally expected that retreatment WILL be performed if, in the opinion of the investigator:
547 DME has worsened from last scheduled visit.
548 DME has recurred since last scheduled visit.
549 New DME has arisen since last scheduled visit.
550 Thickening at or within 500 microns of the macular center is present, unless there has
551 been substantial improvement in macular edema from last scheduled visit in the opinion
552 of the investigator (ie >50% decrease in total macular thickened area OR >50% decrease
553 in retinal thickening (thickening is not retinal thickness, it is the difference between
554 normal retinal thickness and observed retinal thickness) by OCT in the involved
555 subfields (central or inner).
556 It is generally expected that retreatment WILL NOT be performed if, in the opinion of the
557 investigator:
558 DME has resolved.
559 Center thickening present at the previous scheduled visit has resolved, unless there has
560 been substantial worsening of DME elsewhere (eg >50% increase in total macular
561 thickened area OR >50% increase in retinal thickening by OCT in central or inner
562 subfields with previous thickening.
563
564 Retreatment in Phase 1 of the study should only occur at the 3.5 and 8 month visits.
565
566 For each patient, the same laser wavelength shall be used for all retreatments.
567
568 A retreatment session can be completed in single sitting or multiple sittings at the investigator’s
569 discretion, provided that the entire session is completed within 6 weeks. If retreatment is given over
570 more than one sitting, post-treatment photographs (field 2 stereo) will be taken at the end of each
571 sitting.
572
573 Retreatment of Patients in Modified-ETDRS Treatment Group
574 All retreatment in patients assigned to the modified-ETDRS group, will use the same
575 modified-ETDRS treatment technique.
576
577 Retreatment of Patients Mild Macular Grid Treatment Group
578 The first retreatment in patients assigned to the MMG group will use MMG limited to
579 only the area of retinal thickening.
580 Second and subsequent retreatments in patients assigned to the MMG group will use the
581 modified-ETDRS technique (which allows focal treatment to leaking microaneurysms in
582 the area of retinal thickening).
583 The retreatment approach used will be recorded on a data collection form after each sitting.

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584 5.2 Laser Scatter (Panretinal) Photocoagulation (PRP):
585 PRP can be given if it is indicated in the judgment of the investigator. Patients are not eligible for
586 this study if it is expected that they will need PRP within 4 months. In general, PRP should not be
587 given if the patient has less than severe NPDR. In general, PRP should be given promptly for
588 previously untreated eyes exhibiting PDR with high-risk characteristics and can be considered for
589 persons with PDR less than high-risk and for severe NPDR.
590
591 5.2.1 Burn Characteristics
592
593 Size (on retina) 500 microns
594 Exposure 0.1 seconds recommended, 0.05 to 0.2 allowed
595 Intensity mild white
596 Distribution edges 1 burn width apart
597 No. of Sessions/Sittings unrestricted (generally should be completed in <6)
598 Nasal proximity to disk No closer than 500 microns
599 Temp. proximity to center No closer than 3000 microns
600 Superior/inferior limit No further posterior than 1 burn within the temporal arcades
601 Extent Arcades (~3000 microns from the macular center) to at least
602 the equator
603 Min # of Final Burns: 1200
604 Wavelength Green or yellow

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605 CHAPTER 6
606 ADVERSE EVENTS
607
608 6.1 Events To Be Reported
609 Since the study does not involve an investigational drug or device, adverse event reporting will be
610 limited to those events that are possibly related to study procedures and are unanticipated.
611
612 An Unanticipated Adverse Event is defined as an adverse event caused by or associated with a
613 procedure, if that effect or problem was not previously identified in nature or severity. The
614 following occurrences will require reporting:
615 Macular hemorrhage, foveal burn, choroidal neovascularization, chorioretinal
616 anastomosis and Bruch’s membrane break within 4 weeks of laser photocoagulation and
617 thought to be possibly related to the photocoagulation treatment.
618 A laser malfunction that produces harm to the patient.
619 A deviation from the photocoagulation technique that produces visual loss (will be
620 considered an unanticipated event).
621 A severe reaction from fluorescein angiography resulting in hospitalization or death.
622
623 6.2 Definitions
624 Adverse events meeting the above reporting criteria will be reported with reference to: time and
625 date of event, relationship to the device, severity, and final outcome.
