Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema anti-vascular endothelial growth factor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 702
Healthy volunteers: no

Brief summary:
Although multiple studies have clearly demonstrated that ranibizumab therapy is more effective than laser alone for vision gain and avoiding vision loss in patients with central-involved Diabetic Macular Edema (DME), only eyes with poor visual acuity, such as a visual acuity letter score of 78 or worse (approximate Snellen equivalent of 20/32 or worse) were eligible. Eyes that have central-involved DME with "good" visual acuity (20/25 or better) have not been addressed systematically by recent studies for treatment of DME. Baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study (ETDRS) suggest that a substantial percentage of eyes with central-involved DME may retain good vision. The investigators do not know definitively whether eyes with central-involved DME and good vision do better with anti-VEGF (vascular endothelial growth factor) (e.g. aflibercept) therapy initially, or focal/grid laser treatment or observation initially followed by anti-VEGF only if vision worsens.

The primary objective of the protocol is to compare the % of eyes that have lost at least 5 letters of visual acuity at 2 years compared with baseline mean visual acuity in eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-ETDRS letter score of 79 or better) that receive (1) prompt focal/grid photocoagulation + deferred anti-VEGF, (2) observation + deferred anti-VEGF, or (3) prompt anti-VEGF.

Secondary objectives include:

* Comparing other visual acuity outcomes between treatment groups, such as the percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline mean visual acuity, percent of eyes with at least 5 letter gain in visual acuity from baseline, mean visual acuity, mean change in visual acuity, adjusted for baseline mean visual acuity
* For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-VEGF treatment
* Comparing optical coherence tomography (OCT) outcomes, such as the mean change in OCT central subfield (CSF) thickness, adjusted for baseline mean thickness
* Comparing the number of eyes with PDR at randomization, proportion of eyes avoiding vitreous hemorrhage or panretinal photocoagulation (PRP) or vitrectomy for PDR between treatment groups
* Comparing safety outcomes between treatment groups
* Comparing associated treatment and follow-up exam costs between treatment groups

Detailed description:

Arms:
arm 1: Focal/grid laser followed by intravitreal aflibercept if vision worsens arm 2: No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met) arm 3: Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Interventions: intervention 1: Prompt Laser intervention 2: Prompt aflibercept intervention 3: Deferred laser intervention 4: Deferred aflibercept
Intervention descriptions: intervention 1: Focal/grid laser performed at baseline and as needed during follow-up intervention 2: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria intervention 3: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met intervention 4: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Protocol document:
Prot_000.pdf: 
 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL  
 
 
 
 
 
Diabetic Retinopathy Clinical Research 
Network 
 
 
 
Treatment for Central-Involved 
Diabetic Macular Edema in Eyes 
with Very Good Visual Acuity 
 
NCT01909791 
 
 
Version 3.0 
 
April 18, 2014 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL  
 
 
 
Contact Information 
 
 
Coordinating Center 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL  33647 
Phone:  813-975-8690 
Fax:  800-816-7601 
 
Director: Adam Glassman, M.S. 
Email:  aglassman@jaeb.org 
 
Network Chair 
Lee M. Jampol, M.D. 
Department of Ophthalmology 
Northwestern University Medical School 
645 N. Michigan Avenue, #440 
Chicago, IL 60611 
Phone: 312-908-8152 
Fax: 312-503-8152 
l-jampol@northwestern.edu 
 
 
Protocol Chair 
Carl W. Baker, M.D. 
Paducah Retinal Center  
1900 Broadway, Suite 2  
Paducah, KY 42001  
Phone: 270-443-4393 
eyedude3@paducaheyes.com 
 
 
 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL  
 
 
 
Table of Contents 
1 
 
2 
Chapter 1. Background Information and Study Synopsis ..................................................... 1-1 
3 
1.1. 
Rationale ...................................................................................................................... 1-1 
4 
1.1.1 Public Health Impact of DME .................................................................................... 1-1 
5 
1.1.2 Rationale for Anti-VEGF Treatment for DME ........................................................... 1-1 
6 
1.1.3 Evolution of Standard Therapy for DME ................................................................... 1-1 
7 
1.1.4 Eyes with Central-Involved DME and Good Vision .................................................. 1-3 
8 
1.1.5 Rationale for Comparing Prompt Focal/Grid Photocoagulation + Deferred Anti-
9 
VEGF, Observation + Deferred Anti-VEGF, and Prompt Anti-VEGF for DME ............... 1-4 
10 
1.1.6 Aflibercept .................................................................................................................. 1-6 
11 
1.1.7 Summary of Rationale for the Study .......................................................................... 1-7 
12 
1.2 Study Objective ................................................................................................................ 1-7 
13 
1.3 Study Design and Synopsis of Protocol ........................................................................... 1-7 
14 
1.4 General Considerations .................................................................................................. 1-11 
15 
Chapter 2. Initial Screening and Observational Phase .......................................................... 2-1 
16 
2.1 Screening for Observational Phase or Randomized Trial ................................................ 2-1 
17 
2.2 Observational Phase Enrollment ...................................................................................... 2-2 
18 
2.2.1 Eligibility and Informed Consent................................................................................ 2-2 
19 
2.3 Observational Phase Follow-Up and Testing .................................................................. 2-3 
20 
2.3.1 Visit Schedule ............................................................................................................. 2-3 
21 
2.3.2Testing Procedures ....................................................................................................... 2-4 
22 
2.4 Discontinuation of Observational Phase .......................................................................... 2-4 
23 
2.5 Contact Information Provided to the Coordinating Center .............................................. 2-4 
24 
2.6 Study Participant Reimbursement .................................................................................... 2-4 
25 
2.7 Observational Phase Statistical Methods ......................................................................... 2-4 
26 
Chapter 3. Randomized Trial Eligibility and Enrollment ..................................................... 3-6 
27 
3.1 Identifying Eligible Study Participants and Obtaining Informed Consent ........................ 3-6 
28 
3.2 Study Participant Eligibility Criteria ................................................................................. 3-6 
29 
3.2.1 Participant-level Criteria ............................................................................................. 3-6 
30 
3.2.2 Study Eye Criteria ....................................................................................................... 3-7 
31 
3.2.3 Non-Study Eye Criteria ............................................................................................... 3-9 
32 
3.3 Screening Evaluation and Baseline Testing ....................................................................... 3-9 
33 
3.3.1 Historical Information ................................................................................................. 3-9 
34 
3.3.2 Baseline Testing Procedures ..................................................................................... 3-10 
35 
3.4 Enrollment/Randomization of Eligible Study Participants .............................................. 3-11 
36 
Chapter 4. Treatment Regimens ............................................................................................ 4-12 
37 
4.1 Introduction ...................................................................................................................... 4-12 
38 
4.1.1 Prompt Focal/Grid Photocoagulation + Deferred Anti-VEGF Group ...................... 4-12 
39 
4.1.2 Observation + Deferred Anti-VEGF Group ............................................................. 4-12 
40 
4.1.3 Prompt Anti-VEGF Group ........................................................................................ 4-12 
41 
4.2 Focal/Grid Photocoagulation Procedure .......................................................................... 4-12 
42 
4.3 Intravitreal Aflibercept Injection (Eylea®) ....................................................................... 4-13 
43 
4.4 Intravitreal Injection Technique ....................................................................................... 4-13 
44 
4.5 Delay in Giving Injections ............................................................................................... 4-14 
45 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL  
 
 
 
4.6 Deferral of Injections Due to Pregnancy ......................................................................... 4-14 
46 
4.7 Non-Study Eye Injections ................................................................................................ 4-14 
47 
Chapter 5. Follow-up Visits and Treatment .......................................................................... 5-15 
48 
5.1 Visit Schedule .................................................................................................................. 5-15 
49 
5.2 Testing Procedures ........................................................................................................... 5-16 
50 
5.3 Treatment During Follow Up ........................................................................................... 5-17 
51 
5.3.1 Initiation of Intravitreal Anti-VEGF in the Deferred Groups ................................... 5-17 
52 
5.3.2 Intravitreal Injection Retreatment ............................................................................. 5-17 
53 
5.3.3 Initiation of Focal/Grid Photocoagulation While Receiving Anti-VEGF Injections 5-18 
54 
5.3.4 Focal/Grid Photocoagulation Retreatment ................................................................ 5-18 
55 
Chapter 6. Miscellaneous Considerations in Follow-up ......................................................... 6-1 
56 
6.1 Endophthalmitis ................................................................................................................. 6-1 
57 
6.2 Surgery for Vitreous Hemorrhage and Other Complications of Diabetic Retinopathy ..... 6-1 
58 
6.3 Panretinal (Scatter) Photocoagulation (PRP) ..................................................................... 6-1 
59 
6.4 Use of Intravitreal Anti-VEGF for Conditions Other than DME in the Study Eye ........... 6-1 
60 
6.5 Treatment of Macular Edema in Non-study Eye ............................................................... 6-1 
61 
6.6 Diabetes Management ........................................................................................................ 6-1 
62 
6.7 Study Participant Withdrawal and Losses to Follow-up .................................................... 6-1 
63 
6.8 Discontinuation of Study ................................................................................................... 6-2 
64 
6.9 Contact Information Provided to the Coordinating Center ................................................ 6-2 
65 
6.10 Study Participant Reimbursement .................................................................................... 6-2 
66 
Chapter 7. Adverse Events ........................................................................................................ 7-1 
67 
7.1 Definition ........................................................................................................................... 7-1 
68 
7.2 Recording of Adverse Events ............................................................................................ 7-1 
69 
7.3 Reporting Serious or Unexpected Adverse Events ............................................................ 7-2 
70 
7.4 Data and Safety Monitoring Committee Review of Adverse Events ................................ 7-2 
71 
7.5 Risks ................................................................................................................................... 7-2 
72 
7.5.1 Potential Adverse Effects of Anti-VEGF Drug .......................................................... 7-2 
73 
7.5.2 Potential Adverse Effects of Intravitreal Injection ..................................................... 7-3 
74 
7.5.3 Risks of Laser Photocoagulation Treatment ............................................................... 7-4 
75 
7.5.4 Risks of Eye Examination and Tests .......................................................................... 7-4 
76 
Chapter 8. Statistical Methods .................................................................................................. 8-1 
77 
8.1   Sample size ...................................................................................................................... 8-1 
78 
8.1.1 Prompt Intravitreal Anti-VEGF Group Projection ..................................................... 8-1 
79 
8.1.2 Deferred Intravitreal Anti-VEGF Groups Projection ................................................. 8-1 
80 
8.1.3 Sample Size and Power Assumptions and Estimates ................................................. 8-2 
81 
8.1.4 Power Estimation for Primary Outcome ..................................................................... 8-2 
82 
8.2 Statistical Analysis Plan ..................................................................................................... 8-3 
83 
8.2.1 Primary Outcome ........................................................................................................ 8-3 
84 
8.2.2  Secondary Outcomes ................................................................................................. 8-4 
85 
8.2.3 Cost Analysis .............................................................................................................. 8-5 
86 
8.2.4 Safety Analysis Plan ................................................................................................... 8-5 
87 
8.2.5 Additional Tabulations and Analyses ......................................................................... 8-5 
88 
8.2.6  Per-protocol Analysis................................................................................................. 8-6 
89 
8.2.7 Interim Monitoring Plan ............................................................................................. 8-6 
90 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL  
 
 
 
References ................................................................................................................................... 9-1 
91 
92 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-1 
 
                                                                                                                           
93 
Chapter 1.                                                                                          
94 
BACKGROUND INFORMATION AND STUDY SYNOPSIS 
95 
 
96 
1.1. Rationale 
97 
1.1.1 Public Health Impact of DME  
98 
The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 
99 
recent history.1 Estimates suggest that by the year 2030, approximately 439 million individuals 
100 
worldwide will be affected by this chronic disease.2 The increasing global epidemic of diabetes 
101 
implies an increase in rates of associated vascular complications from this chronic disease, which 
102 
includes diabetic retinopathy.  Despite advances in diagnosis and management of ocular disease 
103 
in diabetic patients, eye complications from diabetes mellitus continue to be the leading cause of 
104 
vision loss and new onset blindness in working-age individuals throughout the United States.3   
105 
 
106 
Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of 
107 
central vision. In a review of three early studies concerning the natural history of DME, Ferris 
108 
and Patz found that 53% of 135 eyes with DME, presumably all involving the center of the 
109 
macula, lost two or more lines of visual acuity over a two year period.4 Furthermore, without 
110 
intervention, 33% of 221 eyes included in the Early Treatment Diabetic Retinopathy Study 
111 
(ETDRS) with center-involved DME experienced “moderate visual loss” (defined as a 15 or 
112 
more letter score decrease in visual acuity) over a three year period.5   
113 
 
114 
1.1.2 Rationale for Anti-VEGF Treatment for DME 
115 
Diabetic macular edema results from abnormal leakage of fluid and macromolecules, such as 
116 
lipoproteins, from retinal capillaries into the extravascular space.  This is followed by an influx 
117 
of water into the extravascular space due to increased oncotic pressure.6  The retinal pigment 
118 
epithelium normally acts as a barrier to fluid flow from the choriocapillaris to the retina and also 
119 
actively pumps fluid out of the retina.  Thus, abnormalities in the retinal pigment epithelium may 
120 
contribute to DME by allowing increased fluid access from the choriocapillaries or decreasing 
121 
the normal efflux of fluid from the retina.6  The mechanism of breakdown of the blood retina 
122 
barrier at the level of the retinal capillaries and the retinal pigment epithelium may be mediated 
123 
by changes in tight junction proteins such as occludin.7   
124 
 
125 
Vascular endothelial growth factor (VEGF), a 45 kD homodimeric glycoprotein, potently 
126 
increases retinal capillary permeability and subsequent retinal edema in part by inducing 
127 
breakdown of the blood retina barrier.8  Thus, agents that inhibit VEGF may reduce vascular 
128 
permeability due to diabetes and thereby decrease retinal thickening. 
129 
 
130 
1.1.3 Evolution of Standard Therapy for DME 
131 
For 25 years, focal/grid photocoagulation was the mainstay of treatment for DME.  In the 
132 
ETDRS, focal/grid photocoagulation of eyes with DME reduced the risk of moderate visual loss 
133 
by approximately 50% (from 24% to 12%) three years after initiation of treatment.9  The 
134 
Diabetic Retinopathy Clinical Research Network (DRCR.net)  adopted a modified ETDRS 
135 
focal/grid photocoagulation protocol from the original ETDRS approach as the standard laser 
136 
technique for DME used in all DRCR.net studies.  The  DRCR.net trial, “A Randomized Trial 
137 
Comparing Intravitreal Triamcinolone Acetonide and Focal/grid Photocoagulation for DME”, 
138 
showed that efficacy over 2 years of use with the DRCR.net focal/grid photocoagulation 
139 
technique was comparable to results in similar eyes in the ETDRS, and that intravitreal 
140 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-2 
 
triamcinolone as monotherapy was not superior to use with the focal/grid photocoagulation 
141 
technique for central-involved DME in eyes with some visual acuity loss.10,11 
142 
 
143 
Results from a recent DRCR.net study, “Intravitreal Ranibizumab or Triamcinolone Acetonide in 
144 
Combination with Laser Photocoagulation for Diabetic Macular Edema” (DRCR.net Protocol I), 
145 
indicated that treatment for DME with intravitreal anti-VEGF therapy (0.5 mg ranibizumab) plus 
146 
deferred (>24 weeks) or prompt focal/grid photocoagulation provides visual acuity outcomes at 
147 
one year and two years that are superior to prompt focal/grid photocoagulation alone or 
148 
intravitreal triamcinolone with prompt focal/grid photocoagulation.12 DRCR.net Protocol I 
149 
provided definitive confirmation of the important role of VEGF in DME and the role of anti-
150 
VEGF drugs in the treatment of DME. The study enrolled 854 eyes of 691 study participants 
151 
with DME involving the fovea and with visual acuity (approximate Snellen equivalent) of 20/32 
152 
to 20/320. Eyes were randomly assigned to sham injection + prompt focal/grid photocoagulation 
153 
(N = 293), 0.5-mg ranibizumab + prompt laser (within 3 to10 days, N = 187), and 0.5-mg 
154 
ranibizumab + deferred laser (deferred for at least 24 weeks, N = 188). Treatment with 
155 
ranibizumab was generally continued on a monthly basis unless the participant’s vision stabilized 
156 
or reached 20/20, or the retinal swelling resolved.  Treatment could be stopped if failure criteria 
157 
were met (persistent swelling with poor vision), but this occurred in very few participants (less 
158 
than 5% in any group).  The mean change (+ standard deviation) in visual acuity letter score at 
159 
one year from baseline was significantly greater in the ranibizumab+prompt laser group (+9 ± 
160 
11) and the ranibizumab+deferred laser group (+9 ± 12) as compared with the control laser group 
161 
(+3 ± 13, P < 0.001 for both comparisons) or triamcinolone+prompt laser group (+4 ± 13, P < 
162 
0.001 for both comparisons). The one-year optical coherence tomography (OCT) results 
163 
paralleled the visual acuity results in the ranibizumab and control laser groups. No apparent 
164 
increases in treatment-related systemic events were observed.   
165 
 
166 
DRCR.net Protocol I results provided confirmation of the promising role of ranibizumab therapy 
167 
suggested by phase 2 trials,13, 14 and have been further supported by findings from additional 
168 
phase 3 trials, including RISE, RIDE and RESTORE.15, 16  Participants in RISE and RIDE were 
169 
randomly assigned to 0.5 or 0.3 mg ranibizumab every 4 weeks for at least 2 years versus sham 
170 
injections as treatment for center-involved DME causing vision impairment, with macular laser 
171 
available to all treatment arms starting 3 months after randomization.  The percentage of 
172 
individuals gaining > 15 letters from baseline at 24 months was significantly higher in the 
173 
ranibizumab groups in both studies (RISE:  sham[18.1%], 0.3mg ranibizumab [44.8%], 0.5mg 
174 
ranibizumab [39.2%]; RIDE sham [12.3%], 0.3mg ranibizumab [33.6%], 0.5mg ranibizumab 
175 
[45.7%]).15  In RESTORE, both ranibizumab (0.5 mg) monotherapy and combination 
176 
ranibizumab + laser treatment resulted in better visual acuity outcomes than laser alone at one 
177 
year in patients with center-involved DME causing vision impairment.16  The percentage of 
178 
participants who gained >15 letters from baseline at month 12 were 22.6%, 22.9% and 8.2% in 
179 
the ranibizumab alone, ranibizumab + laser and laser alone groups, respectively.  In general, 
180 
ranibizumab therapy was well-tolerated in these studies although the overall rate of Antiplatelet 
181 
Trialists’ Collaboration events was slightly higher in the 0.3 mg (5.6%) and 0.5 mg (7.2%) 
182 
groups as compared with the sham group (5.2%) in the pooled data from the RISE and RIDE 
183 
studies.17  Deaths were also more frequent in the ranibizumab groups (0.8% and 1.6% of sham 
184 
and 2.4 to 4.8% of ranibizumab treated patients) in these trials.15  The rate of non-fatal 
185 
cerebrovascular events in this pooled analysis was higher in the 0.5 mg group (2%) than in the 
186 
sham (1.2%) or 0.3 mg group (0.8%) but the rate of non-fatal myocardial infarctions was similar 
187 
across treatment groups (2.8%, 2.8% and 2.4% in the sham, 0.3 mg and 0.5 mg groups, 
188 
respectively).  
189 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-3 
 
 
190 
1.1.4 Eyes with Central-Involved DME and Good Vision 
191 
Although the studies described above have clearly demonstrated that ranibizumab therapy is 
192 
more effective than laser alone for vision gain and avoiding vision loss in patients with central-
193 
involved DME, only eyes with a visual acuity letter score of 78 or worse (approximate Snellen 
194 
equivalent of 20/32 or worse) were eligible for DRCR.net Protocol I; similarly designed studies 
195 
of anti-VEGF treatment for DME had the same or lower visual acuity eligibility criteria.15, 16  
196 
Eyes that have central-involved DME with “good” visual acuity (20/25 or better) have not been 
197 
addressed systematically by recent studies for treatment of DME. 
198 
 
