Conditions: Diabetic Macular Edema Hard Lipid Exudates
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: yes

Brief summary:
This is an open-label, Phase I/II study of intravitreally administered 0.3mg ranibizumab in subjects with diabetic macular edema and lipid exudates in the central subfield.

Detailed description:
This is an open-label, Phase I/II study of intravitreally administered 0.3mg ranibizumab in subjects with diabetic macular edema and lipid exudates in the central subfield.

Consented, enrolled subjects will receive multiple open-label intravitreal injections on 0.3mg ranibizumab administered every 30 days for 12 months per the treatment algorithm.

The patients will be randomized to 1 of 2 treatment groups. Group 1: Treatment algorithm based on the Diabetic Retinopathy Clinical Research (DRCR) protocol I 4:2:7 strategy based on the presence of macular edema.

Group 2: Continue treatment until not only the macular edema is resolved but also until the lipid exudate is resolved.

Sample size: 30 eyes Follow-up Schedule: Every 4 weeks throughout the study.

Arms:
arm 1: Treatment using intravitreal ranibizumab 0.3mg based on the DRCR protocol I 4:2:7 strategy based on the presence of macular edema. arm 2: Continued treatment with intravitreal ranibizumab 0.3mg until, not only the macular edema is resolved, but also until the lipid exudate is resolved.

Interventions: intervention 1: ranibizumab 0.3mg
Intervention descriptions: intervention 1: intravitreally administered

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL 
STUDY TITLE: 	
The effect of visual acuity and hard exudate 
resolution in the treatment of diabetic 
macular edema with center involved edema 
and lipid exudates. Phase I/II 
STUDY DRUG 	
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2 
[ranibizumab]) 0.3mg Lucentis 
SPONSOR 	
South Coast Retina Center; Carson, McBeath, 
Boswell Inc. 
4300 Long Beach Blvd Ste 300, Long Beach CA 
90607 
IND: 	
Insert IND Number 
INVESTIGATOR 	Julie Gasperini, MD 
SUB- 	
Michael Roh, MD; John McBeath, MD; Tom 
INVESTIGATORS 	O'heam MD 
DATE FINAL: 	
December 1st, 2014 
AMENDMENT: 
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TABLE OF CONTENTS 
Page:  
1. 
BACKGROUND 	
 
1.1 
Pathophysiology 	
 
1.2 
Treatment 	
 
1.3 
Ranibizumab 	
 
1.4 
Nonclinical Experience with Ran ibizumab 	
 
1.4.1 	
Nonclinical Pharmacokinetics 	
 
1.4.2 	
Nonclinical Toxicology 	
 
1.4.3 	
Stability Studies 	
 
1.5 
Clinical Experience with Ranibizumab 	
 
2. 
OBJECTIVES 	
 
2.1 
Primary Objective 	
 
2.2 
Secondary Objective 	
 
3. 
STUDY DESIGN 	
 
3.1 
Description of the Study 	
 
3.2 
Rationale for Study Design 	
 
3.3 
Outcome Measures 	
 
3.3.1 	
Primary Outcome Measures 	
 
3.3.2 	
Secondary Outcome Measures 	
 
3.4 
Safety Plan 	
 
3.5 
Compliance with Laws and Regulations 	
 
4. 
MATERIALS AND METHODS 	
 
4.1 
Subjects 	
 
4.1.1 	
Subject Selection 	
 
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TABLE OF CONTENTS (cont'd) 
Page 
4.
MATERIALS AND METHODS (cont'd) 
4.1.2 	
Inclusion Criteria 	
 
4.1.3 	
Exclusion Criteria 	
 
4.2 Method of Treatment Assignment 	
 
4.3 Study Treatment 	
 
4.3.1 	
Formulation 	
 
4.3.2 Dosage, Administration, and Storage 	
 
4.4 Concomitant and Excluded Therapies 	
 
4.5 Study Assessments 	
 
4.5.1 	
Assessments during the Treatment Period 	
 
4.5.2 Early Termination Assessments 	
 
4.5.3 READING CENTER Assessments 	
 
4.6 	
Subject Discontinuation 	
 
41 	
Study Discontinuation 	
 
4.8 	
Statistical Methods 	
 
4.8.1 	
Analysis of the Conduct of the Study 	
 
4.8.2 Safety Analyses 	
 
4.8.3 Efficacy Analyses 	
 
4.8.4 Missing Data 	
 
4.8.5 	
Interim Analyses 	
 
4.9 Data Quality Assurance 	
 
5.
ASSESSMENT OF SAFETY 	
 
5.1 	
Adverse Events 	
 
5.2 Serious Adverse Events 	
 
5.3 Methods and Timing for Assessing and Recording Safety Variables 
5.4 	
Evaluations 	
 
5.5 	
Vital Signs 	
 
5.6 	
Procedures for Eliciting, Recording, and Reporting Adverse Events 	 
5.6.1 	
Eliciting Adverse Events 	
 
5.6.2 	
Specific Instructions for Recording Adverse Events 	
 
5.6.3 Med Watch 3500A Reporting Guidelines 	
 
5.6.4 	
Follow-up Information 	
 
5.6.5 Additional Reporting Requirements for IND Holders 
5.6.6 Safety Reporting Fax Cover Sheet 	
 
• 	
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TABLE OF CONTENTS (cont'd) 
Page 
6. INVESTIGATOR REQUIREMENTS 	
 
