Phase I/II Prospective, Randomized, Double-blinded Study of Intravitreal Anti-VEGF Therapy Combined With Proton Beam Radiation Versus Sham Irradiation in Treating Exudative Age-related Macular Degeneration
Phase: PHASE1
Conditions: Exudative Age-related Macular Degeneration
Sponsor: University of California, Davis

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PROTOCOL 
STUDY TITLE: 
Phase I/II Prospective, Randomized, Double-
blinded Study of Intravitreal Anti-VEGF therapy 
combined with Proton Beam Radiation versus 
Sham Irradiation in Treating Exudative Age-
related Macular Degeneration 
STUDY DRUG 
Recombinant humanized anti-VEGF 
monoclonal antibody fragment (rhuFab V2, 
[ranibizumab, Lucentis]) 
Recombinant humanized anti-VEGF 
monoclonal antibody (bevacizumab, Avastin) 
Proton beam radiation 
SPONSOR 
Department of Ophthalmology & Vision 
Science, University of California Davis Medical 
Center 
4860 Y St., Suite 2400, Sacramento, CA  95817 
IND: 
108,360  
INVESTIGATOR 
Susanna S. Park, MD, PhD 
SUB-
INVESTIGATORS 
Inder Dafteri, PhD, Kavita Mishra, MD, David G. 
Telander, MD PhD,  Lawrence S. Morse, MD, 
PhD 
DATE FINAL: 
September 8, 2010 
 

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TABLE OF CONTENTS 
 
                    Page:         
1. 
BACKGROUND ............................................................................................     1 
1.1 
Pathophysiology ................................................................................     1 
1.2 
Treatment ..........................................................................................     5 
1.3 
Ranibizumab ......................................................................................     5 
1.4 
Nonclinical Experience with Ranibizumab .........................................     5 
1.4.1 
Nonclinical Pharmacokinetics ...............................................     5 
1.4.2 
Nonclinical Toxicology ..........................................................     5 
1.4.3 
Stability Studies ....................................................................     6 
1.5 
Clinical Experience with Ranibizumab ...............................................     6 
2. 
OBJECTIVES ...............................................................................................     9 
 
2.1 
Primary Objective    ………………………………………………………     9 
 
2.2 
Secondary Objective …………………………………………………….      9 
 
3. 
STUDY DESIGN ..........................................................................................     9 
3.1 
Description of the Study .....................................................................     9 
3.2 
Rationale for Study Design ................................................................   10 
3.3 
Outcome Measures ...........................................................................   11 
3.3.1 
Primary Outcome Measures .................................................   11 
3.3.2 
Secondary Outcome Measures ............................................   11 
3.4 
Safety Plan ........................................................................................   11 
3.5 
Compliance with Laws and Regulations ............................................   13 
4. 
MATERIALS AND METHODS ......................................................................   13 
4.1 
Subjects .............................................................................................   13 
4.1.1 
Subject Selection .................................................................   13 

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TABLE OF CONTENTS (cont’d) 
 
                   Page 
4. 
MATERIALS AND METHODS (cont’d) 
4.1.2 
Inclusion Criteria ..................................................................   14 
4.1.3 
Exclusion Criteria .................................................................   14 
4.2 
Method of Treatment Assignment ………………………………………   15   
4.3 
Study Treatment ................................................................................   15 
4.3.1 
Formulation ..........................................................................   15 
4.3.2 
Dosage, Administration, and Storage ...................................   16 
4.4 
Concomitant and Excluded Therapies ...............................................   16 
4.5 
Study Assessments ...........................................................................   17 
4.5.1 
Assessments during the Treatment Period ..........................   17 
4.5.2 
Early Termination Assessments ...........................................   17 
4.6  
Subject Discontinuation .....................................................................   17 
4.7  
Study Discontinuation ........................................................................   18 
4.8  
Statistical Methods ……………………………………………………….   18  
 
4.8.1      Analysis of the Conduct of the Study ...................................   18 
4.8.2 
Safety Analyses ...................................................................   19 
4.8.3 
Efficacy Analyses .................................................................   19 
4.8.4 
Missing Data ........................................................................   20 
4.8.5 
Interim Analyses ………………………………………………..   20 
 