199 
Baseline cohort characteristics from the ETDRS suggest that a substantial percentage of eyes 
200 
with central-involved DME may retain good vision.  At baseline in the ETDRS, of all eyes in the 
201 
focal laser and observation group, center involved macular edema on fundus photographs was 
202 
present in approximately 42% of eyes.  Of these eyes, 64% had baseline visual acuity ≥ 79 letters 
203 
(approximately 20/25 or better).  In the subsequent era of OCT-guided determination of central-
204 
involved DME, the DRCR.net randomized trial comparing focal/grid photocoagulation to mild 
205 
macular grid photocoagulation for DME also revealed only a modest correlation between OCT 
206 
central subfield (CSF) thickness and concurrent visual acuity (r=0.52).18 
207 
 
208 
Several questions remain regarding treatment of the cohort of eyes with central-involved DME 
209 
and good visual acuity. Since recent trials for DME treatment have focused enrollment on eyes 
210 
with visual impairment, we do not know definitively whether eyes with central-involved DME 
211 
and good vision do better with anti-VEGF therapy initially, or focal/grid laser treatment or 
212 
observation initially followed by anti-VEGF only if vision worsens. Results from DRCR.net 
213 
Protocol I suggests that anti-VEGF therapy will be effective at reducing retinal thickening, but it 
214 
is unclear whether this will translate into a benefit in visual acuity outcomes that outweighs the 
215 
risks attendant upon multiple intravitreal injections, including endophthalmitis or the 
216 
inconvenience and cost of treatments given as frequently as once a month.  It is also unknown 
217 
how long eyes with central-involved DME and good vision maintain vision of > 20/25 without 
218 
intervention.  
219 
 
220 
Some information regarding the natural history of eyes with center-involved DME (as assessed 
221 
by grading of fundus photographs) and good vision could be obtained from the control group of 
222 
the ETDRS.  However, there was no OCT data collected for this study.  The advent of OCT now 
223 
allows us to determine the presence of and monitor changes in central-involved DME with 
224 
increased sensitivity over the fundus photographic grading method used in the ETDRS.  The 
225 
optimal timing for initiating treatment in this group is uncertain.  The American Academy of 
226 
Ophthalmology’s Preferred Practice Pattern for diabetic retinopathy recommends considering 
227 
focal/grid photocoagulation treatment as soon as DME meets clinically significant criteria.19 
228 
However, many patients may be reluctant to initiate invasive anti-VEGF therapy or laser 
229 
treatment with potential associated side effects when they are visually asymptomatic or have 
230 
good vision.  Given the potentially large numbers of patients with central-involved DME and 
231 
good vision, and the current lack of guidance regarding best treatment practice for this group of 
232 
eyes, an answer to the questions of 1) whether eyes with central-involved DME and good visual 
233 
acuity that receive prompt treatment have better outcomes than eyes in which treatment is 
234 
deferred and 2) whether prompt treatment with focal/grid photocoagulation or intravitreal anti-
235 
VEGF is superior, might substantially impact clinical practice and management of DME for 
236 
many patients with diabetes. 
237 
 
238 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-4 
 
1.1.5 Rationale for Comparing Prompt Focal/Grid Photocoagulation + Deferred Anti-
239 
VEGF, Observation + Deferred Anti-VEGF, and Prompt Anti-VEGF for DME 
240 
Overview of Rationale:  
241 
From a subset of eyes in the ETDRS (unpublished data) that had center-involved DME (as 
242 
assessed on fundus photographs) and visual acuity 20/25 or better, data are available on the 
243 
course of vision loss in this cohort in the setting of laser or observation alone.  The figure below 
244 
(Figure 1) shows the percentage of eyes in this cohort that lost 5 or more letters, which 
245 
investigators consider a clinically relevant vision loss in eyes starting with very good vision.  
246 
Approximately 28% and 41% of eyes in the laser and observation groups, respectively, would 
247 
ultimately have a visual acuity decrease by 2 years that would likely necessitate intervention with 
248 
intravitreal anti-VEGF, the now established treatment for eyes with center-involved DME and 
249 
decreased vision.  On the other hand, by 2 years 72% to 59% of eyes in the laser and observation 
250 
groups, respectively, maintained good vision, indicating that many eyes with DME and good vision 
251 
likely will do very well for at least 2 years without intravitreal injections.  The proposed study will 
252 
evaluate whether it is better to promptly initiate anti-VEGF in eyes with center-involved DME and 
253 
good vision or if it is better start with either laser treatment or observation and defer anti-VEGF 
254 
treatment until vision has worsened.   
255 
 
256 
Figure 1.  Percent of Eyes in ETDRS with CI-DME and VA ≥ 20/25 at the Baseline Visit that 
257 
lost 5 or more letters 
258 
 
259 
 
260 
 
261 
 
262 
This study has three proposed treatment arms: prompt focal/grid photocoagulation + deferred 
263 
intravitreal anti-VEGF (Group A), observation + deferred intravitreal anti-VEGF (Group B), and 
264 
prompt intravitreal anti-VEGF (Group C). The rationale for each of these arms is as follows: 
265 
 
266 
18%
22%
25%
27%
28%
28%
30%
36%
38%
23%
31%
32%
38%
39%
41%
46%
47%
49%
0
10
20
30
40
50
60
Percent
Visit
Focal/Grid Laser
Observation Only
N = 231
N = 110
N = 237
N = 113
N = 246
N = 118


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-5 
 
Group A (prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF):  Even though 
267 
eyes with central-involved DME and baseline visual impairment do not do as well overall when 
268 
treated with laser alone as compared with ranibizumab in DRCR.net Protocol I, a substantial 
269 
proportion of eyes with good baseline vision treated with laser alone demonstrate improved 
270 
vision and decreased retinal thickening.  Of the subset of eyes in the ETDRS with center-
271 
involved DME (as assessed on fundus photographs) that started with baseline visual acuity of 
272 
20/25 or better and were treated with focal laser (N = 113), 81% still had vision of 20/25 or 
273 
better and 76% had no center-involved DME on fundus photographs at 2 years of follow-up, 
274 
compared with 64% with 20/25 or better vision and 49% with no center-involved DME of 
275 
similar eyes in the observation group (N= 224).  At 3 years of 110 eyes in the laser group, 70% 
276 
still had vision of 20/25 or better and 76% had no center-involved DME.  In DRCR.net Protocol 
277 
I, 27% percent of all eyes and 30% of eyes with baseline vision of 20/32 that received sham + 
278 
focal/grid laser achieved resolution of macular edema, with Stratus CSF thickness < 250 µm and 
279 
a 25 µm decrease in thickness from baseline by the 1 year visit.12  Thus, many eyes with central-
280 
involved DME treated with laser may never need anti-VEGF therapy in order to have successful 
281 
visual or anatomic outcomes.  The initial use of focal/grid photocoagulation could offer 
282 
substantial advantages over starting treatment with anti-VEGF in terms of reducing adverse 
283 
events associated with intravitreal injections as well as fewer treatments given over time with 
284 
less frequent follow-up needed and decreased associated costs. As alluded to above, in the 
285 
ETDRS there was a low rate of vision loss in eyes with baseline visual acuity of 20/25 or better 
286 
treated with laser; 25% of this group lost 5 or more letters, and only 11% lost 10 or more letters 
287 
of vision at 1 year, with 28% and 13% of eyes loosing 5 and 10 letters at 2 years, respectively.  
288 
Even if a small group of eyes with central-involved DME treated with laser do not do as well as 
289 
those treated promptly with anti-VEGF therapy initially, if visual outcomes become equivalent 
290 
between these groups after rescue therapy with anti-VEGF treatment, clinicians and patients 
291 
would likely still elect to begin with laser treatment and defer anti-VEGF treatment until a lack 
292 
of response to laser treatment is clearly demonstrated.    
293 
 
294 
Group B (observation + deferred intravitreal anti-VEGF):  Although it has been demonstrated 
295 
that ranibizumab + prompt or deferred laser is well-tolerated and effective in increasing vision 
296 
gain and decreasing vision loss in patients with central-involved DME, the optimal timing for 
297 
initiating anti-VEGF treatment in eyes with central-involved DME is uncertain.  There was no 
298 
significant difference in treatment effect between eyes that were and were not treatment naïve at 
299 
baseline in DRCR.net Protocol I, suggesting that eyes that are not initially treated with anti-
300 
VEGF can benefit from anti-VEGF treatment if they continue to experience visual impairment 
301 
from DME.  On the other hand, three year data from the RISE and RIDE trials suggest that a 2 
302 
year delay in treatment with anti-VEGF in eyes with baseline visual impairment and central-
303 
involved DME may result in worse visual acuity outcomes than those obtained with prompt anti-
304 
VEGF treatment.20  It is unclear whether a shorter delay in treatment with rescue anti-VEGF 
305 
therapy, if vision dropped, would result in visual outcomes more similar to those obtained with 
306 
prompt anti-VEGF treatment.  If this were the case, and visual outcomes were shown to be 
307 
similar in eyes with prompt anti-VEGF as compared with eyes with initial deferral of therapy 
308 
and rescue treatment with anti-VEGF, patients who are asymptomatic with good vision might 
309 
prefer to defer treatment until there is evidence for worsening.  Of the subset of eyes in the 
310 
ETDRS with center-involved DME (as assessed on fundus photographs) that started with 
311 
baseline visual acuity of 20/25 or better and were observed (N = 237), 32% of this group lost 5 or 
312 
more letters of vision at 1 year, with 41% loosing 5 or more letters at 2 years.  Therefore, based 
313 
on this ETDRS, many eyes will do quite well for at least 2 years without laser or anti-VEGF 
314 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-6 
 
therapy.  Thus, deferring all treatment until there are signs of visual acuity worsening is a 
315 
rational approach to avoid treatment that would not be needed. 
316 
 
317 
Group C (prompt intravitreal anti-VEGF):  As reviewed above, there is a preponderance of 
318 
evidence that demonstrates that ranibizumab treatment is effective in reducing retinal thickening 
319 
in eyes with central-involved DME and vision of 20/32 or worse.  Given a similar underlying 
320 
pathophysiology it would seem highly likely that ranibizumab will be similarly effective at 
321 
improving retinal thickening in eyes with central-involved DME and vision that is better than 
322 
20/25. Furthermore, prompt anti-VEGF therapy may be considered superior to prompt focal/grid 
323 
photocoagulation + deferred intravitreal anti-VEGF therapy for some patients if any vision loss 
324 
associated with focal/grid photocoagulation cannot be recovered once anti-VEGF is initiated.  In 
325 
addition, the initiation of prompt intravitreal anti-VEGF therapy may reduce the total number of 
326 
injections needed long-term compared with initiation of intravitreal anti-VEGF once vision loss 
327 
has occurred.     
328 
 
329 
1.1.6 Aflibercept 
330 
The anti-VEGF drug to be used in this trial is intravitreal aflibercept injection, also known as 
331 
VEGF-Trap-Eye or Aflibercept (Eylea®), which is a soluble decoy receptor fusion protein that 
332 
has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.  This 
333 
drug was first reported as a possible treatment for DME in 2009 in a phase one study that 
334 
enrolled five study participants with center-involved DME.21  After a single injection of 4.0 mg 
335 
VEGF-Trap-Eye, five out of five eyes demonstrated reduction in retinal thickening at four weeks 
336 
that was maintained in 4/5 eyes up to six weeks. There was a median improvement in visual 
337 
acuity of nine and three letters at four and six weeks, respectively.  No ocular toxicity was seen 
338 
over the six week observation period.  Results from a larger, phase two trial have been 
339 
subsequently published.22  In this study, 221 participants with center-involved DME were 
340 
randomized to one of five groups: macular laser therapy, 0.5 mg aflibercept every four weeks, 2 
341 
mg aflibercept every four weeks, 2 mg aflibercept every four weeks times 3 doses followed by 
342 
every 8-week dosing, or 2 mg aflibercept every four weeks times three doses followed by as 
343 
needed dosing. Eyes that received aflibercept had greater mean improvement in visual acuity 
344 
from baseline at week 24 as compared with eyes that received macular laser (8.5 to11.4 letter 
345 
score increase versus a 2.5 letter score increase).  The visual gains in the aflibercept arms as 
346 
compared with the macular laser arm were sustained through 52 weeks.23  Over 1 year, rates of 
347 
ocular adverse events were similar to those reported in other trials involving intravitreal 
348 
injections.  Two cases of endophthalmitis and one case of uveitis occurred (all in aflibercept 
349 
treatment groups).  Seven deaths (4.0%) occurred in the groups randomized to VEGF-Trap-Eye 
350 
treatment as compared with 1 (2.3%) in the group treated with laser.  Myocardial infarction or 
351 
cerebrovascular accident occurred in 6 (3.4%) participants treated with aflibercept as compared 
352 
with 1 (2.3%) participant treated with laser alone.  Percentages of study participants that 
353 
experienced events meeting Antiplatelet Trialists’ Collaboration (APTC) Criteria were 5.1% (N 
354 
= 9) in the combined aflibercept groups and 4.5% (2) in the laser group.24 
355 
 
356 
Aflibercept received approval in November 2011 by the United States Food and Drug 
357 
Administration for the treatment of neovascular age-related macular degeneration  at a 
358 
recommended dose of 2 mg every 4 weeks for the first 12 weeks, followed by 2 mg every 8 
359 
weeks thereafter or monthly dosing.25  This approval was based on results from two Phase three 
360 
clinical trials (VIEW 1 and VIEW 2) that assigned participants with neovascular age-related 
361 
macular degeneration one of four dosing regimens:  ranibizumab 0.5 mg every four weeks, 
362 
aflibercept 2 mg every four weeks, aflibercept 0.5 mg every four weeks, and aflibercept 2 mg 
363 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-7 
 
given every eight weeks following three initial monthly doses.26  All three regimens of 
364 
aflibercept were demonstrated as non-inferior to monthly ranibizumab in terms of the proportion 
365 
of subjects who lost fewer than a 15 letter score from baseline. All aflibercept treatment groups 
366 
gained vision from baseline to one year, with mean gains ranging from 7.6 to 10.9 letter score 
367 
across the two studies. Serious ocular adverse events, including endophthalmitis, occurred at 
368 
rates <0.1% per injection in both studies and there did not appear to be a dose or drug-related 
369 
increase in APTC events in either study.  In 2012, Aflibercept was additionally approved by the 
370 
United States Food and Drug Administration for treatment for macular edema due to central 
371 
retinal vein occlusion. The COPERNICUS and GALILEO studies demonstrated that eyes with 
372 
macular edema secondary to central retinal vein occlusion had better visual outcomes at 6 
373 
months and 1 year when treated with at least 6 initial monthly injections of aflibercept as 
374 
compared with sham.27-29  Common ocular adverse events in the COPERNICUS trial were 
375 
conjunctival hemorrhage and eye pain.  APTC events through week 52 occurred in 0.9% (1) of 
376 
the aflibercept-treated eyes and 2.7% (2) of the eyes treated initially with sham and then with 
377 
aflibercept as needed after 6 months.24 
378 
 
379 
1.1.7 Summary of Rationale for the Study 
380 
DRCR.net Protocol I and other studies have demonstrated that ranibizumab therapy is well-
381 
tolerated and more effective than laser alone in increasing vision gain and decreasing vision loss 
382 
for the duration of at least 2 years in patients with central-involved DME causing vision loss.  
383 
However, the optimal treatment has not been established in eyes that maintain good vision 
384 
despite the presence of central-involved DME.  This proposed study will compare prompt 
385 
intravitreal anti-VEGF therapy, prompt focal/grid photocoagulation with deferred intravitreal 
386 
anti-VEGF, and observation with deferred intravitreal anti-VEGF treatment in eyes with central-
387 
involved DME with good vision to help address this question.  Initiating prompt anti-VEGF may 
388 
result in superior visual acuity outcomes and/or reduce the long term number of injections 
389 
needed to maintain good vision.  On the other hand, if prompt anti-VEGF does not result in 
390 
better visual acuity outcomes as compared with deferring anti-VEGF, either in the setting of 
391 
prompt laser or observation, deferring anti-VEGF treatment might decrease rates of adverse 
392 
events associated with intravitreal injections such as endophthalmitis.  Deferral of prompt anti-
393 
VEGF treatment might also result in decreased inconvenience and costs associated with 
394 
potentially monthly anti-VEGF treatments, while possibly preserving visual acuity in eyes with 
395 
central-involved DME.   
396 
 
397 
1.2 Study Objective 
398 
To compare the safety and efficacy of prompt focal/grid photocoagulation + deferred intravitreal 
399 
anti-VEGF, observation + deferred intravitreal anti-VEGF, and prompt intravitreal anti-VEGF in 
400 
eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 
401 
or better (electronic-ETDRS letter score of 79 or better). 
402 
 
403 
1.3 Study Design and Synopsis of Protocol 
404 
 
405 
A. Study Design 
406 
 
407 
 Randomized, controlled, phase III multi-center clinical trial. 
408 
 
409 
B. Major Eligibility Criteria 
410 
 
411 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-8 
 
a. Age >=18 years 
412 
b. Type 1 or type 2 diabetes 
413 
c. Ophthalmoscopic evidence of center-involved DME in study eye confirmed on OCT at 
414 
two consecutive visits within 1 to 28 days; defined by OCT CSF thickness on one of the 
415 
following spectral domain OCT machines: 
416 
 OCT CSF thickness at the screening visit: 
417 
 Zeiss Cirrus: ≥ 290µ in women, and ≥ 305µ in men 
418 
 Heidelberg Spectralis: ≥ 305µ in women, and ≥ 320µ in men 
419 
 OCT CSF thickness at the randomization visit: 
420 
 Zeiss Cirrus: ≥ 275µ in women, and ≥ 290µ in men 
421 
 Heidelberg Spectralis: ≥ 290µ in women, and ≥ 305µ in men 
422 
d. Best corrected visual acuity letter score in study eye ≥ 79 (approximate Snellen 
423 
equivalent 20/25 or better) at two consecutive visits within 1 to 28 days 
424 
e. No history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME in 
425 
the study eye within the prior 12 months. 
426 
 If treatment for DME was given more than 12 months prior: 
427 
o no more than 1 prior focal/grid macular photocoagulation session, AND 
428 
o no more than 4 prior intraocular injections, AND 
429 
o in the investigator’s judgment, the eye may possibly benefit from all of the 
430 
possible study treatments.  
431 
 Enrollment will be limited to a maximum of 50% of the planned sample size with any 
432 
history of prior treatment for DME. Once this number of eyes has been enrolled, any 
433 
history of prior treatment for DME will be an exclusion criterion   
434 
 
435 
C. Observational Phase 
436 
Potential study participants who are not willing or able to participate in the randomized trial may 
437 
be enrolled into an observational phase and subsequently reconsidered for randomization.  The 
438 
objective of the observational phase is to collect additional data on the natural history of the 
439 
cohort.  
440 
 
441 
D. Randomization Phase 
442 
 
443 
1. 
Treatment Groups 
444 
Eligible and willing study participants (one eye per participant) will be assigned randomly 
445 
(1:1:1) to one of the three following groups: 
446 
 
447 
a. Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF 
448 
b. Observation + deferred intravitreal anti-VEGF  
449 
c. Prompt intravitreal anti-VEGF  
450 
For eyes in the deferred intravitreal anti-VEGF groups (either observation or focal/grid 
451 
photocoagulation), intravitreal anti-VEGF will be provided if visual acuity decreases by at least 
452 
10 letters from baseline visual acuity (defined as the mean of the screening and randomization 
453 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-9 
 
visual acuity) at one study visit or 5 to 9 letters from the baseline visual acuity at two consecutive 
454 
study visits, with vision loss presumed to be due to DME. Further details on the treatment 
455 
schedule and criteria for retreatment are described in section 5.3.   
456 
 
457 
The anti-VEGF drug provided will be Eylea® (intravitreal aflibercept injection), which is made 
458 
by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular 
459 
age-related macular degeneration and macular edema due to central retinal vein occlusion. 
460 
 
461 
2. 
Sample Size 
462 
 A minimum of 702 eyes (one per study participant) 
463 
 
464 
3. 
Duration of Follow-up 
465 
 Primary endpoint will be at 2 years  
466 
 
467 
4. 
Follow-up Schedule 
468 
 Treatment Visits: 
469 
 Prompt anti-VEGF group: visits every 4 weeks during first 24 weeks, visits every 4 to 
470 
16 weeks thereafter depending on treatment administered. 
471 
 Deferred anti-VEGF groups (prompt focal/grid photocoagulation and observation 
472 
groups): visits at week 8 and 16, followed by visits every 16 weeks thereafter.* 
473 
 