6.1 	
Study Initiation 	
 
6.2 	
Study Completion 	
 
6.3 Informed Consent Form 	
 
6.4 	
Institutional Review Board or Ethics Committee Approval 	
 
6.5 Case Report Forms 	
 
6.6 	
Study Drug Accountability 	
 
6.7 	
Disclosure of Data 	
 
6.8 Retention of Records 	
 
6.9 Study Close-Out 	
 
REFERENCES 	
 
APPENDICES 
Appendix A: 	
Study Flowchart 	
 
Appendix B: 	
Pre-Injection Procedures for All Subjects 	
 
Appendix C: 	
Analysis of Similar Events 	
 
• 	
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1. BACKGROUND  
1.1 PATHOPHYS1OLOGY 
Diabetes mellitus affects over 350 million people worldwide and diabetic retinopathy is 
the most common microvascular complication of diabetes. Diabetic macular edema 
(DME) is the leading cause of vision loss in patients with diabetes and affects 30% of 
patients who have had diabetes for at least 20 years. In DME, the disruption of the 
blood-retinal barrier results in accumulation of fluid in the neurosensory retina and the 
formation of lipid-rich extravascular deposits known as hard exudate, resulting in loss 
of central vision. Deposits of hard exudate near the fovea are thought to be 
associated with an increased risk of vision loss. 
The pathophysiology that results in the microvascular damage in DME includes 
the direct toxic effects of hyperglycemia, sustained alterations in cell signaling 
pathways, and chronic microvascular inflammation with leukocyte-mediated 
injury. Chronic retinal microvascular damage results in elevation of intraocular 
levels of vascular endothelial growth factor A (VEGF). VEGF levels correlate with 
the breakdown of the blood retinal barrier and are significantly elevated in the eyes 
with exudative retinal disease such as DME. VEGF mediates many important 
physiologic processes and results in vascular hyperpermeability causing leakage of 
intraretinal fluid resulting in macular edema. Anti-VEGF drugs reduce DME by 
decreasing vascular permeability. 
1.2 TREATMENT OF DIABETIC MACULAR EDEMA 
The historic standard of care for DME was macular laser photocoagulation. Multiple 
studies have now demonstrated that anti-VEGF therapy is more effective than laser 
alone for vision gain and avoiding vision loss in patients with center-involved DME, 
and avoids the ocular side effects associated with laser treatment. Anti-VEGF agents 
such as ranibizumab, bevacizumab, aflibercept, have become the preferred treatment 
option for the management of diabetic macular edema in many patients. 
Studies such as RISE/RIDE demonstrated that intravitreal ranibizumab was superior 
to laser alone. The BOLT study demonstrated that intravitreal bevacizumab was 
superior to laser alone. DRCR protocol I demonstrated that intravitreal ranibizumab 
with either prompt or deferred laser provided superior anatomic and functional 
outcome in individuals with DME through 2 years compared with the previous gold 
standard of laser alone and steroids did not have a similar affect. 
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1.3 RAN IBIZUMAB AND LIPID AND HARD EXUDATES 
Ranibizumab is a humanized monoclonal antibody fragment that binds and inhibits 
VEGF-A. Multiple studies have clearly demonstrated that ranibizumab is superior to 
laser alone for vision gain and avoiding vision loss in patients with center involved 
diabetic macular edema. Ranibizumab is FDA approved for the treatment of diabetic 
macular edema in the dose of 0.3mg. 
Deposits of lipid exudates near the fovea are thought to be associated with an 
increased risk of vision loss in DME. The RIDE/RISE hard exudate retrospective 
analysis found that hard exudates were present in 75% of patients at baseline, 
ranibizumab significantly reduces the area of hard exudate over time compared to 
sham, especially in those graded as moderate exudate, but the effect is gradual with a 
detectable affect no earlier than 6 months (as opposed to the rapid improvement in 
macular edema) and the difference between treatment groups became evident at 12 
months. At baseline, there was no correlation between visual acuity and the presence 
of hard exudate in the central subfield in any treatment arm. Post-baseline, there was 
no consistent correlation between presence of HE in the central subfield and VA 
change over time. 
Since ranibizumab has been shown to be an effective treatment for both center 
involved diabetic macular edema and for resolving lipid exudates, the rationale of this 
study is to prospectively determine if continued treatment with intravitreal anti-VEGF 
(ranibizumab) until both center-involved macular edema AND lipid exudates resolve 
will impact final visual acuity. The secondary outcomes would evaluate ranibizumab's 
effect on lipid exudate resolution at the fovea and macula. 
1.4 NONCLINICAL EXPERIENCE WITH RANIBIZUMAB 
1.4.1 Nonclinical Pharmacokinetics 
The pharmacokinetics of ranibizumab has been investigated in rabbits and 
cynomolgus monkeys following intravitreal and intravenous administration. In 
both species, following intravitreal administration, ranibizumab was cleared 
from the vitreous humor with a half-life of 2-3 days. Following single 
intravitreal administration to cynomolgus monkeys, retinal concentrations of 
ranibizumab were approximately one-third of vitreous concentrations and 
declined in parallel with vitreous concentrations. In humans, the intravitreal 
half-life of ranibizumab is estimated to be 7-8 days. Repeated intravitreal 
injections of ranibizumab can lead to detectable antibodies in serum in rabbits 
and cynomolgus monkeys. 
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1.4.2 Nonclinical TOXICOIOQY 
A series of nonclinical studies of ranibizumab administered by intravitreal 
injection to cynomolgus monkeys have been performed (details regarding 
study design and results can be found in the Investigator Brochure). 
1.4.3 Nonclinical Data Supporting the Anti-Edema Activity of Ranibizumab  
In Studies 01-401E-1757 and 01-401G-1757, the effect of ranibizumab on 
vascular leakage was explored using a modified Miles assay in the guinea pig. 
Ranibizumab demonstrated a concentration-dependent effect of blunting the 
vascular permeability induced by VEGF. These results are consistent with the 
decrease in retinal vascular permeability as observed on optical coherence 
tomography (OCT) and fluorescein angiography in AMD and diabetic macular 
edema studies and further support the rationale for the use of ranibizumab in 
CRVO and BRVO, in which vascular permeability plays a significant role in the 
pathology 
1.5 CLINICAL EXPERIENCE WITH RANIB1ZUMAB 
Ranibizumab has been or is being studied in more than 5000 subjects with 
neovascular AMD in a number of Phase I, I/11, II, Ill, and IIlb clinical trials. . 
Ranibizumab is contraindicated in patients with ocular or periocular infections and in 
those with known hypersensitivity to ranibizumab or any of the excipients in 
ranibizumab. Intravitreal injections, including those with ranibizumab, have been 
associated with endophthalmitis and retinal detachment. Proper aseptic injection 
technique should always be used when administering ranibizumab. Increases in !OP 
have been noted within 60 minutes of intravitreal injection with ranibizumab. 
Therefore, 10P as well as perfusion of the optic nerve head should be monitored and 
managed appropriately. Serious adverse events related to the injection procedure 
have occurred in <0.1% of intravitreal injections include endophthalmitis, 
rhegmatogenous retinal detachment, and iatrogenic traumatic cataract. Other serious 
ocular adverse events observed among ranibizumab-treated subjects and occurring in 
<2% of subjects included intraocular inflammation and increased 10P. The most 
common adverse reactions (reported > 6% higher in ranlblzumab-treated subjects 
than control subjects) were conjunctival hemorrhage, eye pain, vitreous floaters, 
increased !OP, and intraocular inflammation. 
Although there was a low rate (<4%) of arterial thromboembolic events (ATEs) 
observed In the ranibizumab clinical trials there is a potential risk of ATEs following 
intravitreal use of inhibitors of VEGF. The rate of ATEs in three studies (FVF2598g, 
FVF2587g, and FVF3192g) in the first year was1.9% of subjects in the combined group 
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of subjects treated with 0.3 mg or 0.5 mg ranibizumab compared with 1.1% of subjects 
in the control arms of the studies. In the second year of Study FVF2598g and 
FVF2587g, the rate of ATEs was 2.6% of subjects in the combined group of those 
treated with 0.3 mg or 0.5 mg ranibizumab compared with 2.9% of subjects in the 
control arm. The most common non-ocular adverse reactions observed in > 15% of 
ranibizumab-treated subjects that occurred more frequently than in control subjects 
included nasopharyngitis, headache, and upper respiratory tract infection. 
The Sailor study (FVF3689g) evaluated the safety of intravitreal ranibizumab in 
a large population of subjects with CNV secondary to AMD. Subjects in Cohort 
1 (N=2378) were randomized (1:1) to receive ranibizumab at a dose level of 0.3 
mg or 0.5 mg; subjects were masked to these dose levels. Treatment was 
administered monthly for three initial doses (Day 0, Month 1, and Month 2), with 
scheduled follow-up visits on Months 3, 6, 9, and 12. Retreatment after the first 
three injections was performed as needed, on the basis of predefined criteria 
with injections no more frequently than every 30 days. 
Cohort 2 (N=1992) consisted of subjects enrolled after the majority of Cohort 1 
subjects had been enrolled, with enrollment continuing until ranibizumab was 
approved or denied by the FDA for US marketing, and if approved, until 
commercially available or 30 September 2006, whichever was earlier. Subjects 
in Cohort 2 received open-label ranibizumab at the 0.5 mg dose level, with an 
initial injection on Day 0 followed by retreatment at the physician's discretion, no 
more frequently than every 30 days. Subjects were monitored for safety for a 
total of 12 months; safety information, including both serious and non-serious 
adverse events, was collected at every clinic visit, with two formal safety visits 
scheduled at Months 6 and 12. 
The study consisted of a 30-day screening period and a 1-year treatment 
period. Treatment duration was approximately 197 days for both dose groups 
in Cohort 1 and 144 days for subjects in Cohort 2. The mean follow-up time 
differed between Cohort 1 and Cohort 2, 337 days versus 254 days, 