4.9 
Data Quality Assurance ………………………………………………….   20 
5.0 ASSESSMENT OF SAFETY ........................................................................   20 
5.1 
Adverse Events .................................................................................   20 
5.2 
Baseline Medical Conditions ..............................................................   22 
5.3 
Evaluations ........................................................................................   22 
5.4 
Vital Signs………………………………………………………………….   22 
5.5 
Procedures for Recording and Reporting Adverse Events ................   22 
 
5.5.1 
Recording Adverse Events ...................................................   22 
 
5.5.2 
Serious Adverse Events .......................................................   23 
 
5.5.3 
Special Reporting Situations ………………………………….    24 
 
5.5.4 
Type and Duration of Follow-up After Adverse Events .........   25 
 
5.5.5 
Regulatory Reporting Requirements for Principal Investigators 
Holding Their Own INDs …………………………………………………   25 
 
 
5.5.5.1  MedWatch 3500A Reporting Guidelines .................   27 
 

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TABLE OF CONTENTS (cont’d) 
 
                   Page 
6. 
INVESTIGATOR REQUIREMENTS .............................................................   28 
6.1 
Study Initiation ...................................................................................   28 
6.2 
Study Completion ..............................................................................   29 
6.3 
Informed Consent Form .....................................................................   29 
6.4 
Institutional Review Board or Ethics Committee Approval .................   31 
6.5 
Case Report Forms ...........................................................................   31 
6.6 
Study Drug Accountability………………………………………………..   32 
6.7 
Disclosure of Data .............................................................................   32  
6.8 
Retention of Records .........................................................................   32 
 
REFERENCES .....................................................................................................   33 
 
 
APPENDICES 
Appendix A: 
Study Flowchart………………………………………………… .....   36    
Appendix B: 
Pre-Injection Procedures for All Subjects…………………………  37 
Appendix C: 
MedWatch Form FDA 3500A………………………….. ...............   39  
Appendix D: 
Analysis of Similar Events …………………………………………   41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
BACKGROUND 
1.1 
PATHOPHYSIOLOGY 
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and 
legal blindness in the elderly population and the incidence is expected to increase dramatically 
in the next few decades as the baby boomer generation ages.1  Exudative age-related macular 
degeneration (eAMD), a more severe and aggressive form of the disease, accounts for 90% of 
the patients with severe vision loss from AMD.2  Exudative AMD is characterized by 
uncontrolled proliferation of neovascular tissue originating from the choroidal circulation deep to 
the retina which appears to be mediated in part by VEGF secreted by the overlying unhealthy 
macula.3  Vision loss associated with eAMD results from retinal bleeding and swelling from the 
choroidal neovascular tissue (CNVM) and can be minimized using anti-VEGF therapy, such as 
ranibizumab (Lucentis) and bevacizumab (Avastin).4,5  Ranibizumab is an active fragment of 
antibody to VEGF which was FDA-approved for treatment of eAMD.  Bevacizumab is a whole 
antibody to VEGF which was FDA-approved for treatment of metastatic cancer but commonly 
used in treating eAMD since it is inexpensive ($50 per dose) and appears comparable in 
efficacy to the more costly ranibizumab (>$2000 per dose).  Both anti-VEGF agents have a 
transient treatment effect, and sustained treatment benefit requires repeated monthly intravitreal 
injection and/or close monitoring for recurrence if therapy is temporarily stopped.6  Although 
these two drugs appear to be well-tolerated, the trauma of each intravitreal injection carries a 
small risk of injection, bleeding, cataract formation and retinal detachment, etc, which may result 
in further vision loss.  In addition, monthly treatment and/or monitoring eye examination are very 
time-consuming and costly.  Thus, a highly effective treatment that is safe and with a more 
sustained treatment effect is needed.  Such a treatment will have a huge impact on the quality 
and cost of eye care for the elderly. 
 
Various therapies for eAMD are being explored currently in order to achieve a more 
sustained treatment effect, including ranibizumab combined with photodynamic therapy and 
newer drugs to inhibit VEGF.7  These therapies all target the vascular component of the 
neovascular tissue growth associated eAMD.  Histologic analysis of CNVM in eyes with  eAMD 
revealed that a bulk of the tissue is composed of avascular fibrous tissue which can continue to 
grow and affect vision.3  In animal tumor models and clinical oncology studies, a marked 
synergism between anti-VEGF therapy and chemotherapy and/or radiation has been noted.8-10  
Anti-VEGF therapy alone resulted in only a transient control of tumor growth.  For sustained 
control of tumor growth, radiation had to be administered within 2 to 6 weeks of initiation of anti-
VEGF therapy (R. Jain, personal communication).  Based on these observations, it would be 

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important to investigate whether anti-VEGF therapy combined with radiation may have a 
similarly synergistic in treating eyes with eAMD.   
 