474 
*For the deferred groups, the follow-up visit interval will be decreased if macular edema is 
475 
worsening on OCT or visual acuity drops 5 to 9 letters, to assess for continued vision loss 
476 
needing anti-VEGF treatment.  Once anti-VEGF is initiated, visits will be every 4 weeks during 
477 
the first 24 weeks of treatment and every 4 to 16 weeks thereafter.  Further details on the follow-
478 
up visit schedule are described in section 5.1. 
479 
 
480 
 Outcome Visits: 
481 
 All participants will have visits at 1 and 2 years for outcome assessment. 
482 
 
483 
5. 
Main Efficacy Outcomes 
484 
Primary:     
485 
 Percent of eyes that have lost at least 5 letters of visual acuity at 2 years compared with 
486 
baseline visual acuity (mean of the two visual acuity letter scores within 1 to 28 days 
487 
required for eligibility).  
488 
 
489 
Secondary:  
490 
 
491 
At 1 and 2 years: 
492 
 
493 
 Percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline 
494 
visual acuity 
495 
 Percent of eyes with at least 5 letter gain in visual acuity from baseline visual acuity 
496 
 Mean change in visual acuity, adjusted for baseline visual acuity 
497 
 Mean change in OCT CSF thickness, adjusted for baseline mean thickness (mean of 
498 
the two OCT central subfield thickness measurements within 1 to 28 days required 
499 
for eligibility) 
500 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-10 
 
 Percent of eyes with at least a 1 and 2 log step increase or decrease on OCT CSF 
501 
thickness 
502 
 Percent of eyes with OCT CSF thickness less than the gender-specific spectral 
503 
domain equivalent of 250 µm on Zeiss Stratus and at least a 10% OCT CSF thickness 
504 
decrease 
505 
 Number of injections and/or focal/grid photocoagulation sessions performed 
506 
 Number of scheduled and unscheduled visits  
507 
 Mean change in low-contrast visual acuity on Electronic Visual Acuity Tester 
508 
 Total cost of follow-up and treatment 
509 
 For eyes randomly assigned to deferred anti-VEGF, the percentage of eyes needing 
510 
anti-VEGF treatment. 
511 
 
512 
6. 
Main Safety Outcomes 
513 
Injection-related: endophthalmitis, retinal detachment, retinal tears, cataract, intraocular 
514 
hemorrhage, increased intraocular pressure. 
515 
Ocular drug-related: inflammation, cataract, cataract surgery, increased intraocular pressure, 
516 
glaucoma medications, glaucoma surgery, new or worsening traction retinal detachment. 
517 
Systemic drug-related: hypertension, cardiovascular events, cerebrovascular events. 
518 
 
519 
 
520 
7. 
Schedule of Study Visits and Examination Procedures 
521 
 
522 
 
Screening* 
0 
Visits Every 
4-16w** 
52w 
104w  
Visit Window 
 
 
(± 1-4w) 
(± 2w) 
(± 4w) 
E-ETDRS best corrected visual 
acuity a 
X 
X 
X 
X 
X 
Low-contrast acuity on EVAb 
 
X 
 
X 
X 
OCT c 
X 
X 
X 
X 
X 
Eye Examd 
 
X 
X 
X 
X 
7-field Fundus Photography c  
 
X 
 
X 
X 
Fluorescein Angiography g   
 
X 
 
 
 
Blood pressure 
 
X 
 
 
 
HbA1c e 
 
X 
Xf 
X 
X 
*= a screening visit is required within 1 to 28 days of randomization in order to confirm the OCT and visual acuity eligibility 
523 
criteria at two consecutive visits.  If the participant is not willing or able to be randomized, they will have the option to enter the 
524 
observational phase at this time if certain criteria are met.   
525 
**= visits every 4 weeks during the first 24 weeks for eyes assigned to prompt anti-VEGF treatment or eyes in the deferred 
526 
groups that have had intravitreal anti-VEGF treatment initiated for DME.  After 24 weeks from initial anti-VEGF treatment for 
527 
DME, visits every 4 to16 weeks based on treatment administered.  For eyes assigned to deferred anti-VEGF, 2 subsequent 8-
528 
week visits after randomization, followed by every 16-week visits until there is worsening or anti-VEGF treatment is initiated.  
529 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  1-11 
 
a= both eyes at each visit; including protocol refraction in the study eye at each visit and in the non-study eye at annual visits. E-
530 
ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester that has been validated against 4-meter 
531 
chart ETDRS testing. 
532 
b= at sites with electronic visual acuity (EVA) low-contrast acuity testing capabilities 
533 
c= study eye only 
534 
d= both eyes at randomization and study eye only at each follow-up visit unless treatment is given in the non-study eye, at which 
535 
point an ocular exam also will be performed on the non-study eye for safety assessment.  Includes slit lamp exam (including 
536 
assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy. 
537 
e= must be performed using the same lab (or DCA Vantage Analyzer) at baseline and follow-up 
538 
f= at 16 weeks (± 4 weeks) only 
539 
 
540 
g = only obtained by a subset of investigators where the investigator routinely performs FA prior to focal/grid laser treatment or 
541 
is willing to do so for the study and agrees to use the FA to guide the focal/grid laser treatment.  FA will also be obtained prior to 
542 
focal/grid laser re-treatment in the laser group on eyes where an FA was obtained at baseline.   
543 
 
544 
1.4 General Considerations 
545 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
546 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
547 
the protocol described herein, and with the standards of Good Clinical Practice. 
548 
 
549 
The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 
550 
Procedures Manual, Photography Testing Procedures Manual, Fluorescein Angiography Testing 
551 
Procedure Manual, and Study Procedures Manual) provide details of the examination procedures 
552 
and intravitreal injection procedure.   
553 
 
554 
Visual acuity testers and OCT technicians will be masked to treatment group at the annual visits.  
555 
Investigators and study participants are not masked to treatment group. 
556 
   
557 
Data will be directly collected in electronic case report forms, which will be considered the 
558 
source data. 
559 
 
560 
There is no restriction on the number of study participants to be enrolled by a site. 
561 
 
562 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  2-1 
 
Chapter 2. INITIAL SCREENING AND OBSERVATIONAL PHASE 
563 
 
564 
2.1 Screening for Observational Phase or Randomized Trial 
565 
Potentially eligible participants will be screened and if eligible, given the option to complete the 
566 
randomization visit.  Patients who are currently not willing or able to be randomized in the main 
567 
trial but meet the criteria below in Section 2.2.1 will be followed as part of an observational 
568 
phase and will be subsequently reconsidered for randomization.  Enrollment into the 
569 
observational phase may continue for the duration of the recruitment period of the main trial.  
570 
However, if the cost of additional participant enrollment into the observational phase is 
571 
prohibitive, a decision will be made whether to continue or stop enrollment into the 
572 
observational phase even if recruitment is ongoing for the trial.    
573 
 
574 
The following flow chart depicts the process for determining whether a participant will enter the 
575 
randomized trial or the observational phase and the subsequent follow-up.        
576 
 
577 
 
578 
 
579 
 
580 
 
581 
 
582 
 
 
583 
Ready/Eligible  
to 
Randomize?
Eligible 
Yes 
Observe? 
No (Treat 
outside study)  
Yes 
Schedule Randomization 
Visit in 1-28 days 
Eligible 
Randomize 
Ineligible 
Follow-up as part of 
Observational Phase  
End of 
Follow-Up? 
No 
Yes 
No (Observe)  
Ready/Eligible 
to Randomize? 
Completed 
Yes 
No 
No (Treat 
outside study)  
Screening Visit 
(OCT/VA) 
Exit Study 
Ineligible for 
observational phase   
Eligible for observational 
phase 
 
2 Year Follow-up 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  2-2 
 
 
584 
2.2 Observational Phase Enrollment  
585 
2.2.1 Eligibility and Informed Consent 
586 
Potential eligibility for the observational phase will be assessed as part of a routine-care 
587 
examination.  Prior to completing any procedures or collecting any data that are not part of usual 
588 
care, written informed consent will be obtained.  A separate consent will be used for 
589 
randomization into the main trial if/when applicable. 
590 
   
591 
Participant-level Criteria 
592 
To be eligible, all of the following inclusion criteria and none of the following exclusion criteria 
593 
must be met: 
594 
 
595 
Inclusions 
596 
1. Age ≥18 years. 
597 
2. Diagnosis of diabetes mellitus (type 1 or type 2). 
598 
3. At least one eye meets the study eye criteria listed below. 
599 
4. Able and willing to provide informed consent. 
600 
5. Not able or willing to be randomized at this time. 
601 
Exclusions 
602 
6. History of chronic renal failure requiring dialysis or kidney transplant. 
603 
7. A condition that, in the opinion of the investigator, would preclude participation in the study 
604 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
605 
control).  
606 
8. Known allergy to any component of the study drug.  
607 
9. Pregnant or intending to become pregnant within the next 2 years. 
608 
10. Individual is expecting to move out of the area of the clinical center to an area not covered by 
609 
another clinical center during the next 2 years. 
610 
 
611 
Study Eye Criteria 
612 
The study participant must have at least one eye meeting all of the inclusion criteria and none of 
613 
the exclusion criteria below.  A study participant can have two study eyes only if both are 
614 
eligible at the time of enrollment.  If one eye will be randomized into the main trial and the 
615 
fellow eye meets criteria below, it may be simultaneously enrolled into the observational phase.    
616 
 
617 
Inclusions 
618 
 
619 
a. Best corrected visual acuity letter score in study eye ≥ 79 (approximate Snellen equivalent 
620 
20/25 or better). 
621 
b. On clinical exam, definite retinal thickening due to DME involving the center of the macula. 
622 
c. DME confirmed on OCT, defined as CSF thickness on one of the following spectral domain 
623 
OCT machines: 
624 
 Zeiss Cirrus: ≥ 290µ in women, and ≥ 305µ in men 
625 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  2-3 
 
 Heidelberg Spectralis: ≥ 305µ in women, and ≥ 320µ in men 
626 
d. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT. 
627 
 
628 
e. The investigator intends to observe at this time (no immediate DME treatment is planned). 
629 
 
630 
Exclusions 
631 
f. Macular edema is considered to be due to a cause other than DME.  
632 
 An eye should not be considered eligible if: (1) the macular edema is considered to be 
633 
related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT 
634 
suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or 
635 
epiretinal membrane) are contributing to the macular edema. 
636 
g. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME 
637 
(such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or 
638 
anti-VEGF) within the prior 12 months. 
639 
 If treatment for DME was given more than 12 months prior: 
640 
o no more than 1 prior focal/grid macular photocoagulation session AND 
641 
o no more than 4 prior intraocular injections 
642 
h. History of intravitreal anti-VEGF for an ocular condition other than DME (e.g. choroidal 
643 
neovascularization, central retinal vein occlusion, PDR) within the prior 6 months or 
644 
anticipated need in the next 6 months. 
645 
i. Any history of vitrectomy. 
646 
j. Aphakia. 
647 
 
648 
2.3 Observational Phase Follow-Up and Testing 
649 
The study eye(s) will be followed in the observational phase until one of the following occurs: 
650 
1. The eye is randomized. 
651 
2. The eye receives non-topical DME treatment as part of usual care. 
652 
3. The participant reaches two years (104 weeks) from enrollment. 
653 
 
654 
2.3.1 Visit Schedule 
655 
The schedule of protocol-specified observational phase visits is as follows: 
656 
 17 weeks (± 4 weeks) 
657 
 34 weeks (± 4 weeks) 
658 
 52 weeks (± 4 weeks) 
659 
 69 weeks (± 4 weeks) 
660 
 86 weeks (± 4 weeks) 
661 
 104 weeks (± 4 weeks) 
662 
 
663 
If the investigator chooses to see the participant more frequently as part of usual care or the 
664 
participant experiences visual acuity loss requiring earlier follow-up, limited data will be 
665 
collected at those visits. 
666 
 
667 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  2-4 
 
2.3.2Testing Procedures 
668 
A history will be elicited from the subject and extracted from available medical records at 
669 
enrollment.  Data to be collected may include:  age, gender, ethnicity and race, diabetes history 
670 
and current management, other medical conditions, as well as ocular diseases, surgeries, and 
671 
treatment. 
672 
 
673 
The following procedures will be performed at each protocol visit unless otherwise specified.  
674 
 
675 
1. E- ETDRS visual acuity testing in each eye (best corrected) 
676 
 A protocol refraction in the study eye(s) is required at all protocol visits.     
677 
2. OCT on the study eye(s)  
678 
3. Ocular exam in the study eye(s), including slit lamp examination, lens assessment, 
679 
measurement of intraocular pressure and dilated ophthalmoscopy 
680 
4. Measurement of blood pressure (enrollment only) 
681 
5. Laboratory Testing- HbA1c (enrollment only) 
682 
 HbA1c does not need to be repeated if available in the prior 3 months.  If not 
683 
available at the time of enrollment, the subject may be enrolled but the test must be 
684 
obtained within 3 weeks after enrollment.  
685 
 
686 
2.4 Discontinuation of Observational Phase 
687 
The observational phase may be discontinued by the Executive Committee prior to the 
688 
preplanned completion of follow-up for all study participants. 
689 
 
690 
2.5 Contact Information Provided to the Coordinating Center 
691 
The Coordinating Center will be provided with contact information for each study participant.  
692 
Permission to obtain such information will be included in the Informed Consent Form.  The 
693 
contact information may be maintained in a secure database and will be maintained separately 
694 
from the study data. 
695 
 
696 
Phone contact from the Coordinating Center will be made if necessary to facilitate the scheduling 
697 
of the study participant for follow-up visits.  A participant-oriented newsletter may be sent twice 
698 
a year.  A study logo item may be sent once a year.  
699 
 
700 
Study participants will be provided with a summary of the study results in a newsletter format 
701 
after completion of the study by all participants.   
702 
 
703 
2.6 Study Participant Reimbursement 
704 
The study will be providing the study participant with a $25 merchandise or money card per 
705 
completed protocol visit.  Additional travel expenses may be paid in cases for participants with 
706 
higher expenses.  
707 
 
708 
2.7 Observational Phase Statistical Methods  
709 
The primary objective of the observational phase is to collect data on the natural history of eyes 
710 
that present with CI-DME and good vision that do not enroll in the randomized trial initially.  
711 
Therefore, the proportion and 95% confidence interval of eyes that meet the following endpoints 
712 
will be determined: 
713 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  2-5 
 
 Never need treatment  
714 
 Receive non-topical DME treatment  
715 
 Are randomized into Protocol V  
716 
 
717 
In addition, data from the observational phase will be used in exploratory analyses to evaluate 
718 
the following: 
719 
 If there are any subgroups for which there appears to be a higher percentage of eyes that 
720 
do not need DME treatment  
721 
 Compare outcome (visual acuity and OCT) data between eyes observed for the duration 
722 
of the observational phase (i.e. never need treatment) and eyes in the randomized 
723 
treatment groups 
724 
 Compare outcome (visual acuity and OCT) data between eyes that are randomized 
725 
immediately and eyes that are randomized after being followed in the observational phase 
726 
initially 
727 
 
728 
Additional details on the statistical approaches will be included in a detailed statistical analysis 
729 
plan.   
730 
 
 
731 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-6 
 
 
732 
 
733 
 
734 
Chapter 3.                                                                                          
735 
RANDOMIZED TRIAL ELIGIBILITY AND ENROLLMENT 
736 
 
737 
3.1 Identifying Eligible Study Participants and Obtaining Informed Consent 
738 
A minimum of 702 eyes (one per participant) are expected to be enrolled into the randomized 
739 
trial.  As the enrollment goal approaches, sites will be notified of the end date for recruitment.  
740 
Study participants who have signed an informed consent form can be randomized up until the 
741 
end date, which means the recruitment goal might be exceeded.   
742 
 
743 
Potential eligibility will be assessed as part of a routine-care examination.  Prior to completing 
744 
any procedures or collecting any data that are not part of usual care, written informed consent 
745 
will be obtained.  For patients who are considered potentially eligible for the study based on a 
746 
routine-care exam, the study protocol will be discussed with the potential study participant by a 
747 
study investigator and clinic coordinator.  The potential study participant will be given the 
748 
Informed Consent Form to read.  Potential study participants will be encouraged to discuss the 
749 
study with family members and their personal physician(s) before deciding whether to participate 
750 
in the study.   
751 
 
752 
Consent may be given in two stages (if approved by the IRB).  The initial stage will provide 
753 
consent to complete any of the screening procedures needed to assess eligibility that have not 
754 
already been performed as part of a usual-care exam.  The second stage will be obtained prior to 
755 
randomization and will be for participation in the study.  A single consent form will have two 
756 
signature/date lines for the study participant:  one for a study participant to give consent for the 
757 
completion of the screening procedures and one for the study participant to document consent for 
758 
the randomized trial.  Study participants will be provided with a copy of the signed Informed 
759 
Consent Form. 
760 
 
761 
Once a study participant is randomized, that participant will be counted regardless of whether the 
762 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
763 
individual until he/she is convinced that the individual is eligible and will accept assignment to 
764 
any one of the three treatment groups. 
765 
 
766 
3.2 Study Participant Eligibility Criteria 
767 
 
768 
3.2.1 Participant-level Criteria 
769 
Inclusion 
770 
To be eligible, the following inclusion criteria must be met: 
771 
1. Age >= 18 years  
772 
 Individuals <18 years old are not being included because DME is so rare in this age 
773 
group that the diagnosis of DME may be questionable.  
774 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
775 
 Any one of the following will be considered to be sufficient evidence that diabetes is 
776 
present:  
777 
 Current regular use of insulin for the treatment of diabetes 
778 
 Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
779 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-7 
 
 Documented diabetes by ADA and/or WHO criteria (see Procedures Manual for 
780 
definitions). 
781 
3. At least one eye meets the study eye criteria listed in section 3.2.2. 
782 
4. Fellow eye meets criteria in section 3.2.3. 
783 
5. Able and willing to provide informed consent. 
784 
 
785 
Exclusion 
786 
An individual is not eligible if any of the following exclusion criteria are present:  
787 
6. History of chronic renal failure requiring dialysis or kidney transplant. 
788 
7. A condition that, in the opinion of the investigator, would preclude participation in the study 
789 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
790 
control).  
791 
8. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months 
792 
prior to randomization or plans to do so in the next 4 months. 
793 
9. Participation in an investigational trial within 30 days of randomization that involved 
794 
treatment with any drug that has not received regulatory approval for the indication being 
795 
studied. 
796 
 Note: study participants cannot receive another investigational drug while participating 
797 
in the study. 
798 
10. Known allergy to any component of the study drug.  
799 
11. Blood pressure >180/110 (systolic above 180 OR diastolic above 110). 
800 
 If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual 
801 
can   become eligible.  
802 
12. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. 
803 
 These drugs should not be used during the study. 
804 
13. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 
805 
within the next 24 months. 
806 
 Women who are potential study participants should be questioned about the potential for 
807 
pregnancy.  Investigator judgment is used to determine when a pregnancy test is needed. 
808 
14. Individual is expecting to move out of the area of the clinical center to an area not covered by 
809 
another clinical center during the 24 months of the study. 
810 
 
811 
3.2.2 Study Eye Criteria 
812 
The study participant must have one eye meeting all of the inclusion criteria and none of the 
813 
exclusion criteria listed below.   
814 
 
815 
A study participant can only have one study eye. If both eyes are eligible at the time of 
816 
randomization, the study eye will be selected by the investigator and subject before 
817 
randomization.  The non-study eye should be considered for enrollment into the observational 
818 
phase. 
819 
 
820 
The eligibility criteria for a study eye are as follows: 
821 
 
822 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-8 
 
Inclusion 
823 
a. Best corrected E-ETDRS visual acuity letter score ≥ 79 (approximate Snellen equivalent 
824 
20/25 or better) at two consecutive visits within 1 to 28 days.  
825 
b. On clinical exam, definite retinal thickening due to DME involving the center of the macula. 
826 
c. Diabetic macular edema confirmed on OCT at two consecutive visits within 1 to 28 days 
827 
(screening and randomization); defined by OCT CSF thickness on one of the following 
828 
spectral domain OCT machines: 
829 
Screening Visit:  
830 
 Zeiss Cirrus: ≥ 290µ in women, and ≥ 305µ in men 
831 
 Heidelberg Spectralis: ≥ 305µ in women, and ≥ 320µ in men 
832 
  