respectively. 
Ranibizumab was well tolerated, and the incidence of ocular SAEs and AEs 
was low and unrelated to dose. The rates of individual key ocular SAEs in 
Cohort 1 were < 1% and were similar across dose groups. Endophthalmitis or 
presumed endophthalmitis developed in 0.2% subjects in the 0.3-mg group and 
0.4% subjects In the 0.5-mg group. The incidence of ocular inflammation, 
including iritis, uveitis, vitritls, and iridocylitis was 1.9% in the 0.3-mg group and 
1.5% in the 0.5-mg group. Overall cataract rates were 5.4% (0.3 mg) and 6.0% 
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(0.5 mg) and were similar when broken down by nuclear, subcapsular, and 
cortical subtypes. The rates of individual key ocular SAEs in Cohort 2 were 
<1%. 
The rates of key non-ocular SAEs and AEs, including Antiplatelet Trialists' 
Collaboration (APTC) ATEs, MI, and vascular death were similar for cohorts 1 
and 2 and 0.3- and 0.5-mg dose groups. The incidence of MI and non-ocular 
hemorrhage was similar across Cohort 1 dose groups. APTC ATEs, including 
vascular and unknown deaths, nonfatal MI, and nonfatal cardiovascular 
accidents, were similar across dose groups. During the 12-month study period, 
0.7% of subjects in the 0.3-mg group and 1.2% of subjects in the 0.5-mg group 
suffered a stroke. The number of vascular deaths and deaths due to unknown 
cause did not differ across dose groups. Rates of key non-ocular SAEs in 
Cohort 2 were generally lower than those in Cohort 1. 
Refer to the Ranibizumab Investigator Brochure or Lucentise Package Insert for 
additional details regarding clinical safety experience with ranibizumab. 
2. 	
OBJECTIVES 
To evaluate the effect of intravitreal ranibizumab 0.3mg on visual acuity and hard 
exudate resolution in the treatment of diabetic macular edema with lipid exudates in the 
central subfield. This group is at high risk of deposition of lipid in the fovea and vision 
loss. The patients would be randomized to 1 of 2 groups. Group 1 would be treated 
with intravitreal ranibizumab 0.3mg until the macular edema is resolved based on the 
DRCR protocol I 4:2:7 strategy. The definition of success would be changed for Group 
2 and treatment would continue until the lipid exudates in the central subfield also 
resolve. 
2.1 Primary Objective 
The primary objective of this study is to evaluate the effect of intravitreal 
ranibizumab 0.3mg on visual acuity in the treatment of center involved diabetic 
macular edema with lipid exudates in the central subfield. 
2.2 Secondary Objectives 
The secondary objective of this study is to evaluate the effect of intravitreal 
ranibizumab 0.3mg on lipid clearing in the central subfield and throughout the 
macular grid in patients with center involved diabetic macular edema with lipid 
exudates in the central subfield. 
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3. 	
STUDY DESIGN  
3.1 DESCRIPTION OF THE STUDY 
This is an open-label, Phase I / II study of intravitreally administered 0.3mg 
ranibizumab in subjects with diabetic macular edema and lipid exudates in the 
central subfield. 
Consented, enrolled subjects will receive multiple open-label intravitreal 
injections of 0.3 mg ranibizumab administered every 30 days for 12 months per 
the treatment algorithm. 
The patients will be randomized to 1 of 2 treatment groups. 
•
Group 1: Treatment algorithm based on the DRCR protocol I 4:2:7 strategy 
based on the presence of macular edema, 
•
Group 2: Continue treatment until not only the macular edema is resolved but 
also until the lipid exudate is resolved. 
Sample size: 30 eyes 
Follow-up Schedule: Every 4 weeks throughout the study. 
3.2 RATIONALE FOR STUDY DESIGN 
DRCR Protocol I 4:2:7 strategy for Group 1 
Prior to the 16-week study visit, treatment study drug was given every 4 weeks 
regardless of the visual acuity or optical coherence tomography (OCT) central subfield 
thickness. 
At the 16 and 20 week study visits, study drug was required monthly unless 'success' 
criteria (defined as visual acuity letter score a84 (20/20) or OCT central subfield 
thickness <300;, in which case study drug injection was at investigator discretion. 
At each visit from 24 to 48 weeks, eyes were categorized as meeting either 'success' 
as defined above, 'improvement', 'no improvement', or 'failure'. Improvement required a 
study drug injection. If an eye was categorized as 'no improvement' because it met 
neither the criteria for 'success' or 'improvement', but had not yet met the criteria for 
'failure' a study drug injection could be given at investigator discretion. Eyes that met 
'failure' criteria could be treated at investigator discretion with study drug injection or 
exited from the study. 
Definitions: 
•
Improvement: either visual acuity improved by a5 letters or OCT central 
subfield thickness improved by 10% since the last injection 
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•
No improvement: Success and failure/futility criteria not met and visual acuity 
letter score improved by <5 letters (or worsened) and OCT central subfield 
thickness decreased by <10% (or increased) since the last injection 
•
Failure: Visual acuity 10 or more letters worse than baseline, OCT central 
subfield thickness 2:300 um, DME judged to be the cause of visual acuity loss 
•
Futility: After 52 week visit: OCT central subfield 300 um, DME judged to be 
the cause of visual acuity loss 
For Group 2 the treatment algorithm definition of 'success' would change to also 
include resolution of lipid exudate. So even if the macular edema has resolved, 
treatment with study drug injection would continue until the lipid exudate in the central 
subfield was resolved. 
3.3 OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
Compare Group 1 and Group 2 for Best correct visual acuity (BCVA), as assessed by 
the number of letters read correctly on the ETDRS eye chart at a starting test distance 
of 4 meters, over 6 and 12 months 
3.3.2 Secondary Outcome Measures 
1. Lipid clearing in the central subfield. 
•
% of patients with improvements in lipid deposits at 6 and 12 months 
•
% of patients with complete resolution at 6 and 12 months 
•
Time to complete resolution (Group 1 compared with Group 2) 
2. Lipid clearing throughout the macular grid. 
•
% of patients with improvements in lipid deposits at 6 and 12 months 
•
% of patients with complete resolution at 6 and 12 months 
•
Time to complete resolution (Group 1 compared with Group 2) 
3. Measures for safety and tolerability are the following: 
•
Incidence and severity of ocular adverse events, as identified by 
eye examination (including visual acuity testing) 
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• Incidence and severity of other adverse events, as identified by 
physical examination, subject reporting, and changes in vital 
signs 
The reading center (Doheny Image Reading Center- Srini Vas Sadda, MD) will 
develop severity standards and a grading scale for the lipid exudates based on 
OCT and fundus photography. 
3.4 SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 
and Appendix A. 
Injection-related: endophthalmitis, retinal detachment, retinal tears, cataract, intraocular 
hemorrhage, increased intraocular pressure, 0 
Ocular drug-related: inflammation, cataract, cataract surgery, increased intraocular 
pressure, glaucoma medications, glaucoma surgery, new or worsening traction retinal 
detachment. 
Systemic drug-related: hypertension, cardiovascular events, and cerebrovascular 
events. 
3.5 COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirements. 
4. 
MATERIALS AND METHODS  
4.1 SUBJECTS 
4.1.1 Subject Selection 
30 subjects from 2 sites in the United States will be enrolled. Eligible subjects 
will be administered and provided with a copy of informed consent. (See 
Appendix A, the study flow chart, for screening assessments.) 
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4.1.2 Inclusion Criteria 
Subjects will be eligible if the following criteria are met: 
•
Ability to provide written informed consent and comply with study 
assessments for the full duration of the study 
•
Age a 18 years 
•
Type 1 or Type 2 Diabetes mellitus 
•
Best corrected ETDRS visual acuity (20/32-20/320) or letter score 78 
to 24 
•
Diabetic macular edema on clinical examination involving the center of the 
macula assessed to be the main cause of visual loss 
•
Retinal thickness measured on spectral domain optical coherence 
tomography (OCT). Zeiss Cirrus: a290pm in women and 305 pm in 
men in the central subfield. Heidelberg Spectralis: 305pm in women 
and 320 pm in men in the central subfield 
•
Lipid exudates involving the central subfield on spectral domain OCT. 
4.1.3 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this 
study: 
•
Treatment for diabetic macular edema within the prior 4 months. 
•
Panretinal photocoagulation within the prior 4 months or anticipated 
need for panretinal photocoagulation within the next 6 months 
•
major ocular surgery within the prior 4 months 
•
myocardial infarction, other cardiac event requiring hospitalization, 
cerebrovascular accident, transient ischemic attack, or treatment for 
acute congestive heart failure occurred within 4 months before 
randomization 
•
Pregnancy (positive pregnancy test) or lactation 
•
Premenopausal women not using adequate contraception. The 
following are considered effective means of contraception: surgical 
sterilization or use of oral contraceptives, barrier contraception with 
either a condom or diaphragm in conjunction with spermicidal gel, an 
IUD, or contraceptive hormone implant or patch. 
▪
Any other condition that the investigator believes would pose a 
significant hazard to the subject if the investigational therapy were 
initiated 
•
Participation in another simultaneous medical investigation or trial 
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4.2 METHOD OF TREATMENT ASSIGNMENT 
Patients will be randomized to either treatment group I or 2 via a computer 
generated randomization schedule. Since this is a small study, to control and 
balance the influence of covarfates, patients with visual acuity of less than 
20/80 or better than 20/80 will be equally randomized to Group I or 2. 
Given that this is a small study, subjects that are exited with less than 6 
months of data can be replaced. 
4.3 STUDY TREATMENT 
4.3.1 Formulation  
0.3-mg Lucentis: 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile, 2-mL mL 
