Clinical trial NCT00105027
Conditions: Macular Edema, Cystoid Retinal Vein Occlusion
Keywords: macular edema central retinal vein occlusion (CRVO) branch retinal vein occlusion (BRVO)
Sponsor: The Emmes Company, LLC
Start date: 2004-10-01; Completion date: 2009-02-01
Enrollment: 682 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The SCORE Study will compare the effectiveness and safety of standard care to intravitreal injection(s) of triamcinolone for treating macular edema (swelling of the central part of the retina) associated with central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO).

Detailed description:
Macular edema is a major cause of vision loss in patients with CRVO and BRVO. Both CRVO and BRVO are common retinal problems and are caused by a blockage in one of the large retinal veins (central retinal vein occlusion - CRVO) or smaller retinal veins (branch retinal vein occlusion - BRVO). Currently, there is no effective treatment for macular edema associated with CRVO and standard care treatment is observation. Grid laser photocoagulation may be effective for some patients for macular edema associated with BRVO, but many patients derive limited benefit from this treatment. Therefore, the development of new treatment modalities for macular edema caused by these two conditions is an important research goal.

Over the last several years, many patients with macular edema from CRVO and BRVO have been treated with an injection of a type of steroid called triamcinolone directly into the eye. This type of injection is called an intravitreal injection. The triamcinolone preparation commonly injected into the eye is Kenalog and is FDA-approved only for use in muscles and joints. The SCORE Study will use a formulation of triamcinolone made specifically for the eye.

The SCORE Study is a multicenter, randomized, Phase III trial to compare the effectiveness and safety of standard care versus triamcinolone injection(s) for the treatment of macular edema associated with CRVO and BRVO. In each of the two disease areas, 630 participants will be randomized (similar to a flip of a coin) in a 1:1:1 ratio to one of three groups: standard care, intravitreal triamcinolone 4 mg, or intravitreal triamcinolone 1 mg. After randomization, participants will be examined every 4 months through 3 years to collect ophthalmic information, including visual acuity, intraocular pressure, optical coherence tomography, and fundus photography . Fluorescein angiography will be performed at 4, 12 and 24 months. Repeat intravitreal injections of triamcinolone and repeat laser treatment will be provided as clinically indicated based on protocol-specific guidelines.

The primary outcome is improvement by 15 or more letters from baseline in best-corrected ETDRS visual acuity score at the 12-month visit. Secondary outcomes include changes from baseline in best-corrected ETDRS visual acuity score, changes in retinal thickness as assessed by stereoscopic color fundus photography and optical coherence tomography, and adverse ocular outcomes.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: Standard Care intervention 2: intravitreal triamcinolone injection intervention 3: intravitreal triamcinolone injection
Intervention descriptions: intervention 1: CRVO: observation; BRVO: standard care intervention 2: 1 mg dose intervention 3: 4 mg

Protocol documents:
Prot_SAP_000.pdf: 
The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
February 10, 2008 
 
 
The Standard Care vs. COrticosteroid for  
REtinal Vein Occlusion (SCORE) Study 
 
 
Two Randomized Trials to Compare the Efficacy and Safety of Intravitreal Injection(s) 
of Triamcinolone Acetonide with Standard Care to Treat Macular Edema: One for 
Central Retinal Vein Occlusion and One for Branch Retinal Vein Occlusion 
 
 
 
Version 7.0 — February 10, 2008 
 
Study Chair 
 
 
 
 
 
Study Co-Chair 
Michael S. Ip, MD 
 
 
 
 
Ingrid U. Scott, MD, MPH 
University of Wisconsin Medical School 
 
Professor of Ophthalmology and 
Dept of Ophthalmology and Visual Sciences 
 
Health Evaluation Sciences 
F4/336 Clinical Science Center  
 
 
Penn State College of Medicine 
600 Highland Avenue  
 
 
 
500 University Drive, HU19 
Madison, WI  53792 
 
 
 
 
Hershey, PA  17033 
Tel:  608-263-4823 
 
 
 
 
Tel:  717-531-5368 
Fax: 608-263-1466 
 
 
 
 
Fax:  717-531-5475 
E-mail:  msip@facstaff.wisc.edu 
 
 
E-mail:  iscott@psu.edu 
 
Principal Investigator  
 
 
 
Principal Investigator 
Data Coordinating Center 
 
 
 
Fundus Photograph Reading Center 
Paul C. VanVeldhuisen, PhD  
 
 
Barbara A. Blodi, MD 
The EMMES Corporation 
 
 
 
406 Science Drive, Suite 400 
401 N. Washington Street, Suite 700 
 
 
Madison, WI  53711 
Rockville, MD  20850-1785 
 
 
 
Tel:  608-263-7290 
Tel:  301-251-1161 x143 
 
 
 
Fax: 608-263-1466 
Fax: 800-546-9262 
 
 
 
 
E-mail:  bablodi@facstaff.wisc.edu 
E-mail:  pvanveldhuisen@emmes.com 
 
NEI Program Officer  
 
 
 
DSMC Chair 
Maryann Redford, DDS, MPH  
 
 
John Connett, PhD 
National Eye Institute  
 
 
 
University of Minnesota 
6120 Executive Blvd., Suite 350 
 
 
Coordinating Centers for Biometric Research 
Bethesda, MD  20892  
 
 
 
2221 University Avenue SE, Room 200 
Tel:  301-451-2020 
 
 
 
 
Minneapolis, MN  55414 
Fax: 301-402-0528 
 
 
 
 
Tel:  612-626-9010 
E-mail:  maryann.redford@nei.nih.gov  
 
Fax: 612-626-9054 
 
 
 
 
 
 
 
E-mail:  john-c@blueox.ccbr.umn.edu 
 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
February 10, 2008 
 
 
i 
Table of Contents 
PRÉCIS 
.................................................................................................................................... 1 
1. 
INTRODUCTION................................................................................................................ 3 
2. 
BACKGROUND AND SCIENTIFIC JUSTIFICATION ................................................ 3 
2.1 Venous Occlusive Disease .................................................................................................... 3 
2.2 Pathogenesis of Macular Edema ......................................................................................... 6 
2.3 Animal and Clinical Studies Using Intravitreal Triamcinolone Acetonide Injections .. 8 
2.4 Other Studies Evaluating Corticosteroid Preparations Other Than Triamcinolone 
Acetonide for Treatment of Macular Edema due to Retinal Vascular Disease ........... 16 
2.4.1 
Efficacy ..................................................................................................................... 16 
2.4.2 
Adverse Effects ......................................................................................................... 17 
2.5 Rationale for the Intravitreal Triamcinolone Acetonide Doses to be Evaluated ......... 18 
2.6 Mechanism of Adverse Effects Associated with Intravitreal Steroids .......................... 20 
2.6.1 
Elevation of Intraocular Pressure .............................................................................. 20 
2.6.2 
Cataract Formation .................................................................................................... 21 
2.6.3 
Endophthalmitis ........................................................................................................ 22 
3. 
OBJECTIVES .................................................................................................................... 24 
4. 
STUDY DESIGN AND METHODS................................................................................. 24 
4.1 Efficacy Assessment ........................................................................................................... 25 
4.1.1 
Primary Efficacy Outcome ........................................................................................ 25 
4.1.2 
Secondary Efficacy Outcomes .................................................................................. 25 
4.2 Safety Assessments ............................................................................................................. 26 
4.2.1 
Safety Outcomes ....................................................................................................... 26 
4.3 Inclusion Criteria ............................................................................................................... 26 
4.3.1 
General Inclusion Criteria ......................................................................................... 26 
4.3.2 
Ocular Inclusion Criteria (study eye) ........................................................................ 26 
4.4 Exclusion Criteria .............................................................................................................. 28 
4.4.1 
General Exclusion Criteria ........................................................................................ 28 
4.4.2 
Ocular Exclusion Criteria (study eye) ....................................................................... 29 
4.4.3 
Fellow (Non-Study) Eye Criteria (the Fellow Eye Must Meet the Following) ......... 31 
4.5 Informed Consent, Screening Evaluation, and Randomization .................................... 32 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
February 10, 2008 
 
 
ii 
4.5.1 
Informed Consent ...................................................................................................... 32 
4.5.2 
Screening Evaluation ................................................................................................ 32 
4.5.3 
Randomization .......................................................................................................... 34 
4.6 Standard Care Groups ...................................................................................................... 35 
4.6.1 
Photocoagulation Procedures .................................................................................... 35 
4.7 Intravitreal Steroid Groups .............................................................................................. 36 
4.7.1 
Intravitreal Injection of Triamcinolone Acetonide.................................................... 36 
4.8 Participant Visit Schedule, Retreatment, Alternate Treatment and Other Treatments37 
4.8.1 
Visit Schedule ........................................................................................................... 37 
4.8.2 
Testing Procedures to be Performed at Follow-up Visits (see Appendix 1) ............. 38 
4.8.3 
Retreatment Assessment ........................................................................................... 39 
4.8.4 
Alternate Treatment for the Study Eye ..................................................................... 42 
4.8.5 
Other Treatments ...................................................................................................... 43 
4.9 Diagnosis and Treatment of Adverse Events ................................................................... 43 
4.9.1 
Endophthalmitis Treatment ....................................................................................... 43 
4.9.2 
Treatment of Elevated Intraocular Pressure (IOP) .................................................... 43 
4.9.3 
Cataract Surgery ........................................................................................................ 44 
4.9.4 
Surgery for Proliferative Retinopathy and Other Complications Due to Retinal Vein 
Occlusion ................................................................................................................. 45 
4.10 Miscellaneous Treatments During Follow-up ................................................................. 46 
4.10.1 
Treatment of Macular Edema in Non-study Eye ...................................................... 46 
4.10.2 
Panretinal Photocoagulation (PRP) Treatment: ........................................................ 46 
5. 
DATA MONITORING AND ADVERSE EVENT REPORTING ................................ 47 
5.1 Data Safety Monitoring Committee ................................................................................. 47 
5.2 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .... 48 
5.3 Procedures for Reporting Adverse Events ...................................................................... 49 
5.3.1 
Routine SCORE DCC Review ................................................................................. 49 
5.3.2 
Adverse Event Severity Grading ............................................................................... 51 
5.3.3 
Relation to Therapy ................................................................................................... 52 
5.3.4 
Adverse Event Reporting Requirements and Procedures for Clinical Sites to the 
SCORE Coordinating Center ................................................................................... 52 
5.3.5 
Reporting Procedures ................................................................................................ 53 
5.3.6 
SCORE Adverse Event Reporting Contact ............................................................... 53 
5.4 Procedure for Reporting of Pregnancy ............................................................................ 54 
6. 
STATISTICAL CONSIDERATIONS ............................................................................. 54 
6.1 Scientific and Regulatory Objectives ............................................................................... 54 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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iii 
6.2 Formal Regulatory Statistical Test of Efficacy ............................................................... 55 
6.3 Scientific Statistical Approach .......................................................................................... 56 
6.3.1 
Two Independent Clinical Trials ............................................................................... 56 
6.3.2 
Three Primary Questions in Each Clinical Trial ....................................................... 56 
6.4 Assumptions for and Result of Sample Size Estimation................................................. 58 
6.4.1 
Study Power .............................................................................................................. 58 
6.4.2 
Estimate of CRVO Primary Efficacy Outcome in the Standard Care Group ........... 58 
6.4.3 
Estimate of BRVO Primary Efficacy Outcome in the Standard Care Group ........... 58 
6.4.4 
Background Information on Efficacy of Intravitreal Injection(s) of Triamcinolone 
Acetonide ................................................................................................................. 59 
6.4.5 
Sample Size Estimate ................................................................................................ 60 
6.5 Safety Outcomes ................................................................................................................. 61 
6.6 Secondary Efficacy Outcomes .......................................................................................... 62 
6.7 Statistical Guidelines for Interim Monitoring by the DSMC ........................................ 63 
6.7.1 
Interim Monitoring for Safety ................................................................................... 63 
6.7.2 
Interim Monitoring for Efficacy ................................................................................ 63 
6.7.3 
Interim Monitoring for Futility ................................................................................. 64 
6.7.4 
Analyses and Results Requested to be Considered Prior to Recommending Early 
Termination .............................................................................................................. 64 
6.7.5 
Study Timeline and DSMC Data Reviews ............................................................... 65 
7. 
CONFIDENTIALITY AND ACCESS TO SOURCE DATA / DOCUMENTS ........... 66 
8. 
SUMMARY OF GOOD CLINICAL PRACTICE COMPLIANCE ............................. 66 
8.1 Investigator Responsibilities (Form FDA-1572) .............................................................. 66 
8.2 Human Subjects Protection............................................................................................... 67 
8.2.1 
Institutional Review Board or Independent Ethics Committee ................................. 67 
8.3 Data Handling and Recordkeeping .................................................................................. 68 
8.3.1 
Case Report Forms .................................................................................................... 68 
8.3.2 
Data Transmittal ........................................................................................................ 68 
8.4 Professional Licensure ....................................................................................................... 69 
8.5 Human Subjects Protection Training .............................................................................. 69 
9. 
REFERENCES ................................................................................................................... 70 
10. APPENDIX I ...................................................................................................................... 74 
 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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iv 
 
Note: A separate Manual of Policies and Procedures (MOPP) developed to accompany this 
protocol will provide additional details and guidance on study operational activities.  A Data 
Management Handbook (DMH) will provide details for data collection procedures and data 
quality management procedures.  Participating sites will be provided the necessary instructions 
and review of the protocol, MOPP and DMH during site visits and/or at investigator meetings.  
The current master protocol (incorporating any approved amendments), MOPP, and DMH are 
always accessible to authorized study staff via the SCORE Study web page at 
http://www.emmes.com/, where a username and password are required for access. 
 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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Précis 
1 
Macular edema is a major cause of vision loss in patients with central retinal vein occlusion 
2 
(CRVO) and branch retinal vein occlusion (BRVO).  Currently, there is no effective treatment for 
3 
macular edema associated with CRVO.  For macular edema associated with BRVO, grid laser 
4 
photocoagulation may be an effective treatment, but many patients derive limited benefit from 
5 
this treatment.  Therefore, the development of new treatment modalities to treat macular edema 
6 
caused by these two conditions is an important research goal.  The Standard Care vs. 
7 
COrticosteroid for REtinal Vein Occlusion (SCORE) Study will compare the efficacy and safety 
8 
of standard care with intravitreal injection(s) of triamcinolone acetonide to treat macular edema 
9 
associated with CRVO and BRVO. 
10 
 
11 
The SCORE Study is designed as a multicenter, randomized, Phase III trial to compare the 
12 
efficacy and safety of standard care versus triamcinolone acetonide injection(s) for the treatment 
13 
of macular edema associated with CRVO and BRVO.  In each of the two disease areas, 486 
14 
participants will be randomized in a 1:1:1 ratio to one of three groups: standard care, intravitreal 
15 
triamcinolone 4 mg, or intravitreal triamcinolone 1 mg.  For CRVO participants, standard care 
16 
consists of observation of the macular edema.  For BRVO participants, standard care consists of 
17 
immediate grid laser photocoagulation for study eyes without a dense macular hemorrhage.  For 
18 
study eyes of BRVO participants with a dense macular hemorrhage, standard care is observation 
19 
followed by grid laser photocoagulation if and when clearing of the hemorrhage permits grid 
20 
laser photocoagulation.  For all three groups, neovascular complications will be treated as 
21 
necessary.  Repeat treatments will be provided as clinically indicated based on protocol-specific 
22 
guidelines.  Participants will be followed for between 1 and 3 years after randomization.  The 
23 
primary efficacy outcome of this study is improvement by 15 or more letters from baseline in 
24 
best-corrected ETDRS visual acuity score at the 12-month visit.  Secondary efficacy outcomes 
25 
include change between baseline and each efficacy outcome assessment visit in best-corrected 
26 
ETDRS visual acuity score, change in retinal thickness at the center of the macula and change in 
27 
area of retinal thickening as assessed by stereoscopic color fundus photography, and change in 
28 
retinal thickness and calculated retinal thickening as assessed by optical coherence tomography.  
29 
Safety outcomes include injection-related adverse events such as infectious endophthalmitis, 
30 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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non-infectious endophthalmitis, retinal detachment, and vitreous hemorrhage and steroid-related 
31 
adverse events, which include cataract and elevated intraocular pressure. 
32 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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1. 
Introduction 
33 
Central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) are common 
34 
retinal vascular diseases.  Macular edema from these two conditions is a frequent cause of vision 
35 
loss and remains a major public health problem.  Furthermore, current treatment modalities for 
36 
macular edema resulting from these conditions are often unsatisfactory.  At present, there is no 
37 
effective treatment for macular edema from CRVO.  Grid laser photocoagulation for macular 
38 
edema from BRVO may, in many cases, be an effective treatment.  However, many patients 
39 
derive limited benefit from this treatment.  A number of new treatment modalities are being 
40 
developed.  The majority of these is either based on complex surgical procedures or is associated 
41 
with increased cost.  The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) 
42 
Study proposes to investigate the less expensive and relatively less invasive treatment of 
43 
intravitreal injection(s) of triamcinolone acetonide for this frequent cause of visual impairment in 
44 
patients with CRVO and BRVO. 
45 
 
46 
The potential adverse effects of corticosteroids include cataract and elevated intraocular pressure 
47 
(IOP).  Delivery of corticosteroids via intravitreal injection adds potential injection-related risks 
48 
of retinal detachment, vitreous hemorrhage, infectious endophthalmitis, and non-infectious 
49 
endophthalmitis.  As a result of these risks, further investigation is warranted to evaluate the risks 
50 
of this treatment modality compared with the potential benefits.  The risks associated with 
51 
intravitreal injection(s) of corticosteroids may be acceptable given the opportunity to reverse 
52 
vision loss from macular edema associated with CRVO or BRVO. 
53 
 
54 
2. 
Background and Scientific Justification 
55 
2.1 Venous Occlusive Disease 
56 
CRVO and BRVO are common retinal vascular disorders.  BRVO has been reported to be 
57 
second only to diabetic retinopathy in the frequency with which it produces retinal vascular 
58 
disease.1  CRVO and BRVO have a characteristic appearance with intraretinal hemorrhage, 
59 
tortuous and dilated retinal veins and, occasionally, optic disc edema.  Macular edema is a 
60 
frequent cause of visual acuity loss in eyes with CRVO and BRVO.1-4  
61 
 
62 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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In the Central Vein Occlusion Study (CVOS) 728 eyes with CRVO were studied.2  Of these 
63 
728 eyes, 155 (21%) had macular edema that reduced visual acuity to 20/50 or worse 
64 
(group M eyes, macular edema).  In the largest group (group P, perfused) that included 547 
65 
eyes, 84% (460 eyes) had angiographic evidence of macular edema involving the fovea at 
66 
baseline. 
67 
 
68 
The natural history of macular edema associated with CRVO was delineated in the CVOS.2-4 
69 
Additionally, the group M arm of the CVOS evaluated the treatment of macular edema with 
70 
grid laser photocoagulation in 155 eyes (77 treated eyes and 78 control eyes) over a 3 year 
71 
follow-up period.  All eyes had macular edema for a minimum of 3 months prior to 
72 
enrollment.  For untreated eyes with an initial visual acuity between 20/50 and 5/200 at 
73 
presentation (n=78 eyes), 42 eyes were available for follow-up at the 3-year visit.  Of these 
74 
eyes, 10 (24%) gained two or more lines of visual acuity at the 3-year follow-up.  Twenty 
75 
eyes (48%) remained within two lines of baseline visual acuity and 12 eyes (29%) lost two or 
76 
more lines of visual acuity at the 3-year follow-up.  At the 3-year follow-up, six eyes (14%) 
77 
gained three or more lines of visual acuity.  Thirty eyes (71%) remained within three lines of 
78 
baseline visual acuity and six eyes (14%) lost three or more lines of visual acuity at the 3-
79 
year follow-up.  The final median visual acuity in untreated eyes was 20/160. 
80 
 
81 
At the 2-year visit, 53 untreated eyes were available for follow-up.  Of these eyes, 10 (19%) 
82 
gained two or more lines of visual acuity.  Thirty-one eyes (58%) remained within two lines 
83 
of baseline visual acuity and 12 eyes (23%) lost two or more lines of visual acuity at the 2-
84 
year follow-up.  At the 2-year follow-up, 6 eyes (11%) gained three or more lines of visual 
85 
acuity.  Thirty-nine eyes (74%) remained within three lines of baseline visual acuity and 
86 
eight eyes (15%) lost three or more lines of visual acuity at the 2-year follow-up. 
87 
 
88 
At the 1-year visit, 72 untreated eyes were available for follow-up.  Of these eyes, 6 (8%) 
89 
gained two or more lines of visual acuity.  Forty-four eyes (61%) remained within two lines 
90 
of baseline visual acuity and 22 eyes (31%) lost two or more lines of visual acuity at the 1-
91 
year follow-up.  At the 1-year follow-up, 4 eyes (6%) gained three or more lines of visual 
92 


The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study 
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acuity.  Fifty-nine eyes (82%) remained within three lines of baseline visual acuity and nine 
93 
eyes (13%) lost three or more lines of visual acuity at the 1-year follow-up. 
94 
 
95 
The CVOS found no significant difference in visual outcome between the treatment and 
96 
observation groups at any follow-up point.  Although there was a definite decrease in 
97 
macular edema on fluorescein angiography in the treatment group when compared to the 
98 
control group, this did not translate to a direct visual improvement.4  Therefore, at present, 
99 
there is no proven therapy for visual impairment due to macular edema associated with 
100 
CRVO.  Thus, it is important to explore other avenues for managing this potentially 
101 
devastating cause of vision loss. 
102 
 
103 
The Branch Vein Occlusion Study (BVOS) reported on the natural history of macular 
104 
edema associated with BRVO.1 All eyes had macular edema for 3 to 18 months prior to 
105 
study entry; eyes with obvious areas of capillary nonperfusion in the macula were excluded 
106 
from the study.  After 3 years, of 35 untreated eyes available for follow-up, only 12 eyes 
107 
(34%) with a presenting visual acuity of 20/40 or worse achieved a visual acuity of 20/40 or 
108 
better.  Furthermore, eight eyes (23%) had 20/200 or worse visual acuity at the final 3-year 
109 
follow-up visit. 
110 
 
111 
The group III arm of the BVOS was designed to evaluate grid photocoagulation treatment 
112 
of macular edema due to BRVO that had persisted for at least 3-months (and less than 18 
113 
months) in eyes with visual acuity of 20/40 or worse.  One hundred thirty nine eyes (71 
114 
treated eyes and 68 control eyes) were studied.  This arm of the study did demonstrate a 
115 
benefit for eyes treated with macular grid photocoagulation.1 Of 43 treated eyes available 
116 
for follow-up at the 3-year visit, 28 eyes (65%) had gained two or more lines of visual 
117 
acuity from baseline and maintained this gain for at least eight months, as compared with 
118 
the same gain in 13 of 35 (37%) untreated eyes. At the 3-year visit, nearly twice as large a 
119 
proportion of treated vs. control eyes had visual acuity of 20/40 or better. 
120 
 
121 
Although the BVOS did demonstrate a visual acuity benefit for eyes treated with grid 
122 
photocoagulation, the BVOS also identified a subset of patients that derive limited benefit 
123 


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from macular grid photocoagulation.  In the BVOS, 40% of treated eyes (n=43) had worse 
124 
than 20/40 vision at 3 years and 12% of treated eyes had 20/200 or worse visual acuity at 3 
125 
years.1 Therefore, for some patients with macula edema associated with BRVO current 
126 
treatment options are limited and other treatment options should be sought.  For example, 
127 
surgical decompression of BRVO via arteriovenous crossing sheathotomy has been 
128 
investigated.5 However, this is an invasive surgical intervention with inherent risks, 
129 
recovery time and expense.  As a result, there is interest in exploring treatment options such 
130 
as intravitreal injection(s) of triamcinolone acetonide.  Table 1 summarizes visual acuity 
131 
data from the two randomized clinical trials discussed above in which the natural history of 
132 
macular edema from CRVO and BRVO was evaluated. 
133 
 
134 
Table 1:  Natural history of macular edema in two randomized 
135 
trials of patients with retinal vein occlusion 
136 
 
137 
Study 
Vision 
improved by 2 
or more lines 
Vision 
unchanged 
(± 2 lines) 
Vision worse by 
2 or more lines 
Number of 
eyes at end 
of study 
period 
Follow-
up period 
 
 
% 
 
No. 
 