833 
Randomization Visit:  
834 
 Zeiss Cirrus: ≥ 275µ in women, and ≥ 290µ in men 
835 
 Heidelberg Spectralis: ≥ 290µ in women, and ≥ 305µ in men 
836 
 
837 
 Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate 
838 
quality.  
839 
d. The investigator is comfortable with the eye being randomly assigned to any of the three 
840 
treatment groups (observation, laser, or anti-VEGF initially).   
841 
 If focal/grid photocoagulation is contraindicated because all leaking microaneurysms 
842 
are too close to the fovea or the investigator believes the DME that is present will not 
843 
benefit from focal/grid photocoagulation, the eye should not be enrolled.   
844 
e. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT and 
845 
fundus photographs. 
846 
 
847 
Exclusions 
848 
The following exclusions apply to the study eye only (i.e., they may be present for the non-study 
849 
eye): 
850 
f. Macular edema is considered to be due to a cause other than DME.  
851 
 An eye should not be considered eligible if: (1) the macular edema is considered to be 
852 
related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT 
853 
suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or 
854 
epiretinal membrane) are contributing to the macular edema. 
855 
g. An ocular condition is present such that, in the opinion of the investigator, any visual acuity 
856 
loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment 
857 
abnormalities, dense subfoveal hard exudates, nonretinal condition).  
858 
h. An ocular condition is present (other than DME) that, in the opinion of the investigator, 
859 
might affect macular edema or alter visual acuity during the course of the study (e.g., vein 
860 
occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).  
861 
i. Cataract is present that, in the opinion of the investigator, may alter visual acuity during the 
862 
course of the study.  
863 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-9 
 
j. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME 
864 
(such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or 
865 
anti-VEGF) within the prior 12 months. 
866 
 If treatment for DME was given more than 12 months prior: 
867 
o no more than 1 prior focal/grid macular photocoagulation session, AND 
868 
o no more than 4 prior intraocular injections, AND 
869 
o in the investigator’s judgment, the eye may possibly benefit from all of the 
870 
possible study treatments.     
871 
 Enrollment will be limited to a maximum of 50% of the planned sample size with any 
872 
history of treatment for DME. Once this number of eyes has been enrolled, any 
873 
history of treatment for DME will be an exclusion criterion.  
874 
k. History of topical steroid or NSAID treatment within 30 days prior to randomization. 
875 
l. History of intravitreal or peribulbar corticosteroid within 4 months prior to randomization for 
876 
an ocular condition other than DME. 
877 
m. History of intravitreal anti-VEGF for an ocular condition other than DME (e.g. choroidal 
878 
neovascularization, central retinal vein occlusion, PDR) within the prior 6 months or 
879 
anticipated need in the 6 months following randomization.   
880 
n. History of PRP within 4 months prior to randomization or anticipated need for PRP in the 6 
881 
months following randomization. 
882 
o. Any history of vitrectomy. 
883 
p. History of major ocular surgery (cataract extraction, scleral buckle, any intraocular surgery, 
884 
etc.) within prior 4 months or anticipated within the next 6 months following randomization.  
885 
q. History of YAG capsulotomy performed within 2 months prior to randomization. 
886 
r. Aphakia. 
887 
s. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant 
888 
blepharitis. 
889 
 
890 
3.2.3 Non-Study Eye Criteria 
891 
If anti-VEGF treatment is indicated for any condition in the non-study eye at any time during the 
892 
study, the investigator must be willing to use the study anti-VEGF drug (2.0 mg aflibercept) for 
893 
the non-study eye.  If the non-study eye is currently being treated with a different anti-VEGF 
894 
drug for any condition, then the investigator and patient must be willing to switch to aflibercept.  
895 
If the investigator or patient is unwilling to change anti-VEGF treatment in the non-study eye, 
896 
the patient should not be enrolled.    
897 
 
898 
3.3 Screening Evaluation and Baseline Testing 
899 
3.3.1 Historical Information 
900 
A history will be elicited from the potential study participant and extracted from available 
901 
medical records.  Data to be collected will include:  age, gender, ethnicity and race, diabetes 
902 
history and current management, other medical conditions, medications being used, as well as 
903 
ocular diseases, surgeries, and treatment. 
904 
 
905 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-10 
 
3.3.2 Baseline Testing Procedures 
906 
The following procedures are needed to assess eligibility and/or to serve as baseline measures for 
907 
the study:   
908 
 If a procedure has been performed (using the study technique and by study certified 
909 
personnel) as part of usual care, it does not need to be repeated specifically for the 
910 
study if it was performed within the defined time windows specified below.  
911 
 The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual 
912 
Acuity-Refraction Testing Procedures Manual, OCT Procedures Manual, 
913 
Photography Testing Procedures Manual, Fluorescein Angiography Testing 
914 
Procedure Manual, and Study Procedures Manual).  Visual acuity testing, ocular 
915 
exam, fundus photography, and OCT will be performed by DRCR.net certified 
916 
personnel.  
917 
 The fundus photographs and fluorescein angiograms will be sent to the Fundus 
918 
Photograph Reading Center for grading. 
919 
 OCTs meeting DRCR.net criteria for manual grading will be sent to a reading center, 
920 
but study participant eligibility is determined by the site (i.e., individuals deemed 
921 
eligible by the investigator will be randomized without pre-randomization reading 
922 
center confirmation). 
923 
 
924 
1. E-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
925 
(including protocol refraction) in each eye (at screening visit and on day of randomization). 
926 
 This testing procedure has been validated against 4-meter ETDRS chart testing.30 
927 
 A best-corrected E-ETDRS visual acuity (using protocol refraction) must be 
928 
performed at two consecutive visits (screening and randomization), 1 to 28 days 
929 
apart, to confirm eligibility.   
930 
2. Low-contrast visual acuity in the study eye using the Electronic Visual Acuity Tester; if site 
931 
has the capability (on day of randomization). 
932 
3. OCT on study eye (at screening and on day of randomization). 
933 
 OCT must be performed at two consecutive visits (screening and randomization), 1 to 
934 
28 days apart, to confirm eligibility.   
935 
4. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, 
936 
lens assessment, and dilated ophthalmoscopy (on day of randomization). 
937 
5. ETDRS protocol 7 modified-field or 4 wide-field digital stereoscopic fundus photography in 
938 
the study eye (within 28 days prior to randomization). 
939 
6. Digital fluorescein angiogram (FA) in the study eye (within 28 days prior randomization) at 
940 
select sites 
941 
a. Only obtained by a subset of investigators where the investigator routinely performs 
942 
FA prior to focal/grid laser treatment or is willing to do so for the study and agrees to 
943 
use the FA to guide the focal/grid laser treatment.     
944 
7. Measurement of blood pressure. 
945 
8. Laboratory Testing- HbA1c. 
946 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  3-11 
 
  If not available at the time of randomization, the individual may be enrolled but the 
947 
test must be obtained within 3 weeks after randomization.  The same lab (or DCA 
948 
Vantage Analyzer) must be used at baseline and follow-up. 
949 
 
950 
3.4 Enrollment/Randomization of Eligible Study Participants  
951 
1. Prior to randomization, the study participant’s understanding of the trial, willingness to 
952 
accept the assigned treatment group, and commitment to the follow-up schedule should be 
953 
reconfirmed.   
954 
2. The baseline treatment (if randomly assigned to prompt focal/grid photocoagulation or 
955 
prompt intravitreal anti-VEGF) must be given on the day of randomization; therefore, a study 
956 
participant should not be randomized until this is possible.    
957 
3. Randomization is completed on the DRCR.net website.   
958 
 Study participants will be randomly assigned (stratified by site and recent or planned 
959 
DME treatment* in the non-study eye) with equal probability to receive either:  
960 
 
961 
o Prompt focal/grid photocoagulation +  deferred intravitreal anti-VEGF  
962 
o Observation +  deferred intravitreal anti-VEGF  
963 
o Prompt intravitreal anti-VEGF  
964 
*Randomization will be stratified by recent (within 4 months) or planned DME treatment 
965 
because of the more frequent visit schedule required as part of usual care for these participants.  
966 
More frequent visits in the deferred groups than required by protocol could result in earlier 
967 
initiation of anti-VEGF in such participants.   
 
968 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  4-12 
 
 
969 
Chapter 4.                                                                                              
970 
TREATMENT REGIMENS 
971 
 
972 
4.1 Introduction 
973 
Each eye is assigned to one of the three treatment groups 
974 
 
975 
The treatment groups are as follows: 
976 
a. Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF 
977 
b. Observation + deferred intravitreal anti-VEGF  
978 
c. Prompt intravitreal anti-VEGF  
979 
Treatment procedures are described below.  The timing and criteria for retreatment are detailed 
980 
in chapter 5.   
981 
 
982 
4.1.1 Prompt Focal/Grid Photocoagulation + Deferred Anti-VEGF Group 
983 
Focal/grid photocoagulation is administered on the day of randomization for eyes assigned to 
984 
prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF.  The timing and criteria 
985 
for retreatment with focal/grid photocoagulation and initiation of anti-VEGF treatment are 
986 
detailed in chapter 5. 
987 
 
988 
4.1.2 Observation + Deferred Anti-VEGF Group  
989 
Treatment is not administered at baseline in eyes assigned to observation + deferred intravitreal 
990 
anti-VEGF.  Timing and criteria for initiation of anti-VEGF treatment are detailed in chapter 4. 
991 
 
992 
4.1.3 Prompt Anti-VEGF Group  
993 
Intravitreal 2.0 mg aflibercept is administered on the day of randomization in eyes assigned to 
994 
the prompt anti-VEGF group.  The timing and criteria for retreatment are detailed in chapter 4.   
995 
 
996 
4.2 Focal/Grid Photocoagulation Procedure 
997 
For study eyes that receive focal/grid photocoagulation, the laser treatment ‘session’ should 
998 
generally be completed in a single ‘sitting’.  The photocoagulation treatment technique, as 
999 
described below, is a modification of the ETDRS technique and is the treatment approach that is 
1000 
commonly used in clinical practice.  Use of fluorescein angiography to direct the treatment is at 
1001 
the discretion of the investigator.   
1002 
 
1003 
Burn Characteristic 
Focal/Grid Photocoagulation (non-PASCAL guidelines)* 
(DRCR.net focal/grid laser technique) 
Direct Treatment 
Directly treat all microaneurysms (MA) in areas of retinal thickening 
between 500 and 3000 µm from the center of the macula (although may 
treat between 300 and 500 µm of macula if central-involved edema persists 
after initial focal photocoagulation, but generally not if the visual acuity is 
better than 20/40).  If a fluorescein is obtained, the FA should be used to 
identify the MAs in the areas defined above.     
Change in MA Color 
with Direct Treatment 
Not required, but at least a mild gray-white burn should be evident beneath 
all microaneurysms 
Spot Size for Direct 
Treatment 
50 µm 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  4-13 
 
Burn Duration for 
Direct Treatment 
0.05 to 0.1 sec 
Grid Treatment 
Applied to all areas with edema not associated with microaneurysms.  If 
fluorescein angiography is obtained, grid is applied to areas of edema with 
angiographic nonperfusion when judged indicated by the investigator.   
Area Considered 
for Grid Treatment 
500 to 3000 µm superiorly, nasally and inferiorly from center of macula  
500 to 3500 µm temporally from macular center  
No burns placed within 500 µm of disc 
Burn Size for Grid 
Treatment 
50 µm 
Burn Duration for 
Grid Treatment 
0.05 to 0.1 sec 
Burn Intensity for Grid 
Treatment 
Barely visible (light gray) 
Burn Separation for 
Grid Treatment 
2 visible burn widths apart 
Wavelength (Grid and 
Direct Treatment) 
Green to yellow wavelengths 
*Additional guidelines for performing laser treatment using the PASCAL are included in the 
1004 
Procedure Manual. 
1005 
 
1006 
Note: 
1007 
 The investigator may choose any laser wavelength for photocoagulation within the green to 
1008 
yellow spectrum.  The wavelength used will be recorded. 
1009 
 Lenses used for the laser treatment cannot increase or reduce the burn size by more than 
1010 
10%.  The Procedure Manual contains a listing of acceptable lenses.   
1011 
 
1012 
4.3 Intravitreal Aflibercept Injection (Eylea®) 
1013 
Eylea® (intravitreal aflibercept injection) is made by Regeneron Pharmaceuticals, Inc. and is 
1014 
approved by the FDA for the treatment of neovascular age-related macular degeneration and 
1015 
macular edema due to central retinal vein occlusion.   
1016 
 
1017 
Study eyes that receive anti-VEGF will receive a dose of 2.0 mg aflibercept in 0.05 cc.  The 
1018 
physical, chemical and pharmaceutical properties and formulation are provided in the Clinical 
1019 
Investigator Brochure. Aflibercept for the study and non-study eye will be distributed by the 
1020 
Network.  
1021 
 
1022 
4.4 Intravitreal Injection Technique 
1023 
The injection is preceded by a povidone iodine prep of the conjunctiva.  Antibiotics in the pre, 
1024 
peri, or post-injection period are not necessary but can be used at investigator discretion if such 
1025 
use is part of his/her usual routine. 
1026 
 
1027 
The injection will be performed using sterile technique.  The full injection procedure is described 
1028 
in the DRCR.net Study Procedures Manual. 
1029 
  
1030 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  4-14 
 
4.5 Delay in Giving Injections 
1031 
If a scheduled injection is not given by the end of the visit window, it can still be given up to 1 
1032 
week prior to the next visit window opening.  If it is not given by that time, it will be considered 
1033 
missed. 
1034 
 
1035 
If an injection is given late, the next scheduled injection should occur no sooner than 3 weeks 
1036 
after the previous injection. 
1037 
 
1038 
4.6 Deferral of Injections Due to Pregnancy 
1039 
Female study participants must be questioned regarding the possibility of pregnancy prior to 
1040 
each injection.  In the event of pregnancy, study injections must be discontinued.   
1041 
 
1042 
4.7 Non-Study Eye Injections 
1043 
If the non-study eye is going to be treated for any condition which requires treatment with an 
1044 
anti-VEGF agent, study provided aflibercept must be used.  However, if intravitreal anti-VEGF 
1045 
treatment is planned on the same day as an intravitreal injection in the study eye, the study eye 
1046 
will be injected first, followed by the non-study eye (see Procedures Manual for additional 
1047 
details).  If a different intravitreal anti-VEGF injection than described above is desired in the 
1048 
non-study eye, a discussion with the Protocol Chair is required first. 
1049 
 
 
1050 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  5-15 
 
 
1051 
Chapter 5.                                                                                                
1052 
FOLLOW-UP VISITS AND TREATMENT 
1053 
 
1054 
5.1 Visit Schedule 
1055 
The schedule of protocol-specified follow-up visits is as follows: 
1056 
 
1057 
Year 1 
1058 
Treatment Assessment Visits: 
1059 
 Prompt anti-VEGF group: visits every 4±1 weeks (with a minimum of 21 days 
1060 
between injections) for the first 24 weeks. After 24 weeks of follow-up, visits every 4 
1061 
to 16 weeks depending on treatment given: 
1062 
 Visits every 4±1 weeks as long as injections are given. 
1063 
 The first two times an injection is deferred, the study participant will return in 
1064 
4 weeks for re-evaluation.  If deferral continues, the study participant will 
1065 
return in 8±2 weeks for re-evaluation before beginning the every 16±4 week 
1066 
schedule.  
1067 
 Deferred anti-VEGF groups (focal/grid photocoagulation and observation groups): 
1068 
 Visits at 8 weeks and 16 weeks (±2 weeks)  after randomization, followed by 
1069 
visits every 16±4  weeks thereafter as long as the eye is stable.* 
1070 
 
1071 
*For the deferred groups, the follow-up visit interval will be more frequent if there is worsening 
1072 
on visual acuity or OCT CSF thickness according to the criteria below (unless focal/grid 
1073 
photocoagulation was administered, in which case follow-up should occur no sooner than 8 
1074 
weeks). 
1075 
 If visual acuity decreases 5 to 9 letters from baseline (mean visual acuity from the 
1076 
screening and randomization visit), the next visit will be in 4±2 weeks to check for 
1077 
continued vision loss needing anti-VEGF treatment (see section 5.3).   
1078 
 If visual acuity is no longer decreased, the next visit will be in 8 weeks to 
1079 
confirm visual acuity is no longer decreased before resuming the every 16-
1080 
week schedule. 
1081 
 If the OCT CSF thickness increases by ≥10% from the last visit, the follow-up 
1082 
interval will be cut in half (e.g. 8 weeks if previously 16 or 4 weeks if previously 8) 
1083 
with a minimum of every 4-week visits to check for vision loss needing anti-VEGF 
1084 
treatment (see section 5.3).     
1085 
 If OCT subsequently improves or stabilizes at two consecutive visits 
1086 
without vision loss, the next interval will be doubled (e.g. 8 weeks if 
1087 
previously 4 or 16 weeks if previously 8) with a maximum of every 16-week 
1088 
visits. 
1089 
 If the OCT CSF thickness becomes ≥400 µm (or the spectral domain equivalent), 
1090 
visits will be every 8 weeks.  
1091 
 If OCT subsequently improves or stabilizes at two consecutive visits 
1092 
without vision loss, 16-week interval visits may be resumed.   
1093 
 Once anti-VEGF is initiated, visits will be every 4 weeks for 24 weeks following 
1094 
initiation of anti-VEGF and every 4 to 16 weeks thereafter (see treatment schedule for 
1095 
prompt anti-VEGF group above for visit schedule after 24 weeks). 
1096 
 
1097 
Outcome Visits: 
1098 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  5-16 
 
 Visit at 52 weeks (±2 weeks) for all participants. 
1099 
 
1100 
Year 2 
1101 
Treatment Assessment Visits: 
1102 
 Eyes receiving intravitreal injections: 
1103 
 Visits every 4±1 weeks (with a minimum of 21 days between injections) for 
1104 
the first 24 weeks following initiation of anti-VEGF treatment and as long 
1105 
as intravitreal injections are given. 
1106 
 After 24 weeks of anti-VEGF treatment, visits every 8 weeks (± 2) to 16 
1107 
weeks (±4) once injections are deferred. 
1108 
Note: The first two times an injection is deferred, the study participant will 
1109 
return in 4 weeks for re-evaluation.  If deferral continues, the study 
1110 
participant will return in 8 weeks for re-evaluation before beginning the 
1111 
every 16 week schedule.  
1112 
 Eyes that have not received anti-VEGF injection during the study: 
1113 
 Visits every 16 weeks unless there is worsening (see criteria described in 
1114 
Year 1 above), at which point the next visit will be in 4 to 8 weeks to check 
1115 
for continued vision loss needing anti-VEGF treatment. 
1116 
 
1117 
Outcome Visit: 
1118 
 Visit at 104 weeks (±4 weeks) for all participants.  This final outcome visit is for data 
1119 
collection only and will not include retreatment evaluation.   
1120 
 
1121 
Additional visits may occur as required for usual care of the study participant.  
1122 
 
1123 
5.2 Testing Procedures 
1124 
The following procedures will be performed at each protocol visit unless otherwise specified. A 
1125 
grid in section 1.3 summarizes the testing performed at each visit.   
1126 
 
1127 
Visual acuity testers (including refractionist) and OCT technicians will be masked to treatment 
1128 
group at the annual visits.   
1129 
 
1130 
1. E-ETDRS visual acuity testing in each eye (best corrected). 
1131 
 A protocol refraction in the study eye is required at all protocol visits.  Refraction in the 
1132 
non-study eye is only required at annual visits.  When a refraction is not performed, the 
1133 
most recently performed refraction is used for the testing. 
1134 
2. Low-contrast visual acuity in the study eye using the EVA at annual visits only; if site has 
1135 
the capability.  
1136 
3. OCT on the study eye.  
1137 
4. Ocular exam on the study eye, including slit lamp examination, lens assessment, 
1138 
measurement of intraocular pressure and dilated ophthalmoscopy. Non-study eyes that have 
1139 
received intravitreal anti-VEGF during the study will also receive an ocular exam for safety 
1140 
assessment. 
1141 
5. Fundus photographs (7 modified or 4 wide-field digital stereoscopic) on the study eye at 
1142 
annual visits only. 
1143 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  5-17 
 
