Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy
Phase: PHASE2
Conditions: Diabetic Macular Edema
Sponsor: Jaeb Center for Health Research

 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15  
 
 
 
 
 
Diabetic Retinopathy Clinical Research 
Network 
 
 
Short-term Evaluation of 
Combination Corticosteroid+Anti-
VEGF Treatment for Persistent  
Central-Involved Diabetic Macular 
Edema Following Anti-VEGF 
Therapy 
 
 
Version 5.0 
 
November 16, 2015 

 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15  
 
 
 
Contact Information 
 
 
Coordinating Center 
Director: Adam R. Glassman, M.S. 
Jaeb Center for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL  33647 
Phone:  813-975-8690 
Fax:  800-816-7601 
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 
Email: l-jampol@northwestern.edu 
 
 
Protocol Chair 
Raj K. Maturi, MD 
Midwest Eye Institute 
200 West 103rd  Street, Suite 1060 
Indianapolis, IN 46290 
Phone: (317) 817-1414   
Fax: (317) 817-1399 
Email: rmaturi@gmail.com 
 
 
 

 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15  
 
  
 
 
Table of Contents 
1 
 
2 
Chapter 1. Background Information and Study Synopsis ..................................................... 1-3 
3 
1.1 
Rationale ..................................................................................................................................................... 1-3 
4 
1.1.1 Public Health Impact of DME ................................................................................................................. 1-3 
5 
1.1.2 Rationale for Anti-VEGF Treatment for DME ....................................................................................... 1-3 
6 
1.1.3 Evolution of Standard Therapy for DME ................................................................................................ 1-3 
7 
1.1.4 Eyes with Persistent DME following Therapy with Anti-VEGF Drugs ................................................. 1-5 
8 
1.1.5 Rationale for Corticosteroid Treatment for DME ................................................................................... 1-5 
9 
1.1.6 Combination Steroid and Anti-VEGF treatment for DME ..................................................................... 1-6 
10 
1.1.7 Available Steroids ................................................................................................................................... 1-7 
11 
1.1.8 Summary of Rationale for the Study ....................................................................................................... 1-7 
12 
1.2 Study Objectives ............................................................................................................................................. 1-8 
13 
1.3 Study Design and Synopsis of Protocol .......................................................................................................... 1-8 
14 
1.4 General Considerations ................................................................................................................................. 1-11 
15 
Chapter 2. Study Participant Eligibility and Enrollment ...................................................... 2-1 
16 
2.1 Identifying Eligible Study Participants and Obtaining Informed Consent ...................................................... 2-1 
17 
2.2 Study Participant Eligibility Criteria ............................................................................................................... 2-1 
18 
2.2.1 Participant-level Criteria ......................................................................................................................... 2-1 
19 
2.2.2 Study Eye Criteria ................................................................................................................................... 2-2 
20 
2.2.3 Non-study Eye Criteria ........................................................................................................................... 2-4 
21 
2.3 Screening Evaluation ...................................................................................................................................... 2-5 
22 
2.3.1 Historical Information ............................................................................................................................. 2-5 
23 
2.3.2 Screening Procedures .............................................................................................................................. 2-5 
24 
2.4 Enrollment of Eligible Study Participants into Run-In Phase ......................................................................... 2-5 
25 
Chapter 3. Run-In Phase ........................................................................................................... 3-1 
26 
3.1 Overview ......................................................................................................................................................... 3-1 
27 
3.2 Visit Schedule ................................................................................................................................................. 3-1 
28 
3.3 Testing Procedures During the Run-In Phase ................................................................................................. 3-1 
29 
3.4 Treatment During the Run-in Phase ................................................................................................................ 3-1 
30 
3.4.1 Anti-VEGF Drug ..................................................................................................................................... 3-1 
31 
3.4.2 Intravitreal Injection Technique .............................................................................................................. 3-2 
32 
3.4.3 Deferral of Injections Due to Pregnancy ................................................................................................. 3-2 
33 
Chapter 4. Randomization Phase ............................................................................................. 4-1 
34 
4.1  Overview ........................................................................................................................................................ 4-1 
35 
4.2 Eligibility Criteria for Randomization ............................................................................................................ 4-1 
36 
4.3 Randomization Visit Testing Procedures ........................................................................................................ 4-1 
37 
4.4 Randomization of Eligible Study Participants ................................................................................................ 4-2 
38 
4.5 Randomization Treatment ............................................................................................................................... 4-3 
39 
4.6 Follow-Up Study Visits During the Randomization Phase ............................................................................. 4-3 
40 
4.7 Follow-Up Testing Procedures During the Randomization Phase .................................................................. 4-3 
41 
4.8 Post-Randomization Treatment....................................................................................................................... 4-4 
42 
4.8.1 Anti-VEGF Drug ..................................................................................................................................... 4-5 
43 
4.8.2 Steroid ..................................................................................................................................................... 4-5 
44 
4.8.3 Intravitreal Injection Technique .............................................................................................................. 4-5 
45 
4.8.4 Sham Injection Technique ....................................................................................................................... 4-5 
46 
4.8.5 Delay in Giving Injections ...................................................................................................................... 4-5 
47 
4.8.6  Deferral of Injections Due to Pregnancy ................................................................................................ 4-5 
48 
Chapter 5. Miscellaneous Considerations in Follow-up ......................................................... 5-1 
49 
5.1 Endophthalmitis .............................................................................................................................................. 5-1 
50 
5.2 Surgery for Vitreous Hemorrhage and Other Complications of Diabetic Retinopathy ................................... 5-1 
51 
5.3 Panretinal (Scatter) Photocoagulation (PRP) .................................................................................................. 5-1 
52 
5.4 Treatment of Macular Edema in Non-study Eye ............................................................................................ 5-1 
53 
5.5 Diabetes Management ..................................................................................................................................... 5-1 
54 
5.6 Management of Ocular Hypertension or Glaucoma ....................................................................................... 5-1 
55 
5.7 Study Participant Withdrawal and Losses to Follow-up ................................................................................. 5-1 
56 

 
 
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5.8 Discontinuation of Study ................................................................................................................................ 5-2 
57 
5.9 Contact Information Provided to the Coordinating Center ............................................................................. 5-2 
58 
5.10 Study Participant Reimbursement ................................................................................................................. 5-2 
59 
Chapter 6. Adverse Events ........................................................................................................ 6-1 
60 
6.1 Definition ........................................................................................................................................................ 6-1 
61 
6.2 Recording of Adverse Events ......................................................................................................................... 6-1 
62 
6.3 Reporting Serious or Unexpected Adverse Events ......................................................................................... 6-1 
63 
6.4 Data and Safety Monitoring Committee Review of Adverse Events .............................................................. 6-2 
64 
6.5 Risks ............................................................................................................................................................... 6-2 
65 
6.5.1 Potential Adverse Effects of Study Drug ................................................................................................ 6-2 
66 
6.5.2 Potential Adverse Effects of Intravitreal Injection .................................................................................. 6-4 
67 
6.5.3 Risks of Eye Examination and Tests ....................................................................................................... 6-4 
68 
Chapter 7. Statistical Methods.................................................................................................. 7-1 
69 
7.1 Sample Size..................................................................................................................................................... 7-1 
70 
7.2 Sample Size Assumptions and Precision Estimates ........................................................................................ 7-1 
71 
7.3 Efficacy Analysis Plan .................................................................................................................................... 7-2 
72 
7.3.1 Primary Outcome Analysis ..................................................................................................................... 7-2 
73 
7.4 Secondary Outcomes ...................................................................................................................................... 7-3 
74 
7.4.1 Secondary Outcomes Analysis ................................................................................................................ 7-4 
75 
7.5 Safety Analysis Plan ....................................................................................................................................... 7-4 
76 
7.6 Additional Analysis Objectives Related to Design of Phase III Trial ............................................................. 7-4 
77 
7.7 Additional Tabulations and Analyses ............................................................................................................. 7-5 
78 
7.8 Interim Monitoring Plan ................................................................................................................................. 7-5 
79 
Chapter 8. References ................................................................................................................ 8-1 
80 
81 

 
 
 
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82 
Chapter 1.                                                                                          
83 
BACKGROUND INFORMATION AND STUDY SYNOPSIS 
84 
 
85 
1.1 Rationale 
86 
 
87 
1.1.1 Public Health Impact of DME  
88 
The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 
89 
recent history,1 and estimates suggest that by the year 2030, approximately 439 million 
90 
individuals worldwide will be affected by this chronic disease.2 The increasing global epidemic 
91 
of diabetes implies an associated increase in rates of vascular complications from this chronic 
92 
disease, including diabetic retinopathy. Despite advances in diagnosis and management of ocular 
93 
disease in patients with diabetes, eye complications from diabetes mellitus continue to be the 
94 
leading cause of vision loss and new onset blindness in working-age individuals throughout the 
95 
United States.3   
96 
 
97 
Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of 
98 
central vision. In a review of three early studies concerning the natural history of DME, Ferris 
99 
and Patz found that 53% of 135 eyes with DME, presumably all involving the center of the 
100 
macula, lost two or more lines of visual acuity over a two-year period.4 Without intervention, 
101 
33% of 221 eyes included in the Early Treatment Diabetic Retinopathy Study (ETDRS) with 
102 
center-involved DME experienced “moderate visual loss” (defined as a 15 or more letter score 
103 
decrease in visual acuity) over a three-year period.5   
104 
 
105 
1.1.2 Rationale for Anti-VEGF Treatment for DME 
106 
DME results from abnormal leakage of fluid and macromolecules, such as lipoproteins, from 
107 
retinal capillaries into the extravascular space. This is followed by an influx of water into the 
108 
extravascular space due to increased oncotic pressure.6 The retinal pigment epithelium normally 
109 
acts as a barrier to fluid flow from the choriocapillaris to the retina and also actively pumps fluid 
110 
out of the retina. Thus, abnormalities in the retinal pigment epithelium may contribute to DME 
111 
by allowing increased fluid access from the choriocapillaries or decreasing the normal efflux of 
112 
fluid from the retina.6 The mechanism of breakdown of the blood retina barrier at the level of the 
113 
retinal capillaries and the retinal pigment epithelium may be mediated by changes in tight 
114 
junction proteins such as occludin.7   
115 
 
116 
Vascular endothelial growth factor (VEGF), a 45 kD homodimeric glycoprotein, potently 
117 
increases retinal capillary permeability and subsequent retinal edema in part by inducing 
118 
breakdown of the blood retina barrier.8 Thus, agents that inhibit VEGF may reduce vascular 
119 
permeability due to diabetes and thereby decrease retinal thickening. 
120 
 
121 
1.1.3 Evolution of Standard Therapy for DME 
122 
For 25 years, focal/grid laser photocoagulation was the mainstay of treatment for DME.  In the 
123 
ETDRS, focal/grid photocoagulation of eyes with DME reduced the risk of moderate visual loss 
124 
by approximately 50% (from 24% to 12%) three years after initiation of treatment.9  A modified 
125 
ETDRS focal/grid photocoagulation protocol adapted from the original ETDRS approach has 
126 
been adopted as the standard laser technique for DME used in all Diabetic Retinopathy Clinical 
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Research Network (DRCR.net) studies.  The DRCR.net trial, “A Randomized Trial Comparing 
128 
Intravitreal Triamcinolone Acetonide and Focal/grid Photocoagulation for DME”, showed that 
129 
efficacy over 2 years of use with the DRCR.net focal/grid laser technique was comparable to 
130 
results in similar eyes in the ETDRS, and that intravitreal triamcinolone as monotherapy was not 
131 
superior to use with the DRCR.net focal/grid laser technique for central-involved DME in eyes 
132 
with some visual acuity loss.10,11 
133 
 
134 
Results from a more recent DRCR.net study, “Intravitreal Ranibizumab or Triamcinolone 
135 
Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema”(DRCR.net 
136 
Protocol I), indicated that treatment for DME with intravitreal anti-VEGF therapy (0.5 mg 
137 
ranibizumab) plus deferred (≥24 weeks) or prompt focal/grid laser provides visual acuity 
138 
outcomes at one year and two years that are superior to prompt focal/grid laser alone or 
139 
intravitreal triamcinolone with prompt focal/grid laser.12 DRCR.net Protocol I provided 
140 
definitive confirmation of the important role of VEGF in DME and the role of anti-VEGF drugs 
141 
in the treatment of DME. The study enrolled 854 eyes of 691 study participants with DME 
142 
involving the fovea and with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320. 
143 
Eyes were randomized to sham injection+prompt focal/grid laser (N = 293), 0.5-mg 
144 
ranibizumab+prompt laser (within 3 to 10 days, N = 187), and 0.5-mg ranibizumab+deferred 
145 
laser (deferred for at least 24 weeks, N = 188). Treatment with ranibizumab was generally 
146 
continued on a monthly basis unless the participant’s vision stabilized or reached 20/20, or the 
147 
retinal swelling resolved or no longer improved.  Treatment could be stopped if failure criteria 
148 
were met (persistent swelling with poor vision), but this occurred in very few participants (less 
149 
than 5% in any group).  The mean change (± standard deviation) in visual acuity letter score at 
150 
one year from baseline was significantly greater in the ranibizumab+prompt laser group (+9 ± 
151 
11) and the ranibizumab+deferred laser group (+9 ± 12) as compared with the control laser group 
152 
(+3 ± 13, P < 0.001 for both comparisons) or triamcinolone+prompt laser group (+4 ± 13, P < 
153 
0.001 for both comparisons). The one-year optical coherence tomography (OCT) results 
154 
paralleled the visual acuity results in the ranibizumab and control laser groups. No apparent 
155 
increases in treatment-related systemic events were observed.   
156 
 