stoppered glass vial. Each single-use vial is designed to deliver 0.05 mL of 6 mg/mL 
ranibizumab aqueous solution with 10 mM histidine HC/, 10%, ct-trehalose dihydrate, 
and 0.01% polysorbate 20, pH 5.5. Each vial contains no preservative and is suitable 
for single use only. 
Further details and molecule characterization will be included in the Investigator 
Brochure. 
4.3.2 Dosage, Administration, and Storage 
a. Dosage:  Ranibizumab 0.3mg 
b. Administration:  
Intravitreal Ranibizumab 0.3mg with follow-up visits every 4 weeks. 
The patients will be randomized to 1 of 2 treatment groups. 
•
Group 1: Treatment algorithm based on the DRCR protocol I 4:2:7 strategy 
based on the presence of macular edema. 
•
Group 2: Continue treatment until not only the macular edema is resolved but 
also until the lipid exudate is resolved. 
DRCR Protocol 14:2:7 strategy for Group 1 
Prior to the 16-week study visit, treatment study drug was given every 4 weeks 
regardless of the visual acuity or optical coherence tomography (OCT) central subfield 
thickness. 
At the 16 and 20 week study visits, study drug was required monthly unless 'success' 
criteria (defined as visual acuity letter score a84 (20/20) or OCT central subfield 
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thickness <300;, in which case study drug injection was at investigator discretion. 
At each visit from 24 to 48 weeks, eyes were categorized as meeting either 'success' 
as defined above, 'improvement', `no improvement', or 'failure'. Improvement required 
a study drug injection. If an eye was categorized as 'no improvement' because it met 
neither the criteria for 'success' or 'improvement', but had not yet met the criteria for 
'failure' a sham or study drug injection could be given at investigator discretion. Eyes 
that met 'failure' criteria could be treated at investigator discretion with study drug 
injection or exited from the study. 
Improvement: either visual acuity improved by 5 letters or OCT central subfield 
thickness improved by ?_10% since the last injection 
No improvement: Success and failure/futility criteria not met and visual acuity letter 
score improved by <5 letters (or worsened) and OCT central subfield thickness 
decreased by <10% (or increased) since the last injection 
Failure: Visual acuity 10 or more letters worse than baseline, OCT central subfield 
thickness ?:300 urn, DME judged to be the cause of visual acuity loss 
Futility: After 52 week visit: OCT central subfield 300 um, DME judged to be the 
cause of visual acuity loss 
For Group 2 the treatment algorithm definition of 'success' would change to also 
include resolution of lipid exudate. So even if the macular edema was resolved, 
treatment with study drug injection would continue until the lipid exudate in the central 
subfield was resolved. 
*See Appendix B for detailed pre-injection procedures. 
c. Storage 
Upon receipt, study drug kits should be refrigerated at 2°C - 8°C (36°F - 46°F). 
DO NOT FREEZE. Do not use beyond the expiration date. Ranibizumab vials 
should remain refrigerated. Protect vials from direct light. Store in original 
carton until time of use. 
RANIBIZUMAB VIALS ARE FOR SINGLE USE ONLY. Vials used for one 
subject may not be used for any other subject. 
4.4 CONCOMITANT AND EXCLUDED THERAPIES. 
Subjects may continue to receive all medications and standard treatments 
administered for their conditions at the discretion of their treating physician. 
Lucentis will be provided for the fellow non-study eye if treatment is indicated. 
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4.5 STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period  
Visit Schedule: Every 4 weeks (+/- 1 week) for 12 months. If an injection is 
administered on visit 12, a follow-up visit will be performed 4 weeks later to assess for 
adverse events and treatment response. If the investigator chooses to see the 
participant more frequently as part of usual care or a participant experiences visual 
acuity loss requiring earlier follow-up, limited data will be collected at those visits. 
Testing Procedures: A history will be elicited from the subject and extracted from 
available medical records at enrollment. Data to be collected may include: age, 
gender, ethnicity and race, diabetes history and current management, other medical 
conditions, as well as ocular diseases, surgeries, and treatment. 
The following procedures will be performed at each protocol visit unless otherwise 
specified. 
1) OCT will be performed at each visit. Fundus Photography (FP) on the study 
eye(s) at baseline and month 3, 6, 9, and 12. If lipids/ exudates resolve at an 
in-between visit, FP will also be performed at that time. A reading center will 
review the images at baseline and month 3, 6, 9, 12, and a lipid resolution visit 
if indicated. 
2) Fluorescein angiogram of both eyes at Visit 0 and 12 
3) Ocular exam in the study eye(s), including slit lamp examination, lens 
assessment, measurement of intraocular pressure and dilated ophthalmoscopy 
4) Measurement of blood pressure (enrollment only) 
5) Best Corrected ETDRS visual acuity testing at 4 meters the study eye and 
both eyes at visit 0 and 12. 
If fundus photography or fluorescein angiogram were performed (using the study 
technique and by study certified personnel) as part of usual care within 4 weeks of 
randomization, it does not need to be repeated specifically for the study. 
OCT, fluorescein angiogram, and fundus photography will all be sent to a reading 
center for manual grading. Study participant eligibility is determined by the site (i.e., 
individuals deemed eligible by the investigator will be randomized without pre-
randomization reading center confirmation). The reading center will create a grading 
scale for the lipid exudate in the center subfield and macular grid. 
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Delay in giving injections: If a scheduled injection is not given by the end of the visit 
window, it can still be given late. 
Non-Study Eye Injections: if the non-study eye is going to be treated for any 
condition which requires treatment with an anti-VEGF agent, study provided 
ranibizumab must be used. However, if intravitreal anti-VEGF treatment is planned on 
the same day as an intravitreal injection in the study eye, the study eye will be 
injected first, followed by the non-study eye. If a different intravitreal anti-VEGF 
injection than described above is desired in the non-study eye, a discussion with the 
PI is required first. 
4.5.2 Early Termination Assessments  
Subjects who withdraw from the study prior to completion should return for an 
early termination evaluation 30 days (±7days) following the last injection/study 
visit for monitoring of all adverse events (serious and non-serious). The 
schedule of assessments for early termination is the same as that for the final 
visit. 
4.5.3 Reading Center 
Summary of Reading Center Grading Plan for Lipid Associated With Diabetic 
Macular Edema 
a. Image acquisition 
The reading center will provide written image acquisition manuals for all 
photographic procedures relevant to this 1ST. In particular for obtaining stereo 
color fundus photographs and spectral domain OCT images. These procedure 
manuals will include a description of image transmittal methods. A project 
manager will be assigned at the reading center who will interact with the clinical 
site personnel. Feedback will be provided on an on-going basis through the course 
of the study regarding the quality of images and compliance with protocols. The 
reading center will not perform an a priori certification of instruments or operators 
for this protocol. 
b. Summary of grading strategy 
All grading will be performed by a experienced, trained grader who has been 
certified for diabetic retinopathy grading. This study will employ a single masked 
grading workflow, but a percentage of cases will be re-graded to confirm 
reproducibility. The initial set of submissions will also be reviewed by the reading 
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center principal investigator (Sadda), as will any questionable or difficult cases (as 
determined by the 1 st  grader) during the course of the study. Grading results will 
be entered into a study database or spreadsheet and will be provided the 1ST PI or 
Genentech for analysis. All grading will be completed within 2 weeks of receipt of 
the image data, assuming there are no problems with the image submission. 
c. Lipid Grading Methodology Overview 
1. Color Fundus Images 
Grading of lipid/ hard exudates on color fundus photographs has been 
defined in previous large clinical trials (specially the ETDRS). We propose 
to use a similar protocol, which will facilitate comparisons with historical 
data. 
Specifically, severity and extent of lipid exudates will be determined by 
comparison of subject color photos to ETDRS reference standards in 
accordance with the ETDRS scale below (Excerpt from Reading Center 
central grading protocol): 
Presence/Severity of Hard Exudates 
Identification a hard exudates is described in Section 4.2.1.7. 
When using standard photographs, the grading of hard exudates is based on the area of retina 
involved in comparison. 
The following scale adapted from the ETDRS grading protocol' is used to evaluate hard 
exudates: 
Gradino Scale 
Findings observed on Colors in Fields 2 — 7 
0 
No hard exudate 
1 
Questionable hard exudate 
2 
Definite hard exudate < Std Photo #3* 
. 
Hard exudate a Std Photo #3* but < Std Photo #5 -  
4' 
. 
Hard exudate a Std Photo #5* but < Std Photo #4* 
Hard exudate a Std Photo #4* 
Cannot Grade 
8 
• Standard Photographs 3, 4, and 5 are not rewired in determining tho severity level of DR and MU not be used unless 
othonviso spec:WWI In a study sprocllic grading protocol. 
• Grades 3, 4. and 5 will not be used unless °Merv/is° specified in a study specific greding proloc01. 
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2. Spectral Domain OCT 
Volume SD-OCT acquisitions (512x128 over a 6x6 mm square centered on 
the fovea) will be obtained for both eyes in each case, though only the 
study eye will be graded here. Lipid or hard exudates are recognized or 
defined on OCT to be discrete areas of increased hyper-reflectivity within 
the neurosensory retina associated with optical shadowing below. Lipid 
severity will be assessed by one or both of two methods: (1) computation of 