626
627 The relationship of any reportable adverse event will be graded by a study investigator: on as
628 possibly, probably, or definitely related to the study procedure.
629
630 The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3)
631 severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse event is
632 not necessarily serious. For example, itching for several days may be rated as severe, but may not
633 be clinically serious.
634
635 6.3 Reporting Requirements for Adverse Events
636 Any reportable adverse event must be reported to the Coordinating Center within one working day
637 of occurrence. A written report on such an event will be sent to the Coordinating Center within five
638 days of occurrence, stating a description of the reaction, any required intervention, and the outcome.
639 Each principal investigator is responsible for informing his/her IRB of serious study-related adverse
640 events and abiding by any other reporting requirements specific to their IRB. Contact information
641 for the Coordinating Center is located in the front of the protocol as well as in the Study Directory.
642
643 6.4 Data and Safety Monitoring Board
644 An independent Data and Safety Monitoring Committee will approve the protocol prior to its
645 initiation and will be informed of all reportable adverse events as defined in section 6.1
646
647 6.5 Risks And Discomforts
648 6.5.1 Photocoagulation
649 Anesthetic drops may be used as a part of the photocoagulation procedure. Risks include allergic
650 reaction, redness of the eye, and possible initially undetected corneal abrasion if the patient
651 scratches the eye while it is numb. Retrobulbar injection of anesthetic may be used in some cases.
652 Risks associated with this procedure are rare and may include: retrobulbar hemorrhage ; perforation

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653 of the eye by the needle; damage to the optic nerve; double vision lasting up to 24 hours or more;
654 drooping of the eye lid lasting up to 24 hours or more; difficulty speaking or breathing;
655 lightheadedness/syncope/vasovagal response; allergy to any components of the injection; life
656 threatening response due to the spread of anesthesia to the brain stem, resulting in epileptic fits,
657 drowsiness, confusion, loss of verbalization, convulsions, respiratory arrest, or cardiac arrest.
658
659 Serious, but rare complications associated with photocoagulation and which may reduce vision
660 include, but are not limited to: macular hemorrhage, foveal burn, choroidal neovascularization,
661 chorioretinal anastomosis Bruch’s Membrane break, creation of a scotoma , immediate or delayed
662 increase in pressure inside the eye, damage to the optic nerve, damage to the iris, damage to the
663 patient’s lens or an intraocular lens, retinal hole, blindness, or loss of the eye.
664
665 6.5.2 Examination Procedures
666 The procedures in this study are part of daily ophthalmologic practice in the United States and pose
667 no additional known risks. Dilating eye drops will be used as part of each exam.
668
669 6.5.3 Fundus Photography
670 Fundus photography carries no risk. The camera flash may cause temporary discomfort for the
671 patient.
672
673 6.5.4 Fluorescein Angiography
674 A yellow dye will be injected intravenously for this procedure. Risks include, but are not limited to:
675 transient change in skin and urine color; nausea; allergic reaction to the dye; anaphylaxis and
676 possible death (less than 1 in 100,000 people). The procedure will not be performed if medically
677 contraindicated.
678
679 6.5. 5 Optical Coherence Tomography
680 OCT carries no known risk. Dilating eye drops will be used as part of each exam.
681
682

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682 CHAPTER 7
683 STATISTICAL CONSIDERATIONS
684
685 7.1 Sample Size and Power Considerations
686 The sample size for the study has been projected to be a minimum of 200 patients. This is a
687 convenience sample based on a enrollment quota of four patients for most sites (sites with more
688 than 4 investigators have a quota of one patient per investigator) and estimating that there will be
689 approximately 50 participating sites.
690
691 For within-group dichotomous outcomes (e.g., worsening of visual acuity by 3 or more lines,
692 improvement of visual acuity by 3 or more lines, resolution of edema), the table below shows the
693 width of a 2-sided 95% confidence interval for various proportions for a sample size of 100.
694
695
Expected Half-width
Proportion of 2-sided
95% CI
.5 .098
.4 .096
.3 .090
.2 .078
.1 .059
696
697
698 For between group exploratory analyses, with a sample size of 200 and assuming no more than 10%
699 loss to follow up and a 2-sided alpha of 0.05, the study will have 90% power to detect a difference
700 in the change from baseline in central retinal thickness (as measured on OCT) between
701 randomization groups of 50 microns assuming that the common standard deviation for the change
702 from baseline is 100 microns. There are little data on which to estimate the standard deviation.