157 
DRCR.net Protocol I results provided confirmation of the promising role of ranibizumab therapy 
158 
suggested by phase 2 trials13, 14 and have been further supported by findings from additional 
159 
phase III trials, including RISE, RIDE and RESTORE.15, 16  Participants in RISE and RIDE were 
160 
randomized to every 4 week 0.5 or 0.3 mg ranibizumab for at least 2 years versus sham 
161 
injections as treatment for center-involved DME causing vision impairment, with macular laser 
162 
available to all treatment arms starting 3 months after randomization.  The percentage of 
163 
individuals gaining ≥ 15 letters from baseline at 24 months was significantly higher in the 
164 
ranibizumab groups in both studies (RISE:  sham- 18.1%, 0.3mg ranibizumab- 44.8%, 0.5mg 
165 
ranibizumab 39.2%; RIDE sham- 12.3%, 0.3mg ranibizumab- 33.6%, 0.5mg ranibizumab 
166 
45.7%).15  In RESTORE, both ranibizumab (0.5mg) monotherapy and combination 
167 
ranibizumab+laser treatment resulted in better visual acuity outcomes than laser alone at one 
168 
year in patients with center-involved DME causing vision impairment.16  The percentage of 
169 
participants who gained ≥ 15 letters from baseline at month 12 were 22.6%, 22.9% and 8.2% in 
170 
the ranibizumab alone, ranibizumab+laser and laser alone groups, respectively.  In general, 
171 
ranibizumab therapy was well-tolerated in these studies, although the overall rate of Antiplatelet 
172 
Trialists’ Collaboration events was slightly higher in the 0.3 mg (5.6%) and 0.5 mg (7.2%) 
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groups as compared with the sham group (5.2%) in the pooled data from the RISE and RIDE 
174 
studies.17  Deaths were also more frequent in the ranibizumab groups (0.8% and 1.6% of sham 
175 
and 2.4-4.8% of ranibizumab treated patients) in these trials.15  The rate of non-fatal 
176 
cerebrovascular events in this pooled analysis was higher in the 0.5mg group (2%) than in the 
177 
sham (1.2%) or 0.3mg group (0.8%) but the rate of non-fatal myocardial infarctions was similar 
178 
across treatment groups (2.8%, 2.8% and 2.4% in the sham, 0.3mg and 0.5mg groups, 
179 
respectively).  
180 
 
181 
1.1.4 Eyes with Persistent DME following Therapy with Anti-VEGF Drugs 
182 
Although the studies described above have clearly demonstrated that anti-VEGF therapy is 
183 
efficacious for improving vision and decreasing retinal thickness in eyes with center-involved 
184 
DME, there is clearly a subgroup of eyes that do not respond completely to anti-VEGF therapy 
185 
for DME.  Indeed, in DRCR.net Protocol I over 50% of ranibizumab-treated eyes did not achieve 
186 
a 2 or more line improvement in visual acuity from baseline at 2 years and more than 40% did 
187 
not achieve complete resolution of retinal thickening (time domain [TD] OCT central subfield 
188 
[CSF] thickness <250 microns) by 2 years.18  Of eyes that were edematous (CSF thickness on TD 
189 
OCT ≥ 250 microns) with visual acuity of 20/32 or worse at the 6-month study visit (N = 145), 
190 
83% - 90% were also thickened at 1 month and subsequent follow-ups.  Seventy-three percent of 
191 
these eyes had CSF thickness ≥ 250 microns at all study visits prior to 6 months. Of eyes that 
192 
were edematous with visual acuity worse than 20/32 at 1 year, 72%-82% of eyes were thickened 
193 
at 6 months and subsequent follow-ups. Forty-eight percent of these eyes had ≥ 250 microns at 
194 
all study visits prior to 1 year. These results suggest that eyes that remain edematous at 6 months 
195 
and 1 year following anti-VEGF treatment have for the most part been consistently thickened 
196 
throughout the treatment period. More recently in a prospective randomized trial of 63 eyes with 
197 
DME assigned to monthly intravitreal injections of 1.5 mg bevacizumab or 0.5 mg ranibizumab 
198 
if CSF thickness on spectral-domain OCT was >275μm, 59% and 37% of bevacizumab and 
199 
ranibizumab eyes respectively had CSF thickness of >275 μm at 48 weeks.19 In summary, there 
200 
is a need to explore alternative or additional therapies for DME  for eyes with persistent 
201 
thickening after anti-VEGF treatment.   
202 
 
203 
1.1.5 Rationale for Corticosteroid Treatment for DME 
204 
Corticosteroids (“steroids”), a class of substances with anti-inflammatory properties, have been 
205 
demonstrated to inhibit the expression of the VEGF gene.20  In a study by Nauck et al, the 
206 
platelet-derived growth-factor (PDGF) induced expression of the VEGF gene in cultures of 
207 
human aortic vascular smooth muscle cells, which was abolished by corticosteroids in a dose-
208 
dependent manner.20 A separate study by Nauck et al demonstrated that corticosteroids abolished 
209 
the induction of VEGF by the pro-inflammatory mediators PDGF and platelet-activating factor 
210 
(PAF) in a time and dose-dependent manner.21 The study was performed using primary cultures 
211 
of human pulmonary fibroblasts and pulmonary vascular smooth muscle cells. 
212 
 
213 
As discussed above, corticosteroids have been experimentally shown to down regulate VEGF 
214 
production and possibly reduce breakdown of the blood-retinal barrier.  Similarly, steroids have 
215 
anti-angiogenic properties, possibly due to attenuation of the effects of VEGF.22, 23  Both of these 
216 
steroid effects have been utilized. For example, triamcinolone acetonide is often used clinically 
217 
as a periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis 
218 
or as a result of intraocular surgery.24, 25  In animal studies, intravitreal triamcinolone acetonide 
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has been used in the prevention of proliferative vitreoretinopathy26 and retinal 
220 
neovascularization.27, 28  In addition, intravitreal triamcinolone acetonide has been used clinically 
221 
in the treatment of proliferative vitreoretinopathy29 and choroidal neovascularization.30-32  
222 
 
223 
Although steroid-associated reduction of vascular permeability in eyes with DME is thought to 
224 
be mediated at least partially through the regulation of VEGF, steroids have a wide-range of anti-
225 
inflammatory actions that include direct effects on leukostasis, ICAM-1 expression, and 
226 
production of tight junction proteins, some of which may be upstream or independent of VEGF 
227 
pathways.33-35  Therefore, rationale exists to assess whether intravitreal steroid treatment 
228 
combined with anti-VEGF therapy is more efficacious in reducing center-involved DME than 
229 
anti-VEGF therapy alone.   
230 
 
231 
Multiple studies, including two phase III randomized controlled trials conducted by the 
232 
DRCR.net have demonstrated that there is a short-term early increase in visual acuity with 
233 
intravitreal steroid treatment for DME.  Although the DRCR.net Protocol B study (“A 
234 
Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation 
235 
for Diabetic Macular Edema”) found that monotherapy with intravitreal steroid is not as 
236 
efficacious as monotherapy with laser treatment alone,10 there are data to suggest that adjunctive 
237 
therapy with intravitreal steroid may have a role in selected eyes with DME. In Protocol I, eyes 
238 
that were pseudophakic at baseline that were treated with intravitreal triamcinolone and laser 
239 
appeared to have similar visual acuity and OCT results as the anti-VEGF-treated eyes.12  Since 
240 
this study is a phase II trial, it will assess a proof of concept for beneficial effect of the 
241 
combination corticosteroid+anti-VEGF agents. Although this study will include both phakic and 
242 
pseudophakic eyes, the short-term primary outcome at 6 months is not expected to be affected by 
243 
the potential cataract development that is associated with corticosteroid use.  Should this study 
244 
show beneficial effect of the combination corticosteroid+anti-VEGF agents in eyes with 
245 
persistent DME short-term, a future longer term phase III trial may be designed to further assess 
246 
the efficacy and safety of this regimen long-term.  
247 
 
248 
Since eligible eyes for this study can be pseudophakic, there is a potential for their macular 
249 
edema to have an inflammatory component from prior cataract surgery in addition to the DME. 
250 
Therefore, eligibility criteria will require that if cataract surgery has been performed, it must 
251 
have been performed at least 9 months before randomization (6 months before enrollment), to 
252 
reduce the chance of a post-cataract surgery macular edema (Irvine-Gass Syndrome) being 
253 
present at baseline.  
254 
 
255 
1.1.6 Combination Steroid and Anti-VEGF treatment for DME 
256 
Several studies have been reported on combined steroid and anti-VEGF treatment for DME.36-40  
257 
Some studies have suggested that there may be benefits with the combined 
258 
bevacizumab/triamcinolone as compared with bevacizumab treatment alone that include earlier 
259 
visual improvement and longer maintenance of treatment effect.38, 39 However, other studies do 
260 
not suggest substantive additional benefit in visual outcome or thickening with combination 
261 
steroid/anti-VEGF treatment over anti-VEGF treatment alone. One such study randomized 150 
262 
eyes to treatment with intravitreal bevacizumab alone, combined intravitreal bevacizumab and 
263 
triamcinolone, or macular focal or modified grid laser.36  Although intravitreal bevacizumab 
264 
treatment yielded better visual outcomes as compared with macular laser treatment, no additional 
265 
benefit in visual acuity or degree of retinal thickening was apparent when adjunctive 
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triamcinolone was also given. However, the triamcinolone dose utilized (2 mg) was half the dose 
267 
that is commonly used in clinical practice for treatment of DME and a substantial proportion of 
268 
the combined anti-VEGF/steroid group (26%) was lost to follow-up before the 36-week primary 
269 
endpoint was achieved.   
270 
 
271 
1.1.7 Available Steroids 
272 
There are several commercially available steroid preparations that have been used intravitreally.  
273 
Currently available steroids include dexamethasone sodium phosphate, the dexamethasone 
274 
intravitreal implant (Ozurdex), triamcinolone acetonide, and preservative-free triamcinolone 
275 
(Triesence). Dexamethasone sodium phosphate is highly potent, but its use is limited by a very 
276 
short half-life (~3.5 hours). Triamcinolone acetonide is readily available, but preservatives in the 
277 
suspension may result in higher rates of pseudoendophthalmitis secondary to ocular 
278 
inflammation. Preservative-free triamcinolone is less immunogenic and can be administered 
279 
through a 27 or 30-gauge needle. Although cases have been reported of “blooming” of this 
280 
steroid after injection, with rapid spread throughout the vitreous and consequent decreased vision 
281 
and inability to evaluate the fundus, the steroid usually settles inferiorly after a period of time.   
282 
 
283 
The steroid that will be used in this study will be the dexamethasone intravitreal implant 
284 
(Ozurdex). This preparation provides sustained delivery of 700 µg of preservative-free 
285 
dexamethasone, and has been approved by the United States Food and Drug Administration 
286 
(FDA) for treatment of noninfectious posterior uveitis as well as macular edema due to retinal 
287 
vein occlusion, and diabetic macular edema.41-43  It is administered through a single-use 22 gauge 
288 
injection system. In patients with diabetes, the implant has been evaluated in an open-label study 
289 
of 55 eyes with persistent DME and a history of vitrectomy at least 3 months prior to the study 
290 
enrollment visit.44  Study eyes received a single intravitreal injection of the dexamethasone 
291 
implant and were then followed over 26 weeks. Both central retinal thickness and mean visual 
292 
acuity were significantly improved as compared with baseline beginning at week 1 with peak 
293 
efficacy seen at week 8 (OCT CSF thickness mean change [95% confidence interval (CI)]: −156 
294 
µm [−190 to  −122 µm], P<0.001; VA mean change [95% CI]: 6 letters [3.9 to 8.1 letters], P 
295 
<0.001).  At week 26 both retinal thickness and visual acuity were significantly better than 
296 
baseline. The most common adverse events found in 10% or more of eyes were conjunctival 
297 
hemorrhage (52.7%), conjunctival hyperemia (20.0%), eye pain (16.4%), increased IOP (16.4%), 
298 
conjunctival edema (12.7%), and vitreous hemorrhage (10.9%). Of the 48 study participants who 
299 
were not on IOP-lowering medication at baseline, 8 (17%) began on IOP-lowering medication 
300 
during the study. 
301 
 