Radiation as a possible therapy for eAMD has been investigated as a therapy in over 15 
clinical trials during the past decade before the advent of anti-VEGF therapy.11-26  The rationale 
for using radiation is that it affects proliferating cells and can treat both the vascular and 
avascular component of the CNVM associated with eAMD.  Furthermore, animal studies have 
shown that low dose radiation (10Gy) can cause normalization of neovascular tissue such that 
vascular permeability is decreased.27  In most clinical trials thus far, radiation was used as sole 
therapy for eAMD.  Over 1000 patients have been treated in total in these trials using various 
doses and fractionation schedule.11-26  Although the therapy was well tolerated with minimal 
serious adverse effect, visual benefit was modest and only noted in some clinical trials.   
 
Currently, a phase 3 multicenter randomized prospective clinical trial has been started 
investigating the effect of intravitreal ranibizumab combined with radiation administered during 
vitrectomy surgery as epiretinal brachytherapy (CABERNET).7  This study is based on the 
results of a pilot study that showed encouraging findings when epiretinal delivery of strontium-90 
radiation to the macula during vitrectomy surgery was combined with anti-VEGF therapy (i.e. 
bevacizumab).28  A sustained treatment effect was noted in 75% of eyes at 1 year and 38% of 
eyes have > 3 lines of visual improvement at 12 months follow-up.  The visual benefit was 
comparable to patients who were treated with monthly ranibizumab therapy  The limitation of 
this combination therapy is that vitrectomy surgery has to be performed in order to administer 
the radiation, exposing the eye to various complications of vitrectomy surgery such as retinal 
detachment, cataract, bleeding and infection.  In addition, the actual dose of radiation delivered 
may not be well-controlled since it is dependent on the distance of the probe to the retinal 
surface which may vary from case to case depending on the surgeon.   
 
Among the various modalities that can be used to deliver radiation to the macula, the 
safest and most efficient way is proton beam.24  This form of radiation is the treatment of choice 
for treating small intraocular tumors since there is minimal lateral spread of radiation, allowing 
the same dose of radiation to be delivered using much fewer fractions.30,31  In two previous 
studies, 16 and 24 Gy of proton beam was delivered in two fractions in patients with eAMD and 
was found to have no adverse effects after two years although radiation retinopathy occurred in 
15% of subjects.15,26  A possible trend toward visual benefit was noted with proton beam 
radiation alone although the visual outcome was not significantly better than untreated eyes.   
 

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Currently, we are conducting a pilot safety and feasibility study combining Lucentis with 
proton beam irradiation (24 Gy in 2 fractions 24 hours apart) in treating eyes with exudative eye 
related macular degeneration (IND # 100,481).  Among the five subjects enrolled in the study, 
no safety concerns have been found, i.e. no radiation retinopathy was noted during the follow-up 
period ranging from 14 to 24 months.  Among three eyes with newly diagnosed exudative age at 
enrollment, a sustained treatment effect has been noted with only 1.1 mean additional 
ranizibuzumab injections being needed, all for minimal macular edema on optical coherence 
tomography, during the 23 to 24 months follow-up period.  All three eyes had > 3 lines of 
improvement in ETDRS best corrected vision acuity (BCVA) with BCVA of 20/40 or better with 
this combination therapy at month 12.  Visual gain was maintained during the second year of the 
study except for 1 eye that had slow loss of vision enlargement of geographic atrophy.  Among 
two eyes that had previously been treated with ranibizumab for exudative AMD at enrollment, 
both eyes required repeated ranibizumab therapy every 1 to 2 months for recurrent or persistent 
macular edema as was required before enrolling in the study.  One of the two eyes had 
improvement of BCVA from 20/40 to 20/20 during the first year of this study which was 
maintained during the second year.  The second eye which had been previously treated with 23 
doses of ranibizumab prior to enrollment for persistent subretinal fluid associated with 
fibrovascular pigment epithelial detachment, had slowly increasing subretinal fluid and 
decreasing vision during the 14 months of this study despite almost monthly ranibizumab 
therapy.   Based on this encouraging pilot data, the Food and Drug Administration 
recommended this randomized prospective phase I/II clinical trial to further evaluate the safety 
and efficacy of this combination therapy.  
 