6. Digital fluorescein angiogram (FA) in the study eye prior to focal/grid laser re-treatment in 
1144 
the laser group on eyes where an FA was obtained at baseline.   
1145 
7. HbA1c at 16 weeks (± 4 weeks) and annual visits only. 
1146 
 The same lab (or DCA Vantage Analyzer) must be used at baseline and follow-up. 
1147 
 
1148 
All of the testing procedures do not need to be performed on the same day, provided that they are 
1149 
completed within the time window of a visit and prior to initiating any retreatment.  
1150 
 
1151 
Testing procedures at unscheduled visits are at investigator discretion.  However, it is 
1152 
recommended that procedures that are performed should follow the standard DRCR.net protocol 
1153 
for each procedure. 
1154 
 
1155 
5.3 Treatment During Follow Up 
1156 
The treatment groups are as follows: 
1157 
a. Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF 
1158 
b. Observation + deferred intravitreal anti-VEGF treatment 
1159 
c. Prompt intravitreal anti-VEGF 
1160 
 
1161 
5.3.1 Initiation of Intravitreal Anti-VEGF in the Deferred Groups  
1162 
For eyes in the deferred anti-VEGF groups (either observation or focal/grid), if there is a 
1163 
decrease in visual acuity presumed to be due to DME of at least 10 letters compared with the 
1164 
baseline visual acuity (mean of the screening and randomization visual acuity) at a single visit or 
1165 
5 to 9 letter decrease compared with baseline visual acuity at two consecutive visits, an injection 
1166 
of anti-VEGF will be given. Once anti-VEGF injections are initiated, retreatment will follow the 
1167 
criteria described in section 5.3.2 below. 
1168 
 
1169 
The protocol chair or designee must be contacted prior to deviation from the injection protocol.   
1170 
 
1171 
5.3.2 Intravitreal Injection Retreatment  
1172 
Once anti-VEGF injections are initiated (either at randomization in the prompt anti-VEGF group 
1173 
or once criteria are met in the deferred groups), the eye will be evaluated at each visit for 
1174 
retreatment. In general, an eye will continue to receive an injection if the eye is improving or 
1175 
worsening on OCT or visual acuity. The first time an eye has not improved or worsened, the eye 
1176 
will receive an injection.  If the eye has not improved or worsened for at least 2 consecutive 4-
1177 
week injections and the OCT CSF thickness is less than the gender specific spectral domain OCT 
1178 
threshold (see below) and visual acuity is 20/20 or better, then injection will be deferred.  If the 
1179 
eye has not improved or worsened for at least 2 consecutive 4-week visits and the OCT CSF 
1180 
thickness is ≥ the gender specific spectral domain OCT threshold or visual acuity is worse than 
1181 
20/20, the following will be done: 
1182 
 If during the first 24 weeks of anti-VEGF treatment, an injection will be given. 
1183 
 At and after 24 weeks, the injection will be deferred. 
1184 
 
1185 
The protocol chair or designee must be contacted prior to deviation from the injection protocol.  
1186 
See the DRCR.net Procedure Manual for additional details. 
1187 
 
1188 
Spectral domain OCT central subfield gender specific threshold: 
1189 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  5-18 
 
 Zeiss Cirrus: 290 microns in women, and 305 microns in men 
1190 
 Heidelberg Spectralis: 305 microns in women, and 320 microns in men 
1191 
 
1192 
5.3.3 Initiation of Focal/Grid Photocoagulation While Receiving Anti-VEGF Injections 
1193 
Once anti-VEGF injections are initiated (either at randomization in the prompt anti-VEGF group 
1194 
or once criteria are met in the deferred groups), focal/grid photocoagulation may be added at 
1195 
investigator discretion if after 24 weeks from the initial injection 1) the OCT CSF thickness is ≥ 
1196 
the spectral domain gender specific OCT CSF threshold (see above) or there is edema that is 
1197 
threatening the fovea AND 2) the eye has not improved on OCT (≥10% decrease) or visual 
1198 
acuity (≥5 letter increase) from the last two consecutive injections.  If after 24 weeks from the 
1199 
initial injection, the eye is worsening on OCT (≥10% increase) or visual acuity (≥5 letter 
1200 
decrease) from the last two consecutive injections, focal/grid photocoagulation should be 
1201 
performed provided the investigator believes that macular edema is present for which focal 
1202 
photocoagulation is indicated.  
1203 
 
1204 
Once focal/grid photocoagulation is added to anti-VEGF, retreatment with focal/grid 
1205 
photocoagulation will follow the criteria described in section 5.3.4 below. 
1206 
 
1207 
5.3.4 Focal/Grid Photocoagulation Retreatment 
1208 
Once focal/grid photocoagulation has been initiated (either at randomization in the prompt 
1209 
focal/grid photocoagulation group or once criteria are met to add to anti-VEGF treatment), 
1210 
retreatment with focal/grid photocoagulation will be given unless one of the following is present: 
1211 
1) focal/grid photocoagulation has been given in the previous 13 weeks, 2) complete focal/grid 
1212 
photocoagulation has already been given in the investigator’s judgment, 3) the OCT CSF 
1213 
thickness is < the spectral domain gender specific OCT CSF threshold and there is no edema 
1214 
threatening the fovea, 4) the eye has improved since the last laser treatment, or 5) all treatable 
1215 
microaneurysms are located only within 500 microns of the foveal center. The protocol chair or 
1216 
designee must be contacted prior to deviating from the focal/grid photocoagulation protocol.  See 
1217 
the DRCR.net Procedure Manual for details. 
1218 
 
1219 
Eyes assigned to prompt focal/grid photocoagulation with deferred anti-VEGF will not receive 
1220 
retreatment with focal/grid photocoagulation once anti-VEGF is initiated, until the criteria in 
1221 
section 5.3.3 above are met. 
1222 
 
1223 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  6-1 
 
Chapter 6.  
1224 
MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
1225 
 
1226 
6.1 Endophthalmitis  
1227 
Diagnosis of endophthalmitis is based on investigator’s judgment.  Obtaining cultures of vitreous 
1228 
and/or aqueous fluid is strongly recommended prior to initiating antibiotic treatment for 
1229 
presumed endophthalmitis. 
1230 
 
1231 
6.2 Surgery for Vitreous Hemorrhage and Other Complications of Diabetic Retinopathy 
1232 
A study eye could develop a vitreous hemorrhage and/or other complications of diabetic 
1233 
retinopathy that may cause visual impairment.  The timing of vitrectomy for the complications of 
1234 
proliferative diabetic retinopathy such as vitreous hemorrhage is left to investigator discretion. 
1235 
 
1236 
6.3 Panretinal (Scatter) Photocoagulation (PRP) 
1237 
PRP can be given if it is indicated in the judgment of the investigator.  Individuals are not 
1238 
eligible for this study if, at the time of randomization, it is expected that they will need PRP 
1239 
within 6 months.  In general, PRP should not be given if the study participant has less than 
1240 
severe non-proliferative diabetic retinopathy.  In general, PRP should be given promptly for 
1241 
previously untreated eyes exhibiting PDR with high-risk characteristics and can be considered 
1242 
for persons with non high-risk PDR or severe non-proliferative diabetic retinopathy. Guidelines 
1243 
for PRP can be found in the Protocol Procedure Manuals on the DRCR.net website. 
1244 
 
1245 
6.4 Use of Intravitreal Anti-VEGF for Conditions Other than DME in the Study Eye 
1246 
If an ocular condition develops in the study eye for which aflibercept is an FDA approved 
1247 
treatment (e.g. neovascular AMD, macular edema following central retinal vein occlusion), the 
1248 
use of study aflibercept is at the discretion of the investigator.  Any off-label use of anti-VEGF in 
1249 
the study eye for an ocular condition other than DME (e.g. PDR, vitreous hemorrhage), will 
1250 
require discussion with and approval by the protocol chair or designee. Study aflibercept must be 
1251 
used for any anti-VEGF treatment in the study eye.   
1252 
 
1253 
6.5 Treatment of Macular Edema in Non-study Eye 
1254 
Treatment of DME in the non-study eye is at investigator discretion. However, if anti-VEGF 
1255 
treatment will be given, study aflibercept must be used (see section 4.7). 
1256 
 
1257 
6.6 Diabetes Management 
1258 
Diabetes management is left to the study participant’s medical care provider. 
1259 
 
1260 
6.7 Study Participant Withdrawal and Losses to Follow-up 
1261 
A study participant has the right to withdraw from the study at any time.  If a study participant is 
1262 
considering withdrawal from the study, the principal investigator should personally speak to the 
1263 
individual about the reasons, and every effort should be made to accommodate him or her.   
1264 
 
1265 
The goal for the study is to have as few losses to follow-up as possible.  The Coordinating Center 
1266 
will assist in the tracking of study participants who cannot be contacted by the site.  The 
1267 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
1268 
 
1269 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
1270 
described for the protocol visits will be performed.  Study participants who have an adverse 
1271 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  6-2 
 
effect attributable to a study treatment or procedure will be asked to continue in follow-up until 
1272 
the adverse event has resolved or stabilized. 
1273 
 
1274 
Study participants who withdraw or are determined to have been ineligible post-randomization 
1275 
will not be replaced. 
1276 
 
1277 
6.8 Discontinuation of Study 
1278 
The study may be discontinued by the Executive Committee (with approval of the Data and 
1279 
Safety Monitoring Committee) prior to the preplanned completion of follow-up for all study 
1280 
participants. 
1281 
 
1282 
6.9 Contact Information Provided to the Coordinating Center 
1283 
The Coordinating Center will be provided with contact information for each study participant.  
1284 
Permission to obtain such information will be included in the Informed Consent Form.  The 
1285 
contact information may be maintained in a secure database and will be maintained separately 
1286 
from the study data. 
1287 
 
1288 
Phone contact from the Coordinating Center will be made with each study participant in the first 
1289 
month after enrollment, and approximately every six months thereafter.  Additional phone 
1290 
contacts from the Coordinating Center will be made if necessary to facilitate the scheduling of 
1291 
the study participant for follow-up visits.  A participant-oriented newsletter may be sent twice a 
1292 
year.  A study logo item may be sent once a year.  
1293 
 
1294 
Study participants will be provided with a summary of the study results in a newsletter format 
1295 
after completion of the study by all participants.   
1296 
 
1297 
6.10 Study Participant Reimbursement 
1298 
The study will be providing the study participant with a $25 merchandise or money card per 
1299 
completed protocol visit.  Additional travel expenses may be paid in cases for participants with 
1300 
higher expenses. 
1301 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  7-1 
 
 
1302 
Chapter 7.                                                                                             
1303 
ADVERSE EVENTS 
1304 
 
1305 
7.1 Definition 
1306 
An adverse event is any untoward medical occurrence in a study participant, irrespective of 
1307 
whether or not the event is considered treatment-related. 
1308 
 
1309 
7.2 Recording of Adverse Events 
1310 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
1311 
events or untoward findings.  The first concern will be the safety of the study participant, and 
1312 
appropriate medical intervention will be made. 
1313 
 
1314 
All adverse events whether volunteered by the subject, discovered by study personnel during 
1315 
questioning, or detected through physical examination, laboratory test, or other means will be 
1316 
reported on an adverse event form online.  Each adverse event form is reviewed by the 
1317 
Coordinating Center to verify the coding and the reporting that is required.  
1318 
 
1319 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1320 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1321 
by the treatment (including treatment of the non-study eye with study treatment). 
1322 
 
1323 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1324 
following general guideline when determining whether an adverse event is related: 
1325 
 
1326 
Yes 
1327 
There is a plausible temporal relationship between the onset of the adverse event and 
1328 
administration of the study treatment, and the adverse event cannot be readily explained by the 
1329 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event 
1330 
follows a known pattern of response to the study treatment; and/or the adverse event abates or 
1331 
resolves upon discontinuation of the study treatment or dose reduction and, if applicable, 
1332 
reappears upon re-challenge. 
1333 
 
1334 
No 
1335 
Evidence exists that the adverse event has an etiology other than the study treatment (e.g., 
1336 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1337 
medication); and/or the adverse event has no plausible temporal relationship to study treatment 
1338 
administration (e.g., cancer diagnosed 2 days after first dose of study drug).    
1339 
 
1340 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 
1341 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
1342 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
1343 
may not be clinically serious. 
1344 
 
1345 
Adverse events will be coded using the MedDRA dictionary.  
1346 
 
1347 
Definitions of relationship and intensity are listed on the DRCRnet website data entry form.   
1348 
 
1349 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  7-2 
 
Adverse events that continue after the study participant’s discontinuation or completion of the 
1350 
study will be followed until their medical outcome is determined or until no further change in the 
1351 
condition is expected.   
1352 
 
1353 
7.3 Reporting Serious or Unexpected Adverse Events 
1354 
A serious adverse event is any untoward occurrence that: 
1355 
 Results in death. 
1356 
 Is life-threatening; (a non life-threatening event which, had it been more severe, might have 
1357 
become life-threatening, is not necessarily considered a serious adverse event). 
1358 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
1359 
 Results in persistent or significant disability/incapacity or substantial disruption of the ability 
1360 
to conduct normal life functions (sight threatening). 
1361 
 Is a congenital anomaly or birth defect. 
1362 
 Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1363 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1364 
the outcomes listed above). 
1365 
 
1366 
Unexpected adverse events are those that are not identified in nature, severity, or frequency in 
1367 
the current Clinical Investigator’s Brochure.   
1368 
 
1369 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
1370 
via completion of the online serious adverse event form. If the study participant required 
1371 
hospitalization, the hospital discharge summary must also be sent to the Coordinating Center.   
1372 
 
1373 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1374 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
1375 
Center becomes aware of the event.   
1376 
 
 
1377 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1378 
abiding by any other reporting requirements specific to their Institutional Review Board.  
1379 
 
1380 
7.4 Data and Safety Monitoring Committee Review of Adverse Events 
1381 
A Data and Safety Monitoring Committee (DSMC) will approve the protocol, template informed 
1382 
consent form, and substantive amendments and provide independent monitoring of adverse 
1383 
events.  Cumulative adverse event data are tabulated semi-annually for review by the DSMC.  
1384 
Following each DSMC data review, a summary will be provided to IRBs.  A list of specific 
1385 
adverse events to be reported expeditiously to the DSMC will be compiled and included as part 
1386 
of the DSMC Standard Operating Procedures document.   
1387 
 
1388 
7.5 Risks 
1389 
7.5.1 Potential Adverse Effects of Anti-VEGF Drug 
1390 
Limited data are available for the use of aflibercept in diabetic cohorts, and published results are 
1391 
only available for short duration follow-up of one year.  The DA VINCI study, a phase II study 
1392 
evaluating aflibercept for treatment of DME, reported common adverse events that were 
1393 
consistent with those previously seen with intravitreal injections.  Over 1 year follow-up, two 
1394 
cases of endophthalmitis and one case of uveitis occurred (all in aflibercept treatment groups).  
1395 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  7-3 
 
Seven deaths (4.0%) occurred in the groups randomized to VEGF-Trap-Eye treatment as 
1396 
compared with 1 (2.3%) in the group treated with laser.  Myocardial infarction or 
1397 
cerebrovascular accident occurred in 6 (3.4%) participants treated with aflibercept as compared 
1398 
with 1 (2.3%) participant treated with laser alone.23  Percentages of study participants that 
1399 
experienced events meeting APTC criteria were 5.1% (N = 9) in the combined aflibercept groups 
1400 
and 4.5% (2) in the laser group.24 In the combined analysis of the VIEW 1 and VIEW 2 phase III 
1401 
studies in age-related macular degeneration, serious ocular adverse events, including 
1402 
endophthalmitis, occurred at rates <0.1% per injection in both studies and there did not appear to 
1403 
be a dose or drug-related increase in APTC events in either study. The rates of APTC arterial 
1404 
thrombolic events were 3.2% and 3.3% in the ranibizumab and the combined aflibercept groups, 
1405 
respectively.31  Common ocular adverse events in the COPERNICUS trial, which enrolled eyes 
1406 
with macular edema secondary to central retinal vein occlusion and randomized them to either 2 
1407 
mg intravitreal aflibercept monthly x 6 months followed by prn aflibercept versus sham injection 
1408 
x 6 months followed by prn aflibercept, were conjunctival hemorrhage (16.7% and 18.9%, 
1409 
respectively) and eye pain (15.8% and 9.5%, respectively). APTC events through week 52 
1410 
occurred in 0.9% (1) of the aflibercept-treated eyes and 2.7% (2) of the eyes treated initially with 
1411 
sham and then with aflibercept as needed after 6 months.24 
1412 
 
1413 
There may be side effects and discomforts that are not yet known.   
1414 
 
1415 
7.5.2 Potential Adverse Effects of Intravitreal Injection 
1416 
Rarely, the drugs used to anesthetize the eye before the injections (proparacaine, tetracaine, or 
1417 
xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat less than 1% of 
1418 
the time.   
1419 
 
1420 
Subconjunctival hemorrhage or floaters will commonly occur as a result of the intravitreal 
1421 
injection.  Mild discomfort, ocular hyperemia, increased lacrimation, discharge or itching lasting 
1422 
for up to a few days is also likely (more than 10% of the time). 
1423 
 
1424 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
1425 
returns to normal spontaneously, but may need to be treated with topical drugs or a 
1426 
paracentesis to lower the pressure.  The likelihood of permanent loss of vision from elevated 
1427 
intraocular pressure is less than 1%. 
1428 
 
1429 
As a result of the injection, endophthalmitis (infection in the eye) could develop.  If this occurs, it is 
1430 
treated by intravitreal injection of antibiotics, but there is a risk of permanent loss of vision including 
1431 
blindness. The risk of endophthalmitis is less than 1%. 
1432 
 
1433 
As a result of the injection, a retinal detachment could occur.  If this occurs, surgery may be 
1434 
needed to repair the retina.  The surgery is usually successful at reattaching the retina.  
1435 
However, a retinal detachment can produce permanent loss of vision and even blindness.  The 
1436 
risk of retinal detachment is less than 1%. 
1437 
 
1438 
The injection could cause a vitreous hemorrhage.  Usually the blood will resolve 
1439 
spontaneously, but if not, surgery may be needed to remove the blood.  Although the surgery 
1440 
usually successfully removes the blood, there is a small risk of permanent loss of vision and 
1441 
even blindness.  The risk of having a vitreous hemorrhage due to the injection is less than 1%. 
1442 
 
1443 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  7-4 
 
7.5.3 Risks of Laser Photocoagulation Treatment 
1444 
Serious complications from laser treatment are rare.  They occur in less than 1 in 1,000 cases. 
1445 
These include damage to the macula, bleeding inside the eye, immediate or delayed increase in 
1446 
pressure inside the eye, damage to the optic nerve, damage to the iris, damage to the lens or an 
1447 
intraocular lens, retinal hole, blindness, and loss of the eye.  If a laser burn occurs too near the 
1448 
center of vision, a scotoma could develop.  After several years, the scars caused by the laser may 
1449 
enlarge and cause vision to decrease. 
1450 
 
1451 
Anesthetic drops and a contact lens may be used as a part of the laser procedure.  Risks include 
1452 
allergic reaction, infection, and corneal abrasion (scratch on the clear front surface of the eye) 
1453 
(all less than 1%).  If any of these problems occur, they usually clear up rapidly.  
1454 
 
1455 
In some cases retrobulbar or peribulbar injection may be used to anesthetize the eye and to 
1456 
reduce eye movements.  Complications of retrobulbar and peribulbar injections are rare (less 
1457 
than 1 in 5000)32.  They include, but are not limited to, the following: retrobulbar hemorrhage 
1458 
(bleeding behind your eyeball); perforation of the eye by the needle; damage to the optic nerve; 
1459 
diplopia lasting up to 24 hours or more; ptosis lasting up to 24 hours or more; difficulty speaking 
1460 
or breathing; lightheadedness/syncope/vasovagal response; allergy to any components of the 
1461 
injection; life threatening response due to the spread of anesthesia to the brain stem, resulting in 
1462 
seizures, drowsiness, confusion, loss of ability to talk, convulsions, stoppage of breathing, or 
1463 
stoppage of heartbeat. All of these complications are rare. 
1464 
 