% 
 
No. 
 
% 
 
No. 
 
 
CVOS 
24% 
10 
48% 
20 
29% 
12 
42 
3 years 
CVOS 
19% 
10 
58% 
31 
23% 
12 
53 
2 years 
CVOS 
8% 
6 
61% 
44 
31% 
22 
72 
1 year 
CVOS* 
6% 
4 
82% 
59 
13% 
9 
72 
1 year 
BVOS 
 
37% 
13 
46% 
16 
17% 
  6 
35 
3 years 
 * Improvement or worsening of vision by 3 or more lines 
138 
CVOS Central Vein Occlusion Study 
139 
BVOS Branch Vein Occlusion Study 
140 
 
141 
2.2 Pathogenesis of Macular Edema 
142 
Macular edema from venous occlusive disease results from the initial insult of thrombus 
143 
formation at the lamina cribrosa or an arteriovenous crossing.  Green et al, in a 
144 
histopathologic study of 29 eyes with CRVO, documented a fresh or recanalized thrombus 
145 
of the central retinal vein in the area of the lamina cribosa as a constant pathologic finding.6 
146 
Frangieh et al, in a histopathologic study of nine eyes with BRVO, documented a fresh or 
147 
recanalized thrombus at the site of vein occlusion in all eyes studied.7 Experimental work in 
148 


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animals has demonstrated that following venous occlusion, a hypoxic environment in the 
149 
retina is produced.8 This is then followed by functional, and later structural changes, in the 
150 
retinal capillaries.  These changes resulted in an immediate increase in retinal capillary 
151 
permeability and accompanying retinal edema. 
152 
 
153 
The increase in retinal capillary permeability and subsequent retinal edema may be the 
154 
result of a breakdown of the blood retina barrier mediated in part by vascular endothelial 
155 
growth factor (VEGF), a 45 kD glycoprotein.9 Aiello et al demonstrated in an in vivo 
156 
model, that VEGF can increase vascular permeability.9  Fifteen eyes of 15 albino Sprague-
157 
Dawley rats received an intravitreal injection of VEGF.  The effect of intravitreal 
158 
administration of VEGF on retinal vascular permeability was assessed by vitreous 
159 
fluorophotometry.  In all 15 eyes which received an intravitreal injection of VEGF, a 
160 
statistically significant increase in vitreous fluorescein leakage was recorded.  In contrast, 
161 
control eyes, which were fellow eyes injected with vehicle alone, did not demonstrate a 
162 
statistically significant increase in vitreous fluorescein leakage.  Vitreous fluorescein 
163 
leakage in eyes injected with VEGF attained a maximum of 227% of control levels.  
164 
Antonetti et al demonstrated that VEGF may regulate vessel permeability by increasing 
165 
phosphorylation of tight junction proteins such as occludin and zonula occluden 1.10  
166 
Sprague-Dawley rats were given intravitreal injections of VEGF and changes in tight 
167 
junction proteins were observed through Western blot analysis.  Treatment with alkaline 
168 
phosphatase revealed that these changes were caused by a change in phosphorylation of 
169 
tight junction proteins.  This model provides, at the molecular level, a potential mechanism 
170 
for VEGF-mediated vascular permeability in the eye.  Similarly, in human non-ocular 
171 
disease states such as ascites, VEGF has been characterized as a potent vascular 
172 
permeability factor (VPF).11 
173 
 
174 
The normal human retina contains little or no VEGF; however, hypoxia causes 
175 
upregulation of VEGF production.12 Disease states characterized by hypoxia-induced 
176 
VEGF upregulation include CRVO and BRVO.9,12  Vinores et al, using 
177 
immunohistochemical staining for VEGF, demonstrated that increased VEGF staining was 
178 
found in retinal neurons and retinal pigment epithelium in human eyes with venous 
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occlusive disease.12  Pe’er et al, evaluated 10 human eyes enucleated for neovascular 
180 
glaucoma from CRVO and used molecular localization with a VEGF-specific probe to 
181 
identify cells producing VEGF messenger RNA (mRNA).13  All of these eyes demonstrated 
182 
upregulated VEGF mRNA expression in the retina.  This hypoxia-induced upregulation of 
183 
VEGF may be inhibited pharmacologically.  Adamis et al demonstrated in a nonhuman 
184 
primate model that anti-VEGF antibodies can inhibit VEGF driven capillary endothelial 
185 
cell proliferation.14 In this study, 16 eyes of nonhuman primates had retinal ischemia 
186 
induced by laser retinal vein occlusion.  Zero of eight eyes receiving neutralizing anti-
187 
VEGF antibodies developed iris neovascularization while five of eight control eyes 
188 
eventually developed iris neovascularization. 
189 
 
190 
As the above discussion suggests, attenuation of the effects of VEGF introduces a rationale 
191 
for treatment of macular edema from venous occlusive disease.  Corticosteroids, a class of 
192 
substances with anti-inflammatory properties, have been demonstrated to inhibit the 
193 
expression of the VEGF gene.15 In a study by Nauck et al, the platelet-derived growth-
194 
factor (PDGF) induced expression of the VEGF gene in cultures of human aortic vascular 
195 
smooth muscle cells was inhibited by corticosteroids in a dose-dependent manner.15 A 
196 
separate study by Nauck et al demonstrated that corticosteroids downregulated the 
197 
induction of VEGF by the pro-inflammatory mediators PDGF and platelet-activating factor 
198 
(PAF) in a time and dose-dependent manner.16  This study was performed using primary 
199 
cultures of human pulmonary fibroblasts and pulmonary vascular smooth muscle cells. 
200 
 
201 
2.3 Animal and Clinical Studies Using Intravitreal Triamcinolone Acetonide 
202 
Injections 
203 
Intravitreal injection of triamcinolone acetonide has been shown to be non-toxic in animal 
204 
studies.17-19 McCuen et al injected 1mg of triamcinolone acetonide into the vitreous cavity 
205 
of 21 rabbit eyes.17  Throughout the 3-month course of follow-up ophthalmoscopy, IOP, 
206 
electroretinography (scotopic and photopic responses) and light and electron microscopy all 
207 
remained normal.  Schindler et al studied the clearance of intravitreally injected 
208 
triamcinolone acetonide (0.5 mg) in 30 rabbit eyes.18 In non-vitrectomized eyes the average 
209 
clearance rate was 41 days.  In eyes having undergone vitrectomy or combination 
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vitrectomy and lensectomy the average clearance rate was 17 days and 7 days, 
211 
respectively.18 It was found that the ophthalmoscopic disappearance of injected 
212 
triamcinolone acetonide correlated well with a spectrophotometric analysis for clearance of 
213 
the drug.  Scholes et al also studied the clearance of intravitreally injected triamcinolone 
214 
acetonide (0.4 mg) in 24 rabbit eyes.19 Using high-performance liquid chromatography 
215 
(HPLC) complete clearance of the drug was noted by 21 days.  Non-detectable drug levels 
216 
(by HPLC) were present before ophthalmoscopic disappearance. 
217 
 
218 
As discussed above, corticosteroids have been experimentally shown to downregulate 
219 
VEGF production and possibly reduce breakdown of the blood-retinal barrier.15,16  
220 
Similarly, steroids have antiangiogenic properties possibly due to attenuation of the effects 
221 
of VEGF.20,21  These properties of steroids are commonly utilized.  Clinically, 
222 
triamcinolone acetonide is used locally as a periocular injection for the treatment of cystoid 
223 
macular edema (CME) secondary to uveitis or as a result of intraocular surgery.22,23  In 
224 
animal studies, intravitreal triamcinolone acetonide has been used in the prevention of 
225 
proliferative vitreoretinopathy24,25 and retinal neovascularization.26,27  Intravitreal 
226 
triamcinolone acetonide has been used clinically in the treatment of proliferative 
227 
vitreoretinopathy28 and choroidal neovascularization.29-31 
228 
 
229 
Recently, intravitreal triamcinolone acetonide has been used clinically in the treatment of 
230 
retinal vascular disease.  A case report by Jonas and Sofker describes a patient with non-
231 
proliferative diabetic retinopathy with a 6-month history of persistent, diffuse macular 
232 
edema despite grid photocoagulation.32 Following one intravitreal injection of 
233 
triamcinolone acetonide (20mg) the visual acuity of this patient improved from 20/200 to 
234 
20/50 over a 5-month follow-up period.  It was also noted that there was marked regression 
235 
of macular edema on clinical examination. 
236 
 
237 
Martidis et al conducted a pilot study of 16 eyes with macular edema due to diabetic 
238 
retinopathy.33,34  All 16 eyes demonstrated persistent macular edema involving the center of 
239 
the macula despite each eye receiving two to six sessions of focal/grid laser 
240 
photocoagulation.  In 11 eyes with a known time of onset of macular edema, the average 
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duration of macular edema was 32 months (range, 13 to 68 months) prior to intravitreal 
242 
triamcinolone acetonide injection.  The other five eyes were known to have macular edema 
243 
for at least 6 months.  All 16 eyes were treated with intravitreal triamcinolone acetonide 
244 
injection and the results are summarized in Tables 2a and 2b. 
245 
 
246 
Baseline central foveal thickness averaged 540 microns for the 16 enrolled eyes when 
247 
measured by optical coherence tomography.  For 14 eyes evaluated at 1-month, mean 
248 
foveal thickness decreased from 533 microns to 242 microns.  Two eyes did not complete 
249 
the 1-month follow-up examination.  Fourteen eyes evaluated at 3-months showed a 
250 
reduction in mean foveal thickness from 528 microns to 224 microns.  Two eyes did not 
251 
complete the 3-month examination; these were different eyes than those that did not 
252 
complete the 1-month examination.  Eight eyes completing six months of follow-up 
253 
showed a reduction in mean foveal thickness from 540 microns to 335 microns.  
254 
 
255 
Mean Snellen visual acuity improved by 2.4, 2.4, and 1.3 lines at the 1, 3, and 6-month 
256 
follow-up intervals, respectively.  No eyes lost vision at 1-month and all but one eye 
257 
showed improvement ranging from one to five lines; nine of 14 (64%) eyes showed 
258 
improvement of two or more lines at this interval.  No eyes lost vision from baseline at 3-
259 
months, and all but one eye showed improvement ranging from one to five lines; nine of 14 
260 
(64%) eyes showed improvement of two or more lines at the 3-month interval.  One eye 
261 
lost a single line from baseline at six months and one eye remained stable; the other six 
262 
eyes maintained improved visual acuity ranging from one to three Snellen lines.  Four of 
263 
eight (50%) eyes maintained a visual acuity improvement of two or more lines from 
264 
baseline at the 6-month follow-up.   
265 
 
266 
Five of 14 eyes that were evaluated at the 1-month follow-up had an IOP that exceeded 21 
267 
mmHg.  The IOP in all five eyes was controlled successfully with one topical aqueous 
268 
suppressant.  Two of 14 eyes that were evaluated at the 3-month follow-up had an IOP that 
269 
exceeded 21 mmHg.  The IOP in both eyes was controlled successfully with one topical 
270 
aqueous suppressant.  One of eight eyes that were evaluated at the 6-month follow-up had 
271 
an IOP that exceeded 21 mmHg.  The IOP in this eye was controlled successfully with one 
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topical aqueous suppressant.  The average IOP increased 45%, 20% and 13% from baseline 
273 
at the 1, 3 and 6-month follow-up intervals, respectively.  
274 
 
275 
Three of the eight eyes completing at least 6 months of follow-up were re-injected 6 months 
276 
after initial injection due to recurrence of macular edema.  Cataract progression that did not 
277 
require surgery was noted in one eye at the 6-month follow-up.  No complications such as 
278 
retinal detachment, endophthalmitis or vitreous hemorrhage were noted in this study.  
279 
 
280 
Greenberg and Martidis studied both eyes of one patient with bilateral diffuse macular 
281 
edema secondary to CRVO.35 The right eye of this 80 year old patient had macular edema 
282 
from a CRVO of 9 months duration when the patient presented with a 2-week history of 
283 
visual acuity loss due to macular edema from a CRVO in the left eye.  Because of the poor 
284 
natural history of untreated macular edema in the right eye of this patient, the left eye 
285 
received an intravitreal injection of triamcinolone acetonide.  It did well both anatomically 
286 
and functionally, with visual acuity improvement from 20/400 to 20/30 after three months 
287 
of follow-up.  Central foveal thickness as measured by optical coherence tomography 
288 
decreased from 589 microns to 160 microns with restoration of a normal foveal contour 
289 
following treatment.  Six months following injection, visual acuity decreased to 20/400 
290 
because of recurrence of retinal thickening that measured 834 microns by optical coherence 
291 
tomography. A second injection was performed and, 1 month later, visual acuity returned to 
292 
20/50 with a decrease in central foveal thickness to 158 microns with a normal foveal 
293 
contour.  This patient has maintained this level of visual acuity for over 6 months following 
294 
the second injection.  Given the response to treatment in the left eye, the right eye (now 
295 
with 16 months of untreated macular edema) was treated with an intravitreal injection of 
296 
triamcinolone acetonide.  There was a prompt reduction in central foveal thickness as 
297 
measured by optical coherence tomography from 735 microns to 195 microns.  However, 
298 
possibly as a result of the duration of macular edema, no visual benefit was noted.  No 
299 
significant elevation of IOP was noted in either eye.   
300 
 
301 
Other clinical case reports by Ip et al and Jonas et al have demonstrated similar results in 
302 
the treatment of macular edema due to CRVO with intravitreal injections of triamcinolone 
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acetonide.36,37  Recently, Park et al evaluated intravitreal triamcinolone injection(s) as a 
304 
treatment of macular edema associated with CRVO.38  Ten eyes of 9 patients with perfused 
305 
CRVO with visual acuity 20/50 or worse were treated with an intravitreal injection of 
306 
triamcinolone acetonide (4mg/0.1cc).  One patient received a repeat injection.  The mean 
307 
duration from time of diagnosis to the intravitreal triamcinolone injection was 15.4 months. 
308 
The mean best-corrected visual acuity improved from 58 letters (range, 37-72) at baseline 
309 
to 78 letters (range 50-100 letters) at last follow-up (mean, 4.8 months).  Volumetric optical 
310 
coherence tomography (VOCT) was performed on 9 of 10 patients at baseline and follow-
311 
up.  VOCT measurements improved from a mean of 4.2 mm3 at baseline to a mean of 2.6 
312 
mm3 at last follow-up (normal range of VOCT is 2.0-2.5 mm3).  Three eyes without a 
313 
previous history of glaucoma required topical antiglaucoma medication.  One eye with a 
314 
previous history of open-angle glaucoma required trabeculectomy surgery. 
315 
 
316 
Table 3 lists the frequency and nature of adverse effects seen in some of the largest clinical 
317 
studies thus far using intravitreal triamcinolone acetonide.  Penfold and Challa studied 30 
318 
eyes with exudative macular degeneration.29,30  No adverse events such as retinal 
319 
detachment, vitreous hemorrhage or endophthalmitis were noted.  However, three of four 
320 
eyes that received a second injection of triamcinolone acetonide experienced rapid 
321 
progression of cataract within 2 months of re-injection.  Two of these four eyes also 
322 
experienced steroid-induced glaucoma with IOP elevation to 37 mmHg.  Both eyes had 
323 
argon laser trabeculoplasty and were treated with topical aqueous suppressants.  One of 
324 
these two eyes required trabeculectomy surgery to control IOP.  In another series, Danis et 
325 
al injected 16 eyes with exudative macular degeneration.31 No adverse events such as 
326 
retinal detachment, vitreous hemorrhage or endophthalmitis were noted.  Four of seven 
327 
phakic patients developed progressive lens opacities that over the 6-month follow-up did 
328 
not require cataract surgery.  Four patients developed transient IOP elevation that required 
329 
one to two topical aqueous suppressants to lower the intraocular pressure to less than 25 
330 
mmHg; all patients eventually had topical therapy discontinued.  No patient had IOP over 
331 
32 mmHg at any point in follow-up. 
332 
 
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The other studies listed in Table 3 all demonstrate a similar adverse event profile.28,39-41  A 
334 
summary of the data from the seven studies listed shows that the frequency of injection-
335 
related adverse events such as endophthalmitis, non-infectious endophthalmitis, retinal 
336 
detachment and vitreous hemorrhage appear rare based on these small studies in the 
337 
published literature.  Corticosteroid-related adverse events, from the data in Table 3, are 
338 
more common.  However, corticosteroid-related adverse events (cataract and elevated IOP) 
339 
appear to be manageable.  For example, of the 221 patients in the seven studies discussed, 
340 
33 patients (15%) were noted to have some elevation of IOP; all patients were managed 
341 
successfully with topical aqueous suppressants except one patient who required argon laser 
342 
trabeculoplasty and one patient who required both argon laser trabeculoplasty and 
343 
trabeculectomy.  Nine patients (4%) required cataract surgery and 24 patients (12%) were 
344 
noted to have progressive lens opacity. 
345 
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Table 2a: Clinical characteristics of sixteen patients treated with intravitreal 
347 
triamcinolone injection for diabetic macular edema not responsive to 
348 
focal/grid photocoagulation 
349 
 
350 
Case 
Eye 
Age 
Lens 
Retinopathy 
Duration 
ME (mo) 
Prior 
Laser 
1 
OS 
72 
Pseudo 
NPDR 
21 
2 
2 
OD 
48 
Phakic 
PDR 
36 
2 
3 
OS 
85 
Phakic 
NPDR 
29 
3 
4 
OS 
76 
Phakic 
NPDR 
13 
2 
5 
OS 
70 
Pseudo 
NPDR 
23 
3 
6 
OD 
68 
Phakic 
NPDR 
47 
5 
7 
OD 
70 
Phakic 
PDR 
>6 
2 
8 
OD 
59 
Phakic 
NPDR 
>6 
2 
9 
OS 
67 
Phakic 
NPDR 
26 
2 
10 
OD 
52 
Phakic 
PDR 
68 
3 
11 
OS 
71 
Pseudo 
NPDR 
50 
6 
12 
OS 
74 
Phakic 
NPDR 
12 
2 
13 
OS 
62 
Phakic 
NPDR 
>6 
2 
14 
OS 
65 
Phakic 
NPDR 
24 
2 
15 
OD 
43 
Phakic 
NPDR 
>6 
2 
16 
OD 
62 
Phakic 
NPDR 
>6 
2 
 
351 
Table 2b: Clinical characteristics of sixteen patients treated with intravitreal 
352 
triamcinolone injection for diabetic macular edema not responsive to 
353 
focal/grid photocoagulation 
354 
 
355 
Visual Acuity 
 
OCT (microns) 
 
IOP (mmHg) 
 F/U 
Reinject 
Initial 
1 mo 
3 mo 
6 mo 
 Initial 1 mo 
3 mo 
6 mo  Initial 1 mo  3 mo 
6 mo  (mo) 
(mo) 
20/400 
20/200 
20/200 
20/200  
612 
378 
214 
236 
 
14 
24 
18 
16 
 
12 
No 
20/80 
20/50 
20/60 
20/100  
569 
171 
132 
519 
 
16 
20 
18 
16 
 
11 
11 
20/200 
20/60 
20/60 
20/60 
 
550 
177 
181 
208 
 
18 
12 
14 
20 
 
11 
No 
20/400 
20/200 
20/100 
20/100  
401 
232 
199 
174 
 
17 
22 
33 
16 
 
10 
No 
20/400 
20/200 
 
20/400  
557 
154 
 
621 
 
15 
28 
 
14 
 
9 
6 
20/200 
 
20/80 
20/100  
583 
 
109 
90 
 
15 
 
17 
23 
 
8 
No 
20/400 
20/60 
 
20/100  
703 
264 
 
588 
 
14 
21 
 
16 
 
7 
6 
20/60 
20/30 
20/30 
20/40 
 
348 
268 
270 
242 
 
10 
17 
13 
13 
 
6 
No 
20/800 
20/100 
20/100 
 
 
564 
397 
360 
 
 
17 
17 
22 
 
 
5 
No 
20/80 
20/60 
20/60 
 
 
585 
199 
188 
 
 
15 
18 
15 
 
 
4 
No 
20/200 
20/200 
20/100 
 
 
510 
260 
265 
 
 
12 
17 
11 
 
 
3 
No 
20/400 
 
20/400 
 
 
596 
 
233 
 
 
14 
 
14 
 
 
3 
No 
20/200 
20/60 
20/40 
 
 
497 
213 
180 
 
 
12 
30 
16 
 
 
3 
No 
20/200 
20/60 
20/60 
 
 
497 
239 
424 
 
 
15 
16 
20 
 
 
3 
No 
20/200 
20/40 
20/40 
20/40 
 
674 
262 
204 
 
 
17 
20 
16 
 
 
3 
No 
20/100 
20/50 
20/40 
 
 
399 
180 
176 
 
 
14 
36 
20 
 
 
3 
No 
 
356 
NPDR: non-proliferative diabetic retinopathy 
357 
PDR: 
proliferative diabetic retinopathy 
358 
ME: 
macular edema 
359 
Pseudo: pseudophakic 
360 
OCT: 
optical coherence tomography 
361 
IOP: 
intraocular pressure
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Table 3: 
Summary of adverse events from seven case series using intravitreal triamcinolone acetonide 
363 
 
364 
 
# Eyes treated 
 
Disease 
 
Dose 
(mg) 
 
IOP rise 
 
 
Cataract 
(surgery) 
 
Lens 
Opacity 
 
R.D. 
 