302 
1.1.8 Summary of Rationale for the Study 
303 
Although anti-VEGF therapy is generally effective as treatment for center-involved DME, some 
304 
anti-VEGF-treated eyes with DME do not achieve visual acuity of 20/20 or complete resolution 
305 
of retinal thickening. Thus, there is a need for alternative or additional treatments that might 
306 
improve visual acuity by reducing retinal edema in eyes with persistent DME despite previous 
307 
anti-VEGF therapy. Intravitreal steroid is not as efficacious as ranibizumab in eyes with DME 
308 
overall, but it has been shown to have a positive effect on DME in some eyes and might add 
309 
benefit in eyes that are already receiving anti-VEGF. This proposed study will assess whether the 
310 
addition of steroid to an anti-VEGF treatment regimen in eyes that have persistent DME despite 
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anti-VEGF treatment increases visual acuity and decreases DME  in the short term, compared 
312 
with continued anti-VEGF treatment alone. 
313 
 
314 
1.2 Study Objectives 
315 
To assess the short-term effects of combination steroid+anti-VEGF therapy on visual acuity and 
316 
retinal thickness on OCT in comparison with that of continued anti-VEGF therapy alone in eyes 
317 
with persistent central-involved DME and visual acuity impairment despite previous anti-VEGF 
318 
treatment. 
319 
 
320 
Furthermore, this phase II study is being conducted (1) to determine whether the conduct of a 
321 
phase III trial has merit based on functional and anatomic outcomes, (2) to estimate recruitment 
322 
potential of a phase III investigation, (3) to provide information needed to design a phase III trial, 
323 
and (4) to assess the safety of administering combination steroid+anti-VEGF therapy in eyes 
324 
with persistent DME. The study is not designed to definitively establish the efficacy of 
325 
corticosteroid+anti-VEGF therapy in the treatment of persistent central-involved DME. 
326 
 
327 
1.3 Study Design and Synopsis of Protocol 
328 
 
329 
A. Study Design 
330 
 
331 
 Randomized, controlled phase II multi-center clinical trial 
332 
 
333 
B. Major Eligibility Criteria 
334 
 
335 
 Age ≥18 years 
336 
 Type 1 or type 2 diabetes 
337 
 The study eye must meet the following criteria: 
338 
 Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen 
339 
equivalent 20/32 to 20/320) 
340 
 Ophthalmoscopic evidence of center-involved DME  
341 
 OCT CSF thickness value (microns): 
342 
 Zeiss Cirrus: ≥290 in women; ≥305 in men 
343 
 Heidelberg Spectralis: ≥305 in women; ≥320 in men 
344 
 At least three intravitreal anti-VEGF injections given within the prior 20 weeks 
345 
 No previous history of glaucoma or steroid intraocular pressure response in either 
346 
eye 
347 
 
348 
C. Run-In Phase 
349 
All potential study participants will be required to participate in a 12-week run-in phase. In order 
350 
to enter the run-in phase, all eligibility criteria must be assessed and met. During the run-in phase, 
351 
study eyes will receive 3 study ranibizumab 0.3mg injections approximately 4 weeks apart.   
352 
 
353 
At the end of the run-in phase (12-week visit), eyes with persistent DME despite prior intravitreal 
354 
anti-VEGF therapy that still meet eligibility criteria (see section 4.2) will be randomized. 
355 
“Persistent DME” at end of the run-in phase is defined as meeting all of the following: 
356 

 
 
 
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1-9 
 
 CSF thickness (microns) on OCT meeting either one of the following two gender 
357 
and OCT machine-specific criteria: 
358 
 Zeiss Cirrus: ≥290 in women; ≥305 in men 
359 
 Heidelberg Spectralis: ≥305 in women; ≥320 in men  
360 
 Visual acuity letter score ≤ 78  and ≥24 (approximate Snellen equivalent 20/32 to 
361 
20/320) 
362 
 DME is the cause of OCT thickening and vision loss by the investigator’s 
363 
judgment 
364 
 
365 
D. Treatment Groups 
366 
Eligible study eyes at the end of the run-in phase will be assigned randomly (1:1) to one of the 
367 
following groups: 
368 
 
369 
 Group A: Sham + intravitreal ranibizumab 
370 
 Group B: Intravitreal dexamethasone +intravitreal ranibizumab  
371 
 
372 
Study participants may have one or two study eyes.  Study participants with two study eyes will 
373 
be randomized to receive continued anti-VEGF therapy (ranibizumab) in one eye and 
374 
dexamethasone +ranibizumab in the other eye. 
375 
 
376 
For both treatment groups, the initial ranibizumab injections must be given on the day of 
377 
randomization. The sham or dexamethasone injection will be given within 0-8 days of the 
378 
ranibizumab injection. Study eyes will be evaluated for retreatment every 4 weeks based on OCT 
379 
and visual acuity. Further details on the treatment schedule and criteria for retreatment are 
380 
included in section 4.8.   
381 
 
382 
E. Sample Size 
383 
A minimum of 150 study eyes (from approximately 125 participants assuming 20% have two 
384 
study eyes)  
385 
 
386 
F. Duration of Follow-up 
387 
 12-week run-in phase prior to randomization 
388 
 Primary outcome at 24 weeks after randomization 
389 
 
390 
G. Follow-up Schedule 
391 
 Follow-up visits occur every 4±1 weeks  
392 
 
393 
H. Main Efficacy Outcomes 
394 
 
395 
At 24 weeks after randomization: 
396 
 
397 
Primary:     
398 
 Mean change in visual acuity letter score, adjusted for visual acuity at time of 
399 
randomization 
400 
 
401 
Secondary:  
402 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15  
              
1-10 
 
 Percent of eyes with at least 10 and at least 15 letter gain (increase) or loss 
403 
(decrease) in E-ETDRS letter score visual acuity  
404 
 Visual acuity area under the curve (AUC) between randomization and 24 weeks 
405 
 Mean change in OCT CSF thickness, adjusted for thickness at time of 
406 
randomization 
407 
 Percent of eyes with ≥1 and ≥2 logOCT step gain or loss in CSF thickness  
408 
 Percent of eyes with OCT CSF thickness (in micros) < the following gender and 
409 
OCT machine-specific values: <290 in women and <305 in men in Zeiss Cirrus; 
410 
<305 in women and <320 in men in Heidelberg Spectralis 
411 
 OCT CSF thickness AUC between randomization and 24 weeks 
412 
 Percent of eyes with worsening or improvement of diabetic retinopathy on clinical 
413 
exam 
414 
 
415 
I. Main Safety Outcomes 
416 
Injected-related: endophthalmitis, retinal detachment, retinal tears, intraocular hemorrhage, 
417 
increased intraocular pressure 
418 
Ocular drug-related: inflammation, increased intraocular pressure, need for ocular anti-
419 
hypertensive, glaucoma surgery, or other IOP-lowering procedures, development or 
420 
worsening of cataract and cataract extraction, intraocular hemorrhage, migration of 
421 
dexamethasone to the anterior chamber and subsequent corneal complications 
422 
Systemic drug-related: Deaths, participants with at least one hospitialization, participants 
423 
with at least one SAE, and cardiovascular events, and cerebrovascular events as defined by 
424 
Antiplatelet Trialists’ Collaboration 
425 
 
426 
J. Schedule of Study Visits and Examination Procedures 
427 
 
428 
Visit 
Enroll in 
Run-In 
Run-In 
Visits* 
Randomization 
0 
4w-24w** 
Visit Window 
 
(+/− 1w) 
 
(+/− 1w) 
E-ETDRS best 
corrected visual 
acuity a 
X 
X 
X 
X 
OCT b 
X 
X 
X 
X 
Eye exam c 
X 
X 
X 
X 
Blood pressure 
X 
 
X 
 
HbA1cd 
 
 
X 
 
* Visits at 4 and 8 (±1) weeks during the run-in phase.  Randomization visit (0) occurs at 12 (± 1) weeks from 
enrollment. 
**Visits every 4 (±1) weeks post-randomization. 
 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15  
              
1-11 
 
a= both eyes at each visit; includes protocol refraction in study eye at each visit and the non-study eye at the 
randomization visit and 24 week visit. E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity 
Tester that has been validated against 4-meter chart ETDRS testing. 
b=study eye 
c=both eyes at enrollment and randomization and study eye only at each follow-up visit. Includes slit lamp exam 
(including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy. 
 d=does not need to be repeated if HbA1c is available from within the prior 3 months. If not available, can be performed 
within 3 weeks after randomization. 
 
 
1.4 General Considerations 
429 
The study is being conducted in compliance with the policies described in the DRCR.net Policies 
430 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
431 
the protocol described herein, and with the standards of Good Clinical Practice. 
432 
 
433 
The DRCR.net Procedures Manuals (Visual Acuity-Refraction Testing Procedures Manual, OCT 
434 
Manuals, and Study Procedures Manual) provide details of the examination procedures and 
435 
intravitreal injection procedure.   
436 
 
437 
Data will be directly collected in electronic case report forms, which will be considered the 
438 
source data. 
439 
 
440 
The participant will be masked to the treatment group assignment. Visual acuity testers 
441 
(including refractionists) and OCT technicians will be masked to treatment group at the primary 
442 
outcome visit (24 weeks). Investigators will not be masked to treatment group assignment.   
443 
 
444 
There is no restriction on the number of study participants to be enrolled by a site. 
445 
 
446 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
447 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
448 
2013). 
449 
 
450 
The risk level is considered to be research involving greater than minimal risk.
451 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-1 
 
452 
Chapter 2.                                                                                          
453 
STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
454 
 
455 
2.1 Identifying Eligible Study Participants and Obtaining Informed Consent 
456 
A minimum of 150 eyes are expected to be enrolled into the randomization phase. Assuming that 
457 
20% of the study participants have two study eyes, this equates with an enrollment of about 125 
458 
study participants, with a goal to enroll an appropriate representation of minorities. As the 
459 
enrollment goal approaches, sites will be notified of the end date for recruitment. Study 
460 
participants who have signed an informed consent form or are in the run-in phase can be 
461 
randomized up until the end date, which means the recruitment goal might be exceeded.   
462 
 
463 
Potential eligibility will be assessed as part of a routine-care examination. Prior to completing 
464 
any procedures or collecting any data that are not part of usual care, written informed consent 
465 
will be obtained. For study participants who are considered potentially eligible for the study 
466 
based on a routine-care exam, the study protocol will be discussed with the study participant by a 
467 
study investigator and clinic coordinator. The study participant will be given the Informed 
468 
Consent Form to read. Study participants will be encouraged to discuss the study with family 
469 
members and their personal physician(s) before deciding whether to participate in the study.   
470 
 
471 
Consent may be given in two stages (if approved by the IRB). The initial stage will provide 
472 
consent to complete any of the screening procedures needed to assess eligibility that have not 
473 
already been performed as part of a usual-care exam. The second stage will be obtained prior to 
474 
enrollment into the run-in phase and will be for participation in the study, including the post-
475 
randomization phase. A single consent form will have two signature and date lines for the study 
476 
participant:  one for the study participant to give consent for the completion of the screening 
477 
procedures and one for the study participant to give consent for the randomized trial.  Study 
478 
participants will be provided with a copy of the signed Informed Consent Form. After the run-in 
479 
phase, participants will have the opportunity to decline continuation into the randomized trial. 
480 
 
481 
2.2 Study Participant Eligibility Criteria 
482 
Eligibility for the run-in phase will be assessed using the criteria below.  See section 4.2 for 
483 
eligibility criteria for randomization. 
484 
 
485 
2.2.1 Participant-level Criteria 
486 
Inclusion 
487 
To be eligible, the following inclusion criteria must be met: 
488 
1. Age ≥ 18 years  
489 
 Individuals <18 years old are not being included because DME is so rare in this age 
490 
group that the diagnosis of DME may be questionable.  
491 
2. Diagnosis of diabetes mellitus (type 1 or type 2)  
492 
 Any one of the following will be considered to be sufficient evidence that diabetes is 
493 
present:  
494 
 Current regular use of insulin for the treatment of diabetes 
495 
 Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes 
496 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-2 
 Documented diabetes by ADA and/or WHO criteria (see Procedures Manual for 
497 
definitions) 
498 
3. At least one eye meets the study eye criteria listed in section 2.2.2. 
499 
4. Fellow eye (if not a study eye) meets criteria in section 2.2.3. 
500 
5. Able and willing to provide informed consent. 
501 
 