1465 
7.5.4 Risks of Eye Examination and Tests 
1466 
There is a very rare risk of an allergic response to the topical medications used to anesthetize the 
1467 
eye or dilate the pupil that occurs in less than 1% of eyes. Dilating drops rarely could cause an 
1468 
acute angle closure glaucoma attack (less than 1 in 1000)33, but this is highly unlikely since the 
1469 
participants in the study will have had their pupils dilated many times previously.   
1470 
 
1471 
There are no known risks associated with OCT or fundus photographs.  The bright flashes used 
1472 
to take the photographs may be annoying, but are not painful and cause no damage.  
1473 
 
1474 
If a fluorescein angiogram is performed, a yellow dye is injected intravenously.  Risks include 
1475 
but are not limited to:  transient change in skin and urine color; nausea (approximately 5%); 
1476 
allergic reaction to the dye, hives and itching (approximately 0.5%); anaphylaxis and possible 
1477 
death (less than 1 in 100,000 people).  The procedure will not be performed if medically 
1478 
contraindicated. 
1479 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-1 
 
 
1480 
 
1481 
Chapter 8.                                                                                              
1482 
STATISTICAL METHODS 
1483 
 
1484 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1485 
analysis plan will be written and finalized prior to the completion of the study.  The analysis plan 
1486 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1487 
 
1488 
The treatment groups are as follows: 
1489 
a. Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF 
1490 
b. Observation + deferred intravitreal anti-VEGF  
1491 
c. Prompt intravitreal anti-VEGF  
1492 
 
1493 
The primary analysis consists of three treatment group comparisons of the proportion of eyes 
1494 
with visual loss of at least 5 letters at the 2 year (104 week) visit. 
1495 
 
1496 
8.1   Sample size  
1497 
The sample size estimate has been computed for the primary study objective, comparing the 
1498 
efficacy of focal/grid photocoagulation + deferred intravitreal anti-VEGF, observation + deferred 
1499 
intravitreal anti-VEGF, and prompt intravitreal anti-VEGF.  The primary analysis consists of 
1500 
three two-group comparisons of the proportion of eyes with a 5 or more letter visual acuity loss 
1501 
at 2 years compared with baseline mean visual acuity (mean of the two screening and 
1502 
randomization visual acuity letter scores obtained within 1 to 28 days required for eligibility).   
1503 
  
1504 
8.1.1 Prompt Intravitreal Anti-VEGF Group Projection 
1505 
For the prompt intravitreal anti-VEGF group, the projected proportion of eyes with a 5 or more 
1506 
letter visual acuity loss was estimated using unpublished data from DRCR.net Protocol I.   This 
1507 
projection includes 28 eyes in Protocol I that had visual acuity of 20/32 at baseline and were 
1508 
randomized to the prompt anti-VEGF + deferred laser treatment arm, of which 1 eye [(4%) 
1509 
95%CI (0.01%, 19.6%)] had a visual acuity decrease of 5 or more letters at 2 years of study 
1510 
follow-up. Although the majority of the eligibility criteria between the current study and Protocol 
1511 
I are the same, the proposed study will only include eyes with visual acuity of 20/25 or better at 
1512 
baseline; therefore our projections could either under or overestimate the observed proportion of 
1513 
eyes with 5 or more letter visual acuity loss at 2 years of follow up in this study.   We will 
1514 
assume that 5% of the prompt intravitreal anti-VEGF group in the proposed study will have a 5 
1515 
or more letter visual acuity loss.     
1516 
              
1517 
8.1.2 Deferred Intravitreal Anti-VEGF Groups Projection 
1518 
The projected losses in visual acuity at 2 years for the focal/grid photocoagulation + deferred 
1519 
intravitreal anti-VEGF group and the observation + deferred intravitreal anti-VEGF group were 
1520 
estimated using ETDRS data of eyes with center-involved DME evaluated by fundus 
1521 
photography and visual acuity ≥ 20/25 at baseline.   
1522 
 
1523 
The projection for the focal/grid photocoagulation + deferred intravitreal anti-VEGF group was 
1524 
based on 120 eyes with center-involved DME in the ETDRS that had visual acuity of 20/25 or 
1525 
better at baseline and were randomized to the ETDRS focal/grid photocoagulation treatment arm, 
1526 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-2 
 
of which 32 eyes [(27%) 95%CI (19%, 36%])] had a visual acuity decrease of 5 or more letters 
1527 
at 2 years of study follow-up. 
1528 
   
1529 
The projection for the observation + deferred intravitreal anti-VEGF group was based on 251 
1530 
eyes with center-involved DME in the ETDRS that had visual acuity of 20/25 or better at 
1531 
baseline and were randomized to the ETDRS observation only treatment arm, of which 98 eyes 
1532 
[(40%) 95%CI (34%, 47%])] had a visual acuity decrease of 5 or more letters at 2 years of study 
1533 
follow-up. 
1534 
 
1535 
Projections based on the above ETDRS data alone could overestimate the proportion of 
1536 
participants expected to have a 5 letter loss at the 2 year visit for each deferred treatment arm in 
1537 
the present study since the ETDRS trial did not provide rescue anti-VEGF.  In order to obtain a 
1538 
conservative estimate, the lower limit of the 95% CI will be used as the expected proportion of 
1539 
eyes with a 5 or more letter visual acuity loss in the absence of rescue anti-VEGF for these 
1540 
treatment groups (i.e. 19% for the laser group and 34% for the observation group). 
1541 
 
1542 
According to protocol I unpublished data, approximately 50% of eyes that were 20/32 at baseline 
1543 
gained 5 or more letters at 2 years of study follow up.  Therefore, it can be hypothesized that 
1544 
approximately half of the ETDRS eyes that lost 5 or more letters by 2 years would regain the 5 
1545 
letters after initiation of anti-VEGF therapy.    
1546 
 
1547 
Thus, the following deferred group projections will be used: 
1548 
 Focal/grid laser + deferred intravitreal anti-VEGF: 10% (approximately half of the lower 
1549 
end of the ETDRS confidence interval) 
1550 
 Observation + deferred intravitreal anti-VEGF: 17% (approximately half of the lower end 
1551 
of the ETDRS confidence interval)  
1552 
 
1553 
8.1.3 Sample Size and Power Assumptions and Estimates 
1554 
A multiple comparison adjustment will be used in order to control type I error rate.  Sample size 
1555 
calculations were performed using the Hochberg multiple comparisons adjustment procedure.  
1556 
This procedure contrasts ordered P values with a set of critical values then rejects all hypotheses 
1557 
with smaller or equal P values to that of the pre-determined alpha level. 
1558 
 
1559 
8.1.4 Power Estimation for Primary Outcome 
1560 
A sample size of 702 eyes (234 eyes per group) was selected, which includes adjustment for 10% 
1561 
lost to follow-up and a 5% increase for interim data monitoring while maintaining pre-specified 
1562 
type I error and power.  Power with 702 eyes for the various pairwise treatment comparisons 
1563 
using the Hochberg procedure is provided in Table 1. The power for the largest pairwise 
1564 
difference is estimated to be 92%.  The power to reject any of the three pairwise treatment 
1565 
comparisons is estimated to be 93%.  For power estimation, the following assumptions were 
1566 
made: 
1567 
 
1568 
 Overall Type 1 error rate is = 0.049 (2-sided), after adjusting for total alpha spending 
1569 
of 0.001 for DSMC data review and interim data analysis.  The Hochberg adjustment 
1570 
will be used to control the overall type 1 error rate for the multiple treatment 
1571 
comparisons.     
1572 
 The estimated proportion of eyes with a visual acuity loss of 5 or more letters in the 
1573 
prompt anti-VEGF treatment group = 5%; 
1574 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-3 
 
 Focal/grid photocoagulation + deferred intravitreal anti-VEGF treatment group = 
1575 
10%; and  
1576 
 Observation + deferred intravitreal anti-VEGF treatment group = 17% 
1577 
 Loss to Follow-up at 2 years: 10% 
1578 
 
1579 
Table 1.  Power for pairwise treatment comparisons using the Hochberg procedure 
1580 
 
Assumed outcome proportions 
(difference in proportions) 
Reject Any  
Pairwise 
Comparison 
Reject the Largest 
Comparison 
  
Reject the Smallest 
Comparison  
  
Anti-VEGF = 5%, Focal/grid laser = 
10%, Observation = 17% 
(Focal/grid – Anti-VEGF = 5%) 
(Observation – Anti-VEGF = 12%) 
93% 
92% 
33% 
 * Note; given the uncertainty in the projected outcomes a power slightly higher than 90% is being selected.    
Because the Hochberg procedure is being used, the power to reject the pairwise comparison of treatment X 
(the treatment with the lowest outcome proportion) vs. Z (the treatment with the highest outcome 
proportion) depends on the outcome proportion in the intermediate group, Y. 
 
1581 
8.2 Statistical Analysis Plan 
1582 
8.2.1 Primary Outcome 
1583 
The primary outcome is a 5 or more letter decrease in visual acuity letter score from baseline 
1584 
visual acuity to 2 years.  Baseline visual acuity is defined as the mean of the two visual acuity 
1585 
measurements required for eligibility.  The primary analysis will be an intent-to-treat analysis 
1586 
that includes all randomized eyes, according to the treatment group assignment at randomization.  
1587 
Similarly, baseline OCT will be the mean of the screening and randomization OCT thickness.      
1588 
 
1589 
Treatment group comparisons will be conducted using binomial regression adjusting for baseline 
1590 
visual acuity and recent or planned DME treatment in the non-study eye at the time of 
1591 
randomization.  If binomial regression is not feasible, then Poisson regression with a robust error 
1592 
variance24 will be used, adjusting for baseline visual acuity and recent or planned DME treatment 
1593 
in the non-study eye at the time of randomization.  If Poisson regression is used, unadjusted risk 
1594 
differences and their unadjusted 95% confidence intervals will be reported to aid in interpretation 
1595 
of the data, but the p-values for the treatment comparisons will be those from the Poisson 
1596 
regression analysis that includes adjustment.  Imbalances between groups in important covariates 
1597 
are not expected to be of sufficient magnitude to produce confounding.  However, presence of 
1598 
confounding will be evaluated in regression models by including baseline covariates related to 
1599 
the patient and study eye.  Additional variables that are associated with the outcome will be 
1600 
included if there is an imbalance in the variables between treatment groups. 
1601 
 
1602 
Missing visual acuity letter scores will be imputed using the multiple imputation technique 
1603 
suggested by Rubin22. This method involves creating multiple “complete” datasets by filling in 
1604 
values for the missing data at the common visit schedule time points. The inferences for the 
1605 
missing values then are computed by averaging across the multiple imputed “complete” datasets. 
1606 
In addition, a sensitivity analysis using the “complete-case” method will be performed.   Under 
1607 
this method only participants with an available 104 week visit outcome are included in the 
1608 
analysis.  If the results from the two methods are discrepant then exploratory analysis will be 
1609 
carried out in order to determine factors that contribute to this difference.   
1610 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-4 
 
 
1611 
Pre-planned subgroup exploratory analysis will be described in the detailed Statistical Analysis 
1612 
Plan and include subgroups defined by (central subfield thickness, age, duration of diabetes, site-
1613 
reported duration of DME, lens status, level of diabetic retinopathy, and leakage patterns 
1614 
identified on FA). 
1615 
 
1616 
There are no data to suggest that the treatment effect will vary by gender or race/ethnicity.  
1617 
However, both of these factors will be evaluated in exploratory analyses.  
1618 
 
1619 
The number of study participants per center is small for many centers, therefore center effects 
1620 
will not be included in the statistical model; however for centers with a large number of study 
1621 
participants, the treatment effect will be assessed.  If a positive overall effect of treatment is 
1622 
found, heterogeneity of treatment effect across centers will be explored using random center 
1623 
effects. 
1624 
 
1625 
8.2.2  Secondary Outcomes 
1626 
The treatment groups will be compared on the following key secondary outcomes of interest at 
1627 
104 weeks: 
1628 
 
1629 
 Percent of eyes with at least 10 and 15 letter losses in visual acuity from baseline 
1630 
visual acuity 
1631 
 Percent of eyes with at least 5 letter gain in visual acuity from baseline visual acuity 
1632 
 Mean change in visual acuity, adjusted for baseline visual acuity 
1633 
 Mean change in OCT CSF thickness, adjusted for baseline thickness 
1634 
 Percent of eyes with at least a 1 and 2 log step increase or decrease on OCT CSF 
1635 
thickness 
1636 
 Percent of eyes with OCT CSF thickness less than the gender-specific spectral 
1637 
domain equivalent of 250 µm on Zeiss Stratus and at least a 10% OCT CSF thickness 
1638 
decrease 
1639 
 Number of injections and/or focal/grid photocoagulation sessions performed 
1640 
 Number of scheduled and unscheduled visits  
1641 
 Mean change in low-contrast visual acuity on Electronic Visual Acuity Tester 
1642 
 Total cost of follow-up and treatment 
1643 
 For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-
1644 
VEGF treatment.  
1645 
 
1646 
In addition, the following will be considered exploratory outcomes: 
1647 
 Visual acuity area under the curve between baseline and annual visits 
1648 
 Among eyes with non-proliferative diabetic retinopathy or PDR at randomization, 
1649 
percent with improvement  in diabetic retinopathy severity 
1650 
 Among eyes with PDR at randomization, proportion of eyes avoiding vitreous 
1651 
hemorrhage or PRP or vitrectomy for PDR  
1652 
 Percent of eyes with worsening diabetic retinopathy graded on color fundus photographs 
1653 
 Time to worsening of diabetic retinopathy on color fundus photographs 
1654 
Percent of eyes with highly focal leakage patterns (to be defined further) on FA randomized 
1655 
to laser treatment that do not require subsequent anti-VEGF treatment 
1656 
 
1657 
 
1658 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-5 
 
Analyses will be adjusted for randomization stratification variables and baseline measures where 
1659 
appropriate.  Binary outcomes will be analyzed using Fisher’s exact test; or for analyses 
1660 
controlling for baseline or stratification factors, binomial regression or a Poisson regression with 
1661 
a robust error variance24 will be used as described for the primary outcome.  Analysis of 
1662 
continuous outcomes will be performed using analysis of covariance.  All linear model 
1663 
assumptions will be verified including linearity and homoscedasticity.  If model assumptions are 
1664 
not met a nonparametric analysis will be considered.   
1665 
 
1666 
Additional secondary analyses mimicking the primary and secondary outcomes at 104 weeks 
1667 
will be conducted at 52 weeks.   
1668 
 
1669 
8.2.3 Cost Analysis 
1670 
The purpose of the cost analysis is to compare the treatment groups with respect to treatment and 
1671 
follow-up costs. The viewpoint adopted is that of a third party payer.  The analysis will be 
1672 
carried out under the complete-case method. 
1673 
 
1674 
Data from the clinical trial on number of clinic visits completed, number of procedures 
1675 
performed including diabetic retinopathy treatment (e.g. OCT, fundus photographs, PRP), 
1676 
number of focal/laser treatments, and number of anti-VEGF treatments over 2 years of study 
1677 
follow-up will be used to estimate an average cost per patient for each treatment arm, using the 
1678 
Medicare Fee Schedule to estimate medical costs.  For this analysis, the estimated average 
1679 
treatment group difference in costs is computed, with variation being characterized by variation 
1680 
in the quantity of services, which will be reported as a 95% confidence interval.  
1681 
           
1682 
8.2.4 Safety Analysis Plan 
1683 
Adverse events will be categorized as study eye, nonstudy eye, and systemic.  Adverse events of 
1684 
interest will include: 
1685 
Injection-related: endophthalmitis, retinal detachment, retinal tears, cataract, intraocular 
1686 
hemorrhage, increased intraocular pressure 
1687 
 
1688 
Ocular drug-related: inflammation, cataract, cataract surgery, increased intraocular pressure, 
1689 
glaucoma medications, glaucoma surgery, new or worsening traction retinal detachment 
1690 
 
1691 
Systemic drug-related: hypertension, cardiovascular events, cerebrovascular events 
1692 
 
1693 
Due to the different visit schedules among the treatment groups, the ratio of adverse events and 
1694 
number of visits will be provided in addition to the number of eyes with an adverse events and 
1695 
the total number of adverse events for each treatment group. This will account for a potential 
1696 
disproportion of reported adverse events observed in the prompt anti-VEGF treatment group as a 
1697 
result of having a more frequent visit schedule.  Further definitions of the events for analysis and 
1698 
the analytic approach will be provided in the detailed statistical analysis plan. 
1699 
 
1700 
8.2.5 Additional Tabulations and Analyses 
1701 
The following will be tabulated according to treatment group: 
1702 
1) Baseline demographic and clinical characteristics 
1703 
2) Visit completion rate 
1704 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  8-6 
 
3) Treatment completion 
1705 
 
1706 
8.2.6  Per-protocol Analysis 
1707 
 A per-protocol analysis of the primary outcome will be conducted in which any eye receiving a 
1708 
treatment for DME other than laser or an anti-VEGF injection will be excluded.  If the results 
1709 
differ from the primary intent-to-treat analysis, exploratory analyses will be performed to 
1710 
evaluate the factors that have contributed to the differences. 
1711 
 
1712 
8.2.7 Interim Monitoring Plan  
1713 
A formal plan for interim data monitoring will be established in consultation with the Data and 
1714 
Safety Monitoring Committee and the details will be provided in the Statistical Analysis Plan. 
1715 
                                              
1716 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  9-1 
 
REFERENCES 
1717 
 
1718 
1. 
Centers for Disease Control and Prevention. State-specific incidence of diabetes among 
1719 
adults--participating states, 1995-1997 and 2005-2007. MMWR Morb Mortal Wkly Rep. 
1720 
Oct 31 2008;57(43):1169-1173. 
1721 
2. 
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 
1722 
and 2030. Diabetes Res Clin Pract. Jan 2010;87(1):4-14. 
1723 
3. 
Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy 
1724 
among adults in the United States. Arch Ophthalmol. Apr 2004;122(4):552-563. 
1725 
4. 
Ferris FL, 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv 
1726 
Ophthalmol. May 1984;28 Suppl:452-461. 
1727 
5. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1728 
diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 1987;27(4):265-
1729 
272. 
1730 
6. 
Ferris FL, 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv 
1731 
Ophthalmol. 1984;28 (suppl)(May):452-461. 
1732 
7. 
Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin 
1733 
Ophthalmol. 1999;14(4):223-232. 
1734 
8. 
Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced 
1735 
retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally 
1736 
effective beta-isoform-selective inhibitor. Diabetes. Sep 1997;46:1473-1480. 
1737 
9. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1738 
diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. 
1739 
Arch Ophthalmol. 1985;103(12):1796-1806. 
1740 
10. 
Diabetic Retinopathy Clinical Research Network. A randomized trial comparing 
1741 
intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular 
1742 
edema. Ophthalmology. Sep 2008;115(9):1447-1449, 1449 e1441-1410. 
1743 
11. 
Diabetic Retinopathy Clinical Research Network. Three-year follow up of a randomized 
1744 
trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic 
1745 
macular edema. Arch Ophthalmol. 2009;127(3):245-251. 
1746 
12. 
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 
1747 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic 
1748 
macular edema. Ophthalmology. Jun 2010;117(6):1064-1077 e1035. 
1749 
13. 
Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the 
1750 
ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. Nov 
1751 
2009;116(11):2175-2181 e2171. 
1752 
14. 
Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards A, et al. A phase II 
1753 
randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. 
1754 
Ophthalmal. 2007;114(10):1860-1867. 
1755 
15. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: 
1756 
Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. Apr 
1757 
2012;119(4):789-801. 
1758 
16. 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study ranibizumab 
1759 
monotherapy or combined with laser versus laser monotherapy for diabetic macular 
1760 
edema. Ophthalmology. Apr 2011;118(4):615-625. 
1761 
17. 
Genentech I. Package Insert: Lucentis.  http://www.drugs.com/pro/lucentis.html. 
1762 
18. 
Browning DJ, Apte RS, Bressler SB, et al. Association of the extent of diabetic macular 
1763 
edema as assessed by optical coherence tomography with visual acuity and retinal 
1764 
outcome variables. Retina. Mar 2009;29(3):300-305. 
1765 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  9-2 
 