Vit 
Heme 
 
Endophth 
 
Non-infectious 
endophthalmitis 
Wingate39 
113 
AMD 
4 
12 
NA 
NA 
NA 
NA 
NA 
NA 
Penfold29 
30 
AMD 
4 
3 
9 
1 
0 
0 
0 
0 
Danis31 
16 
AMD 
4 
4 
0 
4/7 
phakic 
0 
0 
0 
0 
Jonas28 
16 
PVR 
10-20 
0 
0 
0 
0 
0 
0 
1 
Martidis33 
16 
DME 
4 
5 
0 
1 
0 
0 
0 
0 
Jonas40 
4 
NVG 
20 
0 
0 
0 
0 
0 
0 
0 
Jonas41 
26 
DME 
25 
9 
0 
18/18 phakic 
(P=.16) 
0 
0 
0 
0 
7 Studies 
(pooled) 
221 
 
 
 
 
33 (15%) 
9 (4%) 
24 (12%) 
0 
0 
0 
1 
 
365 
AMD 
Age-related macular degeneration 
366 
DME 
Diabetic macular edema 
367 
PVR 
Proliferative vitreoretinopathy 
368 
NVG 
Neovascular glaucoma 
369 
RD 
Retinal detachment 
370 
NA 
Not available; these adverse events were not specifically discussed in the manuscript 
371 
 
372 
 
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2.4 Other Studies Evaluating Corticosteroid Preparations Other Than 
374 
Triamcinolone Acetonide for Treatment of Macular Edema due to Retinal 
375 
Vascular Disease 
376 
2.4.1 Efficacy 
377 
2.4.1.1 Control Delivery Systems (Bausch and Lomb) 
378 
Control Delivery Systems (Bausch and Lomb) is developing a non-
379 
biodegradable, implantable, extended release product that delivers the 
380 
corticosteroid fluocinolone acetonide directly to the posterior segment of the 
381 
eye for a period of 3 years.  A multi-center, randomized, masked trial is 
382 
currently being conducted to evaluate this technology for the treatment of 
383 
diabetic macular edema refractory to prior laser photocoagulation.  Eligible 
384 
visual acuity was between 20/50 to 20/400, inclusive.  This trial enrolled 80 
385 
patients with diabetic macular edema.  Patients were randomly assigned to one 
386 
of three treatment arms:  0.5 mg implant (N=41), 2 mg implant (N=11) or 
387 
standard of care treatment consisting of either repeat laser photocoagulation or 
388 
observation (N=28).  (The 6-month data shown below were presented at the 
389 
combined Vitreous Society and Retina Society Meeting, San Francisco, CA on 
390 
September 30, 2002.  The 12-month data presented below were presented at 
391 
the Association for Research in Vision and Ophthalmology Meeting, Ft. 
392 
Lauderdale, FL on May 8, 2003).  
393 
• At the 6-month follow-up, the proportion of eyes with maintained or 
394 
improved visual acuity was greater in eyes that received the 0.5 mg 
395 
implant than those assigned to standard of care treatment (P<0.01).  
396 
This result was not statistically significant at the 12-month follow-up. 
397 
• At the 6-month follow-up, the proportion of eyes with a two or more 
398 
step decrease in retinal thickening at the center of the fovea was greater 
399 
in eyes that received the 0.5 mg implant than those assigned to 
400 
standard of care treatment (P=0.026).  This result remained statistically 
401 
significant at the 12-month follow-up (P=0.003). 
402 
 
403 


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2.4.1.2 Oculex 
404 
Oculex is developing a biodegradable, implantable, extended release product 
405 
(Posurdex) that delivers the corticosteroid dexamethasone directly to the 
406 
posterior segment of the eye for a period of 35 days.  A phase two clinical trial 
407 
was completed evaluating two dosages of Posurdex, 350 micrograms and 700 
408 
micrograms.  Patients with macular edema due to diabetic retinopathy, retinal 
409 
vascular occlusive disease, Irvine-Gass syndrome or uveitis were included.  
410 
Eligible visual acuity was 20/40-20/200.  Patients were randomized to one of 
411 
three treatment arms:  350 microgram implant, 700 microgram implant or 
412 
observation.  306 patients were enrolled, 172 with diabetic macular edema, 
413 
103 with vein occlusion, 27 with Irvine-Gass syndrome and 14 with uveitic 
414 
macular edema. 
415 
• Patients receiving the 700 microgram implant had a statistically 
416 
significant improvement in visual acuity of two or more lines on the 
417 
ETDRS chart when compared to patients who did not receive the 
418 
implant (P=0.019). 
419 
• Secondary outcomes such as retinal thickness and fluorescein leakage 
420 
also showed statistically significant decreases in patients that received 
421 
the 700 microgram implant when compared to patients who did not 
422 
receive the implant (P=0.001). 
423 
• Patients receiving the 350 microgram implant also demonstrated 
424 
statistically significant decreases in retinal thickness and fluorescein 
425 
leakage, with a trend towards improvement in visual acuity, indicating 
426 
a dose response to the treatment. 
427 
 
428 
2.4.2 Adverse Effects 
429 
2.4.2.1 Control Delivery Systems (Bausch and Lomb) 
430 
Elevated IOP 
431 
• At the 6-month follow-up, 12.2% of patients in the 0.5 mg implant 
432 
group had an IOP elevation to 30 mmHg or more.  All patients were 
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managed with topical antiglaucoma medication.  No eye in the 
434 
standard of care group had such an elevation in IOP. 
435 
• At the 12-month follow-up, 19.5% of patients in the 0.5 mg implant 
436 
group had an IOP elevation that was considered a serious adverse 
437 
event. Three patients in the 0.5 mg implant group required 
438 
trabeculectomy surgery.  No eye in the standard of care group had such 
439 
an elevation in IOP. 
440 
Cataract 
441 
• At the 6-month follow-up, 0.0% of patients in the standard of care 
442 
group had “cataract progression”.  Seventeen percent of patients in the 
443 
0.5 mg group had “cataract progression. 
444 
• At the 12-month follow-up, 0.0% of patients in the standard care group 
445 
had cataract progression defined as a serious adverse event.  Forty-one 
446 
percent of patients in the 0.5 mg group (all study eyes) had cataract 
447 
progression defined as a serious adverse event. 
448 
 
449 
2.4.2.2 Oculex 
450 
Elevated IOP 
451 
• 
An IOP elevation to 25 mmHg or more was noted at some point in 
452 
the study in 32 eyes; all were readily controlled with topical 
453 
antiglaucoma medication. 
454 
Cataract and other side effects 
455 
• 
There was no difference in cataract progression between the study 
456 
groups. 
457 
• 
No other safety concerns were noted. 
458 
 
459 
2.5 Rationale for the Intravitreal Triamcinolone Acetonide Doses to be Evaluated 
460 
The optimal dose of triamcinolone acetonide to maximize efficacy with minimum side 
461 
effects is not known.  A 4 mg dose of Kenalog, a commercially available preparation that is 
462 
FDA labeled for intramuscular or intrabursal use, is principally being used in clinical 
463 


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practice.  However, this dose has been used based on feasibility rather than scientific 
464 
principles. 
465 
 
466 
There is also experience using doses of 1 mg and 2 mg.  These doses anectodally have been 
467 
reported to reduce macular edema.  There is a rationale for using a dose lower than 4 
468 
mg.42,43  Glucocorticoids bind to glucocorticoid receptors in the cell cytoplasm, and the 
469 
steroid-receptor complex moves to the nucleus where it regulates gene expression. The 
470 
steroid-receptor binding occurs with high affinity (low dissociation constant (Kd) which is 
471 
on the order of 5 to 9 nanomolar).  Complete saturation of all the receptors occurs at about 
472 
20 fold higher levels, so about 100 nanomolar.  A 4 mg dose of triamcinolone/4mg of 
473 
vitreous volume yields a final concentration of 7.5 millimolar, or nearly 10,000 fold more 
474 
than the saturation dose. Thus, the effect of a 1 mg dose may be equivalent to that of a 4mg 
475 
dose, because compared to the 10,000 fold saturation, a 4-fold difference in dose is 
476 
inconsequential.  It is also possible that higher doses of corticosteroid could be less 
477 
effective than lower doses due to down-regulation of the receptor.  The steroid implant 
478 
studies provide additional justification for evaluating a lower dose—a 0.5 mg device which 
479 
delivers only 0.5 micrograms per day has been observed to have a rapid effect in reducing 
480 
macular edema (P. Andrew Pearson, personal communication). 
481 
 
482 
There has been limited experience using doses greater than 4 mg.  Jonas’ case series 
483 
described earlier reported results using both a 20mg and a 25mg dose.  However, others 
484 
have not been able to replicate this dose using the preparation procedure described by Jonas 
485 
(Frederick Ferris, personal communication).   
486 
 
487 
In the SCORE Study, 4 mg and 1 mg doses will be evaluated.  The former because it is the 
488 
dose that is currently most commonly used in clinical practice and the latter because there is 
489 
reasonable evidence for efficacy and the potential for lower risk.  Although there is good 
490 
reason to believe that a 1 mg dose will reduce macular edema, it is possible that the 
491 
retreatment rate will be higher with this dose compared with 4 mg since the latter will 
492 
remain active in the eye for a longer duration than the former.  Insufficient data are 
493 
available to warrant evaluating a dose higher than 4mg at this time.  
494 


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495 
2.6 Mechanism of Adverse Effects Associated with Intravitreal Steroids 
496 
2.6.1 Elevation of Intraocular Pressure 
497 
IOP depends on the comparative rates of aqueous production and aqueous drainage, 
498 
primarily through the trabecular meshwork.  Increased IOP occurs from a variety of 
499 
mechanisms such as primary or secondary angle-closure glaucoma, primary or 
500 
secondary open-angle glaucoma, or combined-mechanism glaucoma.  If inadequately 
501 
treated, increased IOP may result in glaucomatous optic nerve changes and loss of 
502 
visual field. 
503 
 
504 
Among the secondary open-angle glaucomas, corticosteroid-induced elevation of IOP 
505 
is one of the most common.  This relationship is well established.  In patients 
506 
susceptible to this phenomenon, the elevation of IOP may occur as a result of topical, 
507 
systemic or peribulbar administration.  For example, following 4-6 weeks of topical 
508 
corticosteroid administration, 5% of subjects may show an elevation in IOP of 
509 
>16mmHg and 30% of subjects may show an elevation of 6-15mmHg.44,45 
510 
 
511 
The mechanism of corticosteroid induced elevation of IOP is incompletely 
512 
understood. Possible theories include46:  a) inhibition of the production of outflow-
513 
enhancing prostaglandins,  b) suppression of trabecular meshwork endothelial cell 
514 
phagocytosis,  c) increased deposition of proteoglycans or glycosaminoglycans in the 
515 
trabecular meshwork with a resultant increase in resistance to outflow,  d) increase in 
516 
cross-linked actin networks in the trabecular meshwork,  e) increase in the expression 
517 
of cellular tight-junction protein,  f) stabilization of lysosomes which allow 
518 
accumulation of hyaluronate or other debris in the trabecular meshwork. 
519 
 
520 
The intravitreal administration of corticosteroid is expected to be associated with an 
521 
increase in IOP in susceptible patients.  Indeed, the literature reviewed in this protocol 
522 
confirm that corticosteroid induced elevation in IOP may result from intravitreal 
523 
corticosteroid administration (Table 3).  The time course for the development of 
524 
corticosteroid induced elevation in IOP as a result of intravitreal injection is presently 
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unknown.  Additionally, the effect of the initial dose administered, the frequency of 
526 
reinjection or the cumulative dose administered over time on the severity of IOP 
527 
elevation is not known.  The experience thus far indicates that the 4 mg and 25 mg 
528 
doses of triamcinolone acetonide appear to result in a relatively similar frequency and 
529 
severity of IOP elevation 33,41 Reinjection of the 4 mg dose at a frequency of more 
530 
than once every four months appears to be associated with more frequent and more 
531 
severe elevation in IOP.29 
532 
 
533 
All patients who receive intravitreal injection of corticosteroid will have IOP 
534 
monitored carefully in this study.  The frequency and severity of IOP elevation will be 
535 
monitored. 
536 
 
537 
2.6.2 Cataract Formation 
538 
An opacity of the lens that results in loss of transparency and/or causes light scatter is 
539 
called a cataract.  The reasons why cataracts occur include:  formation of opaque 
540 
fibers, fibrous metaplasia, epithelial opacification, accumulation of pigment and 
541 
formation of extracellular materials.  These changes can occur as a result of the aging 
542 
process, trauma, radiation, electric shock, in association with systemic disorders, or as 
543 
a result of drugs or chemicals.  The most common types of cataract are cortical, 
544 
nuclear and posterior subcapsular.47 In cortical cataracts, the soluble protein content 
545 
decreases and results in lens alteration.  Nuclear cataracts may form as a result of an 
546 
increase in insoluble protein content along with the accumulation of chromophores.  
547 
Posterior subcapsular cataracts are caused by dysplastic changes in germinal 
548 
epithelium.  These dysplastic cells migrate posteriorly and give rise to bladder cells of 
549 
Wedl, resulting in posterior subcapsular opacity. 
550 
 
551 
Among the toxic causes of cataract, corticosteroid-induced cataract is one of the most 
552 
common.  The relationship between dose and duration of exposure to the formation of 
553 
cataract is unclear.  However, the association between corticosteroids and cataract is 
554 
well established.  Corticosteroid induced cataracts typically show an axial, posterior 
555 
subcapsular opacity which gradually increases in size.  Topical, systemic and 
556 


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peribulbar corticosteroid administration have all been associated with an increased 
557 
risk of cataract formation.48 Even the prolonged administration of inhaled 
558 
corticosteroids has been associated with an increased risk of cataract formation.49 
559 
 
560 
The intravitreal administration of corticosteroid is also expected to be associated with 
561 
cataract formation.  Indeed, the literature reviewed in this protocol confirms that 
562 
cataracts appear to result from intravitreal corticosteroid administration (Table 3).  
563 
The time course for the development of cataract as a result of intravitreal 
564 
corticosteroid injection is presently unknown.  However, it is believed that the 
565 
formation of cataract in response to intravitreal administration is gradual and takes 
566 
place over the course of approximately 1 year.  As with other routes of corticosteroid 
567 
administration, posterior subcapsular cataract appears to be the most common type of 
568 
cataract to form following the intravitreal administration of corticosteroid.  Table 3 
569 
shows that 4% of patients in the 7 pooled studies required cataract surgery and 12% 
570 
had progressive lens opacity.  These studies had at least 3 months of follow-up and, in 
571 
some cases, substantially more. 
572 
 
573 
Corticosteroid induced cataract will be followed closely as an adverse event in this 
574 
study. 
575 
 
576 
2.6.3 Endophthalmitis 
577 
Infectious endophthalmitis is an intraocular inflammatory process due to infection 
578 
with pathogens such as bacteria or fungi.  Clinical features include lid edema, 
579 
conjunctival injection, corneal edema, anterior chamber and vitreous inflammation, 
580 
and hypopyon.  Infectious endophthalmitis can occur following an intraocular 
581 
procedure (e.g. cataract surgery, vitrectomy surgery, intravitreal injection), as a result 
582 
of systemic infection, as a result of trauma, or occur as a late feature of conjunctival 
583 
filtering blebs. 
584 
 
585 
Acute postoperative endophthalmitis following cataract surgery is the most common 
586 
cause. The overall incidence, however, is low and in one survey the incidence 
587 


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following cataract surgery was <1%.50 In the Endophthalmitis Vitrectomy Study 
588 
(EVS), gram-positive organisms accounted for 94% of culture positive cases.51 
589 
 
590 
The incidence and causative pathogens following intravitreal injection of 
591 
corticosteroid are less well defined.  In the published literature, this complication 
592 
appears uncommon (Table 3).  Endophthalmitis following intravitreal injection of 
593 
antiviral agents for the treatment of CMV retinitis also appears to be uncommon 
594 
(personal communication, Daniel F. Martin).  However, the injection of a bolus of 
595 
medication that has immunosuppressive properties may result in a higher incidence of 
596 
postinjection endophthalmitis using corticosteroids.  A standardized protocol to 
597 
prepare eyes for the injection procedure may help to decrease the incidence of this 
598 
complication.  Such a protocol is described in the Manual of Procedures and 
599 
Procedures (MOPP). 
600 
 
601 
The clinical experience to date has been with the use of Kenalog.  Kenalog is a 
602 
commercially available preparation that is FDA labeled for intramuscular or 
603 
intrabursal use.  The available preparation of Kenalog contains, in addition to 
604 
triamcinolone acetonide, 0.99% benzyl alcohol, 0.75% carboxymethylcellulose 
605 
sodium and 0.04% polysorbate 80.52 Although the published literature to date does 
606 
not describe a significant incidence of complications as a result of the Kenalog 
607 
vehicle, anecdotal experience suggests that there may be a significant incidence of 
608 
non-infectious endophthalmitis as a result of the vehicle components [American 
609 
Society of Retinal Specialists listserve from 2002-2003].  As a result of the possibility 
610 
of a sterile reaction to the components of the Kenalog vehicle, it is difficult to be 
611 
certain if an inflammatory reaction is infectious or non-infectious following an 
612 
injection of Kenalog.  Treatment of infectious endophthalmitis requires immediate 
613 
treatment with intravitreal antibiotics with or without vitrectomy surgery depending 
614 
on the clinical situation.  Non-infectious endophthalmitis is usually self-limiting.  A 
615 
sterile, preservative-free triamcinolone preparation will be used in this study. 
616 
 
617 


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Despite the use of a sterile, preservative-free preparation, inflammatory reactions 
618 
following intravitreal injection as well as the frequency of infectious endophthalmitis 
619 
will be monitored carefully in this study. 
620 
 
621 
3. 
Objectives 
622 
The primary objective of the SCORE Study is to compare visual acuity outcome among 3 groups 
623 
of participants: those who are randomly assigned to receive standard care and those randomly 
624 
assigned to receive one of two doses of intravitreal injection(s) of triamcinolone acetonide for 
625 
treatment of macular edema associated with CRVO and BRVO.  Secondary objectives include 
626 
estimating the incidence of infectious endophthalmitis, non-infectious endophthalmitis, retinal 
627 
detachment, vitreous hemorrhage, cataract and elevated IOP in eyes receiving intravitreal 
628 
injection(s) of triamcinolone.  Other secondary objectives include comparing changes in retinal 
629 
thickness and calculated retinal thickening in participants who are randomly assigned to receive 
630 
intravitreal injection(s) of triamcinolone acetonide with those randomly assigned to standard care 
631 
for treatment of macular edema associated with CRVO and BRVO. 
632 
 
633 
4. 
Study Design and Methods 
634 
The SCORE Study is a multicenter, randomized, Phase III trial designed to compare the efficacy 
635 
and safety of standard care with intravitreal injection(s) of triamcinolone acetonide for the 
636 
treatment of macular edema associated with CRVO and BRVO.  Eligible participants within each 
637 
of these two disease entities will be randomized in a 1:1:1 ratio to one of three groups (treatment 
638 
of neovascular complications as necessary in all three groups):   
639 
1. Standard care group: conventional treatment consisting of: 
640 
a. CRVO: 
641 
i. 
Observation of macular edema. 
642 
b. BRVO: 
643 
i. 
Study eyes with dense macular hemorrhage:  Immediate observation.  Grid 
644 
laser photocoagulation will be performed if and when clearance of hemorrhage 
645 
permits grid laser photocoagulation. 
646 


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ii. 
Study eyes without dense macular hemorrhage:  Immediate grid laser 
647 
photocoagulation. 
648 
 
 
 
or 
649 
2. Intravitreal injection(s) of 4 mg of triamcinolone acetonide, 
650 
 
 
 
or 
651 
3. Intravitreal injection(s) of 1 mg of triamcinolone acetonide. 
652 
 
653 
Note:  Patients and investigators will be masked to the triamcinolone acetonide dose used (1 
654 
mg or 4 mg). 
655 
 
656 
4.1 Efficacy Assessment 
657 
4.1.1 Primary Efficacy Outcome 
658 
The primary efficacy outcome of this study is improvement by 15 or more letters from 
659 
baseline in best-corrected ETDRS visual acuity score at the 12-month visit as 
660 
determined by the ETDRS visual acuity protocol.  The primary outcome analysis will 
661 
include the following three comparisons of the proportion of participants having a 15 
662 
ETDRS letter improvement from baseline to 1 year: 
663 
• 4 mg triamcinolone acetonide intravitreal injections with standard care  
664 
• 1 mg triamcinolone acetonide intravitreal injections with standard care  
665 
• 4 mg triamcinolone acetonide intravitreal injections with 1 mg triamcinolone 
666 
acetonide intravitreal injections 
667 
 
668 
4.1.2 Secondary Efficacy Outcomes 
669 
Secondary efficacy outcomes include the following: 
670 
• 
Change between baseline and each efficacy outcome assessment visit in 
671 
best-corrected ETDRS visual acuity score (e.g., mean change from baseline 
672 
in visual acuity, distribution of change from baseline in visual acuity based 
673 
on clinically meaningful cut points of improvement or worsening of visual 
674 
acuity). 
675 


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• 
Change in calculated retinal thickening as assessed by optical coherence 
676 
tomography. 
677 
• 
Change in retinal thickness at the center of the macula as assessed by 
678 
stereoscopic color fundus photography. 
679 
• 
Change in area of retinal thickening as assessed by stereoscopic color fundus 
680 
photography. 
681 
 
682 
4.2 Safety Assessments 
683 
4.2.1 Safety Outcomes 
684 
Safety outcomes will be tabulated by observing the nature, severity and frequency of 
685 
adverse events throughout the three years of the study.  Specific safety outcomes 
686 
include: 
687 
• 
Injection-related events including infectious endophthalmitis, non-infectious 
688 
endophthalmitis, retinal tear or detachment, vitreous hemorrhage, ocular 
689 
discomfort/irritation, ocular tenderness, ocular itching sensation, foreign 
690 
body sensation, blurred vision, floaters, corneal abrasion, subconjunctival 
691 
hemorrhage, conjunctival edema, and conjunctival hyperemia/erythema. 
692 
• 
Steroid-related toxicities including cataract and elevated IOP. 
693 
 
694 
4.3 Inclusion Criteria 
695 
4.3.1 General Inclusion Criteria 
696 
a. 
Ability and willingness to provide informed consent. 
697 
b. 
Sex:  Participants may be male or female. 
698 
c. 
Age: 18 years or older 
699 
 
700 
4.3.2 Ocular Inclusion Criteria (study eye) 
701 
a. 
Participants must have center-involved macular edema secondary to 
702 
either CRVO or BRVO.  Eyes may be enrolled as early as the time 
703 
diagnosis of the macular edema, but not longer than 24 months after 
704 


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diagnosis (by patient history or ophthalmologic diagnosis).  The 
705 
following definitions are used for the purposes of the SCORE Study: 
706 
i. 
A CRVO is defined as an eye that has retinal hemorrhage or other 
707 
biomicroscopic evidence of retinal vein occlusion (e.g. 
708 
telangiectatic capillary bed) and a dilated venous system (or 
709 
previously dilated venous system) in all 4 quadrants. 
710 
ii. 
A BRVO is defined as an eye that has retinal hemorrhage or other 
711 
biomicroscopic evidence of retinal vein occlusion (e.g. 
712 
telangiectatic capillary bed) and a dilated venous system (or 
713 
previously dilated venous system) in 1 quadrant or less of retina 
714 
drained by the affected vein. 
715 
iii. 
A hemiretinal vein occlusion (HRVO) is defined as an eye that 
716 
has retinal hemorrhage or other biomicroscopic evidence of retinal 
717 
vein occlusion (e.g. telangiectatic capillary bed) and a dilated 
718 
venous system (or previously dilated venous system) in more than 
719 
1 quadrant but less than all 4 quadrants.  Typically, a HRVO is a 
720 
retinal vein occlusion that involves 2 altitudinal quadrants.  For 
721 
the purposes of the SCORE Study, eyes with HRVO will be treated 
722 
as eyes with BRVO and analyzed with the BRVO group. 
723 
b. 
ETDRS visual acuity score of greater than or equal to 19 letters 
724 
(approximately 20/400) and less than or equal to 73 letters 
725 
(approximately 20/40) by the ETDRS visual acuity protocol.  
726 
• Note: There will be an enrollment limit of 15% of eyes with visual 
727 
acuity between 19 and 33 letters.  The investigator must believe that 
728 
a study eye with visual acuity between 19 and 33 letters is perfused. 
729 
c. 
Mean retinal thickness on two OCT measurements greater than or equal 
730 
to 250 microns (central subfield). 
731 
d. 
Media clarity, pupillary dilation and participant cooperation sufficient 
732 
for adequate fundus photographs. 
733 
 