502 
Exclusion 
503 
An individual is not eligible if any of the following exclusion criteria are present:  
504 
6. History of chronic renal failure requiring dialysis or kidney transplant. 
505 
7. A condition that, in the opinion of the investigator, would preclude participation in the study 
506 
(e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic 
507 
control).  
508 
8. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months 
509 
prior to randomization or plans to do so in the next 4 months. 
510 
9. Participation in an investigational trial that involved treatment with any drug that has not 
511 
received regulatory approval for the indication being studied within 30 days of enrollment. 
512 
 Note: study participants cannot receive another investigational drug while participating 
513 
in the study. 
514 
10. Known allergy to any component of the study drugs (including povidone iodine prep).  
515 
11. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110). 
516 
 If blood pressure is brought below 180/110 by anti-hypertensive treatment, the individual 
517 
can become eligible.  
518 
12. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient 
519 
ischemic attack, or treatment for acute congestive heart failure within 1 month prior to 
520 
enrollment. 
521 
13. Systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment or 
522 
anticipated use during the study. 
523 
 These drugs cannot be used during the study. 
524 
14. For women of child-bearing potential: pregnant or lactating or intending to become pregnant 
525 
within the next 9 months. 
526 
 Women who are potential study participants should be questioned about the potential for 
527 
pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. 
528 
15. Individual is expecting to move out of the area of the clinical center to an area not covered by 
529 
another clinical center during the next 9 months. 
530 
 
531 
2.2.2 Study Eye Criteria 
532 
The study participant must have one eye meeting all of the inclusion criteria and none of the 
533 
exclusion criteria listed below.   
534 
 
535 
A study participant may have two study eyes only if both are eligible at the time of enrollment 
536 
into the run-in phase.  
537 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-3 
 
538 
The eligibility criteria for a study eye to enter the run-in phase are as follows: 
539 
 
540 
Inclusion 
541 
a. At least 3 injections of anti-VEGF drug (ranibizumab, bevacizumab, or aflibercept) within 
542 
the prior 20 weeks. 
543 
b. Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent 20/32 to 
544 
20/320). 
545 
c. On clinical exam, definite retinal thickening due to DME involving the center of the macula. 
546 
d. OCT CSF thickness (microns), within 8 days of enrollment: 
547 
 Zeiss Cirrus: ≥290 in women; ≥305 in men 
548 
 Heidelberg Spectralis: ≥305 in women; ≥320 in men  
549 
 Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate 
550 
quality  
551 
e. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCTs. 
552 
 
553 
Exclusions 
554 
The following exclusions apply to the study eye only (i.e., they may be present for the non-study 
555 
eye unless otherwise specified): 
556 
f. Macular edema is considered to be due to a cause other than DME.  
557 
 An eye should not be considered eligible if: (1) the macular edema is considered to be 
558 
related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT 
559 
suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or 
560 
epiretinal membrane) are the primary cause of the macular edema. 
561 
g. An ocular condition is present such that, in the opinion of the investigator, visual acuity loss 
562 
would not improve from resolution of macular edema (e.g., foveal atrophy, pigment 
563 
abnormalities, dense subfoveal hard exudates, non-retinal condition, etc.).  
564 
h. An ocular condition is present (other than DME) that, in the opinion of the investigator, 
565 
might affect macular edema or alter visual acuity during the course of the study (e.g., vein 
566 
occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).  
567 
i. Substantial lens or posterior capsule opacity that, in the opinion of the investigator, is likely 
568 
to be decreasing visual acuity by 3 lines or more (i.e., opacity would be reducing acuity to 
569 
20/40 or worse if eye was otherwise normal).  
570 
j. History of intravitreal anti-VEGF drug within 21 days prior to enrollment.  
571 
k. History of intravitreal or peribulbar corticosteroids within 3 months prior to enrollment. 
572 
l. History of macular laser photocoagulation within 4 months prior to enrollment. 
573 
m. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to enrollment or 
574 
anticipated need for PRP in the 6 months following enrollment into run-in phase. 
575 
n. Any history of vitrectomy. 
576 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-4 
o. History of major ocular surgery (including scleral buckle, any intraocular surgery, etc.) 
577 
within prior 4 months or anticipated within the next 6 months following enrollment.  
578 
p. History of cataract extraction within 6 months prior to enrollment or anticipated need for 
579 
cataract extraction within the study follow-up period. 
580 
q. History of YAG capsulotomy performed within 2 months prior to enrollment. 
581 
r. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or substantial 
582 
blepharitis. 
583 
s. Intraocular pressure ≥ 25 mmHg. 
584 
t. History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-
585 
angle glaucoma; note: history of angle-closure glaucoma is not an exclusion criterion).  
586 
  history of ocular hypertension is not an exclusion as long as (1) intraocular pressure is 
587 
<25 mmHg, (2) the subject is using no more than one topical glaucoma medication, (3) 
588 
the most recent visual field, performed within the last 12 months, is normal (if 
589 
abnormalities are present on the visual field they must be attributable to the subject’s 
590 
diabetic retinopathy – if a recent visual field within 12 months is not available, a new one 
591 
should be obtained if IOP is 22 to <25 mmHg), and (4) the optic disc does not appear 
592 
glaucomatous.  
593 
 Note: if the intraocular pressure is 22 to <25 mmHg, then the above criteria for ocular 
594 
hypertension eligibility must be met. 
595 
u. History of steroid-induced intraocular pressure elevation that required IOP-lowering 
596 
treatment. 
597 
v. History of prior herpetic ocular infection. 
598 
w. Exam evidence of ocular toxoplasmosis. 
599 
x. Exam evidence of pseudoexfoliation or any other condition associated with zonular 
600 
dehiscence or lens instability. 
601 
y. Aphakia. 
602 
z. Anterior-chamber intraocular lens present.  
603 
aa. Sutured posterior-chamber intraocular lens with a ruptured posterior capsule present.  
604 
 
605 
2.2.3 Non-study Eye Criteria 
606 
In subjects with only one eye meeting criteria to be a study eye at the time of enrollment into the 
607 
run-in phase, the fellow eye must meet the following criteria: 
608 
a. Intraocular pressure < 25 mmHg. 
609 
b. No history of open-angle glaucoma (either primary open-angle glaucoma or other cause of 
610 
open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).  
611 
 A history of ocular hypertension is not an exclusion as long as (1) intraocular pressure is 
612 
<25 mmHg, (2) the subject is using no more than one topical glaucoma medication, (3) 
613 
the most recent visual field, performed within the last 12 months, is normal (if 
614 
abnormalities are present on the visual field they must be attributable to the subject’s 
615 
diabetic retinopathy), and (4) the optic disc does not appear glaucomatous.  
616 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-5 
 Note: if the intraocular pressure is 22 to <25 mmHg, then the above criteria for ocular 
617 
hypertension eligibility must be met, including obtaining a normal visual field if one is 
618 
not available within the last 12 months. 
619 
c. No history of steroid-induced intraocular pressure elevation that required IOP-lowering 
620 
treatment. 
621 
d. No exam evidence of pseudoexfoliation.  
622 
 
623 
2.3 Screening Evaluation  
624 
2.3.1 Historical Information 
625 
A history will be elicited from the potential study participant and extracted from available 
626 
medical records. Data to be collected will include:  age, sex, ethnicity and race, diabetes history 
627 
and current management, other medical conditions, medications being used, as well as ocular 
628 
diseases, surgeries, and treatment. 
629 
 
630 
2.3.2 Screening Procedures 
631 
The following procedures are needed to assess eligibility for the run-in phase.   
632 
 If a procedure has been performed (using the study technique and by study certified 
633 
personnel) as part of usual care, it does not need to be repeated specifically for the 
634 
study if it was performed within the defined time windows specified below.  
635 
 The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual 
636 
Acuity-Refraction Testing Procedures Manual, OCT Procedures Manual, and Study 
637 
Procedures Manual). Visual acuity testing, ocular exam, and OCT will be performed 
638 
by DRCR.net certified personnel.  
639 
 OCTs obtained for enrollment into the run-in phase of the study eye may be sent to a 
640 
centralized reading center for grading, although participant eligibility is determined 
641 
by the site (i.e., individuals deemed eligible by the investigator will be enrolled into 
642 
run-in phase without pre-enrollment reading center confirmation). Subsequently, if 
643 
the reading center determines that the automated CSF reading by the OCT machine is 
644 
inaccurate, and manual adjustment of the CSF thickness on OCT is less than the OCT 
645 
eligibility criteria, the eye will be dropped from the run-in phase. 
646 
 
647 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity 
648 
Tester (including protocol refraction) in each eye. (within 8 days prior to enrollment) 
649 
 This testing procedure has been validated against 4-meter ETDRS chart testing.45 
650 
2. OCT on study eye (within 8 days prior to enrollment and at least 21 days after any prior 
651 
intravitreal anti-VEGF treatment) 
652 
3. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, 
653 
lens assessment, and dilated ophthalmoscopy  (within 8 days prior to enrollment) 
654 
4. Measurement of blood pressure 
655 
 
656 
2.4 Enrollment of Eligible Study Participants into Run-In Phase 
657 
1. Prior to enrollment, the study participant’s understanding of the trial, willingness to accept 
658 
the assigned treatment group at the end of the run-in phase, and commitment to the follow-up 
659 
schedule should be reconfirmed. 
660 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
2-6 
2. The initial run-in injection(s) must be given on the day of enrollment; therefore, a study 
661 
participant should not be enrolled until this is possible. For study participants with two study 
662 
eyes, both eyes must be treated on the day of enrollment. If the investigator is not willing to 
663 
perform bilateral injections on the same day, only one eye should be enrolled.
664 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
3-1 
Chapter 3.                                                                                              
665 
RUN-IN PHASE 
666 
 
667 
3.1 Overview 
668 
Each study eye is required to complete a 12-week run-in phase. The run-in phase will identify 
669 
study eyes that truly have persistent DME despite anti-VEGF therapy by requiring an additional 3 
670 
injections while also collecting standardized visual acuity and OCT measurements. This chapter 
671 
describes visit schedules, procedures and treatment during the run-in phase of the study.   
672 
 
673 
3.2 Visit Schedule 
674 
The schedule of protocol-specified follow-up visits during the run-in phase is as follows: 
675 
 
676 
 4 weeks (±1 week)  
677 
 8 weeks (±1 week) 
678 
 12 weeks (±1 week) – randomization visit 
679 
 
680 
A minimum of 21 days is required between visits. 
681 
 
682 
3.3 Testing Procedures During the Run-In Phase 
683 
The following will be performed at the 4-week and 8-week run-in phase visits: 
684 
 
685 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
686 
in each eye, including protocol refraction in the study eye  
687 
2. OCT on study eye  
688 
3. Ocular examination on study eye including slit lamp, measurement of intraocular pressure, 
689 
lens assessment, and dilated ophthalmoscopy  
690 
All of the testing procedures do not need to be performed on the same day, provided that they are 
691 
completed within the time window of a visit and prior to initiating any retreatment.  
692 
 
693 
Testing procedures at the 12-week visit to assess eligibility for the randomization phase are 
694 
detailed in section 4.3. 
695 
 
696 
3.4 Treatment During the Run-in Phase 
697 
All study eyes will receive an injection of ranibizumab 0.3 mg at enrollment, 4 weeks, and 8 
698 
weeks.  The injections must be at least 21 days apart. If an eye experienced adverse effects from 
699 
a prior intravitreal injection during the run-in phase precluding future injections or additional 
700 
injections are otherwise contraindicated according to the investigator (e.g. DME is no longer 
701 
present), the eye will not continue in the study. 
702 
  
703 
3.4.1 Anti-VEGF Drug 
704 
Ranibizumab 0.3 mg (Lucentis®) will be the anti-VEGF drug that will be used in the study, both 
705 
during the run-in phase and post-randomization. The physical, chemical and pharmaceutical 
706 
properties and formulation will be provided in the Ranibizumab Clinical Investigator Brochure.   
707 
 
708 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15 
3-2 
3.4.2 Intravitreal Injection Technique 
709 
The injection is preceded by a povidone iodine prep of the conjunctiva. Antibiotics in the pre-, 
710 
peri-, or post-injection period are not necessary but can be used at investigator discretion if such 
711 
use is part of his/her usual routine. 
712 
 
713 
The injection will be performed using sterile technique. The full injection procedure is described 
714 
in the DRCR.net Study Procedures Manual. 
715 
  
716 
3.4.3 Deferral of Injections Due to Pregnancy 
717 
Female study participants must be questioned regarding the possibility of pregnancy prior to 
718 
each injection. In the event of pregnancy, study injections must be discontinued.
719 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
4-1 
Chapter 4.                                                                                                
720 
RANDOMIZATION PHASE 
721 
 