19. 
American Academy of Ophthalmology. Preferred Practice Patterns: Diabetic 
1766 
Retinopathy.  http://www.guideline.gov/summary/summary.aspx?doc_id=13502 
1767 
Accessed Accessed November 9, 2009. 
1768 
20. 
Genentech. Briefing Book: Dermatologic and ophthalmic drugs advisory committee 
1769 
meeting, Lucentis (ranibizumab injection).  
1770 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug
1771 
s/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM313089.pdf. Accessed 
1772 
Accessed: October 12, 2012. 
1773 
21. 
Do DV, Nguyen QD, Shah SM, et al. An exploratory study of the safety, tolerability and 
1774 
bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-
1775 
Eye in patients with diabetic macular oedema. Br J Ophthalmol. Feb 2009;93(2):144-149. 
1776 
22. 
Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary 
1777 
results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. Sep 
1778 
2011;118(9):1819-1826. 
1779 
23. 
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the DA VINCI Study of 
1780 
VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. Aug 
1781 
2012;119(8):1658-1665. 
1782 
24. 
Regeneron Pharmaceuticals. VEGF-Trap-Eye (aflibercept ophthalmic solution) Briefing 
1783 
Document: Ophthalmologic Drugs Advisory Committee 
1784 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug
1785 
s/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM259143.pdf. Accessed 22 
1786 
March 2012. 
1787 
25. 
US FDA approves EYLEA (aflibercept) injection for the treatment of we age-related 
1788 
macular degeneration.  
1789 
http://www.press.bayer.com/baynews/baynews.nsf/0/EB1AAB6D8405A0BDC125794A0
1790 
056C856. Accessed accessed January 1, 2012. 
1791 
26. 
Regeneron Pharmaceuticals I. VEGF TRAP-EYE (aflibercept ophthalmic solution) 
1792 
Ophthalmologic Drugs Advisory Committee Briefing Document.  
1793 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drug
1794 
s/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM259143.pdf. Accessed 
1795 
Accessed January 17, 2012. 
1796 
27. 
Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to 
1797 
central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J 
1798 
Ophthalmol. Mar 2013;97(3):278-284. 
1799 
28. 
Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular 
1800 
edema secondary to central retinal vein occlusion: 1-year results from the phase 3 
1801 
COPERNICUS study edema secondary to central retinal vein occlusion: 1-year results 
1802 
from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-437. 
1803 
29. 
Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for 
1804 
macular edema secondary to central retinal vein occlusion: six-month results of the phase 
1805 
3 COPERNICUS study. Ophthalmology. May 2012;119(5):1024-1032. 
1806 
30. 
Beck RW, Moke PS, Turpin AH, et al. A computerized method of visual acuity testing: 
1807 
adaptation of the early treatment of diabetic retinopathy study testing protocol. Am J 
1808 
Ophthalmol. Feb 2003;135(2):194-205. 
1809 
31. 
Two year results of phase 3 studies with EYLEA (aflibercept) injection in wet AMD 
1810 
show sustained improvement in visual acuity.  http://www.prnewswire.com/news-
1811 
releases/two-year-results-of-phase-3-studies-with-eylea-aflibercept-injection-in-wet-amd-
1812 
show-sustained-improvement-in-visual-acuity-135011348.html. Accessed 13 February 
1813 
2012. 
1814 


 
Treatment of CIDME in Eyes with Good Vision 9-17-13 FINAL                                      
                  9-3 
 
32. 
Schrader WF, Schargus M, Schneider E, Josifova T. Risks and sequelae of scleral 
1815 
perforation during peribulbar or retrobulbar anesthesia. J Cataract Refract Surg. Jun 
1816 
2010;36(6):885-889. 
1817 
33. 
Wolfs RC, Grobbee DE, Hofman A, de Jong PT. Risk of acute angle-closure glaucoma 
1818 
after diagnostic mydriasis in nonselected subjects: the Rotterdam Study. Invest 
1819 
Ophthalmol Vis Sci. Nov 1997;38(12):2683-2687. 
1820 
 
1821 
 
1822 
 
1823 
 
1824 

SAP_001.pdf: 
Diabetic Retinopathy Clinical Research Network 
Treatment for Central-Involved Diabetic Macular Edema in 
Eyes with Very Good Visual Acuity (Protocol V) 
Statistical Analysis Plan 
NCT01909791 
 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Wesley T. Beaulieu 
Michele Melia 
12 April 2017 
Initial version for Protocol version 3.0 
2.0 
Wesley T. Beaulieu 
 
27 July 2018 
Revisions following DSMC review of SAPs 
to harmonize with other DRCR.net SAPs. 
Still applies to Protocol version 3.0. 
Changes made after interim analysis but 
prior to primary analysis. Changes were not 
a result of the interim analysis. Section 9.0 
outlines the changes made and the rational 
for each change. 
 
 


Protocol V Statistical Analysis Plan 
 
 
Page 2 of 18 
1.0 Introduction 
1 
This document outlines the statistical analysis plan for the Diabetic Retinopathy Clinical 
2 
Research Network (DRCR.net) Protocol V comparing prompt focal/grid photocoagulation with 
3 
deferred intravitreous anti-vascular endothelial growth factor (VEGF), observation with deferred 
4 
intravitreous anti-VEGF, and prompt intravitreous anti-VEGF for treatment of central-involved 
5 
diabetic macular edema (CI-DME). The anti-VEGF agent used in this trial is aflibercept 
6 
(Eylea®, Regeneron Pharmaceuticals, Tarrytown, NY). 
7 
The primary objective of the protocol is to determine if there are differences between the three 
8 
treatment groups in the proportion of eyes that lose 5 or more letters of visual acuity from 
9 
baseline at the 2-year (104-week) visit. Several secondary outcomes will be analyzed. These 
10 
include the mean change in visual acuity, the proportion of eyes with 20/20 vision or better, and 
11 
the mean change in OCT central subfield thickness (CST). Analyses with visual acuity or CST as 
12 
outcomes (continuous or binary) will adjust for baseline visual acuity or CST, respectively, as 
13 
the average of the two values from the screening and randomization visits. If the average results 
14 
in a decimal (.5), the value will be rounded up if the randomization value is higher than the 
15 
screening visit value, otherwise it will be rounded down so that the baseline value is always an 
16 
integer. This rounding approach is the same method used in the protocol when calculating 
17 
change in visual acuity for retreatment. 
18 
Study eyes are assigned randomly to the three treatment groups in a 1:1:1 ratio stratified by site 
19 
and recent (within 4 months) or planned DME treatment in the fellow eye (yes or no). 
20 
Participants may have only one study eye enrolled in the randomized trial. The fellow eye may, 
21 
however, be enrolled in the observational phase. Eyes enrolled in the observational phase will be 
22 
used to collect data on the natural history of diabetic macular edema and are used in exploratory 
23 
analyses. For eyes entering the randomized trial from the observational phase, the last 
24 
observational follow-up visit may be used in place of the screening visit. 
25 
2.0 Efficacy Analysis Plan 
26 
2.1 Primary Outcome Analysis 
27 
The primary outcome is a 5 or more letter decrease in visual acuity letter score from baseline at 
28 
104 weeks. The primary analysis will be an intention-to-treat analysis that includes all 
29 
randomized eyes according to the treatment group assignment at randomization. Treatment group 
30 
comparisons will be conducted using binomial regression with an identity link (estimating risk 
31 
difference) and adjusting for baseline visual acuity and recent or planned DME treatment in the 
32 
fellow eye at the time of randomization. If binomial regression is not feasible then Poisson 
33 
regression with a robust error variance and log link (estimating risk ratio) will be used while still 
34 
adjusting for baseline visual acuity and recent or planned DME treatment in the fellow eye at the 
35 
time of randomization (Spiegelman and Hertzmark 2005). If Poisson regression is needed for one 
36 
or more analyses, then Poisson regression may be used for analysis of all binary outcomes to 
37 
harmonize the presentation of results. 
38 


Protocol V Statistical Analysis Plan 
 
 
Page 3 of 18 
The primary analysis will include three two-group comparisons of the proportion of eyes 
39 
meeting the primary outcome at 104 weeks. Experiment-wise Type 1 error rate (α) will be 0.05 
40 
(2-sided). The Hochberg (1988) procedure will be used to control the overall Type 1 error for 
41 
multiple comparisons. This procedure contrasts P values p(1), p(2), p(3), ordered from least to 
42 
greatest, with a set of critical values and rejects all null hypotheses with smaller or equal P 
43 
values to that of any one found less than its critical value. It can be summarized as follows: 
44 
• If p(3) ≤ α, then stop and reject H0(1), H0(2), H0(3) at level α; otherwise fail to reject 
45 
H0(3) and go to the next step 
46 
• If p(2) ≤ α/2 then stop and reject H0(1) and H0(2); otherwise fail to reject H0(2) and go to 
47 
the next step 
48 
• If p(1) ≤ α/3 then stop and reject H0(1); otherwise fail to reject H0(1) 
49 
For the primary analysis, α = 0.05, p(k) = kth highest ordered P value, H0(k) = hypothesis with P 
50 
values p(k), k = 1, 2, 3  
51 
Multiple comparisons will be handled similarly for all secondary and exploratory outcomes (i.e., 
52 
visual acuity, CST, and diabetic retinopathy severity). 
53 
Missing data will be imputed with Markov chain Monte Carlo (MCMC) multiple imputation. 
54 
The imputation model will include treatment group, recent or planned DME treatment in the 
55 
fellow eye, the level of baseline visual acuity in the study eye, and the change in study-eye visual 
56 
acuity from baseline to all common follow-up visits (i.e., 8, 52, and 104 weeks). The primary 
57 
outcome of a 5 or more letter loss in visual acuity from baseline to 104 weeks will be calculated 
58 
from the imputed data sets. To reiterate, continuous missing visual acuity letter scores are what 
59 
will be imputed using the MCMC model; the missing binary primary outcome will be calculated 
60 
using the imputed letter scores. 
61 
A plot showing the primary outcome over time will be constructed using observed data. In 
62 
general, summary statistics (e.g., proportion of eyes losing 5 or more letters from baseline) for all 
63 
outcomes, will be based on observed data while numbers from statistical models (e.g., treatment 
64 
group differences, confidence intervals, and P values) will be based on imputed data, where 
65 
applicable. 
66 
2.1.1 Sensitivity Analyses 
67 
A sensitivity analysis that does not use multiple imputation and only includes observed data (i.e., 
68 
only participants who complete the 104-week visit with no imputation of missing data) will be 
69 
conducted. If the results from the primary analysis and sensitivity analysis are discrepant, an 
70 
exploratory analysis will be carried out to identify factors that contributed to the difference. 
71 
In the event that outcome rates are much lower than expected, i.e. fewer than 5 events in one or 
72 
more treatment groups, a second sensitivity analysis, also using observed data (no imputation), 
73 
will be conducted using exact logistic regression adjusting for baseline visual acuity and recent 
74 


Protocol V Statistical Analysis Plan 
 
 
Page 4 of 18 
or planned DME treatment in the fellow eye. In this case, results from exact logistic regression 
75 
may be more robust than results from binomial regression. If differences from the two analyses 
76 
emerge, exploratory analyses will be carried out to identify factors that contributed to the 
77 
difference. 
78 
2.1.2 Per-Protocol Analysis  
79 
A per-protocol analysis of the primary outcome will be conducted using only observed data (no 
80 
imputation) in which any eye receiving a treatment for DME prior to 2 years other than 
81 
focal/grid photocoagulation or an anti-VEGF injection will be excluded. If the results differ from 
82 
the primary intention-to-treat analysis, exploratory analyses will be performed to identify factors 
83 
that contributed to the difference. The per-protocol analysis will only be performed if more than 
84 
10% of randomized participants would be excluded by these criteria. 
85 
2.1.3 Confounding 
86 
Imbalances between groups in important covariates are not expected to be of sufficient 
87 
magnitude to produce confounding. However, the presence of confounding will be evaluated in 
88 
regression models using observed data by including baseline participant and study eye covariates 
89 
including but not limited to the following: age, duration of diabetes, HbA1c, prior treatment for 
90 
DME, and diabetic retinopathy severity as graded by the photograph reading center. Variables 
91 
associated with the outcome will be included in regression models if there is an imbalance in the 
92 
variables between treatment groups. Imbalance by treatment group will not be judged using 
93 
statistical testing. Instead, imbalance will be judged by whether the size of the imbalance is 
94 
clinically important, i.e., whether the imbalance is large enough to have a clinically important 
95 
effect on the primary outcome. 
96 
2.1.4 Subgroup Analyses 
97 
Pre-planned subgroup analyses will repeat the primary analysis while including an interaction 
98 
term for the baseline subgroup factor by treatment. Only observed data (no imputation) will be 
99 
used for these analyses. Unless the imputation process is done separately for each treatment 
100 
group and the subgroup factor is included in the imputation model, the analysis is biased towards 
101 
the null hypothesis of no interaction when an interaction is present (Sullivan et al., 2016). It is 
102 
recognized that analyzing only observed data also may be biased, but unlike the imputed 
103 
analysis, it is not necessarily biased in the presence of interaction. In addition, the usual 
104 
procedure for combining results across imputed datasets in not necessarily valid for the global 
105 
test of interaction. 
106 
A significant (P ≤ .05) type III test of the interaction term will be taken as an indication that 
107 
subgroup effects need to be explored for full interpretation of the trial results. In addition, within-
108 
subgroup treatment effects and 95% confidence intervals will be estimated from the interaction 
109 
model if the interaction P value is less than .05. It is recognized that the study is not powered to 
110 
detect subgroup effects and that lack of significance for the subgroup tests of interaction is not 
111 
necessarily an indication that subgroup effects do not exist.  
112 


Protocol V Statistical Analysis Plan 
 
 
Page 5 of 18 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
113 
significant treatment effect. In the absence of a significant treatment effect in the primary 
114 
analysis, analyses of subgroups will be interpreted with caution. 
115 
Baseline variables to be evaluated for subgroup effects include the following:  
116 
• OCT central subfield thickness: continuous and < 400 µm vs. ≥ 400 µm 
117 
• Diabetic retinopathy severity level from fundus photographs: continuous (ordinal 
118 
numeric transformation of retinopathy severity grades) and categorical (proliferative 
119 
diabetic retinopathy [PDR] vs. non-proliferative diabetic retinopathy [NPDR] or less) 
120 
• Presence of central epiretinal membrane or vitreomacular traction graded on OCT by the 
121 
central reading center: yes vs. no 
122 
Note that subgroups will only be analyzed if there are at least 20 eyes in each treatment group for 
123 
each subgroup to increase statistical precision. Cutoffs of continuous and ordinal outcomes may 
124 
be modified to achieve a reasonable number of eyes in each group. 
125 
The above subgroups are considered those of primary interest for which a rationale for a 
126 
subgroup effect is hypothesized. For each factor, the rationale for performing the analysis is 
127 
listed in Table 1 below. 
128 
Table 1. Subgroup analyses. 
129 
Factor 
Rationale 
OCT central subfield thickness 
There are conflicting reports in the literature as to whether 
laser is relatively less effective when used in thicker retinas 
as compared to thinner ones when comparing to anti-VEGF 
(i.e., there is an quantitative interaction; anti-VEGF is 
expected to be better than laser for both thick and thin 
retinas, the difference will be greater for thick retinas).  
Diabetic retinopathy severity 
level from fundus photographs 
Eyes with more advanced retinopathy may have better 
outcomes with anti-VEGF, which is known to be effective in 
treating diabetic retinopathy. 
Presence of epiretinal 
membrane or vitreomacular 
traction 
Eyes with epiretinal membrane or vitreomacular traction 
have thickening that is less likely to resolve and may meet 
failure criteria faster and receive anti-VEGF. This could 
make outcomes from the observation and laser groups more 
similar to the anti-VEGF group because they will be treated 
more similarly. 


Protocol V Statistical Analysis Plan 
 
 
Page 6 of 18 
The following subgroup factors also will be evaluated in exploratory analyses. The finding of a 
130 
significant subgroup effect for any of these factors will be interpreted as hypothesis generating 
131 
only and in need of confirmation from further studies. 
132 
• Leakage patterns identified on fluorescein angiography and clinical exam: yes vs. no 
133 
• Presence of circinate ring: yes vs. no 
134 
• Duration of diabetes: continuous and categorical (dichotomized based on a clinically-
135 
relevant cut point) 
136 
• Duration of DME: continuous and categorical (dichotomized based on a clinically-
137 
relevant cut point) 
138 
• Lens status: phakic vs. pseudophakic  
139 
• Prior DME treatment: yes vs. no 
140 
• Prior focal/grid laser for DME: yes vs. no 
141 
• Prior anti-VEGF for DME: yes vs. no 
142 
• Prior panretinal photocoagulation (PRP) treatment: yes vs. no 
143 
• Age: continuous and < 60 vs. ≥ 60 years 
144 
• HbA1c: continuous and < 7.5% vs. ≥ 7.5% 
145 
• Sex: female vs. male 
146 
• Race/Ethnicity: non-Hispanic white vs. black/African American vs. Hispanic (exclude all 
147 
others due to anticipated small sample size) as well as white vs. non-white 
148 
Interaction P values will be calculated using the continuous or ordinal variables where possible 
149 
in addition to the categorizations described above. 
150 
 
2.1.5 Center Effects 
151 
The number of study participants per center is expected to be small for many centers. Therefore, 
152 
center effects will not be included in the statistical model. However, for centers with a large 
153 
number of study participants (N ≥ 20 per treatment group), heterogeneity across centers will be 
154 
explored using random center effects by estimating empirical best linear unbiased predictors 
155 
along with 95% confidence intervals. 
156 
2.2 Secondary Analyses of Visual Acuity 
157 
Additional analyses will be conducted on the visual acuity data, primarily to aid clinicians and 
158 
patients in the interpretation of the primary outcome results and to explore treatment group 
159 
effects at other follow-up times (52 weeks). The secondary visual acuity outcomes and the 
160 
analysis methods are specified in Table 2. All analyses will include adjustments for baseline 
161 
visual acuity and recent or planned DME treatment in the fellow eye. With the exception of low-
162 


Protocol V Statistical Analysis Plan 
 
 
Page 7 of 18 
contrast visual acuity, analyses will use the imputed data sets created for the calculation of the 
163 
primary outcome. For low-contrast visual acuity, a new group of imputed data sets will be 
164 
created as described in section 2.1 except low-contrast visual acuity will be substituted for visual 
165 
acuity. Only eyes with low-contrast visual acuity measurements at baseline will be included 
166 
since not all sites have low-contrast visual acuity capability. 
167 
Table 2. Additional Analyses of Visual Acuity. 
168 
Outcome 
Analysis Technique 
Failure proportion: Worsening ≥ 15 letters 
Binomial regression 
Failure proportion: Worsening ≥ 10 letters 
Binomial regression 
Failure proportion:  Worsening ≥ 5 letters* 
Binomial regression 
Success proportion: Improvement ≥ 5 letters 
Binomial regression 
Proportion with study-eye visual acuity ≥ 84 letters 
(approximately 20/20) 
Binomial regression 
Mean change in visual acuity 
ANCOVA 
Mean change in low-contrast visual acuity† 
ANCOVA 
*At 52 weeks only. The primary analysis evaluates this response at 104 weeks. 
169 
†Adjusting for baseline low-contrast visual acuity instead of visual acuity.  
170 
A plot that shows the mean change in visual acuity from baseline by treatment group over time 
171 
will be constructed with observed data. 
172 
2.3 Analysis of Retinal Thickness Secondary Outcomes 
173 
Several OCT CST outcomes are of interest and will be evaluated at 52 and 104 weeks. Each 
174 
analysis will adjust for baseline CST and recent or planned DME treatment in the fellow eye. All 
175 
CST values will be converted to time-domain equivalents prior to analysis. The outcomes and 
176 
the analysis techniques to be used are specified in Table 3. Analyses will use multiply imputed 
177 
data sets created as described in section 2.1 but substituting CST for visual acuity. 
178 