703 Thus, one of the objectives of the study is to provide data that can be used to estimate sample size
704 for future trials. For between-group dichotomous outcomes based on OCT, the study will have 90%
705 power to detect a relative 50% difference between groups assuming that one group has an outcome
706 rate of 50%.
707
708
709 7.2 Statistical Analysis
710 The analysis plan will be detailed in a separate document and is summarized below.
711
712 The primary outcome for phase 1 is at 12 months. Within each treatment group, point estimates and
713 95% confidence intervals will be computed for the following:
714 Change in the central subfield of the ETDRS grid measured by OCT (in eyes with <250
715 microns mean thickness in the central subfield at baseline, the inner subfield with
716 maximum mean thickness will be used instead).
717 Change in area of retinal thickening or hard exudate (as measured by fundus
718 photography).
719 Change in retinal thickness in areas other than the central subfield.
720 Change in the average diameter of the area of retinal thickening (the square root,
721 expressed in disc diameters, of area expressed in disc areas) at each visit.
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722 Change in area of hard exudate at each visit.
723 Frequency of epiretinal membrane formation as determined by the reading center using
724 fundus photographs and OCT.
725 Proportion of eyes retreated for macular edema at each visit.
726 Change in retinopathy severity level on the ETDRS “eye scale”.
727 Change in visual acuity (mean, worsening by >=3 lines, improving by >=3 lines).
728
729 In exploratory analyses, the treatment groups will be compared using each of these variables. As a
730 general rule, analysis of covariance models will be used for continuous variables and chi-square
731 tests for dichotomous variables. An analysis plan will be constructed to account for the fact that
732 some patients will have one study eye and some patients two study eyes and also for the
733 stratification based on the presence/absence of unthickened retina at baseline.
734
735 For phase 2, the proportion of patients not requiring additional treatment at 12 months in whom
736 DME recurs in each group will be determined and 95% confidence intervals constructed. The
737 proportion in each group will be compared in an exploratory analysis. Patients who are considered
738 to have ‘failed’ laser treatment at 12 months and receive intravitreal steroids will be evaluated with
739 regard to the change in acuity and change in OCT that occurs. Additional analyses will replicate
740 those listed for phase 1. A noted in chapter 1, all phase 2 results will be interpreted with caution.
741
742

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743 References
744
745 1. Early Treatment Diabetic Retinopathy Study (ETDRS). Manual of Operations.Baltimore:
746 ETDRS Coordinating Center University of Maryland,. Baltimore, MD: National Technical
747 Information Center.
748 2. Early Treatment Diabetic Retinopathy Study (ETDRS). Early treatment diabetic retinopathy
749 study design and baseline patient characteristics. ETDRS report 7. Ophthalmology 1991;
750 98:741-756.
751 3. Early Treatment Diabetic Retinopathy Study (ETDRS). Early treatment diabetic retinopathy
752 study group. Grading diabetic retinopathy from stereoscopic color fundus photographs-an
753 extension of the modified Airle House classification. ETDRS report number 10.
754 Ophthalmology 1991; 98:786-806.
755 4. Early Treatment Diabetic Retinopathy Study Group. Classification of diabetic retinopathy
756 from fluorescien angiograms. ETDRS report number 11. Ophthalmology 1991; 98:807-822.
757 5. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic
758 macular edema. ETDRS report number 1. Arch Ophthalmol 1985; 103:1796-1806.
759 6. Hee MR, C W, et al. Quantitative assessment of macular edema with OCT. Arch
760 Ophthalmol 1995; 113:1019-29.
761 7. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and
762 clinical guidelines for photocoagulation of diabetic macular edema: ETDRS report number
763 2. Ophthalmology 1987; 94:761-74.
764 8. Early Treatment Diabetic Retinopathy Study Research Group. Techniques for scatter and
765 local photocoagulation treatment of diabetic retinopathy: ETDRS report no. 3. Int
766 Ophthalmol Clin 1987; 27:254-64.
767 9. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic
768 macular edema: ETDRS report no. 4. Int Ophthalmol Clin 1987; 27:265-72.