722 
4.1  Overview 
723 
After completing the run-in phase of the study, eligibility criteria for the randomization phase 
724 
will be assessed for enrolled eyes at the 12-week run-in visit (“randomization visit”). This 
725 
chapter describes randomization, testing procedures, and follow-up visit and treatment schedules 
726 
during the randomization phase.  
727 
 
728 
4.2 Eligibility Criteria for Randomization 
729 
Once the run-in phase has been completed, the study participant must have at least one eye 
730 
meeting all of the inclusion criteria and none of the exclusion criteria listed below, confirmed at 
731 
the 12-week run-in visit (“randomization visit”) to be eligible for randomization. A study 
732 
participant may have two study eyes only if both are eligible at the time of randomization. 
733 
 
734 
Inclusions 
735 
a. All 3 run-in phase visits and ranibizumab injections were completed within ±10 days of the 
736 
target visit date. 
737 
b. Randomization visit no more than 5 weeks (35 days) from 8-week visit. 
738 
c. At least 21 days since prior study injection.   
739 
d. Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent 20/32 to 
740 
20/320) 
741 
e. On clinical exam, definite retinal thickening due to DME involving the center of the macula. 
742 
f. CSF thickness (microns) on OCT meeting either one of the following two gender- and OCT 
743 
machine-specific criteria:  
744 
i. Zeiss Cirrus: ≥290 in women; ≥305 in men  
745 
ii. Heidelberg Spectralis: ≥305 in women; ≥320 in men  
746 
 
747 
Exclusions 
748 
g. All participant-level exclusion criteria in section 2.2.1 must not have developed or occurred 
749 
during the run-in phase. 
750 
h. All study eye-level exclusion criteria in section 2.2.2 (except the criterion for prior anti-
751 
VEGF treatment) must not have developed or occurred during the run-in phase.  
752 
 
753 
4.3 Randomization Visit Testing Procedures 
754 
The following procedures are needed to assess eligibility for randomization and/or to serve as 
755 
baseline measures for the study analyses.   
756 
 
757 
 The testing procedures are detailed in the DRCR.net Procedures Manuals (Visual 
758 
Acuity-Refraction Testing Procedures Manual, and Study Procedures Manual).  
759 
Visual acuity testing, ocular exam, and OCT will be performed by DRCR.net 
760 
certified personnel.  
761 
 OCTs meeting DRCR.net criteria for manual grading may be sent to a reading center 
762 
but study participants’ eligibility is determined by the site (i.e., individuals deemed 
763 
eligible by the investigator will be randomized without pre-randomization reading 
764 
center confirmation). 
765 
 
766 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
4-2 
1. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
767 
(including protocol refraction) in each eye. (on day of randomization) 
768 
 This testing procedure has been validated against 4-meter ETDRS chart testing.45 
769 
2. OCT on study eye (on day of randomization) 
770 
3. Ocular examination on each eye including slit lamp, measurement of intraocular pressure, 
771 
lens assessment, and dilated ophthalmoscopy  (on day of randomization) 
772 
4. Laboratory Testing- HbA1c 
773 
 HbA1c does not need to be repeated if available in the prior 3 months. If not 
774 
available at the time of randomization, the individual may be enrolled but the test 
775 
must be obtained within 3 weeks after randomization.  
776 
 
777 
5. Measurement of blood pressure 
778 
 
779 
4.4 Randomization of Eligible Study Participants  
780 
1. Prior to randomization, the study participant’s understanding of the trial, willingness to 
781 
accept the assigned treatment group, and commitment to the follow-up schedule should be 
782 
reconfirmed. 
783 
2. The baseline injections must be given on the day of randomization; therefore, a study 
784 
participant should not be randomized until this is possible. For study participants with two 
785 
study eyes, both eyes must be treated on the day of randomization. If the investigator is not 
786 
willing to perform bilateral injections on the same day, only one eye should be randomized. 
787 
3. Randomization is completed on the DRCR.net website.   
788 
 Study participants with one study eye will be randomly assigned, with equal probability, 
789 
to receive either:  
790 
 
791 
o Group A: Sham + intravitreal ranibizumab 0.3 mg 
792 
o Group B: Intravitreal dexamethasone +intravitreal ranibizumab 0.3 mg  
793 
 
794 
Randomization will be stratified by two factors:  
795 
1. Presence or absence of improvement in retinal thickness during the run-in phase, 
796 
defined as reduction in CSF thickness by 10% at any run-in visit, compared with the 
797 
prior visit. 
798 
2. Presence or absence of improvement in visual acuity during the run-in phase, defined 
799 
as 5 or more letter gain in visual acuity at any run-in visit, compared with the prior 
800 
visit.  
801 
 
802 
 For study participants with two study eyes (both eyes eligible at the time of 
803 
randomization): 
804 
o The study participant will be randomized with equal probability to receive either: 
805 
 Group A in the eye with greater OCT improvement and Group B in the 
806 
eye with lower OCT improvement 
807 
 Group B in the eye with greater OCT improvement and Group A in the 
808 
eye with lower OCT improvement 
809 
Note: if both eyes have the same OCT improvement, the right eye will be consider the eye with 
810 
the greater improvement. 
811 
 
812 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
4-3 
4.5 Randomization Treatment 
813 
The treatment groups are as follows: 
814 
 Group A: Sham + intravitreal ranibizumab 0.3 mg 
815 
 Group B: Intravitreal dexamethasone +intravitreal ranibizumab 0.3 mg  
816 
For both treatment groups, the initial ranibizumab injection must be given on the day of 
817 
randomization. The sham or dexamethasone injection will be given within 0-8 days of the 
818 
ranibizumab injection. If the injections are given consecutively on the same day, the sham 
819 
injection must be given first in Group A and the ranibizumab injection must be given first in 
820 
Group B.   
821 
 
822 
Focal/grid laser is not permitted in the study eye. 
823 
 
824 
4.6 Follow-Up Study Visits During the Randomization Phase 
825 
The schedule of protocol-specified follow-up visits post-randomization is as follows: 
826 
 
827 
 4 weeks (±1 week)  
828 
 8 weeks (±1 week) 
829 
 12 weeks (±1 week) 
830 
 16 weeks (±1 week) 
831 
 20 weeks (±1 week) 
832 
 24 weeks (±1 week)– primary outcome visit 
833 
 
834 
A minimum of 21 days is required between injections. An additional visit may be required for 
835 
completion of the second (steroid/sham) injection at randomization and 12 weeks.  
836 
 
837 
4.7 Follow-Up Testing Procedures During the Randomization Phase 
838 
The following procedures will be performed at each protocol visit unless otherwise specified. A 
839 
grid in section 1.3 (J) summarizes the testing performed at each visit.   
840 
 
841 
Visual acuity testers (including refractionist) and OCT technicians will be masked to treatment 
842 
group at the primary outcome visit (24 weeks).   
843 
 
844 
1. Best-corrected E- ETDRS visual acuity testing in each eye 
845 
 A protocol refraction in the study eye is required at all protocol visits. Protocol refraction 
846 
in the non-study eye at the 24 week-visit only. When a refraction is not performed, the 
847 
most-recently performed refraction is used for the testing.   
848 
2. OCT on the study eye  
849 
3. Ocular exam on the study eye, including slit lamp examination, lens assessment, 
850 
measurement of intraocular pressure and dilated ophthalmoscopy  
851 
 
852 
All of the testing procedures do not need to be performed on the same day, provided that they are 
853 
completed within the time window of a visit and prior to initiating any retreatment.  
854 
 
855 
Testing procedures at unscheduled visits are at investigator discretion. However, it is 
856 
recommended that procedures that are performed should follow the standard DRCR.net protocol 
857 
for each procedure. If the study participant returns following a protocol visit specifically to 
858 
receive a study injection, testing prior to the injection is at investigator discretion. 
859 
 
860 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
4-4 
4.8 Post-Randomization Treatment 
861 
From the 4-week visit to the 20-week visit, the study eye is evaluated for retreatment based on 
862 
visual acuity and OCT. If an eye experienced adverse effects from a prior intravitreal injection, 
863 
retreatment with study injections is at the discretion of the investigator; however, non-protocol 
864 
treatment for DME should not be given. Otherwise:   
865 
 If the visual acuity letter score is ≥84 (20/20 or better) and the OCT CSF thickness is < 
866 
the gender-specific spectral domain OCT cutoffs below injection(s) will be deferred: 
867 
o Zeiss Cirrus: 290 in women and 305 in men 
868 
o Heidelberg Spectralis: 305 in women and 320 in men 
869 
 
870 
 If the visual acuity letter score is <84 (worse than 20/20) or OCT CSF thickness ≥ the 
871 
gender-specific spectral domain OCT cutoffs below, injection(s) will be given.   
872 
o Zeiss Cirrus: 290 in women and 305 in men 
873 
o Heidelberg Spectralis: 305 in women and 320 in men 
874 
 
875 
 
876 
If at any time the investigator wishes to treat the study eye(s) with a treatment for DME that is 
877 
different than the protocol treatment due to perceived failure or futility, the protocol chair or 
878 
designee must be contacted for approval prior to administering such treatment.  
879 
 
880 
The type of injection(s) given depends on the time since baseline treatment and treatment 
881 
assignment: 
882 
 
883 
4 and 8-Week Visits:  Ranibizumab Only 
884 
If indicated based on retreatment criteria above, eyes in both treatment groups will receive a 
885 
ranibizumab injection only.  
886 
 
887 
12-Week Visit: Combination Treatment 
888 
If indicated based on retreatment criteria above, combination treatment will be given at the 12-
889 
week visit. The sham or dexamethasone injection will be given within 0-8 days of the 
890 
ranibizumab injection. If the injections are given consecutively on the same day, the sham 
891 
injection must be given first in Group A, and the ranibizumab injection must be given first in 
892 
Group B. If injections are given on different days, then the ranibizumab injection is given first 
893 
and the sham or dexamethasone injections is given within 8 days. If visual acuity and/or OCT are 
894 
re-measured prior to the second injection (at the discretion of the investigator), the sham or 
895 
dexamethasone injection should still be given based on the pre-ranibizumab injection values.   
896 
 
897 
A minimum of 70 days is required between the first (baseline) and second (12-week) sham or 
898 
dexamethasone injections.  
899 
 
900 
16 and 20-Week Visits:  
901 
If combination injections were not given at the 12-week visit for any reason (for example due to 
902 
missed visit or deferring injection based on retreatment criteria above), combination injections 
903 
should be given at the first visit at which retreatment criteria for injections are met (16- or 20-
904 
week visits). 
905 
 
906 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
4-5 
If combination injections were given at the 12-week visit, eyes in both treatment groups will 
907 
receive only a ranibizumab injection at the 16 and 20-week visits if indicated based on the 
908 
retreatment criteria above.   
909 
 
910 
Treatment at the 24 week visit is at investigator discretion; however, study drug cannot be used.   
911 
 
912 
4.8.1 Anti-VEGF Drug 
913 
Ranibizumab 0.3 mg intravitreal injections (Lucentis®) is the anti-VEGF drug that will be used 
914 
in this study. Ranibizumab (Lucentis®) is manufactured by Genentech, Inc. and is approved for 
915 
the treatment of DME in a dose of 0.3 mg. A 0.5 mg dose of ranibizumab is also FDA-approved 
916 
for age-related macular degeneration and macular edema secondary to retinal vein occlusion. 
917 
Ranibizumab 0.3 mg intravitreal injections will be given in 0.05 cc volume. The physical, 
918 
chemical and pharmaceutical properties and formulation will be provided in the Ranibizumab 
919 
Clinical Investigator Brochure. Ranibizumab will be provided by Genentech Inc.  
920 
 
921 
4.8.2 Steroid 
922 
Study eyes assigned to dexamethasone + ranibizumab will receive will receive sustained 
923 
dexamethasone drug delivery system (Ozurdex®). Ozurdex is a pellet consisting of a 0.45 mm in 
924 
diameter and 6.5 mm in length biodegradable polymer matrix of dexamethasone that provides 
925 
sustained delivery of  700μg of preservative-free dexamethasone into the vitreous cavity and 
926 
retina through injection using a single-use special prepackaged applicator. The physical, 
927 
chemical and pharmaceutical properties and formulation are provided in the Clinical Investigator 
928 
Brochure. Ozurdex® will be provided by Allergan Inc.  
929 
  
930 
4.8.3 Intravitreal Injection Technique 
931 
Each injection is preceded by a povidone iodine prep of the conjunctiva. Antibiotics in the pre-, 
932 
peri-, or post-injection period are not necessary but can be used at investigator discretion if such 
933 
use is part of his/her usual routine. 
934 
 
935 
The injection will be performed using sterile technique. The full injection procedure is described 
936 
in the DRCR.net Study Procedures Manual. 
937 
  