734 


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4.4 Exclusion Criteria 
735 
4.4.1 General Exclusion Criteria 
736 
Participants with any of the following conditions are ineligible: 
737 
a. A condition that, in the opinion of the investigator, would preclude 
738 
participation in the study (e.g., chronic alcoholism or drug abuse, 
739 
personality disorder or use of major tranquilizers indicating difficulty in 
740 
long term follow-up, likelihood of survival of less than 3 years). 
741 
b. Participation in an investigational trial within 30 days of study entry that 
742 
involved treatment with any drug that has not received regulatory approval 
743 
at time of study entry. 
744 
c. History of allergy to any corticosteroid or component of the delivery 
745 
vehicle. 
746 
d. Sitting systolic blood pressure greater than 180 mmHg or diastolic blood 
747 
pressure greater than 110 mmHg.  If the initial reading exceeds these 
748 
values, a second reading may be taken two or more hours later; the patient 
749 
may be included (if all other inclusion criteria are met) in the study if the 
750 
second reading demonstrates a systolic blood pressure equal to or less than 
751 
180 mmHg and the diastolic blood pressure is 110 mmHg or less.  If the 
752 
blood pressure is brought to 180 mmHg systolic or less and 110 mmHg 
753 
diastolic or less by antihypertensive treatment, the patient can become 
754 
eligible. 
755 
e. The participant will be moving out of the area of the clinical center to an 
756 
area not covered by another clinical center during the 3 years of the study. 
757 
f. History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids 
758 
within 4 months prior to randomization or corticosteroid eyedrops in 
759 
current use more than 2 times per week. 
760 
• Note:  Patients taking topical, rectal or inhaled corticosteroids are 
761 
eligible for the study. 
762 
g. Positive urine pregnancy test: all women of childbearing potential (those 
763 
who are pre-menopausal and not surgically sterilized) may participate only 
764 
if they have a negative urine pregnancy test, if they do not intend to 
765 


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become pregnant during the timeframe of the study and if they agree to use 
766 
at least one of the following birth control methods: hormonal therapy such 
767 
as oral, implantable or injectable chemical contraceptives; mechanical 
768 
therapy such as spermicide in conjunction with a barrier such as a condom 
769 
or diaphragm; intrauterine device (IUD); or surgical sterilization of 
770 
partner. 
771 
 
772 
4.4.2 Ocular Exclusion Criteria (study eye) 
773 
a. Exam evidence of vitreoretinal interface disease (e.g. vitreomacular 
774 
traction, epiretinal membrane), either on clinical examination or optical 
775 
coherence tomography thought to be contributing to macular edema. 
776 
b. An eye that, in the investigator’s opinion, would not benefit from 
777 
resolution of macular edema such as eyes with foveal atrophy, dense 
778 
pigmentary changes or dense subfoveal hard exudates. 
779 
c. Presence of an ocular condition that, in the opinion of the investigator, 
780 
might affect macular edema or alter visual acuity during the course of the 
781 
study (e.g., age-related macular degeneration, uveitis or other ocular 
782 
inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, prior 
783 
macula-off rhegmatogenous retinal detachment). 
784 
d. Presence of a substantial cataract that, in the opinion of the investigator, is 
785 
likely to be decreasing visual acuity by 3 lines or more (i.e. a 20/40 
786 
cataract). 
787 
e. History of laser photocoagulation for macular edema within 4 months 
788 
prior to randomization. 
789 
• 
Note:  If prior grid laser photocoagulation has been performed, the 
790 
study eye must have either: 
791 
a. 
One or more disc areas of leakage on the fluorescein angiogram 
792 
(FA).  This area of leakage must be contiguous with the fovea 
793 
and have no evidence of prior laser treatment. 
794 
OR 
795 


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b. 
Two or more disc areas of leakage on the fluorescein angiogram 
796 
(FA).  This area of leakage must be contiguous with the fovea 
797 
and have evidence of clearly inadequate prior laser treatment. 
798 
f. History of intravitreal corticosteroid injection. 
799 
g. History of peribulbar or retrobulbar corticosteroid use for any reason 
800 
within 6 months prior to randomization. 
801 
h. History of panretinal scatter photocoagulation (PRP) or sector laser 
802 
photocoagulation within four months prior to randomization or anticipated 
803 
within the next four months following randomization. 
804 
i. History of pars plana vitrectomy. 
805 
j. History of major ocular surgery (including cataract extraction, scleral 
806 
buckle, any intraocular surgery, etc.) within 6 months prior to 
807 
randomization or anticipated within the next 6 months following 
808 
randomization. 
809 
k. History of YAG capsulotomy performed within 2 months prior to 
810 
randomization. 
811 
l. IOP greater than or equal to 25 mm Hg.  
812 
m. Exam evidence of pseudoexfoliation. 
813 
n. History of steroid-induced IOP elevation that required IOP-lowering 
814 
treatment. 
815 
o. History of open angle glaucoma (either primary open angle glaucoma or 
816 
other cause of open angle glaucoma; note: prior angle closure glaucoma is 
817 
not an exclusion). 
818 
• A history of ocular hypertension (or IOP greater than or equal to 22 
819 
mm Hg without a prior diagnosis of ocular hypertension) is not an 
820 
exclusion as long as (1) IOP is less than 25 mm Hg, (2) the patient is 
821 
using no more than one topical glaucoma medication, (3) the most 
822 
recent visual field, performed within the last 12 months, is normal (if 
823 
abnormalities are present on the visual field they must be attributable 
824 
to the patient’s macular disease), and (4) the optic nerve does not 
825 
appear glaucomatous. 
826 


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• Note:  If IOP is 22 to less than 25 mm Hg, then the above criteria for 
827 
ocular hypertension eligibility must be met.  
828 
p. History of herpetic ocular infection. 
829 
q. History of ocular toxoplasmosis. 
830 
r. Aphakia. 
831 
s. Exam evidence of external ocular infection, including conjunctivitis, 
832 
chalazion or significant blepharitis. 
833 
t. History of macular detachment. 
834 
u. Exam evidence of any diabetic retinopathy, defined as eyes of diabetic 
835 
patients with more than one microaneurysm outside the area of the vein 
836 
occlusion (inclusive of both eyes). 
837 
v. History of idiopathic central serous chorioretinopathy. 
838 
4.4.3 Fellow (Non-Study) Eye Criteria (the Fellow Eye Must Meet the 
839 
Following) 
840 
a. ETDRS visual acuity score of greater than or equal to 19 letters 
841 
(approximately 20/400) 
842 
b. No prior history of intravitreal corticosteroid injection. 
843 
c. IOP less than 25 mm Hg. 
844 
d. No exam evidence of pseudoexfoliation. 
845 
e. No history of steroid-induced IOP elevation that required IOP lowering 
846 
treatment. 
847 
f. No history of open-angle glaucoma (either primary open-angle glaucoma 
848 
or other cause of open-angle glaucoma; note: angle-closure glaucoma is 
849 
not an exclusion). 
850 
• A history of ocular hypertension (or IOP greater than or equal to 22 
851 
mm Hg without a prior diagnosis of ocular hypertension) is not an 
852 
exclusion as long as (1) IOP is less than 25 mm Hg, (2) the patient is 
853 
using no more than one topical glaucoma medication, (3) the most 
854 
recent visual field, performed within the last 12 months, is normal (if 
855 
abnormalities are present on the visual field they must be attributable 
856 


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to the patient’s macular disease), and (4) the optic nerve does not 
857 
appear glaucomatous. 
858 
• Note:  If the IOP is 22 to less than 25 mm Hg, then the above criteria 
859 
for ocular hypertension must be met 
860 
4.5 Informed Consent, Screening Evaluation, and Randomization 
861 
4.5.1 Informed Consent 
862 
Potential participants in the SCORE Study will be assessed as part of routine-care 
863 
examinations.  Prior to completing any procedures or collecting any data that are not 
864 
part of usual medical care, written informed consent will be obtained.  The informed 
865 
consent should be reviewed with the patient at this visit and signed with the 
866 
understanding that the patient may or may not be eligible.  Consent may be given in 
867 
two stages (if approved by the IRB), with one consent signature obtained prior to 
868 
screening procedures specific to the SCORE Study that are needed to assess 
869 
eligibility.  The second stage will be obtained prior to randomization and will be for 
870 
participation in the SCORE Study.  Thus, a single consent form will have two 
871 
signature/date lines for the patient: one for the patient to consent to the screening 
872 
procedures and one for the patient to consent for the randomized trial.  Patients will 
873 
be encouraged to discuss the SCORE Study with family members and their personal 
874 
physician(s) before deciding on study participation.  Two identical consent forms are 
875 
signed.  One original consent form is to be kept in the participant’s study file and a 
876 
copy of an original is placed in the participant’s clinical chart.  The other original 
877 
signed consent is for the participant to take home.  The informed consent describes 
878 
the study, randomization procedure, intravitreal steroid treatment and participant 
879 
responsibilities.  Randomization will occur following confirmation of the patient’s 
880 
eligibility for the study and decision to enter the study. 
881 
 
882 
4.5.2 Screening Evaluation 
883 
a. An interview is conducted, including demographic information, medical 
884 
history including ocular history and current medications.  This history is 
885 
taken in order to ascertain whether there is any medical, ocular, or 
886 
medication condition that may indicate ineligibility.  Participants who are 
887 


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taking aspirin or warfarin are eligible for the study.  However, 
888 
participants may be requested to refrain from taking warfarin a few days 
889 
prior to the randomization visit and/or any retreatment visits if they are 
890 
assigned to receive corticosteroid treatment; this decision is at the 
891 
discretion of the investigator and the patient’s primary care physician.   
892 
b. Visual acuity and manifest refraction (done within 8 days prior to 
893 
randomization).  Visual acuity testing and manifest refraction are done 
894 
using electronic ETDRS (E-ETDRS) visual acuity testing at 3 meters 
895 
using the Electronic Visual Acuity Tester by a SCORE certified 
896 
technician.  This testing procedure has been validated against 4 meter 
897 
standard ETDRS chart testing.    Given the critical importance of visual 
898 
acuity in this study, the best-corrected E-ETDRS visual acuity must be 
899 
obtained in this very careful and standardized manner.  Additionally, a 
900 
“masked” visual acuity examiner with no knowledge of treatment 
901 
assignments will perform visual acuity testing  at the 4-month, 12-month, 
902 
24-month and 36-month visits.  This “masked” examiner will be an 
903 
individual not involved with the study except for the purpose of performing 
904 
visual acuity testing.  For example, this individual may be a clinic 
905 
technician or a study coordinator for another clinical trial, but may not be 
906 
the study coordinator for this trial.  
907 
c. IOP (done within 21 days prior to randomization).  The IOP of both eyes 
908 
will be measured prior to randomization.  IOP will be measured using a 
909 
sterile Goldmann applanation tonometer (see MOPP for procedure 
910 
details). 
911 
d. Ophthalmic examination including dilated ophthalmoscopy (done within 
912 
21 days prior to randomization).  The participant's ocular status is 
913 
evaluated by a study participating ophthalmologist for conditions that may 
914 
make the participant ineligible as well as information necessary to 
915 
complete the study forms.  Lens assessment for cataract at the slit lamp 
916 
will be performed with grading according to a modified Age-Related Eye 
917 
Disease Study (AREDS) grading system. 
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e. Fundus photographs, fluorescein angiography and optical coherence 
919 
tomography (done within 21 days prior to randomization).  Good quality 
920 
stereoscopic color fundus photographs (7 fields of the study eye and 3 
921 
fields of the fellow eye) and a fluorescein angiogram as well as two optical 
922 
coherence tomography measurements per eye are required for all 
923 
participants.  The mean of the 2 OCT measurements will be used to assess 
924 
eligibility. These procedures are described in: University of Wisconsin-
925 
Madison Fundus Photograph Reading Center Fluorescein Angiography 
926 
and Optical Coherence Tomography protocols. 
927 
f. Blood pressure measurement (done within 21 days prior to 
928 
randomization). 
929 
g. For women of childbearing potential: Urine pregnancy test (done within 21 
930 
days prior to randomization). 
931 
 
932 
4.5.3 Randomization 
933 
A secure Internet-based eligibility, enrollment and randomization system is integrated 
934 
into the SCORE Study.  One eye of each participant will be randomly assigned to 
935 
either treatment with intravitreal triamcinolone acetonide in one of two doses (4 mg 
936 
or 1 mg) vs. observation (CRVO) or intravitreal triamcinolone acetonide in one of 
937 
two doses (4 mg or 1 mg) vs. observation/grid laser photocoagulation (BRVO).  
938 
Treatment assignments, generated by the SCORE Data Coordinating Center, will be 
939 
stratified according to the following disease groups:  CRVO, BRVO without dense 
940 
macular hemorrhage, and BRVO with dense macular hemorrhage; and baseline visual 
941 
acuity according to the following categories: good visual acuity (59-73 letters: 20/40 
942 
to 20/63), moderate visual acuity (49-58 letters: 20/80 to 20/100), and poor visual 
943 
acuity (19-48 letters: 20/125-20/400).  In participants with both eyes eligible and 
944 
when both eyes have the same disease (CRVO or BRVO), the eye to be randomized 
945 
into the SCORE Study will be at the discretion of the physician and patient.  Only one 
946 
eye per participant may be randomized into the SCORE study.  In participants with 
947 
both eyes eligible, but where the disease is different (i.e. CRVO in one eye and 
948 


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BRVO in the other eye) the eye to be randomized into the SCORE Study will also be 
949 
at the discretion of the physician and patient. 
950 
 
951 
4.6  Standard Care Groups 
952 
For study eyes with CRVO, standard care consists of observation of the macular edema.  
953 
For study eyes of BRVO participants with a dense macular hemorrhage, standard care is 
954 
observation followed by grid laser photocoagulation if and when clearing of the 
955 
hemorrhage permits grid laser photocoagulation.  For study eyes of BRVO participants 
956 
without a dense macular hemorrhage at enrollment, standard care consists of immediate 
957 
grid laser photocoagulation.  The determination of a dense hemorrhage in the center of the 
958 
macula (and thus the timing of the grid laser photocoagulation) is left to the discretion of 
959 
the investigator.  For all three groups, neovascular complications will be treated as 
960 
necessary. 
961 
 
962 
The timing of, and criteria for, retreatment with laser photocoagulation are detailed in 
963 
Section 4.8.3. 
964 
 
965 
4.6.1 Photocoagulation Procedures 
966 
Participants with BRVO assigned to standard care who are eligible for laser (i.e., no 
967 
dense macular hemorrhage) will have laser photocoagulation performed to treat both 
968 
focal leaks, if any, and areas of diffuse retinal thickening.  The investigator has the 
969 
flexibility to determine the total number of burns required for treatment.  However, 
970 
the total number of burns delivered will depend on the number of focal leaks present, 
971 
if any, and the area of diffuse retinal thickening present.  If the eye is not eligible for 
972 
laser photocoagulation at the randomization visit because of the presence of dense 
973 
macular hemorrhage, the participant will be re-evaluated at 4-month intervals.  If the 
974 
macular hemorrhage clears, laser photocoagulation will be performed at that time. 
975 
The following guidelines should be followed: 
976 


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Grid Laser Photocoagulation Procedure 
977 
 
Size 
 
50-100 um 
 
Exposure 
 
0.05-0.1 seconds 
 
Intensity 
 
Mild 
 
Number 
 
Cover areas of diffuse retinal thickening and treat focal leaks if 
any are present 
 
Placement 
 
1-2 burn width apart (500-3000um from center of fovea) 
 
Wavelength 
 
Green to yellow 
 
978 
 
979 
4.7   Intravitreal Steroid Groups  
980 
Study eyes of CRVO and BRVO participants randomized to intravitreal steroid injection(s) 
981 
will be given triamcinolone acetonide, in a masked fashion, in one of two doses (1 mg or 4 
982 
mg), depending on the treatment assignment. 
983 
 
984 
The timing of, and criteria for, retreatment with intravitreal triamcinolone injections are 
985 
detailed in section 4.8.3. 
986 
 
987 
4.7.1 Intravitreal Injection of Triamcinolone Acetonide 
988 
The study drug formulation (triamcinolone acetonide) used in the SCORE Study has 
989 
been developed by Allergan, Inc. (Irvine, CA).  The physical, chemical and 
990 
pharmaceutical properties of the study drug and formulation are detailed in the 
991 
Clinical Investigator’s Brochure.  Topical antibiotic drops will be administered in the 
992 
study eye prior to injection (on the day of injection) and for three days post injection.  
993 
Prior to injection, a standard prep will include povidone iodine and a sterile lid 
994 
speculum. The same technique is followed for both the initial treatment and for 
995 
retreatment.  The full injection procedure is described in the SCORE Study MOPP. 
996 
 
997 


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4.8  Participant Visit Schedule, Retreatment, Alternate Treatment and Other 
998 
Treatments 
999 
Note: The SCORE Study protocol under protocol versions 6.0 and earlier specified 3 
1000 
year follow-up on all study participants.  Under Protocol version 7.0 and higher 
1001 
(February 10, 2008), the last day of enrollment is February 29, 2008 and the last day 
1002 
of participant follow-up is February 28, 2009 to allow all participants at least one 
1003 
year of follow-up for primary efficacy assessment.  Testing procedures at a study 
1004 
participant’s final study visit, which will take place at one of the following visits: M12, 
1005 
M16, M20, M24, M28, M32, or M36, will be performed as described in Section 4.8.2.  
1006 
Patients who are injected in February 2009 will still need to come in for their Day 4 
1007 
and Month 1 safety visits, even though these safety visits may be late, i.e. they may 
1008 
occur after February 28, 2009.  (Late safety visits are required to safeguard patient 
1009 
safety, but, to ensure comparability between groups, late safety visits will not be part 
1010 
of the trial safety analysis).  All study participants active under Protocol Version 7.0 
1011 
who will not reach their Month 36 visit by February 28, 2009 will be asked to sign an 
1012 
addendum to the informed consent form. 
1013 
4.8.1 Visit Schedule 
1014 
Appendix 1 shows the follow-up visit schedule for all participants through month 36. 
1015 
Participants in each of the 3 treatment groups will have follow-up visits every 4 
1016 
months.  The visit windows are ± 2 weeks during the first 12 months and ± 8 weeks 
1017 
after 12 months. 
1018 
• The visits at 4 months (± 2 weeks), 12 months (± 2 weeks), 24 months (± 
1019 
8 weeks), and 36 months (± 8 weeks) are designated for outcome 
1020 
assessment visits.  At these visits, certain additional testing is performed 
1021 
that is not performed at other visits. 
1022 
• For the visits at 8, 16, 20, 28, and 32-months, the end of the visit window 
1023 
may be extended if necessary so that the visit occurs no sooner than 3.5 
1024 
months since the last treatment. 
1025 
Additional visits may occur as required for usual care of the study participant 
1026 
• In the intravitreal triamcinolone groups, post-injection safety visits will be 
1027 
performed at 4 days and 4 weeks after each intravitreal injection. 
1028 


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• Assessment of ocular symptoms or ocular problems other than for macular 
1029 
edema or the follow-up of adverse events may require additional visits.  
1030 
These visits are to be scheduled promptly at the investigator’s discretion. 
1031 
 
1032 
4.8.2 Testing Procedures to be Performed at Follow-up Visits (see Appendix 1) 
1033 
The following procedures will be performed at each 4-month follow-up visit on both 
1034 
eyes unless otherwise specified. 
1035 
1. E-ETDRS visual acuity.  Protocol refraction will be performed at the 4, 
1036 
12, 24 and 36 month visits.  At other visits, the need for a refraction is 
1037 
determined by the investigator based on usual care considerations.  A 
1038 
refraction should be performed when there is a change in visual acuity of 
1039 
15 or more letters (better or worse) from the visual acuity score at the time 
1040 
of the last refraction. 
1041 
2. IOP measurement using the Goldmann tonometer. 
1042 
3. Ophthalmic examination, including a dilated fundus examination and a 
1043 
slit-lamp examination. 
1044 
4. Fundus photography. Three field fundus photography will be performed on 
1045 
the study eye at all visits except at 12, 24, and 36 months, at which time 
1046 
seven field fundus photography will be performed. Three field fundus 
1047 
photography will be performed on the non-study eye at 12, 24, and 36 
1048 
months. 
1049 
5. Optical coherence tomography.  To be performed on both eyes at 4, 12, 24, 
1050 
and 36 months and on the study eye only at other visits. 
1051 
6. Lens assessment, using modified AREDS standard lens photographs, for 
1052 
cataract will be performed at 4, 12, 24, and 36 months. 
1053 
7. Fluorescein angiography will be performed at 4, 12, and 24 months.  The 
1054 
fluorescein angiography protocol directs image capture from both eyes, 
1055 
with emphasis on the study eye. 
1056 
8. Blood pressure measurements will be performed at 12, 24, and 36 months. 
1057 
 
1058 


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Visual acuity, IOP, and an ophthalmic examination will be performed at the 4-
1059 
day (+/-3 days) and 4-week (+/-7 days) post-injection safety visits.  At 
1060 
unscheduled visits, the procedures performed will be determined by the 
1061 
investigator. 
1062 
4.8.3 Retreatment Assessment 
1063 
At each 4-month visit during follow-up, the investigator will assess whether persistent 
1064 
or recurrent macular edema is present that warrants retreatment with the 
1065 
randomization assigned treatment. 
1066 
 
1067 
Only those eyes assigned to intravitreal triamcinolone and those eyes eligible for laser 
1068 
photocoagulation (i.e. eyes with BRVO and without a dense macular hemorrhage) are 
1069 
eligible for retreatment. 
1070 
 
1071 
Retreatment, when indicated, will be performed within 4 weeks after the follow-up 
1072 
visit.  Retreatment should not be performed sooner than 3.5 months from the time of 
1073 
the last treatment. 
1074 
 
1075 
If retreatment is deferred because the patient has responded well to prior treatment, 
1076 
then the patient can either be scheduled to be seen in 4 months or can be seen sooner 
1077 
at investigator’s discretion. 
1078 
 
1079 
4.8.3.1 
Retreatment Criteria 
1080 
In general, the patient will be retreated with the randomization-assigned 
1081 
treatment unless there are specific reasons not to retreat, in which case the 
1082 
investigator may decide to postpone treatment, although postponing treatment 
1083 
is not required.  The reasons for not retreating include: 
1084 
 
1085 
1. Treatment has been successful and may not need to be repeated if one of 
1086 
the following is present:  
1087 


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a. The investigator considers the center of the macula nearly flat. (Note: 
1088 
for the purposes of this study, as a guideline, the center of the macula 
1089 
should not be considered flat if the OCT central subfield is greater 
1090 
than 225 microns). 
1091 
b. ETDRS visual acuity score of 79 or more letters (approximately 20/25 
1092 
or better). 
1093 
c. In the opinion of the investigator, there has been substantial 
1094 
improvement in macular edema from the last treatment session (e.g., > 
1095 
50% decrease in retinal thickening [thickening is not retinal thickness; 
1096 
it is the difference between normal retinal thickness and observed 
1097 
retinal thickness] in the central subfield) AND further spontaneous 
1098 
improvement (without additional treatment) in macular edema might 
1099 
be expected. 
1100 
 
1101 
2. Additional treatment is contraindicated because either the patient had a 
1102 
significant adverse effect from prior treatment or maximum treatment has 
1103 
already been received.  Examples include the following:   
1104 
• 
The participant had an IOP elevation after a previous steroid 
1105 
injection that required treatment to lower the IOP.  (Note: an 
1106 
investigator may choose to retreat a participant who developed 
1107 
IOP elevation that has been controlled or is currently controlled 
1108 
with treatment as long as IOP currently is 35 mm Hg or less.  If 
1109 
the IOP is greater than 35 mm Hg, then the IOP must be lowered 
1110 
before retreatment is given).  
1111 
• 
In the investigator’s judgment, maximum safe laser 
1112 
photocoagulation has been performed and therefore additional 
1113 
laser photocoagulation is contraindicated 
1114 
 