Protocol V Statistical Analysis Plan 
 
 
Page 8 of 18 
Table 3. Analyses of Retinal Thickness. 
179 
Outcome 
Analysis Technique 
Mean change in OCT CST 
ANCOVA 
Success proportion: 2 log step increase in CST 
Binomial regression 
Success proportion: 1 log step increase in CST 
Binomial regression 
Failure proportion: 1 log step decrease in CST 
Binomial regression 
Failure proportion: 2 log step decrease in CST 
Binomial regression 
Proportion of eyes with CST less than gender-specific 
spectral domain equivalent of 250 µm on Zeiss Stratus 
and at least a 10% CST decrease from baseline* 
Binomial regression 
Success proportion: 10% CST decrease from baseline 
Binomial regression 
Mean change in OCT retinal volume 
ANCOVA 
*No imputation of missing data because machine-specific, rather than time-domain equivalent, values are used 
180 
A plot that shows the mean change in OCT CST from baseline by treatment group over time will 
181 
be constructed with observed data. 
182 
2.4 Exploratory Outcomes 
183 
2.4.1 Change in Visual Acuity Area Under the Curve 
184 
Change in visual acuity area under the curve (AUC) will be computed for each participant from 
185 
baseline to 104 weeks using the imputed data sets. Analysis of covariance adjusting for baseline 
186 
visual acuity and recent or planned DME treatment will be used to test for differences between 
187 
the treatment groups. 
188 
Only common visits (baseline, 8, 52, and 104 weeks) will be used in the AUC analysis. AUC 
189 
will be calculated for each participant according to the trapezoidal rule: 
190 
𝐴𝐴𝐴𝐴𝐴𝐴= ෍൬𝑉𝑉𝑖𝑖+ 𝑉𝑉𝑖𝑖+1
2
× 𝑑𝑑൰
𝑛𝑛
𝑖𝑖=1
  
191 
Where Vi is the change in visual acuity from baseline measured at the ith visit, d is the number of 
192 
days between visits i and i+1, and n is the number of common visits included in the analysis. For 
193 
example, the 104-week outcome has n = 4 as the analysis will include visits at baseline, 8, 52, 
194 
and 104 weeks. Note that the change in visual acuity from baseline is equal to 0 at baseline. For 
195 
presentation, AUC will be divided by the number of days between baseline and the 104-week 
196 
visit so that the value shown will have units of letters rather than letter⋅days. This statistic can 
197 
then be interpreted as the average change in visual acuity over the time between baseline and the 
198 
104-week visit. 
199 


Protocol V Statistical Analysis Plan 
 
 
Page 9 of 18 
2.4.2 Diabetic Retinopathy 
200 
Several outcomes of interest related to diabetic retinopathy (DR) will be assessed at 52 and 104 
201 
weeks using observed data only (no imputation). All analyses will adjust for baseline DR 
202 
severity and recent or planned DME treatment. The outcomes and the analysis techniques to be 
203 
used are specified in Table 4, while definitions for DR improvement and worsening outcomes 
204 
are given in Table 5. 
205 
Table 4. Analyses of Diabetic Retinopathy Severity. 
206 
Outcome 
Analysis Technique 
Proportion with improvement in DR severity graded on color 
fundus photographs 
Binomial regression 
Proportion of eyes with worsening of DR graded on color 
fundus photographs 
Binomial regression 
Time to worsening of DR on color fundus photographs over 
2 years 
Cox proportional hazards 
regression 
Among eyes with PDR at randomization, development of 
vitreous hemorrhage or receipt of PRP, anti-VEGF for PDR, 
or vitrectomy for PDR 
Cox proportional hazards 
regression 
Table 5. Definitions for Improvement and Worsening of Diabetic Retinopathy on Photos 
207 
Baseline 
Worsening 
(if FU ≥) 
Improvement 
(if FU ≤) 
NPDR 
10/12 
35 
Exclude 
14/15/20 
43 
Exclude 
35 
47 
10/12 
43 
53 
14/15/20 
47 
60 
35 
53 
60 
43 
PDR 
60 
65 
Exclude 
61 
71 
53 or 60* 
65 
75 
53 or 60* 
71 
81 
61 
75 
81 
65 
81 
Exclude 
71 
85 
Exclude 
75 
FU, follow up 
208 
*If an eye had PRP prior to baseline (on clinical exam), changing from ≥ 61 to 60 will be defined as improvement. If 
209 
an eye did not have PRP prior to baseline, changing from 61/65 to 53 will be defined as improvement. 
210 


Protocol V Statistical Analysis Plan 
 
 
Page 10 of 18 
For the time-to-worsening analysis, participants who are lost to follow up will be considered 
211 
censored on the day of their last visit. Participants that do not experience worsening of DR and 
212 
complete the 104-week visit will be considered censored on the day of that visit. Hazard ratios 
213 
will be presented along with the cumulative probability of worsening within each group to aid in 
214 
interpretation. 
215 
A Kaplan-Meier curve showing time-to-worsening of DR by treatment group will be constructed 
216 
along with the number of participants at risk at baseline and 52 weeks, and the number of events 
217 
through 52 and 104 weeks. 
218 
2.4.3 Additional Exploratory Outcomes 
219 
The proportion of eyes with focal leakage patterns on fluorescein angiography randomized to 
220 
prompt focal/grid photocoagulation with deferred intravitreous anti-VEGF that did not require 
221 
subsequent anti-VEGF treatment will be tabulated. 
222 
3.0 Eyes in the Observational Phase 
223 
Eyes in the observational phase will be followed until one of the following occurs: 
224 
1. 
The eye is randomized 
225 
2. 
The eye receives non-topical DME treatment as part of usual care 
226 
3. 
The participant reaches 2 years (104 weeks) from enrollment 
227 
The primary objective of the observational phase is to collect data on the natural history of eyes 
228 
that present with CI-DME and good vision that do not enroll in the randomized trial initially. 
229 
Therefore, the proportion and 95% Wilson (Score) confidence interval (Newcombe 1998) of 
230 
eyes that meet the following endpoints will be determined: 
231 
• Never need treatment  
232 
• Receive non-topical DME treatment 
233 
• Are randomized into Protocol V 
234 
Eyes completing 104 weeks of follow up and eyes lost to follow up in the observational phase 
235 
that do not receive non-topical DME treatment or enter the randomized trial will be counted as 
236 
never needing treatment. 
237 
3.1 Observational Phase Exploratory Analyses 
238 
In addition, data from the observational phase will be used in exploratory analyses to identify 
239 
subgroups not needing DME treatment, to explore outcomes in eyes never needing treatment, 
240 
and to explore outcomes in eyes randomized immediately vs. after enrolling in the observational 
241 
phase. The specifics of these analyses will be developed later. 
242 


Protocol V Statistical Analysis Plan 
 
 
Page 11 of 18 
4.0 Economic Analysis 
243 
The purpose of the economic analysis is to compare the treatment groups with respect to cost and 
244 
cost-effectiveness. The analysis plan is briefly described and will be detailed in a separate 
245 
document. 
246 
Resource utilization data will be calculated using the number of clinic visits, along with the 
247 
number and types of diagnostic and therapeutic ocular procedures performed on each group. To 
248 
capture patient resource utilization, cost data for all diagnostic and therapeutic procedures 
249 
performed will be tabulated to obtain a total cost for eye care services over 2 years of follow up. 
250 
To capture the health-related quality-of-life associated with receipt of the three interventions 
251 
over the course of the trial, two methods will be used. The first method will be to convert the 
252 
visual acuities from the better-seeing eye over the two years of the trial into Quality-Adjusted 
253 
Life-Years (QALYs) using the methods of Brown et al (2003). This method has been used 
254 
widely in prior cost-effectiveness analyses of ophthalmologic interventions. The second method 
255 
will use the best-corrected visual acuities from the treated eye, regardless of whether it is the 
256 
better or worse-seeing eye. Resource use, costs and QALYS will be aggregated over the two 
257 
years of the trial. The incremental cost-effectiveness ratio (ICER) will calculated by taking the 
258 
incremental cost of prompt anti-VEGF over prompt focal/grid photocoagulation with deferred 
259 
intravitreous anti-VEGF or observation with deferred anti-VEGF and dividing them by the 
260 
incremental QALYs of prompt anti-VEGF over prompt focal/grid photocoagulation with 
261 
deferred intravitreous anti-VEGF or observation with deferred anti-VEGF. A probabilistic 
262 
sensitivity analysis will be conducted to better characterize overall uncertainty in the results. 
263 
5.0 Safety Analysis 
264 
Adverse events will be categorized as study eye, fellow eye, and systemic. All randomized eyes 
265 
will be included in the safety analyses and analyzed according to treatment group assignment at 
266 
randomization. An additional tabulation will be made for adverse events possibly related to study 
267 
treatment. For the 104-week primary analysis, any adverse event that occurred at least once prior 
268 
to the 104-week visit (or 728 days if the participant did not complete the 104-week visit) will be 
269 
reported. If the overall test has P ≤ .05, then pairwise comparisons between groups will be 
270 
performed with no further adjustment for multiple comparisons. For all analyses, the hypothesis 
271 
test of no difference between treatment groups will be conducted. 
272 
Due to the different visit schedules among the treatment groups, the ratio of adverse events and 
273 
number of visits will be provided in addition to the number of eyes with an adverse event and the 
274 
total number of adverse events for each treatment group. This will attempt to account for a 
275 
potential disproportion of reported adverse events observed in the prompt anti-VEGF treatment 
276 
group because of having more visits. 
277 
5.1 Ocular Adverse Events (Injection and Drug-Related) 
278 
Ocular adverse events will be tabulated separately for the three treatment groups. The frequency 
279 
of the event occurring at least once per study eye will be calculated. Eye-level outcomes will be 
280 
compared between treatment groups using Fisher’s exact test. 
281 


Protocol V Statistical Analysis Plan 
 
 
Page 12 of 18 
The following adverse events will be assessed: 
282 
• Endophthalmitis 
283 
• Any retinal detachment (rhegmatogenous, tractional, combined rhegmatogenous and 
284 
tractional, or not otherwise specified) 
285 
o Rhegmatogenous retinal detachment (tabulated without formal analysis) 
286 
o Tractional retinal detachment (tabulated without formal analysis) 
287 
• Retinal tear 
288 
• Cataract 
289 
• Cataract surgery 
290 
• Vitreous hemorrhage 
291 
• Ocular inflammation 
292 
• Intraocular pressure (IOP) elevation (any of the following) 
293 
o Increase of IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
294 
o IOP ≥ 30 mmHg (at a follow-up visit) 
295 
o Initiation of glaucoma medications 
296 
o Glaucoma procedure  
297 
• Neovascularization of the iris or neovascular glaucoma 
298 
5.2 Systemic Adverse Events 
299 
Systemic adverse events will tabulated separately for the three treatment groups. The frequency 
300 
of the event occurring at least once per participant will be calculated. Rates of systemic adverse 
301 
events will be compared using Fisher’s exact test. 
302 
Primary: 
303 
• Death 
304 
• Serious adverse event (at least one) 
305 
• Hospitalizations (at least one) 
306 
• Cardiovascular and cerebrovascular events according to the Antiplatelet Trialists’ 
307 
Collaboration (excerpted from BMJ Jan 8, 1994): 
308 
o Non-fatal myocardial infarction 
309 
o Non-fatal stroke (counted only if symptoms lasted at least 24 hours) 
310 
o Death attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular (does 
311 
not need to be ischemic in origin), or unknown cause 
312 


Protocol V Statistical Analysis Plan 
 
 
Page 13 of 18 
o At least one event (non-fatal myocardial infarction, non-fatal stroke, or death 
313 
attributed to potential vascular or unknown cause) 
314 
Note that transient ischemic attack, angina, possible myocardial infarction, and possible stroke 
315 
are not counted. Non-fatal myocardial infarction and non-fatal stroke require that the patient is 
316 
alive at the end of the study. If not, then only the death is counted. 
317 
Secondary (for tabulation without formal statistical comparison): 
318 
• Hypertension 
319 
• Frequency of at least one event per participant in each Medical Dictionary for Regulatory 
320 
Activities (MedDRA) system organ class 
321 
6.0 Additional Tabulations and Analyses 
322 
The following will be tabulated according to treatment group: 
323 
• Baseline demographic and clinical characteristics 
324 
• Visit completion rate for each visit 
325 
• Protocol deviations 
326 
The following treatment-related quantities will be tabulated by treatment group for patients that 
327 
complete the 52- and 104-week visits: 
328 
• Number of injections 
329 
• Number of focal/grid photocoagulation sessions performed 
330 
• Number of visit (scheduled or unscheduled) 
331 
The proportion of eyes needing anti-VEGF treatment (deferred anti-VEGF groups only) also will 
332 
be tabulated. All participants will be included in the calculation of the proportion, regardless of 
333 
loss to follow up or visit completion. 
334 
7.0 Interim Monitoring Plan 
335 
A formal plan for interim data monitoring was established in consultation with the Data and 
336 
Safety Monitoring Committee. The details are provided in the following document: 
337 
F:\user\aDRCRN\Protocols\Protocol V - Anti-VEGF vs Laser for CI DME with Excellent 
338 
VA\Statistics\Interim analysis\Protocol V Interim Monitoring Plan v1.0 10-08-14.docx 
339 


Protocol V Statistical Analysis Plan 
 
 
Page 14 of 18 
8.0 General Principles for Analysis 
340 
8.1 Analysis Cohort 
341 
Unless otherwise stated, all treatment comparison analyses will follow the intention-to-treat 
342 
principle with all randomized eyes included and each eye analyzed according to the randomized 
343 
treatment assignment, regardless of treatment actually received. 
344 
8.2 Visit Windows for Analysis 
345 
For common visits, the analysis windows will be defined according to Table 6. 
346 
Table 6. Analysis Windows for Common Visits 
347 
Visit (Protocol Window) 
Target 
Analysis Window 
8 weeks ± 1 or 2 weeks* 
56 days 
28 – 84 days   
(8 ± 4 weeks) 
52 weeks ± 2 weeks 
364 days 
308 – 420 days 
(52 ± 8 weeks) 
104 weeks ± 4 weeks 
728 days 
644 – 812 days 
(104 ± 12 weeks) 
*Within 2 weeks for deferred anti-VEGF arms and within 1 week for prompt anti-VEGF arm 
348 
8.3 Missing Data 
349 
The strategy for handling missing data generally is included with the description of each 
350 
analysis. Where not otherwise specified, only participants with non-missing data are included in 
351 
the analysis. 
352 
8.4 Outliers 
353 
To help ensure that statistical outliers do not have undue impact on analyses of continuous visual 
354 
acuity and CST outcomes, these variables will be truncated to ± 3 standard deviations, with the 
355 
standard deviation based upon observed data from 104-week completers at the 104-week visit, 
356 
irrespective of treatment group. Truncation will be performed after imputation of missing data, 
357 
where applicable. Change in visual acuity AUC will be calculated from imputed, truncated data, 
358 
with no truncation of the AUC outcome itself. 
359 
8.5 Model Assumptions 
360 
All model assumptions, including linearity, normality of residuals, heteroscedasticity, and 
361 
proportional hazards will be verified. If model assumptions are not reasonably satisfied, 
362 
covariates may be categorized or excluded, and a non-parametric approach, robust method, or 
363 
transformation may be considered. 
364 


Protocol V Statistical Analysis Plan 
 
 
Page 15 of 18 
9.0 Rationale for Key Changes  
365 
9.1 Version 1.0 to 2.0 
366 
The following changes were made in version 2.0. Changes were made prior to the primary 
367 
analysis but after interim analysis. However, changes were not in response to the results of the 
368 
analysis. 
369 
• Section 2.1 
370 
o Removed the provision for using Poisson regression with an identity link if 
371 
binomial regression with an identity link fails to converge. Poisson regression 
372 
with the canonical log link will be used in this situation because it is more stable. 
373 
In addition, Poisson regression with identity link was not pre-specified in the 
374 
protocol. 
375 
o Removed allocation of .001 alpha for DMSC review. The primary analysis will 
376 
now be conducted with alpha of .05 rather than .049. The DSMC was supportive 
377 
of this change, as such an allocation was considered arbitrary.  
378 
• Sections 2.1.1 to 2.1.5 
379 
o Added provision that the sensitivity analysis with exact logistic regression will 
380 
only be performed if there are fewer than 5 events in any of the treatment groups. 
381 
The purpose of this analysis is to validate the results of the primary analysis if 
382 
event rates are much lower than expected. If there are at least 5 events in each 
383 
group, then the primary analysis is expected to be reliable. 
384 
o Added provision that the per-protocol analysis will be performed only if more 
385 
than 10% of randomized eyes would be excluded by the per protocol criteria. It is 
386 
thought that any less than this is unlikely to have an effect on the results. 
387 
o Added clarification that within-subgroup estimates of treatment effect will only be 
388 
presented if the P value for the interaction term is ≤ .05. 
389 
o Increased the minimum number of eyes per treatment group per subgroup that 
390 
will be required for a subgroup analysis to be performed from 10 to 20. Having 
391 
fewer than 20 eyes in a group could lead to imprecise and unreliable estimates. 
392 
o Reclassified leakage pattern on fluorescein angiogram as an exploratory subgroup 
393 
analysis because subgroup categories are still being defined. 
394 
o Added presence of circinate ring as an exploratory subgroup analysis because it is 
395 
of interest to investigators. 
396 


Protocol V Statistical Analysis Plan 
 
 
Page 16 of 18 
o Added duration of diabetes, duration of DME, and lens status as exploratory 
397 
subgroup analyses because they are listed in the protocol. 
398 
o Changed the minimum number of eyes per treatment group per center required for 
399 
analysis of center effects from 30 to 20 to harmonize with the minimum number 
400 
required for subgroup analyses. 
401 
• Sections 2.2 to 2.4 
402 
o Clarified that the proportion of eyes with CST below gender- and machine-
403 
specific cutoffs will be analyzed without imputation of missing data because this 
404 
outcome is calculated based on machine-specific values rather than the time-
405 
domain converted values that will be imputed for other analyses. 
406 
o Added retinal volume as a secondary outcome for consistency with other 
407 
protocols. 
408 
o Changed analysis method from binomial regression to cox proportional hazards 
409 
regression for development of a PDR event or receipt of treatment to treat a PDR 
410 
event. Since the component outcomes can occur at any time, the time-to-event 
411 
approach will increase statistical precision. 
412 
• Section 3.0 
413 
o Replaced exact mid-P confidence intervals with Wilson (Score) confidence 
414 
intervals for analysis of observational phase data because the exact intervals are 
415 
unnecessarily conservative (Newcombe 1998). In addition, the Wilson interval 
416 
has a simple formula for calculation. 
417 
• Section 5.0 
418 
o Changed alpha level of safety analyses from .01 to .05. The DSMC was 
419 
supportive of this change as safety analyses in this trial should be viewed as 
420 
exploratory. 
421 
o Added cataract as a safety outcome because it was pre-specified in the protocol. 
422 
o Added neovascular glaucoma to form a composite safety outcome with 
423 
neovascularization of the iris as these outcomes are on the same disease pathway 
424 
(neovascularization of the iris is a precursor to neovascular glaucoma). In 
425 
addition, event rates for both outcomes are expected to be low in this population. 
426 
o Combined death of unknown cause with death attributed to cardiac, cerebral, 
427 
hemorrhagic, embolic, or other vascular cause into one outcome for consistency 
428 
with other protocols. 
429 


Protocol V Statistical Analysis Plan 
 
 
Page 17 of 18 
o Added composite APTC safety outcome for consistency with other protocols.  
430 
• Section 8.4 
431 
o Modified the handling of outliers in the AUC analysis for consistency with other 
432 
protocols. 
 
433 


Protocol V Statistical Analysis Plan 
 
 
Page 18 of 18 
References 
434 
Brown NM, Brown GC, Sharma S, Landy J. Health care economic analyses and value-based 
435 
medicine. Surv Ophthalmol. 2003;48(2):204-23. 
436 
Hochberg Y. A Sharper Bonferroni Procedure for Multiple Significance Testing. Biometrika. 
437 
1988;75:800–803. 
438 
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven 
439 
methods. Stat Med. 1998;17:857-872. 
440 
Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. 
441 
Am J Epidemiol. 2005;162(3):199-200. 
442 
Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of 
443 
choice for handling missing data in randomized trials? Stat Methods Med Res. 2016. DOI: 
444 
https://doi.org/10.1177/0962280216683570. 
445