actual lipid volume based on manual segmentation of dense volume scans 
(this is a time-consuming, but precise method), (2) semi-quantitative 
determination of lipid severity within sections of a detailed (16 square grid). 
These two metrics will be correlated with one another. If the semi-
quantitative method proves effective (i.e. correlates well with the precise 
volume), this may be the preferred approach. 
4.6 SUBJECT DISCONTINUATION 
Subjects have a right to withdraw from the study at any time. 
The subject may be withdrawn from the study for any reasons: if it is in the 
best interest of the subject, intercurrent illness, adverse events, or worsening 
condition. The South Coast Retina Center or Julie Gasperini MD (PI) may 
request the withdrawal of a subject because of protocol violations, 
administrative reasons, or any other valid and ethical reasons. 
If a subject discontinues from the study, he or she will not be allowed to 
re-enter the study. 
Reasons for subject discontinuation may include, but are not limited to, the 
following: 
•
Sensory rhegmatogenous retinal detachment or Stage 3 or 4 macular 
hole 
•
Investigator determination that it is not in the best interest of the subject 
to continue participation 
•
Pregnancy 
•
Need for anti-VEGF therapy other than ranibizumab in the study eye, 
unless as a part of the prospective investigational study design 
•
SAE 
•
Any other safety concerns 
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In the event of an adverse event in the study eye that is considered by the 
investigator to be severe in intensity, serious consideration should be given to 
discontinuing the subject from the study. 
4.7 STUDY DISCONTINUATION 
This study may be terminated by South Coast Retina Center or Genentech at 
any time. Reasons for terminating the study may include the following: 
• The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to subjects 
Subject enrollment is unsatisfactory 
Data recording is inaccurate or incomplete 
4.8 STATISTICAL METHODS 
4.8A Analysis of the Conduct of the Study  
There is no formal sample size calculation in a pilot/phase I or 
pharmacokinetic/pharmacodynamics study. As this is a phase I/II study, a 
sample size of 30 patients is chosen, making sure that it is feasible financially 
to conduct the study and logistically to complete the study within 2 year / 
years. 
If and when the study is planned for a phase II/III randomized control trial, 
appropriate statistical analysis will be determined. 
4.8.2 Safety Analyses  
Any adverse events, laboratory assessments, physical examinations, vital 
signs, ocular examinations and measurements from all 30 subjects will be 
utilized to summarize safety data for this pilot study. 
4.8.3 Efficacy Analyses  
a. Primary Endpoint 
Best correct visual acuity (BCVA), as assessed by the number of letters read 
correctly on the ETDRS eye chart at a starting test distance of 4 meters, at Month 
Sand 12. 
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c. Secondary Endpoints 
1. Lipid clearing in the central subfield: 
•
% of patients with improvements in lipid deposits at 6 and 12 months 
•
% of patients with complete resolution at 6 and 12 months 
2. Lipid clearing throughout the macular grid: 
•
% of patients with improvements in lipid deposits at 6 and 12 months 
•
% of patients with complete resolution at 6 and 12 months 
4.8.4 Missing Data 
Analyses of efficacy and safety will be based on available cases, without 
imputation for missing values. 
4.8.5 Interim Analyses 
No formal schedule of interim analyses is planned. Reports of adverse events 
from this study may be reviewed and summarized periodically while the study 
is ongoing to ensure the safety of subjects. 
4.9 DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures. 
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5. ASSESSMENT OF SAFETY 
Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to ranibizumab, all events 
of death, and any study specific issue of concem. 
5.1 ADVERSE EVENTS 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
[diabetic macular edema] that were not present prior to the AE reporting period. 
Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 
5.2 SERIOUS ADVERSE EVENTS 
An AE should be classified as an SAE if the following criteria are met: 
•
It results in death (i.e., the AE actually causes or leads to death). 
•
It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
•
It requires or prolongs inpatient hospitalization. 
•
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject's ability to conduct normal life functions). 
•
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
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It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
5.3 METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed 
or reported during the study, are collected and reported to the FDA, appropriate 
IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of study treatment [or "initiation of any non-
standard of care study procedures"] and ends 30 days [or insert othertime period] 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should 
only report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by 
its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the {study drug) (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
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Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the {study drug ranibizumab), and the AE cannot be readily 
explained by the subject's clinical state, intercurrent illness, or concomitant therapies; 
and/or the AE follows a known pattern of response to the {study drug); and/or the AE 
abates or resolves upon discontinuation of the {study drug) or dose reduction and, if 
applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the {study drug) (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to {study drug) 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected adverse events are those adverse events that are listed or characterized in 
the Package Insert or current Investigator Brochure. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which 
the specificity or severity is not consistent with the description in the P.I. or I.B. For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. 
only referred to elevated hepatic enzymes or hepatitis. 
5.4 EVALUATIONS 
Reviews of body systems will be performed. 
Ophthalmologic evaluations will include slit lamp examination, dilated binocular 
indirect high-magnification ophthalmoscopy, measurements of BCVA and 
intraocular pressure, and finger-count testing. (See Section 4.5 for a detailed 
description of the study assessments.) 
5.6 VITAL SIGNS 
Pulse and blood pressure will be measured at protocol-specified study visits 
(see Section 4.5). 
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5.6 PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
5.6.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should 
be adopted. Examples of non-directive questions include: 
•
"How have you felt since your last clinical visit?" 
•
"Have you had any new or changed health problems since you were last 
here?" 
5.6.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterisks, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, report "Unexplained 
Death". 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE 
only If the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., "more frequent 
headaches"). 
•
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d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical 
or surgical procedure as a result of an AE, the event responsible for the procedure, 
not the procedure itself, should be reported as the SAE. For example, if a subject is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
•
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
•
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
•
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 
90 days after the last dose of study drug, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the (study drug} should be reported as an SAE. 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior {study drug} 
exposure. If the investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject who 
participated in the study, this should be reported as an SAE. 
g. Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum 
to exchange monthly line listings of cases received by the other party. If discrepancies 
are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution. 
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h. AEs of Special Interest (AESIs) 
REs of Special Interest are defined as a potential safety problem, identified as a result 
of safety monitoring of the Product 
Lucentis Events of Special Interest are: 
•
Retinal pigment epithelial tear 
•
Increased intraocular pressure to > 30mm Hg not responsive to maximal 
topical !OP-lowering drugs measured on 2 separate days 
•
Traumatic cataract 
•
Endophthalmitis 
•
I ntraocular inflammation of greater than 2+ cells (including vitritis and 
uveitis) 
•
Retinal detachment 
•
ATEs, including stroke 
i. SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion 
to Genentech Drug Safety at: 
(650) 225-4682 OR (650) 225-5288 
•
Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available. 
•
Serious AE reports that are related to the ranibizumab and AEs of Special 
Interest (regardless of causality) will be transmitted to Genentech within fifteen 
(15) calendar days of the Awareness Date. 
•
Serious AE reports that are unrelated to the ranibizumab will be transmitted to 
Genentech within thirty (30) calendar days of the Awareness Date. 
Additional Reporting Requirements to Genentech include the following: 
•
Any reports of pregnancy following the start of administration with the [study 
drug ranibizumab] will be transmitted to Genentech within thirty (30) calendar 
days of the Awareness Date. 
•
All Non-serious Adverse Events originating from the Study will be forwarded in 
a quarterly report to Genentech. 
Note: Investigators should also report events to their 1RB as required. 
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5.6.3 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
•
Protocol description (and number, if assigned) 
•
Description of event, severity, treatment, and outcome if known 
•
Supportive laboratory results and diagnostics 
•
Investigator's assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