938 
4.8.4 Sham Injection Technique 
939 
The prep will be performed as for an intravitreal injection. Either a syringe without the needle 
940 
attached or the dexamethasone applicator will be used. The hub of the syringe or the applicator 
941 
will be pressed against the conjunctival surface to simulate the force of an actual injection. 
942 
 
943 
4.8.5 Delay in Giving Injections 
944 
If a scheduled injection is not given by the end of the visit window, it can still be given up to 1 
945 
week prior to the next visit window opening. If it is not given by that time, it will be considered 
946 
missed. 
947 
 
948 
If an injection is given late, the next scheduled injection should occur no sooner than 3 weeks 
949 
after the previous injection. 
950 
 
951 
4.8.6  Deferral of Injections Due to Pregnancy 
952 
Female study participants must be questioned regarding the possibility of pregnancy prior to 
953 
each injection. In the event of pregnancy, study injections must be discontinued.   
954 
955 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
5-1 
Chapter 5.  
956 
MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 
957 
 
958 
5.1 Endophthalmitis  
959 
Diagnosis of endophthalmitis is based on investigator’s judgment. Obtaining cultures of vitreous 
960 
and/or aqueous fluid is strongly recommended prior to initiating antibiotic treatment for 
961 
presumed endophthalmitis. 
962 
 
963 
5.2 Surgery for Vitreous Hemorrhage and Other Complications of Diabetic Retinopathy 
964 
A study eye could develop a vitreous hemorrhage and/or other complications of diabetic 
965 
retinopathy that may cause visual impairment. The timing of vitrectomy for the complications of 
966 
proliferative diabetic retinopathy such as vitreous hemorrhage is left to investigator discretion. 
967 
 
968 
5.3 Panretinal (Scatter) Photocoagulation (PRP) 
969 
PRP can be given if it is indicated in the judgment of the investigator. Individuals are not eligible 
970 
for this study if, at the time of enrollment, it is expected that they will need PRP within 6 months.  
971 
In general, PRP should not be given if the study participant has less than severe non-proliferative 
972 
diabetic retinopathy.  In general, PRP should be given promptly for previously untreated eyes 
973 
exhibiting PDR with high-risk characteristics and can be considered for persons with non-high-
974 
risk PDR or severe non-proliferative diabetic retinopathy. Guidelines for PRP can be found in 
975 
the Protocol Procedure Manuals on the DRCR.net website. 
976 
 
977 
5.4 Treatment of Macular Edema in Non-study Eye 
978 
Treatment of DME in the non-study eye is at investigator discretion. 
979 
 
980 
5.5 Diabetes Management 
981 
Diabetes management is left to the study participant’s medical care provider. 
982 
 
983 
5.6 Management of Ocular Hypertension or Glaucoma 
984 
Treatment of rise in intraocular pressure is at investigator discretion. 
985 
 
986 
5.7 Study Participant Withdrawal and Losses to Follow-up 
987 
A study participant has the right to withdraw from the study at any time. If a study participant is 
988 
considering withdrawal from the study, the principal investigator should personally speak to the 
989 
individual about the reasons, and every effort should be made to accommodate him/her.   
990 
 
991 
The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 
992 
will assist in the tracking of study participants who cannot be contacted by the site. The 
993 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
994 
 
995 
Study participants who withdraw will be asked to have a final closeout visit at which the testing 
996 
described for the protocol visits will be performed. Study participants who have an adverse effect 
997 
attributable to a study treatment or procedure will be asked to continue in follow-up until the 
998 
adverse event has resolved or stabilized. 
999 
 
1000 
Study participants who withdraw or are determined to have been ineligible post-randomization 
1001 
will not be replaced. 
1002 
 
1003 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
5-2 
5.8 Discontinuation of Study 
1004 
The study may be discontinued by the Executive Committee (with approval of the Data and 
1005 
Safety Monitoring Committee) prior to the preplanned completion of follow-up for all study 
1006 
participants. 
1007 
 
1008 
5.9 Contact Information Provided to the Coordinating Center 
1009 
The Coordinating Center will be provided with contact information for each study participant.  
1010 
Permission to obtain such information will be included in the Informed Consent Form. The contact 
1011 
information may be maintained in a secure database and will be maintained separately from the 
1012 
study data. 
1013 
 
1014 
Phone contact from the Coordinating Center will be made with each study participant in the first 
1015 
month after randomization and prior to the 24-week visit. Additional phone contacts from the 
1016 
Coordinating Center will be made if necessary to facilitate the scheduling of the study participant 
1017 
for follow-up visits. A participant-oriented newsletter and/or study logo item may be sent during 
1018 
the study.  
1019 
 
1020 
Study participants will be provided with a summary of the study results in a newsletter format 
1021 
after completion of the study by all participants.   
1022 
 
1023 
5.10 Study Participant Reimbursement 
1024 
The study will be providing the study participant with a $25 gift card per completed protocol 
1025 
visit. Additional travel expenses will be paid in select cases for participants with higher 
1026 
expenses. 
1027 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
6-1 
Chapter 6.                                                                                             
1028 
ADVERSE EVENTS 
1029 
 
1030 
6.1 Definition 
1031 
An adverse event is any untoward medical occurrence in a study participant, irrespective of 
1032 
whether or not the event is considered treatment-related. 
1033 
 
1034 
6.2 Recording of Adverse Events 
1035 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
1036 
events or untoward findings. The first concern will be the safety of the study participant, and 
1037 
appropriate medical intervention will be made. 
1038 
 
1039 
The investigator will elicit reports of adverse events from the study participant at each visit and 
1040 
complete all adverse event forms online.  Each adverse event form is reviewed by the 
1041 
Coordinating Center to verify the coding and the reporting that is required.      
1042 
 
1043 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1044 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1045 
by the treatment.    
1046 
 
1047 
The intensity of adverse events will be rated on a three-point scale:  (1) mild, (2) moderate, or (3) 
1048 
severe.  It is emphasized that the term severe is a measure of intensity:  thus, a severe adverse 
1049 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
1050 
but may not be clinically serious. 
1051 
 
1052 
Adverse events will be coded using the MedDRA dictionary.  
1053 
 
1054 
Definitions of relationship and intensity are listed on the DRCR.net website data entry form.   
1055 
 
1056 
Adverse events that continue after the study participant’s discontinuation or completion of the 
1057 
study will be followed until their medical outcome is determined or until no further change in the 
1058 
condition is expected.   
1059 
 
1060 
6.3 Reporting Serious or Unexpected Adverse Events 
1061 
A serious adverse event is any untoward occurrence that: 
1062 
 Results in death 
1063 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1064 
become life-threatening, is not necessarily considered a serious adverse event) 
1065 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
1066 
 Results in significant disability/incapacity (sight threatening)  
1067 
 Is a congenital anomaly/birth defect 
1068 
Unexpected adverse events are those that are not identified in nature, severity, or frequency in 
1069 
the current Clinical Investigator’s Brochure or the current package insert.   
1070 
 
1071 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately 
1072 
via completion of the online serious adverse event form. 
1073 
 
1074 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
6-2 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1075 
both serious and unexpected.  Notification will be made within 10 days after the Coordinating 
1076 
Center becomes aware of the event.   
1077 
 
1078 
Each principal investigator is responsible for informing his/her IRB of serious study-related 
1079 
adverse events and abiding by any other reporting requirements specific to their IRB.  
1080 
 
1081 
6.4 Data and Safety Monitoring Committee Review of Adverse Events 
1082 
A Data and Safety Monitoring Committee (DSMC) will approve the protocol, template informed 
1083 
consent form, and substantive amendments and provide independent monitoring of adverse 
1084 
events. Cumulative adverse event data are tabulated semi-annually for review by the Data and 
1085 
Safety Monitoring Committee (DSMC). Following each DSMC data review, a summary will be 
1086 
provided to IRBs. A list of specific adverse events to be reported expeditiously to the DSMC will 
1087 
be compiled and included as part of the DSMC Standard Operating Procedures document.   
1088 
 
1089 
6.5 Risks 
1090 
6.5.1 Potential Adverse Effects of Study Drug 
1091 
6.5.1.1 Anti-VEGF 
1092 
     
1093 
Ranibizumab is well tolerated in people. More than 5000 individuals have been treated with 
1094 
injections of ranibizumab in clinical studies to date, however the full safety profile with long-
1095 
term injections is not yet known. Some participants in ongoing clinical studies have developed 
1096 
inflammation in the eye (uveitis) which can be treated with anti-inflammatory drops.  Increased 
1097 
eye pressure leading to glaucoma or cataract has also resulted from injections of ranibizumab. 
1098 
Other ocular adverse events that have occurred in ongoing clinical studies are believed to be due 
1099 
to the intravitreal injection itself and not the study drug (Section 6.5.2 Potential Adverse Effects 
1100 
of Intravitreal Injection).   
1101 
 
1102 
Some study participants have experienced systemic adverse events that may possibly be related 
1103 
to ranibizumab. There is evidence that intravitreally administered ranibizumab is associated with 
1104 
a decrease in serum VEGF concentrations, but it has not been established whether this decrease 
1105 
results in clinically significant adverse events.46  Until cumulative safety data are analyzed, 
1106 
precise incidence figures are unknown and a causal relationship cannot be ruled out.  These 
1107 
include arterial thromboembolic events and other events potentially related to systemic VEGF 
1108 
inhibition. In a phase IIIb study to evaluate the long-term safety and efficacy of ranibizumab 
1109 
(The Safety Assessment of Intravitreous Lucentis for AMD (SAILOR trial), which randomized 
1110 
patients with wet age-related macular degeneration to 0.5 mg ranibizumab or 0.3 mg 
1111 
ranibizumab, there was a higher rate of cerebrovascular stroke in the group that received the 
1112 
higher drug dose (1.2 vs. 0.7%), although this trend did not achieve statistical significance.47  It 
1113 
appeared that patients who had a prior history of stroke may be at greater risk for having a stroke 
1114 
after receiving ranibizumab, although there was a low incidence of stroke overall in this group.  
1115 
 
1116 
Additional data regarding systemic safety of ranibizumab in a diabetic population is also 
1117 
available from the DRCR.net Protocol I primary results.12  This study enrolled a combined total 
1118 
of 375 patients in the two ranibizumab arms, who received an average of eight to nine 
1119 
intravitreal injections of 0.5 mg ranibizumab over the first year of treatment. There was no 
1120 
indication of an increased risk of cardiovascular or cerebrovascular events in the ranibizumab-
1121 
treated study participants as compared with the triamcinolone-treated study participants or study 
1122 
participants who received no intravitreal drug. Indeed, lower rates of cardiovascular events, as 
1123 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
6-3 
defined by the Antiplatelet Trialists’ Collaboration, were seen in the ranibizumab groups as 
1124 
compared with the sham group at both one (3% versus 8%) and two (5% versus 12%) years. In 
1125 
the RISE and RIDE studies, ranibizumab therapy was also well-tolerated overall, although the 
1126 
rate of Antiplatelet Trialists’ Collaboration events was slightly higher in the 0.3 mg (5.6%) and 
1127 
0.5 mg (7.2%) groups as compared with the sham group (5.2%) in the pooled RISE and RIDE 
1128 
results. Deaths were also more frequent in the ranibizumab groups (0.8% and 1.6% of sham and 
1129 
2.4-4.8% of ranibizumab treated patients) in these trials.15 The rate of non-fatal cerebrovascular 
1130 
events in this pooled analysis was higher in the 0.5 mg group (2%) than in the sham (1.2%) or 
1131 
0.3 mg group (0.8%) but the rate of non-fatal myocardial infarctions was similar across treatment 
1132 
groups (2.8%, 2.8% and 2.4% in the sham, 0.3mg and 0.5mg groups, respectively). On the other 
1133 
hand, mortality was reported to be below expected in subjects who received ranibizumab for 
1134 
AMD with the standardized mortality rate of 0.75 (95% confidence interval, 0.62-0.89).48 In 
1135 
hospital and death records review, Kemp et al. reported higher 12-month myocardial infarction 
1136 
rate in patient who received vascular endothelial growth factor inhibitor (1,267 patients) than 
1137 
those who received photodynamic therapy (399 patients) for AMD or those in nontreated 
1138 
community sample (1,763 patients) (1.9/100 vs. 0.8 and 0.7, respectively) with no differences 
1139 
observed between patients treated with bevacizumab and ranibizumab.49   
1140 
 
1141 
There may be side effects and discomforts that are not yet known.  Long-term studies in animals 
1142 
have not been performed to evaluate the carcinogenic potential of ranibizumab or its effect on 
1143 
fertility. 
1144 
 