1115 
3. Additional treatment seems "apparently futile": 
1116 
Additional treatment will be defined as "apparently futile" if 8 or more 
1117 
months transpire, during which there have been 2 procedures (either laser 
1118 


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photocoagulation or intravitreal triamcinolone injection, according to the 
1119 
randomization assigned treatment), and during which there is no evidence 
1120 
of at least “borderline improvement.”   
1121 
An eye is considered to have at least "borderline improvement" if it meets 
1122 
either of the following criteria compared with the findings at the beginning 
1123 
of the 8 or more months period: 
1124 
a. An increase in visual acuity score of 5 or more letters.  
1125 
or 
1126 
b. A decrease in calculated retinal thickening (measured thickness minus 
1127 
175 microns in the OCT central subfield of the six-radial scan map) 
1128 
that is at least 50 microns and represents at least a 20% reduction in 
1129 
calculated retinal thickening (measured thickness minus 175 microns) 
1130 
compared with the findings at the beginning of the 8 or more months 
1131 
period. 
1132 
If the eye meets the criteria for additional treatment being “apparently futile”, the 
1133 
treating ophthalmologist may elect to discontinue further treatment at this visit.  
1134 
However, the treating ophthalmologist is not obligated to discontinue treatment at 
1135 
this visit and may perform an additional treatment (either laser photocoagulation 
1136 
or intravitreal triamcinolone injection, according to the randomization assigned 
1137 
treatment) if desired. 
1138 
 
1139 
Example of “Apparently Futile” at 20 Months After Study Enrollment 
1140 
An eye improved in visual acuity from 55 letters (approximately 20/80) to 70 
1141 
letters (approximately 20/40) and in OCT from 400 to 300 microns during the 
1142 
first year of follow-up (i.e., at the 12-month follow-up the visual acuity was 70 
1143 
letters (approximately 20/40) and the OCT measured 300 microns) and had 
1144 
intravitreal injections at baseline, 6, 12, and 16 months.  Between 12 and 20 
1145 
months the eye never had a visual acuity measured at better than 70 letters 
1146 
(approximately 20/40) and the smallest OCT thickness measured was 290 (less 
1147 
than 50 microns reduction from 300 microns measured at 12 months).  Because 
1148 


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there is no evidence of at least “borderline improvement” during these last 8 
1149 
months, the treating ophthalmologist may wish to discontinue treatment at this 
1150 
visit.  However, continued treatment is not forbidden.  If treatment is 
1151 
discontinued, the investigator may choose to reinstate treatment at a subsequent 
1152 
visit (such as, if the investigator believes that vision and/or retinal thickening has 
1153 
worsened).  
1154 
 
1155 
If the OCT thickness at the beginning of the 8 or more months period had been 
1156 
500µm, a reduction of at least 65µm would have been required to meet the at 
1157 
least borderline improvement definition (beginning calculated retinal thickening 
1158 
500-175 = 325; 20% reduction = 65µm). 
1159 
 
1160 
Note:  This example is for a patient assigned to receive intravitreal triamcinolone 
1161 
injection.  However, this example is also applicable for patients with BRVO and 
1162 
without a dense macular hemorrhage who have received laser photocoagulation. 
1163 
 
1164 
4.8.4 Alternate Treatment for the Study Eye  
1165 
Although it is preferable that study eyes assigned to standard care (i.e., laser 
1166 
photocoagulation for BRVO eyes without a dense macular hemorrhage or 
1167 
observation for CRVO eyes or observation for BRVO eyes with a dense macular 
1168 
hemorrhage) not be treated with intravitreal triamcinolone acetonide and for study 
1169 
eyes assigned to intravitreal triamcinolone acetonide not be treated with laser 
1170 
photocoagulation, it is recognized that there may be situations where the 
1171 
investigator strongly believes that the alternate treatment should be provided. 
1172 
 
1173 
An eye may be treated with the alternate treatment when it has experienced: 
1174 
1. 
A 15-letter decrease from baseline in best-corrected visual acuity that is 
1175 
present at two consecutive 4-month interval visits.   
1176 
AND 
1177 


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2. 
The decrease in visual acuity is due to persistent or recurrent macular edema 
1178 
(i.e. not due to cataract or other abnormality) that is documented on OCT. 
1179 
(Note: for the purposes of this study, as a guideline, the center of the macula 
1180 
should not be considered flat if the OCT central subfield is >225 microns). 
1181 
 
1182 
When the above criteria are met, an eye assigned to a standard care group may 
1183 
receive (but is not required to receive) intravitreal triamcinolone (4 mg dose, study 
1184 
formulation) and BRVO eyes without a dense macular hemorrhage assigned to 
1185 
intravitreal triamcinolone injection may receive (but are not required to receive) 
1186 
laser photocoagulation. When the above criteria are met, the investigator should 
1187 
only provide the alternate treatment if the investigator strongly believes that the 
1188 
alternate treatment is in the patient’s best interest. 
1189 
 
1190 
4.8.5 Other Treatments  
1191 
If, in the investigator’s judgment, the study eye requires additional treatment other 
1192 
than laser photocoagulation or intravitreal triamcinolone injection, then the Study 
1193 
Chair or Co-Chair should be contacted to discuss possible treatments.  However, 
1194 
anti-inflammatory topical medication may be prescribed for treatment of the study 
1195 
eye without Study Chair or Co-Chair consultation. 
1196 
 
1197 
4.9  Diagnosis and Treatment of Adverse Events 
1198 
4.9.1 Endophthalmitis Treatment 
1199 
The decision to treat a patient for an endophthalmitis or a suspected endophthalmitis 
1200 
will be guided by the clinical judgment of the investigator.  The treatment method 
1201 
(pars plana vitrectomy vs. vitreous tap) and choice of antimicrobial agents is also at 
1202 
the discretion of the investigator and should follow current standard practice patterns. 
1203 
 The decision to use intravitreal steroids (e.g. dexamethasone) for the treatment of 
1204 
endophthalmitis is also at the discretion of the investigator. 
1205 
 
1206 
4.9.2 Treatment of Elevated Intraocular Pressure (IOP) 
1207 


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It is expected that some patients will have an IOP rise that may require treatment to 
1208 
lower the IOP. 
1209 
 
1210 
Treatment of elevated IOP will be instituted whenever the IOP is greater than or equal 
1211 
to 30 mm Hg.   The treatment to prescribe will be at investigator discretion and may 
1212 
include referral to another ophthalmologist.  If the IOP is between 22 and 30 mm Hg, 
1213 
then the IOP should be measured again within one month and treated if greater than or 
1214 
equal to 30 mm Hg.  IOP greater than 25 mm Hg at consecutive 4-month visits should 
1215 
be treated.  If IOP is greater than 25 mm Hg for 4 months, then a visual field should 
1216 
be performed to evaluate for glaucomatous damage. 
1217 
 
1218 
The treatment to prescribe is at the discretion of the investigator and may include 
1219 
referral to another ophthalmologist.  One treatment regimen that can be followed was 
1220 
used in the Collaborative Initial Glaucoma Treatment Study53 and is listed below:  
1221 
 
1222 
Participants may receive a sequence of medications, which may begin with a topical 
1223 
beta-blocker, followed by an alternate single topical therapeutic agent, dual topical 
1224 
therapy, triple topical therapy, an alternate combination of triple topical therapy, and 
1225 
an optional additional topical and/or oral medication or medications.  If further 
1226 
treatment is required, the next treatment step may be argon laser trabeculoplasty, 
1227 
followed by trabeculectomy, medication, trabeculectomy with an antifibrotic agent, 
1228 
and medication. 
1229 
 
1230 
4.9.3 Cataract Surgery 
1231 
It is expected that some study participants in both the intravitreal steroid arms and the 
1232 
standard care arms will develop cataract within the study period.  The decision to 
1233 
perform cataract surgery is at the discretion of the investigator and the patient.  
1234 
Indications for cataract surgery should follow guidelines developed by the American 
1235 
Academy of Ophthalmology, Preferred Practice Pattern (Cataract in the Adult Eye, 
1236 
Anterior Segment Panel, 2001, page 15).  Similar guidelines have been adopted by the 
1237 
Department of Health and Human Services (Medicare Program; Limitations on 
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Medicare Coverage of Cataract Surgery, October 6, 1995): 
1239 
Indications for Cataract Surgery: 
1240 
1. Visual function that no longer meets the participant’s needs and for which 
1241 
cataract surgery provides a reasonable likelihood of improvement. 
1242 
2. Lens opacity that inhibits optimal management of posterior segment disease. 
1243 
3. The lens causes inflammation (phakolysis, phakoanaphylaxis), angle 
1244 
closure, or medically unmanageable open-angle glaucoma. 
1245 
 
1246 
Participants in both the intravitreal steroid groups and the standard care groups 
1247 
should be assessed for the development of cataract in a similar fashion. Cataract 
1248 
surgery may be performed at any time that this is indicated clinically. 
1249 
 
1250 
4.9.4 Surgery for Proliferative Retinopathy and Other Complications Due to 
1251 
Retinal Vein Occlusion 
1252 
It is expected that some study participants will develop vitreous hemorrhage and/or 
1253 
other complications of retinal vein occlusion that may cause visual impairment.  
1254 
Vitrectomy for the complications of proliferative retinopathy such as vitreous 
1255 
hemorrhage should be delayed, if clinically feasible, because vitreous hemorrhage 
1256 
may resolve, obviating the need for vitrectomy.  Furthermore, vitrectomy is thought to 
1257 
reduce the half-life of intravitreal steroids such that participants assigned to the 
1258 
steroid treatment arms may experience reduced benefit from intravitreal steroid 
1259 
injections following vitrectomy. 
1260 
 
1261 
A suggested treatment plan that may be followed for eyes with vitreous hemorrhage 
1262 
and/or other complications of retinal vein occlusion is as follows: 
1263 
1. Eyes with visually significant, non-clearing vitreous hemorrhage should 
1264 
have vitrectomy performed if there is no significant clearing in 3 months. 
1265 
2. Eyes with traction retinal detachment involving or threatening the fovea 
1266 
should have vitrectomy performed as soon as clinically indicated. 
1267 
3. Eyes with a combined traction-rhegmatogenous retinal detachment should 
1268 
have vitrectomy performed as soon as clinically indicated. 
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4. Eyes with extensive and progressive fibrovascular proliferation should have 
1270 
vitrectomy performed as soon as clinically indicated. 
1271 
5. Eyes with vitreoretinal interface disease such as from vitreomacular traction 
1272 
or an epiretinal membrane can, at the discretion of the investigator, have 
1273 
vitrectomy performed if the investigator believes that the primary cause of 
1274 
macular edema and reduced visual acuity is due to the vitreoretinal interface 
1275 
disease.   
1276 
 
1277 
4.10 
Miscellaneous Treatments During Follow-up 
1278 
4.10.1 Treatment of Macular Edema in Non-study Eye 
1279 
If a non-study eye that was not eligible for enrollment develops macular edema 
1280 
associated with retinal vein occlusion requiring treatment, the treatment will depend 
1281 
on the randomization group of the study eye.  The following also applies to the non-
1282 
study eye of a patient who presents with both eyes eligible for the SCORE study at 
1283 
screening and when both eyes have the same disease (CRVO or BRVO) or if each eye 
1284 
has a different disease (i.e. one eye has a CRVO and the other eye has a BRVO). 
1285 
• 
If the study eye was assigned to an intravitreal corticosteroid group, then 
1286 
the non-study eye will receive standard care to avoid treating both eyes 
1287 
with intravitreal corticosteroids.   
1288 
• 
If the study eye was assigned to standard care, then the non-study eye may 
1289 
be treated with either intravitreal corticosteroids (study preparation, 4 mg 
1290 
dose only) or standard care at investigator/patient discretion.  A non-study 
1291 
eye treated with the study steroid preparation will undergo the same follow-
1292 
up schedule, retreatment regimen and adverse event monitoring as study 
1293 
eyes in the SCORE Study. 
1294 
 
1295 
4.10.2 Panretinal Photocoagulation (PRP) Treatment: 
1296 
PRP or sector PRP can be given if it is indicated in the judgment of the investigator 
1297 
and following guidelines established by the CVOS and BVOS.  Recall that 
1298 
participants are not eligible for the SCORE Study if, at the time of randomization, it 
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is expected that they will need PRP within 4 months.  The following guidelines 
1300 
should be followed: 
1301 
Burn Characteristics 
1302 
 
1303 
Size (on retina) 
500 microns 
Exposure 
0.1 seconds recommended, 0.05 to 0.2 allowed 
Intensity 
mild white 
Distribution 
edges 1 burn width apart 
No. of Sessions/Sittings 
unrestricted (each session generally should be completed in <6 sittings) 
Nasal proximity to disk 
No closer than 500 microns 
Temp. proximity to center 
No closer than 3000 microns 
Superior/inferior limit 
No further posterior than 1 burn within the temporal arcades 
Wavelength 
Green to yellow (red can be used if vitreous hemorrhage is present 
precluding use of green or yellow) 
 
1304 
5. 
Data Monitoring and Adverse Event Reporting 
1305 
5.1 Data Safety Monitoring Committee 
1306 
The SCORE Data and Safety Monitoring Committee (DSMC) is responsible for reviewing 
1307 
the study design and, as appropriate, recommending design changes to the SCORE 
1308 
Executive Committee and the NEI.  The DSMC also may recommend to the NEI to 
1309 
suspend enrollment if adverse events predominate.  In addition, the DSMC assesses study 
1310 
data, particularly for adverse and/or beneficial effects of treatment.  The DSMC is expected 
1311 
to meet at least every six months and will review all accumulating study data including 
1312 
adverse events.  The SCORE Data Coordinating Center (DCC) will report to the DSMC 
1313 
expeditiously, on a case-by-case basis, specific adverse events described in the DSMC 
1314 
Standard Operating Procedure document.  In addition, the DSMC will review early safety 
1315 
data on patients from the SCORE Study and from the Diabetic Retinopathy Clinical 
1316 
Research Network (DRCR.net) study on intravitreal triamcinolone and diabetic macular 
1317 
edema.  Both studies are served by the same DSMC and both studies will use the same drug 
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formulation.  The SCORE Study will not proceed if there are any serious concerns 
1319 
identified with the formulation or the injection procedure.  The monitoring plan that the 
1320 
DSMC will follow is: 
1321 
• An initial report will include the day 4 follow-up data from the first 5 patients 
1322 
(combined in the DRCRnet and SCORE studies) who receive an intravitreal 
1323 
triamcinolone injection.  No additional patients will receive an intravitreal 
1324 
injection until these data have been obtained and it is clear that there are no 
1325 
immediate safety concerns. 
1326 
• A second report will be compiled after 5 patients have completed the 4-week post 
1327 
injection exam.  It will include the 4-day data on a second group of 5 patients. 
1328 
Note: no more than 10 patients will receive intravitreal injections until the first 5 
1329 
patients have completed at least 4 weeks of follow up.  Thereafter, assuming that 
1330 
there have not been any unexpected consequences of the injections, enrollment 
1331 
will be opened to all sites. 
1332 
• A third report will be compiled after 10 patients who receive an intravitreal 
1333 
triamcinolone injection have completed the 4-week post injection exam. 
1334 
Thereafter, assuming that there have been no safety concerns, the data will be reviewed 
1335 
on a monthly basis by the DSMC until the committee is comfortable with reviewing the 
1336 
data on a less frequent schedule. 
1337 
 
1338 
5.2 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters 
1339 
Each clinical site is responsible for reporting all adverse events, including toxicities, that 
1340 
occur to SCORE participants enrolled at their site, regardless of relatedness to study 
1341 
therapy or procedure.  Reporting of all adverse event data is expected upon recognition. 
1342 
 
1343 
Serious adverse events (SAEs), as defined in Section 5.3.1.2 must be reported to the 
1344 
SCORE DCC within 24 hours of recognition.  Study investigators must report serious 
1345 
adverse events to their local ethics review committee (or IRB) promptly in accordance with 
1346 
local regulations or policies in addition to the SCORE DCC.  The SCORE DCC may 
1347 
request additional information regarding adverse events from investigators following their 
1348 
initial review. 
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1350 
5.3 Procedures for Reporting Adverse Events  
1351 
Clinical sites are required to report all adverse events via the SCORE electronic data 
1352 
capture system (AdvantageEDCSM).  Each site will receive training on reporting 
1353 
requirements.  Electronic forms that are designed to collect adverse event data will be 
1354 
available for input at any time, including between scheduled visits. 
1355 
 
1356 
When a reported adverse event is determined to be serious, unexpected, and to have a 
1357 
reasonable possibility to be related to the test product or procedure, or otherwise reportable 
1358 
to regulatory agencies or drug manufacturers, the SCORE DCC will prepare an initial 
1359 
report as described below.  Cumulative reports of other adverse events not considered 
1360 
serious will also be prepared by the SCORE DCC and reviewed by the Medical Monitor on 
1361 
at least a monthly basis, and by the DSMC on a routine basis at least semi-annually. 
1362 
 
1363 
5.3.1 Routine SCORE DCC Review 
1364 
The SCORE DCC Medical Monitor will be provided relevant material in order to 
1365 
assess whether there are safety concerns that may require expedited reporting to the 
1366 
FDA, DSMC, local ethics committee (or IRB), study investigators, the pharmaceutical 
1367 
manufacturer, or the study sponsor (National Eye Institute).  A report of new adverse 
1368 
events will be reviewed each weekday by the SCORE DCC.  Other data are reviewed 
1369 
weekly by the SCORE DCC. 
1370 
 
1371 
5.3.1.1 Definition of Adverse Event 
1372 
An adverse event (AE) is defined as any untoward medical occurrence in a 
1373 
patient or clinical investigation subject administered a pharmaceutical product 
1374 
and that does not necessarily have a causal relationship with this treatment.  An 
1375 
adverse event can therefore be any unfavorable and unintended sign (including 
1376 
an abnormal laboratory finding), symptom, or disease temporally associated 
1377 
with the use of a medicinal (investigational) product, whether or not related to 
1378 
the medicinal (investigational) product. 
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• Unexpected Adverse Drug Reaction – An adverse reaction, the nature or 
1380 
severity of which is not consistent with the applicable product 
1381 
information (e.g. Investigator’s Brochure for an unapproved 
1382 
investigational product or package insert / summary of product 
1383 
characteristics for an approved product.). 
1384 
 
1385 
Throughout the study, all adverse events must be recorded in the 
1386 
AdvantageEDC, regardless of the severity or relationship to study medication or 
1387 
procedure.  If an adverse event is caused by a combination of treatment and 
1388 
disease, the adverse event should be graded as it is observed.  Early in the 
1389 
development of a therapy, when little is known about the therapy’s safety 
1390 
profile, it is especially important to maintain a high level of suspicion and report 
1391 
adverse events that may be treatment-related adverse events.  This reporting may 
1392 
facilitate identification of idiosyncratic or low frequency treatment-related 
1393 
adverse events. 
1394 
 
1395 
5.3.1.2 Serious Adverse Event (SAE) 
1396 
A serious adverse event (SAE) is defined as any adverse event occurring at 
1397 
any dose that results in any of the following outcomes: 
1398 
a. Death; 
1399 
b. Life-threatening adverse event*; 
1400 
c. In-patient hospitalization or prolongation of existing hospitalization; 
1401 
d. Persistent or significant disability / incapacity; 
1402 
e. Congenital anomaly / birth defect. 
1403 
* Including any adverse drug experience that places the patient or subject, 
1404 
in the view of the investigator, at immediate risk of death from the reaction 
1405 
as it occurred (i.e., it does not include a reaction that, had it occurred in a 
1406 
more severe form, might have caused death). 
1407 
 
1408 
Important medical events that may not result in death, be life-threatening, or 
1409 
require hospitalization may be considered a serious adverse event when, 
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based upon appropriate medical judgment, they may jeopardize the patient 
1411 
or subject and may require medical or surgical intervention to prevent one of 
1412 
the outcomes listed in this definition. 
1413 
 
1414 
5.3.1.3 Expected and Unexpected Adverse Event 
1415 
All adverse events, be they routine or serious, will be classified as either 
1416 
expected or unexpected.  Any adverse therapeutic experience that is associated 
1417 
with the study therapy or procedure and is listed as such in an investigational 
1418 
plan, investigational brochure, protocol or informed consent is an expected 
1419 
event.  In contrast, any adverse therapeutic experience, the specificity or severity 
1420 
of which is not consistent with the investigational plan, investigator brochure, 
1421 
protocol, or informed consent for the therapy is an unexpected event. 
1422 
 
1423 
5.3.2   Adverse Event Severity Grading 
1424 
Severity grades are assigned by the study site to indicate the severity of all adverse 
1425 
experiences.  The SCORE Study has adapted usage of The National Cancer Institute's 
1426 
Common Terminology Criteria for Adverse Events (CTCAE) for application in adverse 
1427 
event reporting.  A copy of the CTCAE system can be found on the SCORE website: 
1428 
(http://www.emmes.com/). 
1429 
 
1430 
The CTCAE provides a term and a grade that closely describes the adverse event.  
1431 
The CTCAE grade for each adverse event should be associated with a severity 
1432 
category:  Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-
1433 
threatening) and Grade 5 (Death).  If the adverse event is not included in the CTCAE, 
1434 
the following general definitions should be used in determining severity: 
1435 
 
1436 
Grade 1   Mild 
 
Transient or mild discomforts (<48 hours), no or minimal 
1437 
medical intervention/therapy required, hospitalization not 
1438 
necessary (nonprescription or single-use prescription 
1439 
therapy may be employed to relieve symptoms, e.g., 
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aspirin for simple headache, acetaminophen for post-
1441 
surgical pain).  Mild adverse effects are an expected 
1442 
consequence of the SCORE protocol used here, and 
1443 
standard supportive therapies (per institutional guidelines) 
1444 
are permitted. 
1445 
Grade 2   Moderate 
Mild to moderate limitation in activity, some assistance 
1446 
may be needed; no or minimal intervention/therapy 
1447 
required, hospitalization possible. 
1448 
Grade 3   Severe  
Marked limitation in activity, some assistance usually 
1449 
required; medical intervention/therapy required, 
1450 
hospitalization possible. 
1451 
Grade 4  Life-threatening Extreme limitation in activity, significant assistance 
1452 
required; significant medical/therapy intervention 
1453 
required, hospitalization or hospice care probable. 
1454 
Grade 5   Death  
Death. 
1455 
 
1456 
5.3.3 Relation to Therapy 
1457 
The physician acting as the Principal Investigator at each study site or his/her 
1458 
physician designee should make the determination of therapy-relatedness of an 
1459 
adverse experience.  A therapy-related determination must be made for every adverse 
1460 
event, regardless of severity or event type (routine AE or SAE).  A causal relationship 
1461 
is present if a determination is made that there is a reasonable possibility that the 
1462 
adverse event may have been caused by the study drug. 
1463 
 
1464 
5.3.4 Adverse Event Reporting Requirements and Procedures for Clinical Sites 
1465 
to the SCORE Coordinating Center 
1466 
All adverse events, deaths, infections, and hospitalizations, regardless of severity, 
1467 
expectedness, or potential association with the investigational drug, will be entered on 
1468 
the appropriate form in the AdvantageEDC. 
1469 
 
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5.3.4.1 Requirements 
1471 
Clinical sites are required to enter all known adverse event data from all 
1472 
events into the electronic adverse event form in the AdvantageEDC. 
1473 
 