5.6.4 Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
•
Adding to the original MedWatch 3500A report and submitting it as follow-up 
•
Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form 
•
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or 
follow-up information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and adverse event was reported. 
For questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as it becomes 
available and/or upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html 
5.6.5 Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
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7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to 
the use of [study drug ranibizumabi. An unexpected adverse event is one that is not 
already described in the [study drug ranibizumab] Investigator Brochure. Such reports 
are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of 
first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered 
reasonably or possibly related to the use of (study drug ranibizumab). An unexpected 
adverse event is one that is not already described in the [study drug ranibizumab] 
investigator brochure. 
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a Medwatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter). 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
All written IND Safety Reports submitted to the FDA by the Investigator must 
also be faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
And to the Site IRB: 
Western Institutional Review Board: 
1019 39th Avenue SE Suite 120._i Puyallup, WA 98374-2115 
Office (360) 252-2500, (800)562-4789 
Fax (360) 252-2498 
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Email: clientservices@wirb.com 
For questions related to safety reporting, please contact Genentech Drug 
Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be faxed to Genentech Drug 
Safety: 
Fax: (660) 225-4682 or (650) 225-5288 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied 
to Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should 
be sent to Genentech. Copies of such reports should be mailed to the assigned 
contact for the study: lucentisgsr coa-degene.com  , SRT fax number 866-728-4622 
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5.6.6 SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
Initial Report Date 	
[DD] / [MON] / [YY] 
Follow-up Report Date 	 [DD] / [MON] / [YY] 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
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6.0 
INVESTIGATOR REQUIREMENTS  
6.1 STUDY INITIATION 
Before the start of this study, the following documents must be on file with 
South Coast Retina Center or its appointed representative: 
•
FDA correspondence letter assigning an IND number or an IND waiver 
letter 
•
Original U.S. FDA Form 1571 (if applicable) 
•
Original U.S. FDA Form 1572 (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal 
Investigator (if applicable) 
•
The names of any sub-investigators must appear on this form. 
Investigators must also complete all regulatory documentation as 
required by local and national regulations. 
•
Current curricula vitae of the Principal Investigator 
•
Medical License 
•
Written documentation of IRB approval of the protocol (identified by 
[South Coast Retina Center], protocol number or title and date of 
approval) 
•
IRB Approved protocol 
•
Fully executed contract 
•
Documentation of registration into clinical research vvebsite (e.g., 
www.clinicaltrials.gov)  (as applicable) 
•
Investigator Brochure Signature Receipt 
6.2 STUDY COMPLETION 
The following data and materials are required by [South Coast Retina 
Center] before a study can be considered complete or terminated: 
•
Laboratory findings, clinical data, and all special test results from 
screening through the end of the study follow-up period (if applicable) 
•
Case Report Forms properly completed by appropriate study personnel 
and signed and dated by the investigator (if applicable) 
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•
Copies of protocol amendments and IRB approval/notification (if 
applicable) 
•
A summary of the study prepared by the Principal Investigator (will 
accept 1RB summary close letter) (if applicable) 
•
All regulatory documents (e.g., curricula vitae for each Principal 
Investigator, U.S. FDA Form 1571 and 1572) 
6.3 INFORMED CONSENT 
Informed consent documents will be provided to each subject. 
The informed consent document must be signed and dated by the subject or 
the subject's legally authorized representative before his or her participation in 
the study. The case history for each subject shall document that informed 
consent was obtained prior to participation in the study. A copy of the 
informed consent document must be provided to the subject or the subject's 
legally authorized representative. If applicable, it will be provided in a certified 
translation of the local language. 
Signed consent forms must remain in each subject's study file and must be 
available for verification at any time. 
The following basic elements must be included: 
•
A statement that the study involves research, an explanation of the 
purposes of the research and the expected duration of the patient's 
participation, a description of the procedures to be followed, and 
identification of any procedures or drug used for purposes which are 
experimental 
•
A description of any reasonably foreseeable risks or discomforts to the 
patients 
•
A description of any benefits to the patient or to others which may 
reasonably be expected from the research. A description that there may 
be no benefit from this research. 
•
A disclosure of appropriate alternative procedures or courses of 
treatment, If any, that might be advantageous to the patient 
•
A statement describing the extent, if any, to which confidentiality 
records identifying the patient will be maintained and that notes the 
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possibility that the FDA and the South Coast Retina Center and the 
drug manufacturer may inspect the records 
For research involving more than minimal risk, an explanation as to 
whether any compensation and any medical treatments are available 
should injury occur and, if so, what they consist of or where further 
information may be obtained 
•
An explanation of whom to contact for answers to pertinent questions 
about the research and research patient's rights, and whom to contact 
in the event of a research-related injury to the patient 
•
A statement that participation is voluntary, that refusal to participate will 
involve no penalty or loss of benefits to which the patient is otherwise 
entitled, and that the patient may discontinue participation at any time 
without penalty or loss of benefits to which the patient is otherwise 
entitled 
6.4 INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the 1RB/EC for review and must be approved 
before the study is initiated. The study will be conducted in accordance with 
U.S. FDA, applicable national and local health authorities, and IRB/EC 
requirements. 
The Principal Investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the 1RB/EC must be updated at least once a year. 
The Principal Investigator must also keep the IRB/EC informed of any 
significant adverse events. 
Investigators are required to promptly notify their respective IRB/EC of all 
adverse drug reactions that are both serious and unexpected. This generally 
refers to serious adverse events that are not already identified in the 
Investigator Brochure and that are considered possibly or probably related to 
the study drug by the investigator. Some IRBs or ECs may have other specific 
adverse event requirements that investigators are expected to adhere to. 
Investigators must immediately forward to their 1RB/EC any written safety 
report or update provided by South Coast Retina Center (e.g., IND safety 
report, Investigator Brochure, safety amendments and updates, etc.). 
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6.6 CASE REPORT FORMS 
All CRFs should be filled out completely by appropriate personnel. The CRF 
should be reviewed, signed, and dated by the investigator. 
All CRFs should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced 
CRF copies. When making changes or corrections, cross out the original entry 
with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID ON THE ORIGINAL. 
6.6 STUDY DRUG ACCOUNTABILITY 
The Investigator is responsible for the control and distribution of study drug. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure. 
6.7 DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and 
disclosure to third parties other than those noted below is prohibited. 
Upon the subject's permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his 
or her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, the drug 
manufacturer and the IRB/EC for each study site, if appropriate. 
6.8 RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational 
drug, including CRFs, consent forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 2 years 
after the investigation is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified. 
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6.9 STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical 
Study Report (final study report). Additionally, any literature articles that are a 
result of the study should be sent to Genentech. Copies of such reports should 
be faxed to the assigned Clinical Operations contact for the study: 
Lucentis 1ST Program email: lucentisgsr coa-dagene.com .  
Fax: 866-728-4622 
REFERENCES 
1. Diabetic Retinopathy Clinical Research Network. DRCR.net 
2. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy 
among adults in the United States. Arch Ophthalmol. Apr 2004;122(4):552-563. 
3. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for 
diabetic macular edema: ETDRS report number 4. Int Ophthalmol Clin. 
1987;27(4):265- 272. 
4. Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy, Semin 
Ophthalma 1999;14(4):223-232. 
5. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating 
ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for 
diabetic macular edema. Ophthalmology. Jun 2010;117(6):1064-1077 e1035. 
6. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the 
ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 
Nov 2009;116(11):2175-2181 e2171. 
7. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards A, et al. A phase 