1145 
6.5.1.2 Steroid  
1146 
The 0.7 mg dexamethasone implant (Ozurdex) generally appeared to be safe and well-tolerated 
1147 
in phase III studies in which it was evaluated as treatment for macular edema secondary to retinal 
1148 
vein occlusion.42  No cases of endophthalmitis occurred in these studies which included 1,256 
1149 
study participants followed for 12 months after enrollment. The 12-month incidence of 
1150 
subconjunctival hemorrhage ranged from 22.3%- 24.9% in study eyes, some of which received 1 
1151 
and some of which received 2 implants at either the 0.7 mg or 0.35 mg dose.  Cataract 
1152 
progression occurred in 29.8% of phakic eyes that received two 0.7 mg implants versus only 
1153 
5.7% of sham-treated phakic eyes. An increase in IOP of 10 mmHg or more was observed in 
1154 
eyes that received two 0.7 mg implants at rates of 12.6% after the first implant and 15.4% after 
1155 
the second treatment. A total of 32.8% of study eyes receiving two 0.7 mg implants had at least a 
1156 
10 mmHg increase in IOP from baseline during the 12 months of follow-up. Of eyes that 
1157 
received a 0.7 mg implant at baseline, 25.5% were started on an IOP-lowering medication during 
1158 
the first 180 days of the study. When a single 0.7 mg dexamethasone implant was administered 
1159 
in 55 vitrectomized eyes with DME,44 the most common adverse events were conjunctival 
1160 
hemorrhage (52.7%), conjunctival hyperemia (20.0%), eye pain (16.4%), increased IOP (16.4%), 
1161 
conjunctival edema (12.7%), and vitreous hemorrhage (10.9%).  Of the 48 study participants 
1162 
who were not on IOP-lowering medication at baseline, 8 (17%) began on IOP-lowering 
1163 
medication during the study. Additional adverse events that occurred in more than 5% but less 
1164 
than 10% of eyes were maculopathy (either epiretinal membrane or macular thickening), anterior 
1165 
chamber cells, foreign body sensation, iritis, and floaters. Migration of Ozurdex to the anterior 
1166 
chamber with subsequent corneal edema is a rare complication of Ozurdex injections. This risk is 
1167 
associated with with aphakic eyes,50-52 and pseudophakic eyes with anterior chamber intraocular 
1168 
lens and iridectomy or disruption of the posterior capsule.53-55 In one study of 342 eyes with 
1169 
macular edema due to retinal vein occlusion treated with Ozurdex, two eyes (~0.5%) had 
1170 
Ozurdex dislocated to the anterior chamber requiring surgical repositioning in the vitreous 
1171 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
6-4 
cavitity.55  
1172 
 
1173 
6.5.2 Potential Adverse Effects of Intravitreal Injection 
1174 
Rarely, the drugs used to anesthetize the eye before the injections (proparacaine, tetracaine, or 
1175 
xylocaine) can cause an allergic reaction, seizures, and an irregular heartbeat.   
1176 
 
1177 
Subconjunctival hemorrhage or floaters will commonly occur as a result of the intravitreal 
1178 
injection. Mild discomfort, ocular hyperemia, increased lacrimation, discharge or itching lasting 
1179 
for a few days is also likely. 
1180 
 
1181 
Immediately following the injection, there may be elevation of intraocular pressure. It usually 
1182 
returns to normal spontaneously, but may need to be treated with topical drugs or a 
1183 
paracentesis to lower the pressure. The likelihood of permanent loss of vision from elevated 
1184 
intraocular pressure is less than 1%. 
1185 
 
1186 
As a result of the injection, endophthalmitis (infection in the eye) could develop. If this occurs, it is 
1187 
treated by intravitreal injection of antibiotics, but there is a risk of permanent loss of vision including 
1188 
blindness. The risk of endophthalmitis is less than 1%. 
1189 
 
1190 
As a result of the injection, a retinal detachment could occur.  If this occurs, surgery may be 
1191 
needed to repair the retina. The surgery is usually successful at reattaching the retina.  
1192 
However, a retinal detachment can produce permanent loss of vision and even blindness.  The 
1193 
risk of retinal detachment is less than 1%. 
1194 
 
1195 
The injection could cause a vitreous hemorrhage.  Usually the blood will resolve 
1196 
spontaneously, but if not, surgery may be needed to remove the blood.  Although the surgery 
1197 
usually successfully removes the blood, there is a small risk of permanent loss of vision and 
1198 
even blindness.  The risk of having a vitreous hemorrhage due to the injection is less than 1%. 
1199 
 
1200 
 
1201 
6.5.3 Risks of Eye Examination and Tests 
1202 
There is a rare risk of an allergic response to the topical medications used to anesthetize the eye 
1203 
or dilate the pupil. Dilating drops rarely could cause an acute angle closure glaucoma attack, but 
1204 
this is highly unlikely since the participants in the study will have had their pupils dilated many 
1205 
times previously.   
1206 
 
1207 
There are no known risks associated with OCT.  
1208 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
7-1 
Chapter 7.                                                                                       
1209 
STATISTICAL METHODS 
1210 
 
1211 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
1212 
analysis plan will be written and finalized prior to the completion of the study. The analysis plan 
1213 
synopsis in this chapter contains the framework of the anticipated final analysis plan.  
1214 
 
1215 
This phase II clinical trial is conducted to assess the short term effect of combination steroid + 
1216 
anti-VEGF therapy on visual acuity and OCT retinal thickness, in comparison with that of 
1217 
continued anti-VEGF therapy alone, in eyes with persistent central-involved DME and visual 
1218 
acuity impairment despite previous anti-VEGF treatment. The primary outcome of the study will 
1219 
be the mean change in visual acuity at the 24-week post-randomization visit, adjusted for the 
1220 
baseline (randomization) visual acuity. 
1221 
 
1222 
The treatment groups include the following: 
1223 
 Group A: Sham + intravitreal ranibizumab 0.3 mg 
1224 
 Group B: Intravitreal dexamethasone +intravitreal ranibizumab 0.3 mg  
1225 
 
1226 
7.1 Sample Size 
1227 
This phase II study will include 75 study eyes (from approximately 62 participants) in each 
1228 
treatment group.  
1229 
 
1230 
The primary analysis consists of a statistical estimation of the difference in mean change in visual 
1231 
acuity letter score at the 24-week post-randomization visit, adjusted for the baseline visual acuity 
1232 
and correlation between eyes, between the sham + ranibizumab group and the combination of 
1233 
corticosteroid+ ranibizumab group.  
1234 
 
1235 
7.2 Sample Size Assumptions and Precision Estimates 
1236 
To estimate the standard deviation (SD) of change in visual acuity from baseline (randomization) 
1237 
to the 24-week visit (primary outcome visit), data from the DRCR.net Protocol I were reviewed.  
1238 
Of eyes that completed the 1-year visit, 61 eyes were identified at the 32-week visit to have 1) 
1239 
OCT CSF≥250 μm, 2) VA between 20/320 to 20/32; and 3) received at least 3 ranibizumab 
1240 
injections from the 16-week visit to prior to the 32 week-visit. All these eyes had received at least 
1241 
3 ranibizumab injections prior to the 16-week visit and met the OCT and VA thresholds above, 
1242 
mimicking the minimum number of injections required for enrollment into the run-in phase of this 
1243 
protocol. The mean change in visual acuity letter score from the 32-week visit (to mimic 
1244 
randomization visit of this protocol) to the 52-week visit (to mimic the 24-week visit of this 
1245 
protocol) for these 61 eyes, adjusted for baseline visual acuity, was +1.9 (95%CI: +0.1 to +3.7). 
1246 
The standard deviation for the mean change in visual acuity letter score adjusted for correlation 
1247 
with baseline visual acuity value was 6.9 letter score (95% CI: 5.9 to 8.4).   
1248 
 
1249 
The following table shows half-widths of 95%CI on the difference in mean visual acuity change 
1250 
between treatment groups for a range of SDs and sample sizes. For the sample size in each group 
1251 
of 70 (increased to 75 for approximately 5% lost to follow-up)  that will be used, a two-sided 95% 
1252 
CI for the difference of the two means in visual acuity change from randomization to 24-week visit 
1253 
will extend 2.3 visual acuity letter score in either direction from the observed difference in means, 
1254 
assuming that the common standard deviation is a letter score of 7  (~the midpoint for the estimated 
1255 
standard deviation), not adjusting for correlation between eyes in participants with two study eyes. 
1256 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
7-2 
Similarly, half-width of the 95% CI using a standard deviation of 9 (~ the upper confidence limit 
1257 
for the estimated standard deviation) will be a letter score of 3.0.  Adjustment in the primary 
1258 
analysis for between-eye correlation is expected to slightly reduce the expected width of the 
1259 
confidence interval over the tabled values.   
1260 
 
1261 
Based on the above information, with an alpha of 0.05, if the true visual acuity mean difference is 
1262 
5 letters and the standard deviation is 9 then there is 90% power to detect a difference in visual 
1263 
acuity change between treatment groups.   
1264 
 
1265 
Half-Width of a 95% Confidence Interval for the Difference in Mean visual acuity Change  
1266 
Standard 
Deviation 
Sample Size Per Group 
 
25 
50 
70 
100 
125 
6 
3.3 
2.4 
2.0 
1.7 
1.5 
7 
3.9 
2.7 
2.3 
1.9 
1.7 
8 
4.4 
3.1 
2.7 
2.2 
2.0 
9 
5.0 
3.5 
3.0 
2.5 
2.2 
10 
5.5 
3.9 
3.3 
2.8 
2.5 
11 
6.1 
4.3 
3.6 
3.0 
2.7 
12 
6.7 
4.7 
4.0 
3.3 
3.0 
 
1267 
7.3 Efficacy Analysis Plan  
1268 
7.3.1 Primary Outcome Analysis 
1269 
The primary analysis consists of the estimation of the difference in mean change between the 
1270 
treatment groups in visual acuity letter score from randomization to the 24-week post-
1271 
randomization visit, adjusted for randomization visual acuity and correlation between eyes of 
1272 
participants with two study eyes. 
1273 
 
1274 
The estimation of treatment group difference in mean change in visual acuity from randomization 
1275 
to the 24-week visit will be performed using an analysis of covariance (ANCOVA) model, with 
1276 
the change in visual acuity measurements at 24 weeks fitted as the dependent variable, and the 
1277 
treatment group as the independent variable, adjusting for the randomization stratification factor, 
1278 
and for the baseline measurement (visual acuity value at randomization visit) by including each as 
1279 
a covariate in the model. The treatment effect will be reported as the mean difference (and standard 
1280 
deviation) between treatment groups in change of visual acuity letter score from randomization to 
1281 
24-week visit with 95%CI from ANCOVA model. The significance level used for the final primary 
1282 
analysis will be 0.05. The study is not powered to establish treatment efficacy; however, treatment 
1283 
comparison will be conducted for visual acuity and OCT retinal thickness outcomes to assess 
1284 
treatment effect. 
1285 
 
1286 
There will be two analyses: an “intent-to-treat” analysis (ITT) and a “per-protocol” analysis: 
1287 
 The intent-to-treat analysis will include all randomized eyes.  Rubin’s multiple 
1288 
imputation method will be used to impute missing data at the 24-week visit.   
1289 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
7-3 
 The per-protocol analysis will be performed including only participants who complete all 
1290 
required injections without receiving any non-protocol treatments and have data at the 
1291 
24-week visit.   
1292 
 The intent-to-treat analysis is considered the primary analysis. If the intent-to-treat and 
1293 
per-protocol analyses yield the same results, the per-protocol analysis will be used to 
1294 
provide supportive evidence of the magnitude of treatment effect among patients who 
1295 
received the treatment.  If the results of the two methods differ, exploratory analyses will 
1296 
be performed to evaluate the factors that have contributed to the differences. A sensitivity 
1297 
analysis will be conducted to compare the results from multiple imputation with those 
1298 
using a per-protocol analysis only including study participants who completed the 24-
1299 
week visit and with results from last-observation-carried-forward.   
1300 
 
1301 
Generalized estimating equations (GEE) will be used to adjust for the correlation between eyes 
1302 
of patients who have two study eyes. 
1303 
 
1304 
Although expected to be under-powered, pre-planned subgroup analyses will be conducted in the 
1305 
same way as the primary analysis and include stratification by improvement in OCT CSF thickness 
1306 
during run-in phase visits by ≥10% at any visit, and improvement in VA during run-in phase by 5 
1307 
or more letters at any visit. Other subgroup analyses will be described in the detailed Statistical 
1308 
Analysis Plan. These subgroup analyses will be used to guide choice of pre-planned subgroup 
1309 
analyses in the phase III trial.  
1310 
 