769 10. Klein R, Klein BE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of
770 Diabetic Retinopathy, IV: diabetic macular edema. Ophthalmology 1984; 91:1464-1474.
771 11. Diabetes Control and Complication Trial Research Group. The effect of intensive treatment
772 of diabetes on the development and progression of long-term complications in insulin-
773 dependent diabetes mellitus. N Engl J Med 1993; 329:977-986.
774 12. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas
775 or insulin compared with conventional treatment and risk of complications in patients with
776 type 2 diabetes. UKPDS 33. Lancet 1998; 352:837-853.
777 13. The Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and
778 Complications Research Group. Retinopathy and nephropathy in patients with type 1
779 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342:381-389.
780 14. Swart. Histology of macular photocoagulation. Ophthalmology 1986; 93:959-963.
781 15. Gabel VP, Birngurber R, Hillenkamp F. Visible and near infrared light obsorption in
782 pigment epithelium and choroids.
783 16. Schatz, al e. Progressive enlargement of laer scars following grid laser photocoagulation for
784 diffuse diabetic macular edema. Arch Ophthalmol 1991; 109.
785 17. Roider J. Laser treatment of retinal diseases by subthreshold laser effect. Semin
786 Ophthalmolo 1999; 14:19-26.
787 18. Mainster MA, White TJ, Tips JH, et al. Retinal temperature increases produced by intense
788 light sources. J Opt Soc Adm 1970; 60:264-270.
789 19. Akduman L, Olk R.J. Subthreshold (invisible) modified grid diode laser photocagulation in
790 diffuse diabetic macular edema (DDME). Ophthalmic Surg Lasers 1999; 30:706-14.
791 20. Stanga PE, Reck AC, Hamilton AM. Micropluse laser in the treatment of diabetic macular
792 edema. Semin Ophthalmolo 1999; 14:210-3.
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793
794 21. Friberg TR. Subthreshold (invisible) modified grid diode laser photocoagulation and diffuse
795 diabetic macular edema (DDME). Ophthalmic Surg Lasers 1999; 30:705.
796 22. Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic
797 macular edema. Ophthalmology 1986; 93:938-50.
798 23. Chong LP, Soriano D, Ramos AR. Sublethal laser damage to the RPE buy micro-pulse diode
799 laser I primate eye. Invest Ophthalmol 1996; 37:s694.
800 24. Roider J, Michaud N, Flotte T, al e. Response of the RPR to selective photogoagulation.
801 Arch Ophthalmol 1992; 110:1786-1792.
802 25. Olk R.J. Ophthalmology 1990:1101-1113.
803 26. Striph, Hart, Olk R.J. Ophthalmology 1988:1673-1679.
804 27. Lee C, R.J. Olk. Modified grid laser photocagulation for diffused diabetic macular
805 edema:long term visual results. Ophthalmology 1991; 98:1594-1602.
806 28. Ogata N, Tombran-Tink J, Jo N, Matsumara N. Upregulation of pigment epithelium-derived
807 factor after laser photocoagulation. Am J Ophthalmol 2001; 132:427-9.
808 29. Ogata N, Ando A, Uyama M, Matsumara N. Expression of cytokines and transcription
809 factors in photogoagulated human retinal pigment epithelial cells. Graefes Arch Clin Exp
810 Ophthalmol 2001; 239:87-95.
811 30. Shinoda K, Ishida S, Kawashima S, et al. Clinical factors related to the aqueous levels of
812 vasular endothelial growth factor and hepatacyte growth factor in proliferative diabetic
813 retinopathy. Curr Eye Res 2000; 21:655-61.
814 31. Spranger J, Hammes HP, Pressner KT, Schatz H, Pfeiffer AF. Release of the angiogenesis
815 inhibitor angiostatin in patients with proliferative diabetic retinpathy: association with
816 retinal photocoagulation. Diabetologia 2000; 43:1404-7.
817 32. Xiao M, McLeod D, Cranley J, Williams GA, Boulton M. Growth factor staining patters in
818 the pig retina following retinal laser photogoagulation. Br J Ophthalmol 1999; 83:728-36.
819 33. Ferris FLr, Davis MD, Aiello LM. Treatment of diabetic retinopathy. N Engl J Med 1999;
820 26:667-78.
821

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