1474 
Serious adverse events are required to be entered into the AdvantageEDC 
1475 
within 24 hours of recognition.  If all information required on the event form 
1476 
has not been obtained, the site should submit what is available.  Additional 
1477 
information, as it becomes available, can be submitted at a later date. 
1478 
 
1479 
5.3.5 Reporting Procedures 
1480 
For reporting of AEs and SAEs, the Site Coordinator will: 
1481 
1. Complete an Adverse Event form (page 1) in the SCORE data entry 
1482 
system. 
1483 
2. If the site determines that the event is serious, the site will complete, in 
1484 
detail, the Adverse Event Summary (page 2 of the Adverse Event Form). 
1485 
3. The SCORE Medical Monitor will review the Adverse Event Summary 
1486 
and complete an Adverse Event Review form (page 3 of the Adverse 
1487 
Event form). 
1488 
4. If follow-up information is required, the SCORE DCC will contact the 
1489 
site. 
1490 
5. If rapid reporting is required, the SCORE DCC will prepare a MedWatch 
1491 
and forward copies of the completed MedWatch to the SCORE Study 
1492 
Chair and Co-Chair, DSMC Chair, and IND sponsor who will send the 
1493 
MedWatch to the FDA. 
1494 
 
1495 
5.3.6 SCORE Adverse Event Reporting Contact 
1496 
The SCORE Project Director (listed in the Data Management Handbook as well as 
1497 
the current MOPP) may be contacted at the SCORE DCC, The EMMES Corporation, 
1498 
located in Rockville, Maryland.  Be sure to clearly indicate the protocol number and 
1499 
the location of your site when contacting the SCORE DCC.  Back-up personnel and 
1500 
procedures are in place to assure that if the Project Director is not available, other 
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personnel at the SCORE DCC can adequately handle requests or adverse event 
1502 
reporting requirements.  For urgent AE requests that occur after business hours (8:30 
1503 
– 5:00 Eastern Time), contact: 
1504 
Maria Figueroa, MBA, CCRP 
1505 
SCORE Project Director 
1506 
The EMMES Corporation 
1507 
Tel. (240) 344-1935 
1508 
 
1509 
5.4 Procedure for Reporting of Pregnancy 
1510 
At the time a site Principal Investigator or Study Coordinator becomes aware that a study 
1511 
participant has become pregnant during the study, the Principal Investigator or Study 
1512 
Coordinator will prepare a report on the pregnancy to be sent to the SCORE DCC that 
1513 
includes the following elements: 
1514 
• Participant (mother’s) coded study identifier(s); 
1515 
• Date of last menstrual period; 
1516 
• Date of enrollment; 
1517 
• Date(s) of fluorescein angiogram(s); and 
1518 
• Date of last intravitreal injection or laser treatment, if any. 
1519 
 
1520 
Any pregnancy that occurs during the study should be followed until the time of delivery, 
1521 
miscarriage or abortion.  A report with any relevant information on the condition of the 
1522 
fetus or infant at birth should be forwarded to the SCORE DCC, including: 
1523 
• Mother’s coded study identifier(s); 
1524 
• Gestational age at delivery, miscarriage, or abortion; 
1525 
• Birth weight, gender, length, and head circumference, if available; 
1526 
• Apgar scores recorded after birth, if available; 
1527 
• Any abnormalities.  Report all abnormalities as a serious adverse event. 
1528 
 
1529 
6. 
Statistical Considerations 
1530 
6.1 
Scientific and Regulatory Objectives 
1531 
The SCORE Study’s scientific and regulatory objectives are to compare the efficacy and 
1532 
safety of standard care with intravitreal injection(s) of triamcinolone acetonide (4 mg or 1 
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mg) to treat macular edema associated with CRVO and BRVO.  Although scientific goals 
1534 
parallel regulatory goals, regulatory requirements demand some divergence of scientific 
1535 
statistical methods from regulatory statistical methods for testing the null hypothesis of no 
1536 
treatment effect of triamcinolone acetonide.  Section 6.2 describes the formal test to be 
1537 
performed for drug registration, while the remaining sections describe the scientific 
1538 
statistical approach.  The DSMC will be responsible for monitoring the SCORE Study 
1539 
following the scientific plan only. 
1540 
 
1541 
6.2 
Formal Regulatory Statistical Test of Efficacy 
1542 
For regulatory purposes, the SCORE Study will be configured as two separate and 
1543 
independent clinical trials “A” and “B”, each trial to serve as confirmatory of the other.  To 
1544 
accomplish this, clinical sites will be allocated before recruitment commences to either trial 
1545 
“A” or trial “B”, using a method that strives for comparable geographic patterns and 
1546 
distributions of enrollees per center.  Within each trial, CRVO and BRVO disease areas 
1547 
will be pooled for analysis and three primary efficacy analyses performed after no more 
1548 
than one year of follow-up.  A detailed description of the method of assigning sites to Trial 
1549 
“A” and Trial “B” is provided in the SCORE Study Manual of Procedures and Policies 
1550 
(MOPP).  The assignment of sites to Trial “A” and Trial “B” will be made prior to 
1551 
recruitment of subjects.  One analysis will compare 1 mg steroid versus standard care, one 
1552 
will compare 4 mg steroid versus standard care, and one will compare 1 mg versus 4 mg 
1553 
steroid.  The comparison will be with respect to the primary outcome measure.  The 
1554 
primary outcome measure indicates whether or not a study eye of a participant experiences 
1555 
an improvement of 15 or more letters from baseline in best-corrected ETDRS visual acuity 
1556 
score.  The significance of the three comparisons will be obtained by Hochberg’s 
1557 
sequentially rejective procedure, as described in detail in the MOPP, section 6.2.  The 
1558 
overall alpha for the A trial will be no more than 0.05, and similarly for the independent B 
1559 
trial (more specifically, the alpha for each of the “A” and “B” trials will be diminished from 
1560 
0.05 by the amount of alpha previously spent on interim scientific efficacy assessments).  
1561 
Within trial “A” and within trial “B”, an initial analysis of treatment effect will be carried 
1562 
out by logistic regression to determine whether a statistical interaction exists between 
1563 
disease group (BRVO and CRVO) and treatment group (standard care, 4 mg steroid, and 1 
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mg steroid).  A finding of no interaction effect will provide justification for pooling the 
1565 
CRVO and BRVO participants within trial “A” and trial “B” and the primary efficacy 
1566 
analyses for regulatory purposes, as described above, will be carried out by means of 
1567 
logistic regression adjusting for disease area, baseline visual acuity, and center.  A 
1568 
statistically significant interaction effect will require separate primary efficacy analyses for 
1569 
CRVO and for BRVO within trial “A” and with trial “B”. 
1570 
 
1571 
6.3 Scientific Statistical Approach 
1572 
6.3.1 
Two Independent Clinical Trials 
1573 
The SCORE Study consists of two separate independent clinical trials - one for 
1574 
CRVO and one for BRVO.  Each of these clinical trials has its own overall Type I 
1575 
error (alpha) = .05. 
1576 
 
1577 
6.3.2 
Three Primary Questions in Each Clinical Trial 
1578 
Each of these clinical trials asks three questions.  One question is the comparison of 
1579 
standard care to 4 mg intravitreal injection(s) of triamcinolone acetonide.  A second 
1580 
question is the comparison of standard care to 1 mg intravitreal injection(s) of 
1581 
triamcinolone acetonide.  The third question compares 1 mg to 4 mg intravitreal 
1582 
injections.  Within each clinical trial, the significance of the comparisons will be 
1583 
obtained by Hochberg’s sequentially rejective procedure using an alpha level of 0.05 
1584 
(see the MOPP, section 6.4).  
1585 
6.3.3 
Primary Efficacy Outcome Measure and Time Point 
1586 
Improvement by 15 or more letters from the randomization visit visual acuity to the 
1587 
12-month follow-up visual acuity is the primary efficacy outcome measure.  Visual 
1588 
acuity is to be measured using E-ETDRS visual acuity testing. 
1589 
 
1590 
6.3.3.1 
Primary Efficacy Analysis Method 
1591 
The three treatment comparisons (1 mg versus standard care, 4 mg versus 
1592 
standard care, and 1 mg versus 4 mg) will be made by means of logistic 
1593 
regression adjusting for baseline visual acuity, clinical site, and presence of 
1594 
baseline macular hemorrhage in participants with BRVO. The test statistic 
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will be compared to the critical value of the efficacy monitoring guideline 
1596 
(section 6.7.2).  Family-wise error will be controlled at no more than 0.05 by 
1597 
Hochberg’s sequentially rejective method, modified for interim monitoring as 
1598 
specified in the MOPP. 
1599 
 
1600 
The analysis will be on the basis of intent to treat (ITT), treating missing 
1601 
observations as missing completely at random [i.e., missing data from study 
1602 
participants will be dropped from the analysis and noncompliance (or 
1603 
treatment crossover) ignored].   
1604 
 
1605 
6.3.3.2 
Additional Analysis Methods for Consistency of Primary 
1606 
Efficacy Result 
1607 
We will investigate two other ITT variants: (1) last-observation-carried-
1608 
forward (LOCF) and (2) performing a sensitivity analysis in which outcomes 
1609 
will be assigned to missing eyes so as to explore both the minimum and 
1610 
maximum possible estimates of treatment effects.  A per-protocol analysis, 
1611 
excluded from which will be those study participants who drop out, cross over 
1612 
to another treatment group, or violate the protocol, also will be conducted 
1613 
including only study eyes that have completed 12-month visual acuity data.  
1614 
Logistic regression analysis will be performed to adjust for any potential 
1615 
imbalances in baseline characteristics observed between treatment groups, 
1616 
with the odds ratio used as a measure of increased or decreased risk.  
1617 
Important baseline differences, not necessarily based on tests of statistical 
1618 
significance, will be investigated as to their ability to confound the association 
1619 
between the treatment groups and the primary outcome.  Although the intent-
1620 
to-treat analysis described in section 6.3.3.1 is considered to be the definitive 
1621 
analysis, these additional analyses (e.g. other ITT variants, per-protocol) will 
1622 
be used to explore the consistency of the result and provide more information 
1623 
as to the benefit or lack of benefit of the treatment. 
1624 
 
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6.4 Assumptions for and Result of Sample Size Estimation 
1626 
6.4.1 Study Power 
1627 
The study power is set for each trial at 80%.   
1628 
 
1629 
6.4.2 Estimate of CRVO Primary Efficacy Outcome in the Standard Care Group 
1630 
The Central Vein Occlusion Study (CVOS) demonstrated that in participants with 
1631 
macular edema for more than 3 months secondary to a CRVO, macular grid laser 
1632 
photocoagulation, as compared to no treatment, did not improve visual acuity.4 There 
1633 
were no significant differences between treated and untreated participants in either 
1634 
level of visual acuity or change in visual acuity across all follow-up visits.  The data 
1635 
from the CVOS demonstrate that at 2 years from baseline 18% of treated eyes (10 of 
1636 
57 eyes) and 11% of untreated eyes (6 of 53 eyes) experienced a gain of three or more 
1637 
lines of visual acuity.  At 1 year, approximately 6% in both the treated and untreated 
1638 
eyes showed a gain of three or more lines of visual acuity.  From these data, it is 
1639 
conservatively estimated that approximately 15% of untreated eyes with CRVO will 
1640 
experience a gain of three or more lines of visual acuity at 1 year. 
1641 
 
1642 
6.4.3 Estimate of BRVO Primary Efficacy Outcome in the Standard Care Group 
1643 
In the Branch Vein Occlusion Study (BVOS), macular grid laser photocoagulation 
1644 
was demonstrated to be effective in improving visual acuity in some eyes with BRVO 
1645 
complicated by macular edema.1 Treatment resulted in a two or more line 
1646 
improvement in visual acuity for two or more consecutive visits in approximately 
1647 
45% of eyes at the 2-year follow-up.  At one year, approximately 20% of treated eyes 
1648 
gained two or more lines of visual acuity at two or more consecutive visits.  Patients 
1649 
in the BVOS all had absence of dense macular hemorrhage before enrollment.  In the 
1650 
SCORE Study, we anticipate as many as 50% of participants may have a dense 
1651 
macular hemorrhage at enrollment and therefore will have grid laser treatment 
1652 
postponed until the hemorrhage clears to permit treatment.  It is uncertain how the 
1653 
inclusion of these eyes will affect efficacy in the standard care arm of the SCORE 
1654 
study.  From these data, it is conservatively estimated that approximately 35% of 
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standard care eyes will experience a gain of three or more lines of visual acuity at 1 
1656 
year. 
1657 
 
1658 
6.4.4 Background Information on Efficacy of Intravitreal Injection(s) of 
1659 
Triamcinolone Acetonide 
1660 
In Table 4, we provide outcomes of treatment with intravitreal steroid injections 
1661 
based on six published reports of case series.  Data concerning diabetic macular 
1662 
edema (DME) are included because of the similarity (VEGF related vascular 
1663 
permeability) between DME and macular edema due to retinal vein occlusion. 
1664 
Table 4 
1665 
 
 
# of 
eyes 
treated 
 
Disease 
 
Dose 
(mg) 
 
Anatomical 
improvement 
 
Mean baseline 
visual acuity 
 
Mean visual 
acuity at 
endpoint 
 
Follow-
up 
(mos) 
 
Martidis33 
 
16 
 
DME 
 
  4 
 
11/16 (69%) 
 
20/200 
 
20/80 
 
3 
 
Jonas41 
 
26 
 
DME 
 
25 
 
21/21 (FA) 
 
20/160 
 
20/100 
   
6.6 
 
Jonas37 
 
  2 
 
CRVO 
 
25 
 
2/2 (100%) 
 
20/160 
 
20/125 
 
3 
 
Greenberg35 
 
  2 
 
CRVO 
 
  4 
 
2/2 (100%) 
 
20/400 
 
20/160 
   
4.5 
 
Ip36 
 
  2 
 
CRVO 
 
  4 
 
1/2 (50%) 
 
20/200 
 
20/100 
 
6 
 
Park38 
 
10 
 
CRVO 
 
4 
 
10/10 (100%) 
 
20/80 
 
20/32 
 
4.8 
 
1666 
Except for Park et al,38 the six case series above did not use standardized methods to 
1667 
measure visual acuity.  However, all six studies indicate a high likelihood of 
1668 
significant visual acuity improvement for treatment of macular edema with 
1669 
intravitreal triamcinolone acetonide.  The report by Martidis33 showed 11 of 16 
1670 
DME eyes (69%) having a 3-line improvement in visual acuity at the last follow-up 
1671 
visit for each eye, which was either 3 or 6 months after the intravitreal injection.  
1672 
Park et al38 showed that 7/10 (70%) had a 3 or more line improvement after a mean 
1673 
of 4.8 months follow up.  Further, unpublished data (Martidis et al and Ip et al), 
1674 
some of which were presented at the 2002 Retina Congress (San Francisco, CA), 
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provide additional evidence of the efficacy of this treatment for macular edema 
1676 
secondary to retinal vein occlusion and diabetic macular edema.  Martidis et al, at 
1677 
the 2002 Retina Congress, reported additional information on efficacy for DME: 
1678 
73/125 (58%) had a two or more Snellen line improvement at an average follow-up 
1679 
of 6.7-months.  For BRVO with prior laser treatment, 6/13 (46%) had a three or 
1680 
more Snellen line improvement at 6 months.  Ip et al, at the 2002 Retina Congress, 
1681 
reported additional information on efficacy for CRVO (three Snellen line 
1682 
improvement): 3/8 (38%) had a three or more Snellen line improvement at 6 
1683 
months.   
1684 
 
1685 
6.4.4.1 
Estimate for CRVO Primary Efficacy Outcome in the 
1686 
Intravitreal Injection(s) Groups 
1687 
For CRVO eyes, our projected rate of improvement of 15 or more letters at 
1688 
one year is 30% in the 1 mg and in the 4 mg injection group.   
1689 
 
1690 
6.4.4.2 
Estimate for BRVO Primary Efficacy Outcome in the 
1691 
Intravitreal Injection(s) Groups 
1692 
For BRVO eyes in the SCORE Study, in which all eyes will not have had prior 
1693 
laser treatment, we expect efficacy for eyes receiving intravitreal injection(s) 
1694 
of triamcinolone to be higher, and project 53% will have an improvement of 
1695 
15 or more letters at 1 year in the 1 mg and in the 4 mg group. 
1696 
6.4.5 Sample Size Estimate 
1697 
The sample size estimate (number per group) was computed assuming the efficacy in 
1698 
the two steroid doses are the same.  If the efficacy in the 4 mg group is higher than the 
1699 
1 mg group, and given the other preceding assumptions, the study power will be 
1700 
higher for the standard care versus 4 mg comparison.  This was considered important 
1701 
because the 4 mg dose is the basis for all available information. 
1702 
 
1703 


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Sample Size Estimate 
1704 
 
 
Type I error (alpha) = .025, study power = 80% 
1705 
 
 
 
 
 
CRVO  
 
BRVO 
1706 
 
 
Standard care  
15% 
 
 
35% 
1707 
 
 
1 mg or 4 mg  
30% 
 
 
53% 
1708 
 
 
N per group 
 
147 
 
 
147 
1709 
The allocation ratio will be 1:1:1 for standard care: 1 mg: 4 mg.  The number per 
1710 
group has been increased by 10% to allow for some missing data at 12 months 
1711 
(number per group=162).  Thus, the total sample estimate for the CRVO trial is 486 
1712 
(3 times 162) and for the BRVO trial the total sample estimate is 486 (3 times 162).   
1713 
 
1714 
6.5 Safety Outcomes 
1715 
Safety outcomes that will be assessed include serious adverse events and specific ocular 
1716 
events requested by the Data and Safety Monitoring Committee.  The SCORE Study DCC 
1717 
and DSMC will continuously monitor the following safety indicator variables: 
1718 
• Cataract 
1719 
• IOP exceeding 35 while on maximal medical therapy 
1720 
• Filtration surgery to lower IOP 
1721 
• Non-infectious endophthalmitis 
1722 
• Any of: infectious endophthalmitis, retinal detachment, vitreous hemorrhage, loss of 
1723 
20 ETDRS letters at 4 days or 4 week post injection, a new-onset retinal arterial 
1724 
occlusion, a transition from a branch to a central retinal vein occlusion, a new, 
1725 
clearly independent branch retinal vein occlusion, or anterior ischemic optic 
1726 
neuropathy. 
1727 
Table 5 indicates the precision with which the SCORE Study will be able to estimate rates 
1728 
of safety events at the end of the trial.  Three sample sizes are provided in Table 5: 
1729 
• N=162: within each study arm. 
1730 
• N=324: pooling the 1 mg and 4 mg intravitreal injection arms within CRVO or 
1731 
BRVO disease area OR pooling the 1 mg or 4 mg intravitreal injection arm across 
1732 
each disease area. 
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• N=648: pooling the 1 mg and 4 mg intravitreal injection arms across each disease 
1734 
area. 
1735 
For example, if the true rate is 0.25 and the sample size is 162, the 10% quantile for the 
1736 
lower 95% confidence limits is 0.15, and the 90% quantile for the upper 95% confidence 
1737 
limit and half-width are 0.36 and 0.07, respectively. 
1738 
 
1739 
Table 5:  90% limits for 95% confidence intervals of rates of safety events,  
1740 
as a function of the true rate p and the sample size N 
1741 
 
1742 
 
N=162 
N=324 
N=648 
P 
Lower 
CL 
Upper 
CL 
Half 
width 
Lower 
CL 
Upper 
CL 
Half-
width 
Lower 
CL 
Upper 
CL 
Half-
width 
0.01 
0.00 
0.05 
0.02 
0.00 
0.04 
0.02 
0.00 
0.03 
0.01 
0.03 
0.00 
0.09 
0.04 
0.01 
0.07 
0.02 
0.01 
0.06 
0.02 
0.05 
0.01 
0.13 
0.04 
0.02 
0.10 
0.03 
0.03 
0.08 
0.02 
0.1 
0.03 
0.19 
0.05 
0.05 
0.16 
0.04 
0.06 
0.14 
0.03 
0.15 
0.07 
0.25 
0.06 
0.09 
0.22 
0.04 
0.11 
0.20 
0.03 
0.25 
0.15 
0.37 
0.07 
0.18 
0.33 
0.05 
0.20 
0.31 
0.03 
0.5 
0.37 
0.63 
0.08 
0.41 
0.59 
0.06 
0.44 
0.57 
0.04 
 
1743 
6.6 Secondary Efficacy Outcomes 
1744 
Secondary efficacy outcomes will be analyzed by comparing each triamcinolone group (4 
1745 
mg or 1 mg) to standard care as well as by comparing 4 mg vs 1 mg intravitreal 
1746 
triamcinolone for the secondary efficacy outcome variables listed below.  The secondary 
1747 
efficacy outcomes include the following: 
1748 
• Change between baseline and each efficacy outcome assessment visit in best-
1749 
corrected ETDRS visual acuity score (e.g., mean change from baseline in visual 
1750 
acuity, distribution of change from baseline in visual acuity based on clinically 
1751 
meaningful cut points of improvement or worsening of visual acuity). 
1752 
• Change in calculated retinal thickening as assessed by optical coherence 
1753 
tomography. 
1754 
• Change in retinal thickness at the center of the macula as assessed by stereoscopic 
1755 
color fundus photography. 
1756 
• Change in area of retinal thickening as assessed by stereoscopic color fundus 
1757 
photography. 
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1759 
6.7 Statistical Guidelines for Interim Monitoring by the DSMC 
1760 
6.7.1 Interim Monitoring for Safety 
1761 
The SCORE Study will use repeated confidence intervals to continuously monitor the 
1762 
safety indicator variables mentioned in section 6.5.  Safety rates will be reported 
1763 
separately in the two disease areas, but injection arms will be pooled to increase 
1764 
accuracy of the estimates.   
1765 
 
1766 
6.7.2 Interim Monitoring for Efficacy 
1767 
The primary efficacy outcome occurs at 12 months from the randomization visit.  The 
1768 
recruitment pattern is unpredictable.  Information concerning the primary outcome 
1769 
will accrue as participants complete their 12-month visit and thus "information time" 
1770 
is the percent of the 486 patients in each trial expected to have completed this visit. 
1771 
 
1772 
Of the Type I error (alpha) = .05 for each trial, alpha = 0.005 will be allocated for 
1773 
interim monitoring and the remaining alpha = 0.045 will be reserved for the final 
1774 
analysis.  With alpha =0.045 for the final analysis, the estimate of the sample size 
1775 
does not need to be increased for interim monitoring.  Interim testing will be carried 
1776 
out using the Lan-DeMets interim monitoring boundary with an O’Brien-Fleming-
1777 
type spending function where at most 0.005 cumulative alpha can be spent prior to the 
1778 
final analysis.  The "height of the hurdle" is highest when the information fraction is 
1779 
smallest and decreases as additional patients complete 12 months.  The "height of the 
1780 
hurdle" can be calculated for each DSMC meeting based on the number of patients 
1781 
expected to have completed the 12-month visit and the alpha spent by previous 
1782 
"looks" by the DSMC.  With the specification that the total alpha for interim 
1783 
monitoring is 0.005, the maximum amount the DSMC can "spend" is 0.005.  If the 
1784 
DSMC looks more often, it will “spend” less per look. 
1785 
 
1786 


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Formally, if t is the information fraction, B(t) is the 2-sided cumulative O’Brien-
1787 
Fleming-type spending function of Lan & DeMets with final value B(1) = 0.005, and 
1788 
S(t) is the two-sided cumulative spending function used by SCORE, then 
1789 
 