1311 
Imbalances between groups in important covariates are not expected to be of sufficient magnitude 
1312 
to produce confounding; however, a second analysis that adjusts for imbalanced baseline 
1313 
covariates will be performed.  If results are similar to the primary analysis, the primary analysis 
1314 
will be accepted as the definitive analysis; otherwise, the reasons for the difference will be 
1315 
explored. 
1316 
 
1317 
There are no data to suggest that the treatment effect will vary by sex or race and ethnicity.  
1318 
However, both of these factors will be evaluated in exploratory analyses. 
1319 
 
1320 
7.4 Secondary Outcomes 
1321 
In addition to the primary outcome, the following secondary outcomes will be estimated, and their 
1322 
95% CI will be obtained in each treatment group and compared between treatment groups: 
1323 
 
1324 
 Percent of eyes with at least 10 and at least 15 letter gain (increase) or loss (decrease) in 
1325 
E-ETDRS letter score visual acuity at 24 weeks 
1326 
 Visual acuity AUC between randomization and 24 weeks 
1327 
 Mean change in OCT CSF thickness, adjusted for thickness at time or randomization, 
1328 
using ITT, and per-protocol analyses 
1329 
 Percent of eyes with ≥1 and ≥2 logOCT step gain or loss in CSF thickness at 24-week 
1330 
visit 
1331 
 Percent of eyes with OCT CSF thickness (in micros) < the following gender and OCT 
1332 
machine-specific values at 24-week visit: <290 in women and <305 in men in Zeiss 
1333 
Cirrus; <305 in women and <320 in men in Heidelberg Spectralis  
1334 
 OCT CSF thickness area under the curve (AUC) between randomization and 24 weeks 
1335 
 Percent of eyes with worsening or improvement of diabetic retinopathy on clinical exam 
1336 
 
1337 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
7-4 
 
1338 
7.4.1 Secondary Outcomes Analysis 
1339 
Analyses of secondary outcomes will be conducted as follows: 
1340 
Binary outcomes will be analyzed using logistic regression to control for baseline level of the 
1341 
outcome.  Continuous outcome comparisons will be performed using ANCOVA with adjustment 
1342 
for baseline values. All linear model assumptions will be verified including linearity, normality 
1343 
of residuals, and homoscedasticity. If model assumptions are not met, a nonparametric analogue 
1344 
for ANCOVA will be considered. Multple imputation method will be implemented for missing 
1345 
data.  GEE will be used to adjust for correlation between eyes of participants with two study 
1346 
eyes. 
1347 
 
1348 
 
1349 
7.5 Safety Analysis Plan 
1350 
Adverse events will be categorized as study eye, non-study eye, and systemic. The events will be 
1351 
tabulated and compared between treatment groups. Separate analyses will compare related adverse 
1352 
events between groups.  
1353 
 
1354 
Specific adverse events of interest will include: 
1355 
Injected-related: increased intraocular pressure, endophthalmitis, retinal detachment, retinal 
1356 
tears, intraocular hemorrhage  
1357 
Ocular drug-related: increased intraocular pressure, need for ocular anti-hypertensives, 
1358 
glaucoma surgery or other IOP-lowering procedures, development or worsening of cataract 
1359 
and cataract extraction, intraocular hemorrhage, inflammation, migration of Ozurdex to the 
1360 
anterior chamber and subsequent corneal complications 
1361 
Systemic drug-related: Deaths, participants with at least one hospitialization, participants 
1362 
with at least one SAE, and cardiovascular events and cerebrovascular events as defined by 
1363 
Antiplatelet Trialists’ Collaboration 
1364 
o Systemic adverse events for participants with two study eyes will be evaluated 
1365 
separately from participants with one study eye. 
1366 
 
1367 
 
1368 
Further definitions of the events for analysis and the analytic approach will be provided in the 
1369 
detailed statistical analysis plan. 
1370 
  
1371 
 
1372 
7.6 Additional Analysis Objectives Related to Design of Phase III Trial 
1373 
If the results of this study support proceeding with a phase III trial, information from this study 
1374 
will 1) be used to estimate recruitment potential; and 2) contribute to designing the phase III 
1375 
trial. The standard deviation of the difference in mean change in visual acuity will be used in the 
1376 
sample size calculation of the phase III trial. The recruitment potential for a phase III trial will be 
1377 
assessed based on the average monthly enrollment of participants into this study. The sample 
1378 
size estimate that would be calculated for a phase III trial weighed against recruitment projection 
1379 
from this phase II trial will aid in the assessment of feasibility of a phase III trial in terms of 
1380 
recruitment.  
1381 
 
1382 
Additional outcomes that will be assessed to aid in the design of a phase III trial include: 1) success 
1383 
of the run-in phase in identifying eyes with “persistent DME” following anti-VEGF therapy (for 
1384 
example, depending on proportion of enrolled eyes that are randomized, the run-in phase duration 
1385 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
7-5 
or criteria for randomization may be adjusted), 2) success of masking via sham injections and 3) 
1386 
duration of steroid effect.  
1387 
 
1388 
7.7 Additional Tabulations and Analyses 
1389 
The following will be tabulated according to treatment group: 
1390 
1) Baseline demographic and clinical characteristics (subject and ocular-level data) 
1391 
2) Visit completion rate for each visit 
1392 
3) Protocol deviations 
1393 
 
1394 
7.8 Interim Monitoring Plan 
1395 
Formal interim efficacy analyses are not planned.  However, at approximately 6-month intervals 
1396 
the DSMC will review a compiled ocular and systemic adverse event data report as well as visual 
1397 
acuity by treatment group.   
1398 
 
1399 
A minimal amount of alpha spending (0.0001) will be allocated for each DSMC review of the 
1400 
data and depending on the actual number of reviews, the final overall type 1 error at the end of 
1401 
the trial will be adjusted accordingly. 
1402 

 
 
 
Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
8-1 
Chapter 8. REFERENCES 
1403 
 
1404 
1. 
Centers for Disease Control and Prevention. State-specific incidence of diabetes among 
1405 
adults--participating states, 1995-1997 and 2005-2007. MMWR Morb Mortal Wkly Rep. 
1406 
Oct 31 2008;57(43):1169-1173. 
1407 
2. 
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 
1408 
and 2030. Diabetes Res Clin Pract. Jan 2010;87(1):4-14. 
1409 
3. 
Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy 
1410 
among adults in the United States. Arch Ophthalmol. Apr 2004;122(4):552-563. 
1411 
4. 
Ferris F, Patz A. Macular edema: a complication of diabetic retinopathy. Surv 
1412 
Ophthalmol. 1984;28 (suppl)(May):452-461. 
1413 
5. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1414 
diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 1987;27(4):265-
1415 
272. 
1416 
6. 
Ferris FL, 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv 
1417 
Ophthalmol. 1984;28 (suppl)(May):452-461. 
1418 
7. 
Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin 
1419 
Ophthalmol. 1999;14(4):223-232. 
1420 
8. 
Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced 
1421 
retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally 
1422 
effective beta-isoform-selective inhibitor. Diabetes. Sep 1997;46:1473-1480. 
1423 
9. 
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
1424 
diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. 
1425 
Arch Ophthalmol. 1985;103(12):1796-1806. 
1426 
10. 
Diabetic Retinopathy Clinical Research Network. A randomized trial comparing 
1427 
intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular 
1428 
edema. Ophthalmology. Sep 2008;115(9):1447-1449, 1449 e1441-1410. 
1429 
11. 
Diabetic Retinopathy Clinical Research Network. Three-year follow up of a randomized 
1430 
trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic 
1431 
macular edema. Arch Ophthalmol. 2009;127(3):245-251. 
1432 
12. 
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 
1433 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic 
1434 
macular edema. Ophthalmology. Jun 2010;117(6):1064-1077 e1035. 
1435 
13. 
Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the 
1436 
ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. Nov 
1437 
2009;116(11):2175-2181 e2171. 
1438 
14. 
Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards A, et al. A phase II 
1439 
randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. 
1440 
Ophthalmal. 2007;114(10):1860-1867. 
1441 
15. 
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: 
1442 
Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. Apr 
1443 
2012;119(4):789-801. 
1444 
16. 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study ranibizumab 
1445 
monotherapy or combined with laser versus laser monotherapy for diabetic macular 
1446 
edema. Ophthalmology. Apr 2011;118(4):615-625. 
1447 
17. 
Genentech I. Package Insert: Lucentis.  http://www.drugs.com/pro/lucentis.html. 
1448 
18. 
Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus 
1449 
prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. 
1450 
Ophthalmology. Apr 2011;118(4):609-614. 
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Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
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19. 
Nepomuceno AB, Takaki E, Paes De Almeida FP, et al. A Prospective Randomized Trial 
1452 
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1453 
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1454 
20. 
Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteriods 
1455 
inhibit the expression of the vascular endothelial growth factor gene in human vascular 
1456 
smooth muscle cells. Euro J Pharmacol. 1998;341(2-3):309-315. 
1457 
21. 
Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by 
1458 
platelet-activating factor and platelet-derived growth factor is downregulated by 
1459 
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1460 
22. 
Folkman J, Ingber DE. Angiostatic steroids.  Method of discovery and mechanism of 
1461 
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1462 
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Diaz-Florez L, Gutierrez R, Varela H. Angiogenesis: an update. Histol Histopathol. 
1463 
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1464 
24. 
Yoshikawa K, Kotake S, Ichiishi A, Sasamoto Y, Kosaka S, Matsuda H. Posterior sub-
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Tenon injections of repository corticosteroids in uveitis patients with cystoid macular 
1466 
edema. Jpn J Ophthalmol. 1995;39(1):71-76. 
1467 
25. 
Thach AB, Dugel PU, Flindall RJ, Sipperley JO, Sneed SR. A comparison of retrobulbar 
1468 
versus sub-Tenon's corticosteroid therapy for cystoid macular edema refractory to typical 
1469 
medications. Ophthalmology. 1997;104(12):2003-2008. 
1470 
26. 
Tano Y, Chandler D, Machemer R. Treatment of intraocular proliferation with 
1471 
intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 1980;90:810-816. 
1472 
27. 
Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL. The effects of intravitreal 
1473 
triamcinolone acetonide on experimental pre-retinal neovascularization. Graefes Arch 
1474 
Clin Exp Ophthalmol. 1993;231:34-40. 
1475 
28. 
Danis RP, Bingaman DP, Yang Y, Ladd B. Inhibition of preretinal and optic nerve head 
1476 
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1477 
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1478 
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Jonas JB, Hayler JK, Panda-Jones S. Intravitreal injection of crystalline cortisone as 
1479 
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1480 
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1481 
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Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and 
1482 
intravitreal triamcinolone.  A pilot study. Aust N Z J Ophthalmol. 1995;23:293-298. 
1483 
31. 
Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative 
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macular degeneration and intravitreal triamcinolone: 18 month follow up. Aust N Z J 
1485 
Ophthalmol. 1998;26:277-281. 
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Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in 
1487 
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1488 
33. 
Wang K, Wang Y, Gao L, Li X, Li M, Guo J. Dexamethasone inhibits leukocyte 
1489 
accumulation and vascular permeability in retina of streptozotocin-induced diabetic rats 
1490 
via reducing vascular endothelial growth factor and intercellular adhesion molecule-1 
1491 
expression. Biol Pharm Bull. Aug 2008;31(8):1541-1546. 
1492 
34. 
Zhang X, Bao S, Lai D, Rapkins RW, Gillies MC. Intravitreal triamcinolone acetonide 
1493 
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1494 
and its receptors in early diabetic rat retinas. Diabetes. Apr 2008;57(4):1026-1033. 
1495 
35. 
Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction 
1496 
gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. Nov 
1497 
2005;30(11):949-957. 
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Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
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36. 
Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab 
1499 
alone or combined with triamcinolone versus macular photocoagulation in diabetic 
1500 
macular edema. Ophthalmology. Jun 2009;116(6):1142-1150. 
1501 
37. 
Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal Bevacizumab (Avastin) 
1502 
injection alone or combined with Triamcinolone versus macular photocoagulation as 
1503 
primary treatment of diabetic macular edema. RETINA. 2007;27:1187-1195. 
1504 
38. 
Faghihi H, Roohipoor R, Mohammadi SF, et al. Intravitreal bevacizumab versus 
1505 
combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic 
1506 
macular edema. Eur J Ophthalmol. Nov-Dec 2008;18(6):941-948. 
1507 
39. 
Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without 
1508 
triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized 
1509 
clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008;246:483-489. 
1510 
40. 
Tsilimbaris MK, Pandeleondidis V, Panagiototglou T, et al. Intravitreal combination of 
1511 
triamcinolone acetonide and bevacizumab (Kenacort-Avastin) in diffuse diabetic macular 
1512 
edema. Semin Ophthalmol. Nov-Dec 2009;24(6):225-230. 
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Combination Steroid+Anti-VEGF for Persistent DME (V5.0) CLEAN 11-16-15                                 
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