II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. 
OphthalmaL 2007;114(10):1860-1867, 
8. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: 
Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. Apr 
2012;119(4):789-801. 
9.
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular 
edema. Ophthalmology. Apr 2011;118(4):615-625. 
10.Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the DA VINCI Study of 
VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. Aug 
2012;119(8)1658-1665. 
11. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular 
edema secondary to central retinal vein occlusion: 1-year results from the phase 3 
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COPERNICUS study edema secondary to central retinal vein occlusion: 1-year 
results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429- 
437. 
12.Two year results of phase 3 studies with EYLEA (aflibercept) injection in wet AMD 
show sustained improvement in visual acuity. http://www.prnewswire.cominews-
releasesitwo-year-results-of-phase-3-studies-with-eylea-aflibercept-injection-in-wet-
amd- show-sustained-improvement-in-visual-acuity-135011348.html. Accessed 13 
February 2012. 
13.List references alphabetically, and format them using the Vancouver style 
described below. 
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APPENDIX A 
Study Flowchart 
Pretreatment 
Assessments During Treatment 
Other Assessments 
_ 
Screena  
Randomization 
/ Visit 03 
_ 	
. 
Visits 111 b 
Visit 
12b 
Visit 13b 
Lipid Resolution 
Visit (if not on a 
visit where FP is 
scheduled) 
Informed consent 
_ 
x 
x 
Demographic data 
x 
_ 
ETDRS best 
corrected visual 
acuity b 
x 
x 
x 
x 
Eye Exam d 
x 
x 
x 
Medical History & 
Blood pressure 
x 
Fundus 
Photography (FP) 
x 
Month 3, 6, 9 
12 
x 
x 
x 
SD-OCT 
x 
x 
x 
x 
Fluorescein 
Angiogram 
x 
x 
Ranibizumab 
treatment e 
x 
_ 
x 
x 
SAE monitoring 
x 
x 
x 
x 
a The screening and randomization visit (visit 0) can be on the same day.. 
b All visits are every 4weeks (+1-1 week) for 1 year, if an injection is administered at visit 12, then a follow up 
exam will occur 4 weeks later (visit 13) to assess AEs and therapeutic response. 
Includes refraction in both eyes on visit 0 and 12 and in the study eye on all other study visits unless 
treatment is given in the non study eye 
Eye Exam includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, 
and dilated ophthalmoscopy. 
b  Ranibizumab treatment is administered per the protocol 
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APPENDIX B 
Pre-Injection Procedures for All Subjects 
The following procedures will be implemented to minimize the risk of potential 
adverse events associated with serial intravitreal injections (e.g., endophthalmitis). 
Aseptic technique will be observed by clinic staff involved in the injection tray 
assembly, anesthetic preparation, and study drug preparation and administration. In 
addition to the procedures outlined below, added safety measures in adherence to 
specific institutional policies associated with intravitreal injections will be observed. 
The intravitreal injection procedure will follow the DRCR.net non-protocol specific 
injection procedure. 
The Diabetic Retinopathy Clinical Research Network Non Protocol—Specific Injection 
Procedure 
A. Intravitreal Injection Procedure 
NOTE: If an injection is to be given in the non-study eye at the same visit as a study 
eye injection, all required injection procedures described below must be completed in 
the study eye prior to initiating any pre-injection preparation of the non-study eye. In 
addition, the drug to be used in the non-study eye should not be present in the room 
prior to completion of all study eye injection procedures. All required injection 
procedures listed below must be performed on the non-study eye. 
1. Pre-Injection 
a.
On the day of injection, topical antibiotic drops may be administered at the 
discretion of the investigator as part of standard care, but are not required as part of a 
study procedure. 
b. The treating investigator and a second person should confirm which is the study 
eye to receive the intravitreal injection (if applicable) while directly viewing a 
computer screen with this information or a print out of a computer screen with this 
information that indicates the study eye and with this information at hand, mark that 
eye (with a sticker or marking pen) above the corresponding eyebrow. 
c.
Two individuals (the injecting ophthalmologist and another individual e.g. the 
coordinator) must confirm the study drug number from the vial obtained from the 
refrigerator (if applicable) with a print out from the website or while directly viewing a 
computer screen with this information prior to injection to ensure accuracy. 
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d. When the study participant is ready for the injection, apply at least one drop of 
topical anesthetic (solution or gel) to the eye. 
e. The eye then will be prepared for injection using the following sequence of steps: 
1. Consider placing 2-3 drops of 5% povidone iodine in the lower fornix and/or 
using sterile cotton-tipped applicators soaked in 5% or 10% povidone iodine to 
swab the upper and lower eyelid margins and the upper and lower eyelashes 
(Optional). 
2. Place a sterile eyelid speculum to stabilize the eyelids.DConsider additional 
anesthesia with the application of one or two cotton- tipped applicators soaked 
in topical anesthetic over the intended injection site for at least 30 seconds. A 
subconjunctival anesthetic can be used if the investigator believes that topical 
anesthetic is not sufficient to minimize discomfort. Protocol Chair approval is 
required for use of retrobulbar anesthetic. The use of lidocaine gel or other 
types of viscous anesthetic (e.g. TetraViscTM) is permitted. 
3. Encourage the study participant to look superonasally during the application of 
povidone iodine. Apply one of the following to the conjunctiva directly over and 
surrounding the intended injection site: 
a. A cotton-tipped applicator soaked in 5% or 10% povidone iodine 
b. A 10% povidone iodine Swabstick 
c. At least 1-3 drops of 5% povidone iodine (at least enough to cover the 
intended injection site) 
4. Allow 30-60 seconds for the povidone iodine to be in contact with the injection 
site before injection. 
NOTE: As indicated above, injection preparation must include the use of povidone-iodine 
either applied directly to the injection site using topical drops, a cotton-tipped applicator, or 
swabstick. If a study participant experiences an adverse reaction to povidone-iodine, other 
approaches to limit the exposure of povidone-iodine may be permitted. However, a 
DRCR.net study participant may not receive a study intravitreal injection without use of 
povidone-iodine directly to the injection site just prior to the injection. 
Examples of approaches that may be used in study participants with prior adverse reactions 
associated with povidone-iodine include using a limited amount of povidone-iodine by 
placing a swab directly on the injection site after the lid speculum has been placed, 
subsequently ensuring that nothing further touches that site before the injection. 
Alternatively, investigators could consider using povidone-iodine and then gently irrigating 
the eye with sterile saline after the injection to try to rinse away any remaining povidone-
iodine. In the extremely rare circumstance, if the study participant is perceived likely to have 
a severe adverse reaction associated with povidone-iodine and an alternative approach such 
as those discussed above is not viable, study intravitreal injection cannot be given at that 
study visit and the investigator should discuss the circumstance with the Protocol Chair or 
other investigator as designated by the Coordinating Center. 
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2. Injection 
a. The position of the injection site is located at 3.0mm-4.0mm posterior to the limbus. 
b. The surgeon prepares the proper volume of drug to be injected by drawing 0.2mL 
into the syringe using the sterile 19-gauge filtered needle provided. The 19-gauge 
needle should then be removed and the sterile 30-gauge needle provided should be 
placed onto the syringe. A 32-gauge needle may be used in place of the provided 30- 
gauge needle, if preferred. With the needle cap removed, fluid is expelled at an 
approximately 45-degree angle until the plunger is advanced to 50 pL (0.05 mL). The 
syringe is now ready for injection. 
c. Inject the drug into the vitreous cavity pointing toward the optic nerve via the pars 
plana. 
3. Post-Injection 
a. Remove the lid speculum and avoid any excess pressure on the eye. 
b. Assess for any complications either via indirect ophthalmoscopy to confirm that the 
central retinal artery is perfused (even if it is pulsating) or a vision check to confirm 
that there is some perception of vision in the study eye (for example, able to count 
fingers or perceive hand motion or light perception). 
c. At the discretion of the investigator topical antibiotic drops or ointment supplied as 
part of standard care but not part of the study may be provided to the study 
participant and used Q ID for 3 days (inclusive of the day of injection). 
NOTE if indirect ophthalmoscopy is checked it should be recorded. If the KW is checked 
multiple times, the last 10P taken before the study participant leaves the physician's office 
should be recorded. 
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APPENDIX C 
Analysis of Similar Events Template for IND Safety Reports 
IND Safety Report 
Case Summary 
This section will be initiated by a research coordinator and may be modified by 
principal investigators if necessary. The case summary should describe the reported 
AE in detail, including a description of what happened and a summary of all relevant 
clinical information (e.g. medical status prior to the event, signs, symptoms, 
diagnoses, clinical course, treatment, outcome, etc.) The IND safety report should 
not identify the subject ID #, reporting investigator, or the site as this information may 
compromise the study blind. 
PREVIOUS REPORTS 
The information for this section comes from Principal Investigator and the search of 
similar events. This section should be written by the responsible principal 
investigator. 
Select one of the following two statements after reviewing the search of similar 
events results. 
	