( ) for 0
1
( )
0.05 for 
1
B t
t
S t
t
≤<

= 
=

 
1790 
 
1791 
At each interim inspection, the three comparisons will be made using the Lan-DeMets 
1792 
methodology, and the results combined using Hochberg’s sequentially rejective 
1793 
procedure as described in the MOPP, section 6.4. 
1794 
6.7.3 Interim Monitoring for Futility 
1795 
The DSMC will consider futility as well as safety and efficacy.  One method of 
1796 
statistically assessing futility is to use conditional power to estimate the likelihood of 
1797 
statistical significance given the observed efficacy results and various possible 
1798 
choices for the remaining results.   
1799 
 
1800 
6.7.4 Analyses and Results Requested to be Considered Prior to 
1801 
Recommending Early Termination 
1802 
 
1803 
Before recommending early termination, the DSMC will consider: 
1804 
• internal consistency of primary and secondary results 
1805 
• internal consistency of primary and secondary results by subgroups 
1806 
defined by baseline characteristics (e.g. visual acuity categories, categories 
1807 
based on length of history of CRVO or BRVO, and time period of 
1808 
enrollment) 
1809 
• distribution of baseline prognostic factors among the three groups 
1810 
(standard care, 4 mg, 1 mg) 
1811 
• consistency of primary and secondary results across clinical centers and 
1812 
among centers enrolling larger numbers of patients 
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• possible bias in assessment of primary and secondary response variables, 
1814 
particularly visual acuity, given the unmasked implementation of standard 
1815 
care versus intravitreal triamcinolone 
1816 
• possible impact of missing data from missed patient visits for assessment 
1817 
of the primary and secondary response variables 
1818 
• possible differences in concomitant interventions or medications. 
1819 
6.7.5 Study Timeline and DSMC Data Reviews 
1820 
The DSMC will meet to review study data starting in November 2004, and every 6 
1821 
months until 3-year follow-up is concluded on all study participants.  Table 6 depicts 
1822 
the fractions of the population enrolled, with 1 year follow-up, and with 3 year 
1823 
follow-up, assuming that enrollment is constant, starts in August 2004, and takes 18 
1824 
months.  Under this assumption, there will be 10 DSMC meetings.  Formal interim 
1825 
inspection for 1-year efficacy will take place only during the four meetings when the 
1826 
information fraction is nonzero, that is, in November and May of 2005 and 2006. 
1827 
 
1828 
Table 6:  Study Timeline for DSMC Data Reviews 
1829 
 
1830 
Date of DSMC Meeting 
Fraction  
Enrolled 
With 1-year 
follow-up 
With 3-year 
follow-up 
November 2004 
2/9 
 
 
May 2005 
5/9 
 
 
November 2005 
8/9 
2/9 
 
May 2006 
1 
5/9 
 
November 2006 
 
8/9 
 
May 2007 
 
1 
 
November 2007 
 
 
2/9 
May 2008 
 
 
5/9 
November 2008 
 
 
8/9 
May 2009 
 
 
1 
 
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7. 
Confidentiality and Access to Source Data / Documents 
1832 
The investigators will maintain the highest degree of confidentiality permitted for the clinical and 
1833 
research information obtained from participants in this clinical study.  Medical and research 
1834 
records should be maintained in the strictest confidence.  However, as part of the quality 
1835 
assurance and legal responsibilities of an investigator, the site must permit authorized 
1836 
representatives of the sponsor(s), the SCORE Coordinating Center, and regulatory agencies to 
1837 
examine (and when permitted or required by applicable law, to copy) clinical records for the 
1838 
purposes of quality assurance reviews, audits and evaluation of the study safety and progress. 
1839 
Unless required by the law, no copying of records with personally identifying information will be 
1840 
permitted.  Only the coded identity associated with documents or other participant data may be 
1841 
copied (obscuring any personally identifying information) or transmitted to the SCORE 
1842 
Coordinating Center.  Authorized representatives as noted above are bound to maintain the strict 
1843 
confidentiality of medical and research information that may be linked to identified individuals. 
1844 
The site will normally be notified in advance of monitoring and auditing visits. 
1845 
 
1846 
8. 
Summary of Good Clinical Practice Compliance 
1847 
This trial will be conducted in accordance with Good Clinical Practice (GCP) using the guidance 
1848 
documents and practices offered by ICH and FDA, and in accordance with the Declarations of 
1849 
Helsinki and the policies and procedures for the SCORE Coordinating Center at The EMMES 
1850 
Corporation.  This study will also comply with the regulations under 21 CFR Parts 50, 54, 56, 
1851 
and 312 under an IND application authorized by FDA.  
1852 
 
1853 
8.1 Investigator Responsibilities (Form FDA-1572) 
1854 
A Statement of Investigator (Form FDA-1572) including the names of all of the 
1855 
sub-investigators and selected key study personnel (e.g., pharmacist, study nurse and/or 
1856 
study Coordinator, ophthalmic technician or optometric staff may be listed if desired) 
1857 
directly involved in the study will be completed and signed by the Principal Investigator at 
1858 
each site. The general responsibilities of the Investigator as acknowledged on the Form 
1859 
FDA-1572 are governed under the regulations in 21 CFR Parts 50, 54, 56, 312, and HIPAA. 
1860 
 The study drug or test article may be administered only in accordance with the approved 
1861 
protocol and under the supervision of the Investigator or a sub-investigator listed on this 
1862 


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form.  The Investigator must maintain accurate and complete study records, including 
1863 
records for disposition of the test article, and an accurate and complete record of all 
1864 
submissions made to and received from the local Institutional Review Board (IRB) or 
1865 
Independent Ethics Committee (IEC), including a copy of all reports and documents 
1866 
submitted.  Adverse experiences that are reported to the FDA as IND Safety Reports must 
1867 
be submitted promptly to the local IRB/IEC and the SCORE Coordinating Center. 
1868 
 
1869 
Progress reports must be submitted by the Investigator to the IRB/IEC at least once per 
1870 
year.  The IRB/IEC must be promptly notified of completion or termination of the study.  
1871 
Within three months of study completion or termination, a final report from the Investigator 
1872 
must be provided to the IRB/IEC. 
1873 
 
1874 
The curriculum vitæ (CV) or a résumé for each investigator, sub-investigator, and key study 
1875 
personnel must also be supplied if named on the Form FDA-1572.  This form and related 
1876 
CVs must be supplied to the SCORE Coordinating Center prior to initiating the trial at each 
1877 
site.  When necessary due to personnel changes, updated versions of the Form FDA-1572 
1878 
must be forwarded to the SCORE Coordinating Center and copies of all versions must be 
1879 
maintained in study records at each site.  Any CV or résumé collected at the beginning of a 
1880 
study should be current, and would need to be updated during the study only if substantial 
1881 
changes or additions are warranted (e.g., change of position or affiliation, certifications or 
1882 
licensure, or significant new publications relevant to the study protocol). 
1883 
 
1884 
8.2 Human Subjects Protection 
1885 
8.2.1 Institutional Review Board or Independent Ethics Committee 
1886 
Each participating institution must have an IRB or IEC constituted and operating in 
1887 
accordance with the regulations under 21 CFR Part 56 and authorized by the 
1888 
institution to review and approved materials for this trial.  Because of the use of US 
1889 
Federal funds in this trial, all participating institutions must have a current Assurance 
1890 
of Compliance (either FWA or MPA) regarding their IRB/IEC on file with the DHHS 
1891 
Office of Human Research Protections (OHRP) before any award can be made to that 
1892 


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institution and before participants may be enrolled in the trial.  In addition, each 
1893 
reviewing IRB or IEC must be registered with OHRP.  A list of IRB/IEC voting 
1894 
members, their titles or occupations, and their institutional affiliations, as well as a 
1895 
copy of the Assurance of Compliance, must be kept available by the institution for 
1896 
inspection and copying by authorized study monitors, auditors, and regulatory 
1897 
officials. 
1898 
 
1899 
8.3 Data Handling and Recordkeeping 
1900 
The Principal Investigator at the Participating Clinical Center is responsible for maintaining 
1901 
adherence to study procedures within the clinic.  He or she must spend adequate time at the 
1902 
clinic observing study procedures and must hold regular discussions with staff, either 
1903 
one-to-one or in-group meetings, to review various aspects of the study and to solve 
1904 
problems that may arise.  Other clinic staff members have a responsibility to report to the PI 
1905 
problems that could affect the quality of the data.  The PI will designate one staff member 
1906 
to be the Clinic Coordinator for the clinic, with specific responsibility for reporting 
1907 
problems that have affected or can potentially affect the quality of data collected. 
1908 
 
1909 
The Clinic Coordinator should be thoroughly familiar with clinic activities and equipment 
1910 
and the MOPP.  The Clinic Coordinator should maintain an up-to-date copy of the MOPP 
1911 
close at hand and encourage all clinic personnel to consult it frequently.  During Full Group 
1912 
Meetings the Clinic Coordinators will have the opportunity to meet with the Protocol 
1913 
Monitor to discuss mutual problems. 
1914 
 
1915 
8.3.1 Case Report Forms 
1916 
Clinical data will be entered on electronic Case Report Forms (CRFs) in accordance 
1917 
with the procedures specified in the current MOPP and Data Management Handbook 
1918 
(DMH) for this trial. 
1919 
 
1920 
8.3.2 Data Transmittal 
1921 
The primary method of data transmittal to the SCORE Coordinating Center will be via 
1922 
the secure AdvantageEDC maintained by The EMMES Corporation.  The current 
1923 


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MOPP, DMH and access to the AdvantageEDC are available to authorized users via 
1924 
the SCORE DCC Internet web site, located at http://www.emmes.com/ where an 
1925 
assigned username and password are required for access.  All data transfers between 
1926 
the investigational site and SCORE DCC via the AdvantageEDC are encrypted using 
1927 
SSL technologies to assure confidential data transfer.  
1928 
 
1929 
8.4 Professional Licensure 
1930 
Physicians must provide evidence of current medical licensure applicable to the study 
1931 
location(s) if they are practicing medicine and undertake to diagnose and/or treat 
1932 
participants (including administration of the test article) in this study.  A physician who is a 
1933 
site Principal Investigator must also provide evidence of ophthalmology training before 
1934 
study initiation. 
1935 
 
1936 
8.5 Human Subjects Protection Training 
1937 
Documented training is required for each of the key personnel in the ethical conduct of 
1938 
clinical studies and in the protection of human subjects.  
1939 


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9. 
References 
1. The Branch Vein Occlusion Study Group.  Argon laser photocoagulation for macular 
edema in branch vein occlusion.  Am J Ophthalmol 1984;98:271-282. 
2. Central Vein Occlusion Study Group.  Baseline and early natural history report.  The 
Central Vein Occlusion Study.  Arch Ophthalmol 1993:111:1087-1095. 
3. The Central Vein Occlusion Study Group.  Natural history and clinical management of 
central retinal vein occlusion.  Arch Ophthalmol 1997;115:486-491. 
4. The Central Vein Occlusion Study Group.  Evaluation of grid pattern photocoagulation 
for macular edema in central vein occlusion.  The Central Vein Occlusion Study Group 
M Report.  Ophthalmology 1995;102(10):1425-1433. 
5. Opremcak EM and Bruce RA. Surgical decompression of branch retinal vein occlusion via 
arteriovenous crossing sheathotomy. A prospective review of 15 cases. Retina 1999;19:1-5. 
6. Green WR, Chan CC, Hutchins GM, Terry JM.  Central Retinal Vein Occlusion:  A 
prospective histopathologic study of 29 eyes in 28 cases.  Trans Am Ophthalmol Soc 
1981;79:371-422. 
7. Frangieh GT, Green WR, Barraquer-Somers E, Finkelstein D.  Histopathologic study of 
nine branch retinal vein occlusions.  Arch Ophthalmol 1982;100:1132-1140. 
8. Hockley DJ, Tripathi RC, Ashton N.  Experimental branch vein occlusion in rhesus 
monkeys. III.  Histopathological and electron microscopical studies.  Br J Ophthalmol 
1979;63:393-411. 
9. Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways 
K, Jirousek M, Smith LEH, King GL.  Vascular endothelial growth factor-induced 
retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally 
effective beta-isoform-selective inhibitor.  Diabetes 1997;46:1473-1480. 
10. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW.  Vascular endothelial 
growth factor induces rapid phosphorylation of tight junction proteins occludin and 
zonula occluden 1.  J Biol Chem 1999;274:23463-23467. 
11. Senger DR, Galli SJ, Dvorak AM, Peruzzi CA, Harvey VS, Dvorak HF.  Tumor cells 
secrete a vascular permeability factor (VPF) that promotes accumulation of ascites fluid. 
Science 1983;219:983-985. 
12. Vinores SA, Youssri AI, Luna JD, Chen Y-S, Bhargave S, Vinores MA, Schoenfeld C-
L, Peng B, Chan CH-CH, LaRochelle W, Green WR, Campochiaro PA.  Upregulation 
of vascular endothelial growth factor in ischemic and non-ischemic human and 
experimental retinal disease.  Histol Histopathol 1997;12:99-109. 
13. Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E.  Vascular endothelial growth 
factor upregulation in human central retinal vein occlusion. Ophthalmology 
1998;105:412-416. 
14. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D’Amore 
PA, Miller JW.  Inhibition of vascular endothelial growth factor prevents retinal 
ischemia-associated iris neovascularization in a nonhuman primate.  Arch Ophthalmol 
1996;114:66-71. 
15. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M.  
Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in 
human vascular smooth muscle cells.  Euro J Pharmacol 1998;341:309-315. 


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16. Nauck M, Roth M, Tamm M, Eickelberg O, Wieland H, Stulz P, Perruchoud AP. 
Induction of vascular endothelial growth factor by platelet-activating factor and platelet-
derived growth-factor is downregulated by corticosteroids.  Am J Resp Cell Mol Biol 
1997;16:398-406. 
17. McCuen B, Bessler M, Tano Y, Chandler D, Machemer R.  The lack of toxicity of 
intravitreally administered triamcinolone acetonide.  Am J Ophthalmol 1981;91:785-788. 
18. Schindler RH, Chandler DB, Thresher R, Machemer R.  The clearance of intravitreal 
trimcinolone acetonide.  Am J Ophthalmol 1982;93:415-17. 
19. Scholes GN, O’Brien WJ, Abrams GW, Kubicek MF.  Clearance of triamcinolone from 
vitreous.  Arch Ophthalmol 1985;103:1567-1569. 
20. Folkman J, Ingber DE. Angiostatic steroids.  Ann Surg 1987;206:374-383. 
21. Diaz-Flores L, Gutierrez R, Varela H. Angiogenesis:  an update.  Histol Histopathol 
1994;9:807-843. 
22. Yoshikawa K, Kotake S, Ichiishi A, Sasamoto Y, Kosaka S, Matsuda H.  Posterior sub-
Tenon injections of repository corticosteroids in uveitis patients with cystoid macular 
edema.  Jap J Ophthalmol 1995;39:71-76. 
23. Thach AB, Dugel PU, Flindall RJ, Sipperley JO, Sneed SR.  A comparison of retrobulbar 
versus sub-Tenon’s corticosteroid therapy for cystoid macular edema refractory to topical 
medications.  Ophthalmology 1997;104:2003-2008. 
24. Tano Y, Chandler D, Machemer R.  Treatment of intraocular proliferation with 
intravitreal injection of triamcinolone acetonide.  Am J Ophthalmol 1980;90:810-816. 
25. Machemer R, Sugita G, Tano Y.  Treatment of intraocular proliferations with intravitreal 
steroids.  Tr Am Ophth Soc 1979;77:171-178. 
26. Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL.  The effects of intravitreal 
triamcinolone acetonide on experimental pre-retinal neovascularization.  Graefe’s Arch 
Clin Exp Ophthalmol 1993;231:34-40. 
27. Danis RP, Bingaman DP, Yang Y, Ladd B.  Inhibition of preretinal and optic nerve head 
neovascularization in pigs by intravitreal triamcinolone acetonide.  Ophthalmology 
1996;103:2099-2104. 
28. Jonas JB, Hayler JK, Panda-Jonas S. Intravitreal injection of crystalline cortisone as 
adjunctive treatment of proliferative vitreoretinopathy.  Br J Ophthalmol 2000;84:1064-
1067. 
29. Penfold PL, Gyory JF, Hunyor AB, Billson FA.  Exudative macular degeneration and 
intravitreal triamcinolone.  A pilot study. Aust N Z J Ophthalmol 1995;23:293-298. 
30. Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor ABL, Billson FA.  Exudative 
macular degeneration and intravitreal triamcinolone:  18-month follow-up.  Aust N Z J 
Ophthalmol 1998;26:277-281. 
31. Danis RP, Ciulla TA, Pratt LM, Anliker W.  Intravitreal triamcinolone acetonide in 
exudative age-related macular degeneration.  Retina 2000;20:244-250. 
32. Jonas JB and Sofker A.  Intraocular injection of crystalline cortisone as adjunctive 
treatment of diabetic macular edema.  Am J Ophthalmol 2001;132:425-427. 
33. Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C. 
Intravitreal triamcinolone for refractory diabetic macular edema.  Ophthalmology 
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34. Martidis A, Rogers AH, Greenberg PB, Ip MS, Duker JS, Reichel E, Baumal CR, 
Puliafito CA.  Intravitreal triaminoclone acetonide for refractory diabetic macular edema. 
Invest Ophthalmol Vis Sci (Suppl) 42(4):S741, 2001. 
35. Greenberg PB, Martidis A, Rogers AH, Duker JS, Reichel E.  Intravitreal triamcinolone 
acetonide for macular oedema due to central retinal vein occlusion.  Br J Ophthalmol 
2002;86:247-248. 
36. Ip MS, Kumar KS.  Intravitreous triamcinolone acetonide as treatment for macular edema 
from central retinal vein occlusion.  Arch Ophthalmol 2002;120:1217-1219. 
37. Jonas JB, Kreissig I, Degenring RF.  Intravitreal triamcinolone acetonide as treatment of 
macular edema in central retinal vein occlusion.  Graefe’s Arch Clin Exp Ophthalmol 
2002;240:782-783. 
38. Park CH, Jaffe GJ, Fekrat S.  Intravitreal triamcinolone in eyes with cystoid macular 
edema associated with central retinal vein occlusion. Am J Ophthalmol 2003;136:419-425. 
39. Wingate RJ, Beaumont PE.  Intravitreal triamcinolone acetonide and elevated intraocular 
pressure.  Aust NZ J Ophthalmol 1999;27:431-432. 
40. Jonas JB, Hayler JK, Sofker A, Panda-Jones S.  Regression of neovascular iris vessels by 
intravitreal injection of crystalline cortisone. J Glaucoma 2001:10:284-287. 
41. Jonas JB, Kreissig I, Sofker A, Degenring RF.  Intravitreal injection of triamcinolone for 
diffuse diabetic macular edema.  Arch Ophthalmol 2003:121:57-61. 
42. Bergh F.  Binding characteristics of the glucocorticoid receptor in peripheral blood 
lymphocytes in multiple sclerosis. J. Neurol 1999;246:292-8. 
43. Schottelius A. Higher expression of glucocorticoid receptor in peripheral mononuclear 
cells in inflammatory bowel disease. Am J Gastroenterol 1994; 95:2000. 
44. Armaly MF.  Statistical attributes of the steroid hypertensive response in the clinically 
normal eye.  Invest Ophthalmol Vis Sci 1965;4:187-197. 
45. Becker B.  Intraocular pressure response to topical corticosteroids. Invest Ophthalmol Vis 
Sci 1965;4:198-205. 
46. Goldberg I.  Ocular inflammatory and corticosteroid-induced glaucoma. In Ophthalmology 
(eds. Yanoff M and Duker JS). pp.12.17.1-12.17.6. Mosby International Ltd., London, UK 
1999. 
47. Cumming RG, Mitchell P, Leeder SR.  Use of inhaled corticosteroids and the risk of 
cataracts.  New Engl J Med 1997;337:8-14. 
48. Butcher JM. Austin M, McGalliard, Bourke RD. Bilateral cataracts and glaucoma 
induced by long term use of steroid eye drops.  BMJ 1994;309:43.  
49. Garbe E, Suissa S, LeLorier J.  Association of inhaled corticosteroids use with cataract 
extraction in elderly patients.  JAMA 1998;280:539-543. 
50. Aaberg TM Jr, Flynn HW Jr.  Nosocomial postoperative endophthalmitis. Invest Ophthalmol 
Vis Sci 1996; 37: S775. 
51. Endophthalmitis Vitrectomy Study Group. Results of the endophthalmitis vitrectomy 
study. Arch Ophthalmol 1995;113:1479-1496. 
52. Hida T, Chandler D, Arena J, Machemer R.  Experimental and clinical observations of 
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1986; 101:190-195.  


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53. Musch DC, Lichter PR, Guire KE, Standardi CL and the CIGTS Study Group.  The 
Collaborative Initial Glaucoma Treatment Study, Study Design, Methods, and Baseline 
Characteristics of Enrolled Patients.  Ophthalmology 1999;106:653-662. 
 


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10. Appendix I 
 


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Appendix 1:  Scheduled Study Evaluations 
 
Baseline 
4-month interval follow-up visits 
Safety2 
M4 
M8 
M12 
M16 
M20 
M24 
M28 
M32 
M36 
D4 
M1 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy test 
X3 
 
 
 
 
 
 
 
 
 
 
 
Medical/ocular 
history 
X3 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
X3 
 
 
X 
 
 
X 
 
 
X 
 
 
Visual acuity 
X4,5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X7 
X7 
Manifest 
refraction 
X5 
X5 
 
X5 
 
 
X5 
 
 
X5 
 
 
IOP 
X3,5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X7 
X7 
Ophthalmic 
examination8 
X3,5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X7 
X7 
Lens 
assessment9 
X3,5 
X5 
 
X5 
 
 
X5 
 
 
X5 
 
 
Fundus photos 
 
 
 
 
 
 
 
 
 
 
 
 
Study Eye 
M7F3 
M3F 
M3F 
M7F 
M3F 
M3F 
M7F 
M3F 
M3F 
M7F 
 
 
Non-study Eye 
M3F3 
 
 
M3F 
 
 
M3F 
 
 
M3F 
 
 
FA 
X3 
X 
 
X 
 
 
X 
 
 
 
 
 
OCT 
X5,10 
X5 
X6 
X5 
X6 
X6 
X5 
X6 
X6 
X5 
 
 
Steroid 
injection 
/Laser1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
M= month 
 
 
 M7F= Modified 7-Field photos 
Q= every 
 
 
 M3F= Modified 3-Field photos 
D= day 
 
1 
Retreatment with steroid injections or laser photocoagulation (if applicable) should be administered at 4-month intervals 
unless there are specific reasons not to treat in which case the investigator may decide to postpone treatment (see protocol 
section 4.8.3). 
2 
Safety visits are performed at Day 4 and Month 1 after each injection. 
3 
To be performed within 21 days prior to randomization.  
4 
To be performed within 8 days prior to randomization  
5 
Examination data to be collected on both eyes. 
6 
Examination data to be collected on study eye only. 
7 
Examination data to be collected on the injected eye only. 
8 
Examination includes both a dilated fundus examination and a slit-lamp examination. 
9 
To be performed using the modified AREDS lens grading system. 
10 
OCT measurements will be performed twice on the same day in both eyes.  This will occur within 21 days prior to 
randomization. 
 
Note:  Visit windows at M8, M16, M20, M28, M32 may be extended, if necessary, so that the visit 
occurs no sooner than 3.5 months from the last treatment. 

ICF_001.pdf: 
SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
1
INFORMED CONSENT:  The Standard Care versus COrticosteroid for REtinal Vein 
Occlusion (SCORE) Study  
 
 
TITLE OF PROJECT: The Standard Care versus COrticosteroid for REtinal Vein Occlusion 
(SCORE) Study: Two Randomized Trials to Compare the Efficacy and Safety of Intravitreal 
Injection(s) of Triamcinolone Acetonide with Standard Care to Treat Macular Edema: One for 
Central Retinal Vein Occlusion and One for Branch Retinal Vein Occlusion 
 
PURPOSE OF THE STUDY 
Request to participate: 
You are being asked to participate in this research study because you have macular edema 
(swelling in the center of the retina) from a blockage in a retinal vein (a retinal blood vessel): 
either a central retinal vein occlusion (CRVO) (a blockage in a larger retinal blood vessel) or 
branch retinal vein occlusion (BRVO) (a blockage in a smaller retinal blood vessel).  The study 
is designed to find out if injection(s) of steroid into the eye are safe and effective in the treatment 
of macular edema compared to standard treatment. 
 
Triamcinolone acetonide is a steroid approved by the United States Food and Drug 
Administration (FDA) for injection into joints and muscles for treatment of inflammatory 
conditions. Triamcinolone acetonide works by reducing inflammation (swelling).  Triamcinolone 
acetonide has not been approved by the FDA for use in the eye, and is considered an 
investigational drug when used to treat macular edema (eye disease). 
 
Several thousand patients have received injections into the eye of a preparation of triamcinolone 
acetonide called Kenalog.  Kenalog is not made to use in the eye.  Use of Kenalog has been 
associated with eye inflammation in some patients and it is believed that this may be because 
there are preservatives along with the triamcinolone acetonide in the Kenalog preparation.  The 
preparation of triamcinolone acetonide being used in the study is specially made for injection 
into the eye and does not contain any preservatives. 
 
 
Your participation in this study is voluntary.  The study procedures and the possible risks, 
discomforts and benefits of participation are described below.  Please read the information 
carefully and discuss any questions you have with your doctors before you decide whether or not 
to participate. 
 
If you choose to participate in this study, you must sign this form, which includes your 
authorization for the use and disclosure of your health information that is collected as part of 
your participation in this study.  If you do not provide permission for the use and disclosure of 
your health information, you will not be able to participate in this study. 
 
Background: 
The retina is a part of the eye that is similar to the film in a camera and produces images for the 
brain to understand.  The macula is the part of the retina that you use to read or see fine detail. 
Retinal veins drain blood away from the retina back to your heart.  A blockage in one of the large 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
2
retinal veins (central retinal vein occlusion - CRVO) or smaller retinal veins (branch retinal vein 
occlusion - BRVO) can result in fluid in the center of the retina (macular edema).  This can result 
in decreased vision in that eye.  Injecting a steroid directly into your eye may improve the vision 
in your eye, but also carries risks.  This study is being done to compare the risks and benefits of 
this treatment. 
 
If the vision loss is due to fluid in the retina associated with CRVO, laser treatment has not been 
shown to improve the vision.  No other proven treatments are available to try to improve the 
vision.  In some cases, vision may improve without treatment over many months to years.  If you 
have a CRVO, standard care consists of observation of the fluid in the retina as well as 
monitoring the eye for the development of other complications such as increased eye pressure or 
the growth of abnormal blood vessels which may require treatment.  For patients with CRVO, 
this study is designed to find out if injection(s) of steroid into the eye is safe and if this can lead 
to improved vision compared with patients with CRVO who receive standard care (observation).  
 
If the vision loss is due to fluid in the retina associated with BRVO, laser treatment alone has 
been proven to help restore the vision in some patients.  However, despite laser treatment, there 
are some patients who do not experience an improvement in vision and improved treatments for 
this condition need to be developed.  If you have a BRVO, standard treatment consists of laser 
treatment to the retina if excessive blood is not present in the retina along with fluid in the retina 
(macular edema).  If excessive blood is present in the retina, standard treatment consists of 
observation until enough blood has been reabsorbed so that laser treatment can be performed.  
For patients with BRVO, this study is designed to find out if injection(s) of steroid into the eye is 
safe and if this can lead to improved vision compared with patients with BRVO who receive 
standard care (observation or laser treatment to the retina, depending on how much blood is 
present in the retina). 
 
Purpose: 
The purpose of this study is to find out if injection(s) of triamcinolone acetonide into the eye are 
safe and effective in the treatment of macular edema in eyes with central retinal vein occlusion 
(CRVO) or branch retinal vein occlusion (BRVO) compared to standard treatment. 
 
PROCEDURE 
Approximately 972 people will participate in this study at various medical centers in the United 
States.  There will be at least 12 study visits over a period of up to 3 years if you are assigned to 
a group that is to receive injection(s).  If you are assigned to a standard care group, there will be 
at least 10 study visits over a period of 3 years.  If you are assigned to a group that is to receive 
injection(s) or if you receive laser treatment as part of the standard care group, you may require 
additional visits, depending on whether or not you require additional treatment. 
 
If you agree to participate in this study, you will have some tests to see if you are eligible.  You 
will be asked questions about your medical and medication history, and you will have your blood 
pressure measured.  If you are a woman and can bear children you will be asked to give a urine 
sample to see if you are pregnant.  See Section on Pregnancy and Contraception. 
 
 


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In addition, you will have a complete eye examination for both eyes, including: 
• Visual acuity:  You will be asked to read letters on a special eye chart. 
• Fluorescein angiography:  Fluorescein angiography is a test in which a dye is injected into a 
vein in your arm.  The dye travels throughout the body, including the eyes.  With a camera 
and flashes of light, a series of photographs of the retina is taken as the dye passes through it. 
The photographs will show where and what kinds of changes have occurred in the retina.  
The test takes about 20 minutes. 
• Optical coherence tomography (OCT):  This is a test that uses a light source to examine 
the retina and measure the thickness of the retina.  You will be asked to sit in front of the 
machine and you will be asked by either a technician or photographer to look into a pattern 
of flashing and rotating red and green lights first with one eye then the other.  The procedure 
takes approximately 5 minutes per eye to perform. 
• Eye examination:  An assessment of the cornea, lens, and retina, after dilating drops have 
been administered, will be performed. Also, the pressure in your eyes will be measured. 
 
During some of the eye examinations, fundus photography will be performed.  Fundus 
photography is a procedure in which bright lights will be shone into your eyes and pictures will 
be taken of the back of your eye (retina). 
 
If your study doctor determines that you are eligible for the study, you will be randomly assigned 
(by chance, like the flip of a coin) to receive either injection(s) of triamcinolone acetonide or 
standard treatment.  If you have CRVO, standard treatment is observation.  If you have BRVO 
and an excessive amount of blood in the retina, standard treatment is observation.  If you have 
BRVO and excessive blood is not present in the retina, standard treatment is laser treatment.  
 
If both of your eyes meet the criteria for being part of the study, only one of your eyes will be 
randomly selected to receive either steroid injection(s) or standard treatment.  The other eye 
cannot be entered into the study.   
 
If you are randomized to receive an injection of steroid medication, you will receive one of 2 
doses (4 mg or 1 mg).  This study is designed such that you have a 1 in 3 (33%) chance of 
receiving a steroid injection with the 4 mg dose, a 1 in 3 (33%) chance of receiving a steroid 
medication with the 1 mg dose, and a 1 in 3 (33%) chance of receiving standard treatment. 
During the study period, you will be examined at least every 4 months and, depending on how 
your eye responds to treatment, you may be retreated as often as every 4 months.  Thus, if you 
are randomized to receive steroid injection(s), you may receive an injection as often as every 4 
months.  Similarly, if you have a BRVO that does not have excessive blood present in the retina 
and are randomized to standard treatment, you may receive multiple laser treatments. 
 
Before receiving the injection with triamcinolone acetonide, a local anesthetic (numbing 
medication) will be placed with a cotton tipped applicator into the lower part of your eye in the 
clear tissue that surrounds the white of your eye.  Regardless of the diagnosis of your macular 
edema (CRVO or BRVO), if you are assigned to receive triamcinolone acetonide, after a few 
minutes, the study drug will be injected into your vitreous, which is the jelly-like substance 
inside your eye located between the back of your lens and your retina.  If you are assigned to a 
standard treatment arm, no injection will be given.  If you receive an injection, before leaving, 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
4
your doctor will give you an antibiotic eyedrop to place in your eye for 3 days following the 
injection. 
 
For the laser treatment procedure, if you are assigned to a standard care group and your eye 
doctor determines that laser treatment to the retina may benefit you, 1 or 2 drops of a numbing 
agent are applied to the surface of the eye.  A special contact lens is then placed on the eye 
during the laser beam application.  You will be asked to remain still while the laser beam is 
applied.  Minimal discomfort is anticipated during the laser beam treatment. 
 
If you have BRVO and are assigned to a standard treatment arm, you will receive immediate 
laser treatment unless there is too much blood in the retina to permit laser treatment to be given.  
If your doctor is unable to perform laser treatment at the time you enroll in the study because 
there is too much blood in the retina, you will be observed and laser treatment will be given if the 
blood clears enough to permit application of laser treatment. 
 
If you have CRVO, no laser treatment will be given for macular edema, regardless of your 
assignment to the treatment arms. 
 
Follow-up visits will occur at least every 4 months. The need and timing of additional visits 
depends on your course of treatment.  For example, if you receive an injection, you will also be 
examined within 1 week of each injection and 1 month following each injection.  At each visit, 
your vision will be checked.  Your eyes will be dilated for an eye examination and the pressure 
of your eye measured.  Photographs of your retina will be taken, and OCT will be performed at 
certain study visits. Fluorescein angiography will be performed at Months 4, 12, and 24.  In 
addition, at Months 12, 24, and 36 you will have your blood pressure measured. 
 
RISKS 
Possible risks of the injection include the following: 
1) We anticipate an approximately 100% chance of seeing floaters (things floating around 
inside your eye), which almost always resolve within a few days to weeks. 
2) We anticipate a low chance [estimated at less than 1 in 100 (1%)] of retinal detachment 
(separation of the film-like layer of cells at the back of the eye) which may require 
surgery to treat.  If a retinal detachment occurs and surgery is required, the surgery is 
usually successful.  However, a retinal detachment can produce permanent loss of vision 
and even blindness. 
3) We anticipate a low chance [estimated at less than 1 in 100 (1%)] of vitreous hemorrhage 
(bleeding in the gel inside the eye) which usually resolves within a few weeks.  If it does 
not go away, surgery may be needed to remove the blood.  This surgery is usually 
successful.  However, a vitreous hemorrhage can produce permanent loss of vision and 
even blindness. 
4) We anticipate a low chance [estimated at less than 1 in 100 (1%)] of endophthalmitis 
(infection of an entire eye) which would require treatment with antibiotic injections into 
the eye and possibly surgery.  This treatment is usually successful.  However, 
endophthalmitis can produce permanent loss of vision and even blindness. 
5) Tiny droplets, about the size of the period on this page, have been observed in the 
vitreous cavity following injection of the SCORE Study steroid preparation.  As of 


SCORE Study Informed Consent version 5.0 
 
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5
October 5, 2006, this has been reported in 6 study participants out of 256 study 
participants (2.3%) who have received an intravitreal steroid injection in the study.  
These droplets have been reported before with intravitreal injection of various other 
medications.  The source of the droplets is believed to be silicone oil that is used as a 
lubricant in the syringes and needles employed to deliver the medication.  Silicone oil in 
large amounts is sometimes put into the vitreous during retinal detachment surgery.  The 
amount of silicone oil in the eye after an intravitreal injection is a very tiny amount.  We 
do not have any evidence that droplets of silicone oil are harmful to the eye.  None of the 
participants in the study has reported any problems with their vision or any other 
problems due to the droplets.  It is possible that the droplets could cause you to see 
floaters at certain times depending on the background in your field of view and the 
lighting. 
 
Possible risks associated with triamcinolone acetonide include the following:  
1) We anticipate that many patients will experience cataract (clouding of the lens of the eye) 
after treatment.  We do not know how often a cataract develops from the steroid 
injection.  However, we think there is a good chance that a cataract will develop.  If a 
cataract develops, cataract surgery may be needed.  In most cases, this surgery is 
effective in removing the cataract. 
2) An increase in eye pressure could happen right after the injection or it could happen 
weeks to months later.  If the eye pressure is high right after the injection, eye drops may 
be given to help lower the eye pressure.  If the pressure is still high, fluid may be 
removed from the front part of the eye with a small needle.  If the eye pressure goes up 
after several weeks to months, eye drops may be needed to lower the eye pressure.  If the 
eye drops do not lower the eye pressure, it may be necessary to have surgery to lower the 
eye pressure.  There is an approximately 3 in 10 (30%) chance of increased pressure in 
the eye which is usually reversible and can be treated with medications (e.g. eyedrops) 
but may require surgery.  It is estimated that the chance of requiring surgery to lower eye 
pressure (called trabeculectomy surgery) is less than 1 in 20 (5%). 
 
There may be additional conditions associated with the injection and triamcinolone acetonide 
that are not known at this time. 
 
Fluorescein angiography:  After the orange-colored dye is injected into your arm, your skin 
may turn yellow for several hours.  The yellow color will disappear as your kidney removes the 
dye from your body.  Because the dye passes through your kidneys, your urine will turn dark 
orange for up to 24 hours after the exam.  Some participants may be slightly nauseous (upset 
stomach) during the exam, but their nausea usually lasts only a few seconds, and rarely, some 
may vomit.  There is also a chance of fainting and a chance of bruising (black and blue mark) at 
the site of injection.  If the dye leaks out of your vein during the injection, some of the skin 
around the injection site may feel like it is burning or become yellow.  The burning sensation 
usually lasts only a few minutes, and the yellow color goes away in a few days.  As with any 
drug, it is possible that you could experience an allergic reaction to the dye.  Such allergic 
reactions include: itching, skin rash, an acute or sudden drop in blood pressure to shock levels 
with loss of consciousness and/or associated with seizures, including the possibility of death (the 
risk of death is about 1 in 250,000). 
 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
6
Optical coherence tomography (OCT):  For the OCT, your pupils will be dilated.  Your pupils 
will remain dilated for 4 to 6 hours.  This may result in excess glare in brightly lit areas.  
Sunglasses will reduce this problem.  You should not drive if your vision is impaired. 
 
Risks of eye examination and dilation:  Dilation of your pupils may cause some temporary 
glare and blurring of vision.  Occasionally, there may be an allergic reaction to the medication.  
If this should occur, medication to control the allergic reaction will be administered.  Rarely, 
dilation may cause the pressure in the eye to go up; if this should occur, you will be treated with 
eyedrops and, if necessary, laser surgery. 
 
It is possible that complications and side effects of the study treatment that are unknown at this 
time may occur.  You will be told of any new findings that develop which may affect your 
willingness to continue in the study. 
 
PREGNANCY AND CONTRACEPTION 
Pregnancy:  If you are a woman and can bear children, you will have a urine pregnancy test at 
the beginning of the study.  If you are pregnant, you will not be allowed in the study.  If you 
become pregnant during the study, you must inform the physician or the study coordinator that 
you are pregnant. 
 
Contraception:  The effect of the dye injected for the fluorescein angiography procedure on a 
fetus is unknown.  If you are a woman who is sexually active and can bear children, you or your 
partner must use a reliable form of birth control from the time you enroll in the study until you 
are no longer in the study. 
 
BENEFITS 
It is possible that you may not benefit from your participation in the study.  No direct medical 
benefit to you can be assured from your participation in this study.  As a result of your 
participation, your macular edema may improve; however, this cannot be guaranteed.  If you are 
randomized to a standard treatment arm, no therapy with the study drug will be given and, 
therefore, you will not receive direct benefit from participation in this study.  However, 
information obtained in this study may be of future benefit to both you and other patients with 
macular edema. 
 
ALTERNATIVES 
The information obtained from this study will have no bearing on your medical treatment.  You 
may choose to not participate in this study.  For CRVO there are currently no proven treatments 
available.  For BRVO you may choose to undergo laser treatment if your doctor determines you 
are eligible (for example, if there is not too much blood associated with the fluid in your retina) 
or to receive no treatment at all. 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
7
 
CONFIDENTIALITY& YOUR PROTECTED HEALTH INFORMATION 
(Section Required by the HIPAA Privacy Rule – 45 CFR 164.508) 
 
By signing this form, you are giving permission for the use and disclosure of your health 
information that is collected as part of your participation in this study. 
 
A. What health information about you may be used or disclosed? 
The results of your examinations and testing that are part of this study will be reported to the 
SCORE Data Coordinating Center in Rockville, Maryland along with information from all other 
participants in the study at this and all other participating clinics across the country.  The 
photographs of your eyes, angiograms, and OCTs from your evaluations will be sent to the Fundus 
Photograph Reading Center for this study.  The Fundus Photograph Reading Center is located at the 
Department of Ophthalmology & Visual Sciences at the University of Wisconsin – Madison in 
Madison, WI.  This information will be identified to the SCORE Data Coordinating Center and the 
Fundus Photograph Reading Center only by a code number assigned to you.  Federal privacy 
regulations provide safeguards for privacy, security, and authorized access.  Except where required 
by law and as noted in the paragraph below, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier in study records 
disclosed outside of your eye doctor’s office. 
 
Results of the study will be reported in medical journals and may be presented at scientific 
meetings.  However, at no time will any of the patients in the study be identified in any publication 
or at any meeting.  Confidentiality of your records will be maintained and all records will be kept 
in accordance with current legal requirements.  The research team will discuss the results of your 
tests with you during the study.  You will be informed of the results of the study at the time they are 
made public. 
 
B. Who may use or disclose and see or receive your health information? 
Reviewers of your health information may include representatives of the SCORE Data Coordinating 
Center (Rockville, MD), the Fundus Photograph Reading Center (Madison, WI) and Pharmaceutical 
Partner (Allergan, Inc., Irvine, CA) who are involved in the conduct of the study, the analysis of the 
data and the manufacturing of the study drug, any review board that oversees human investigations 
regulations for your doctor’s office or institution, or any federal agency that oversees the conduct of 
clinical trials.  If your research record is reviewed by any of these groups, they may also need to 
review your entire medical record. 
 
C. Why do they need to see or receive your health information? 
As part of this study, the persons or entities listed above (see paragraph B) may see, receive, or 
use your health information to help conduct the study and/or to evaluate the results.  Your records 
may also be reviewed in order to meet federal or state regulations. 
 
D. Is there an expiration date? 
No.  Your authorization for the use and disclosure of your health information will continue 
indefinitely.  


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
8
 
E. May you stop or cancel your permission for the use and disclosure of your health 
information? 
Yes.  You may stop or cancel your permission for the use and disclosure of your health 
information at any time.  You need only to contact your doctor or one of the medical staff at 
(telephone number) and provide a notice of cancellation to him/her in writing.  However, when 
you stop or cancel your permission for the use and disclosure of your health information, you 
will no longer be part of the study. 
 
When you stop or cancel your permission for the use and disclosure of your health information 
or when you withdraw from the study directly, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an 
adverse event occurs, your entire medical record may need to be reviewed.  All data that have 
already been collected for study purposes up to the time of cancellation or withdrawal, and any 
new information about any adverse event related or potentially related to the study, will be sent 
to the SCORE Data Coordinating Center. 
 
F. Is your health information protected after it has been given to others? 
It is possible that your health information may be given out or disclosed again if the recipients 
named above (see paragraph B) are not required by law to protect the privacy of your health 
information.  The SCORE Study DCC will make very effort to comply with the Privacy 
Regulations as required by law. 
 
FINANCIAL RESPONSIBILITY 
Any costs borne by you that may result from your participation in this study are your 
responsibility.  The triamcinolone acetonide (study drug) will be provided at no cost to you.  All 
other charges associated with your continuing medical care, including the injection procedure (if 
applicable), the traditional laser treatment (if applicable), photography and room charges, will be 
billed to you or your insurance provider in the normal fashion. If you develop a complication as a 
result of participation in this study (e.g. cataract or glaucoma) and require treatment for the 
complication (e.g. cataract surgery or surgery for glaucoma), the cost of the cataract surgery or 
surgery for glaucoma will be billed to you or your insurance provider in the normal fashion.  
 
If you experience an unexpected adverse reaction as a direct result of the study drug being 
administered in this study, your reasonable expenses for medical treatment of such reaction will 
be reimbursed by the drug manufacturer, Allergan, to the extent that these expenses are not 
covered by medical, third party, or government insurance or programs. 
 
In select cases, reimbursement for travel related expenses may be available as need warrants. 
 
COMPENSATION AND INJURY STATEMENT 
If injury occurs due to your involvement in this study, medical treatment will be available.  You 
or your insurance company will be responsible for the costs of this medical care, unless you 
experience an unexpected problem that is a direct result of the new formulation of triamcinolone 
being administered in this study.  If this should occur, your reasonable expenses for medical 
treatment of such reaction will be reimbursed by the drug manufacturer, Allergan, to the extent 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
9
that these expenses are not covered by medical, third party, or government insurance or 
programs.  Compensation for lost wages and/or direct or indirect losses is not available. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL STATEMENT 
You may withdraw from the research study at any time.  Your participation is completely 
voluntary.  You may stop participating at any time, and you may refuse to answer any question if 
you don’t wish to answer.  Even if you do not want to join the study, or if you stop participating 
in it, you will still have the same quality of medical care available to you at the local site.  The 
investigators reserve the right to remove you from the study without your consent at such time 
that they feel it is in your best interest medically or for administrative reasons. 
 
OFFER TO ANSWER ANY QUESTIONS 
In case of a research-related injury, or if you have any questions, please contact Dr. X (Principal 
Investigator) at X (XXX) XXX-XXXX.  You may ask questions in the future if you do not 
understand something that is being done.  If you have any questions regarding your rights as a 
study subject, you may contact the Institutional Review Board administrator (Lesley S. Zajac at 
1-813-975-8690).  You will be given a signed copy of this form to keep.  You will be informed 
of significant new findings that may alter your continued participation in this study. 
 
Subject's Name (printed)  
 
 
 
 
 
 
 
Description of Representative’s Authority to Act for the Study Subject  
__________________________________________________ (if applicable) 
 
AGREEMENT TO HAVE THE TESTING DONE TO SEE IF I AM ELIGIBLE FOR THIS STUDY 
 
By signing below, I agree to have this testing done.  I authorize the use and disclosure of my 
health information collected as part of the eligibility testing. 
 
 
_________________________________________  
 
 
_____________ 
Signature of Subject or Authorized Representative  
 
 
Date 
 
 
_________________________________________  
 
 
_____________ 
Witness 
 
 
 
 
 
 
 
 
Date 
 
APPROVAL DATE 
 
 
 
 
 
Jaeb Center for Health Research 
Institutional Review Board 
JUL 09 2007 


SCORE Study Informed Consent version 5.0 
 
October 6, 2006 
 
10
 
AGREEMENT TO PARTICIPATE IN THIS STUDY 
 
I have read the explanation about this study.  I have been given the opportunity to discuss the 
study and to ask questions.  I hereby give my consent to take part in this study.  I authorize the 
use and disclosure of my health information collected as part of my participation in this study. 
 
 
_________________________________________  
 
 
_____________ 
Signature of Subject or Authorized Representative  
 
 
Date 
 
 
 
_________________________________________  
 
 
_____________ 
Witness 
 
 
 
 
 
 
 
 
Date 
 
 
I have personally explained the research to the subject or the subject’s legally authorized 
representative and answered all questions.  I believe that he/she understands the information 
described in this informed consent and freely consents to participate. 
 
 
______________________________________ 
Signature of person obtaining informed consent 
APPROVAL DATE 
 
 
 
 
 
Jaeb Center for Health Research 
Institutional Review Board 
JUL 09 2007