Under IND 	
(insert IND#), the following IND safety reports of similar 
AEs have been previously submitted: 
MCN 	
Reported Event 	
Submission Date 
OR 
	
2. Under IND 	
(insert IND#), no IND safety reports of similar AEs have 
been submitted previously. 
In addition to previously submitted IND safety reports of similar events, this section 
can also summarize pervious serious reports of the same/similar event that were 
considered unrelated to the investigational product at the time of the reporting. 
These events would remain blinded, unless a decision to unblind is made by an 
Independent Monitoring Committee for reasons of subject protection. The decision 
on what similar events to summarize In this section should be made after reviewing 
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the similar events report generated by Clinical Data Management. If a safety signal is 
particularly worrisome (e.g., a study stopping type of event), a more extensive 
evaluation may be required. 
Assessment of Relationship 
After evaluation the new case report and reviewing any relevant previous reports of 
similar events, the PI selects one of the following boilerplate conclusion statements, if 
applicable. The PI may also craft an alternative conclusion. 
1. Based on review of available data, South Coast Retina Center believes there 
is a reasonable possibility of a cause-and-effect relationship between 
administration of 	
(insert study drug name) and the occurrence 
of 	
( insert AE). 
Additional information on risk factors and/or treatment of the AE may be 
provided if warranted. 
OR 
2. Based on review of available data, the South Coast Retina Center does not 
believe that there is a reasonable possibility of a cause-and-effect relationship 
between administration of 	
(insert study drug name) and the 
occurrence of 	
(insert AE). 
Explain if warranted. Do not speculate. 
OR 
3. Based on review of available data, the South Coast Retina Center cannot 
establish or exclude the possibility of a cause-and-effect relationship between 
administration of 	 (insert study drug name) and the occurrence of 
	 (insert AE). 
Explain if warranted. Do not speculate. 
After review of the clinical details and investigator's comments pertaining to this AE, 
and based on experience to date, the South Coast Retina Center does not believe 
that changes to the conduct of this clinical trial are warranted. This statement can be 
modified if changes to the conduct of the clinical trial are made. 
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