TABLE 1:  Summary of Clinical Trials Using Radiation as Therapy for Exudative AMD. 
 
Study  
 
Dose  
# Treated 
Results 
 
Zambarakji et al 
 8 x 2 Gy 
83 
 
62% lost 3 or more lines after 2 yrs 
2006  
 
12 x 2 Gy 
83 
 
53% lost 3 or more lines after 2 yrs 
(f/u 2 yrs) 
 
 
 
 
 
15% Radiation retinopathy 
Proton beam  
 
 
 
 
No visually significant complications 
 
 
 
 
 
 
 
No difference between two doses 
 
Barak et al.  
10x2 Gy 
22 Treated 
No difference in vision or FANG 
2005  
 
12x2 Gy 
10 Treated 
among various doses of radiation 

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(f/u 1 yr) 
 
14x2 Gy 
11 Treated 
No Control 
Stereotactic EBT 
16x2 Gy 
11 Treated 
No significant complications 
 
 
 
18x2 Gy 
 8  Treated 
 
 
 
20x2 Gy 
32 Treated 
 
 
 
Marcus et al.  
5 x 4 Gy 
41 Treated 
Smaller lesion, less fibrosis with Rx 
2004  
 
 
 
(10 sites) 
Modest visual benefit at 6 mos 
(f/u 1yr) 
 
 
 
Randomized  
No Visual Benefit at 1 yr 
EBT  
 
 
 
(88 enrolled) 1 case of mild radiation retinopathy 
 
Prettenhofer et al. 14.4Gy 
40 Treated 
No visual benefit or FANG benefit 
2004 
 
 
25.2Gy 
40 Treated 
  
but no control 
(f/u 4 yrs) 
 
 
 
 
 
Churei et al.  
10x2 Gy 
21 Treated 
Vision loss--40% vs 81% (p 0.03) 
2004 
 
 
 
 
Nonrandomized 
Improved FANG (p 0.03) 
(f/u 2 yrs) 
 
 
 
Controlled 
 
No radiation complication 
EBT 
 
Cuilla et al.  
2x 8 Gy 
20 Treated 
No significant benefit with Rx 
2002  
 
 
 
Randomized Trend toward visual stabilization 
(f/u 1 yr) 
 
 
 
Controlled 
Proton Beam  
 
 
(37 enrolled) 
 
Hart et all 
 
6 x 2 Gy 
100 Treated 71% vs 61% 3 line loss (p 0.08) 
2002  
 
 
 
Randomized 
(f/u 2 yrs) 
 
 
 
Controlled 
 
EBT  
 
 
 
(199 enrolled) 
 
Valmaggia et al. 
1 x 1 Gy 
161 Treated 3.23 mean lines lost 
2002  
 
4 x 2 Gy 
Randomized 1.73 mean lines lost (p 0.01) 
(f/u 1.5yr) 
 
4 x 4 Gy 
 
 
1.93 mean lines lost (p 0.08) 
EBT  
 
 
 
 
 
No control or complications 
 
 
 

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Marcus et al.  
7 x 2 Gy 
41 Treated 
No significant difference 
2001  
 
 
 
Randomized 
(f/u 1 yr) 
 
 
 
(83 enrolled) 
EBT 
 
Flexal et al.  
1 x 8 Gy 
24 Treated 
44% stabilized or improved at 1 yr 
2000  
 
1 x 14Gy 
24 Treated 
75% stabilized or improved at 1 yr 
(f/u 22 mos)  
 
 
 
 
No control 
Proton Beam  
 
 
 
 
1 case of vision loss from radiation with 14 Gy  
 
RADS  
 
8 x 2 Gy 
101 Treated No benefit at 1 yr 
1999  
 
 
 
Randomized No radiation complication 
(f/u 1 yr) 
 
 
 
Controlled 
 
EBT  
 
 
 
(205 enrolled) 
 
Char et al. 
 
1 x 7.5Gy 
13 Treated 
Slightly less visual loss (p<0.05) 
1999  
 
 
 
Randomized No FANG difference 
(f/u mean 17 mos)  
 
Controlled 
No Complications 
EBT  
 
 
 
(27 enrolled) 
 
Spaide et al.  
5 x 2 Gy 
91 Treated 
No benefit or complications 
1998  
 
 
 
Nonrandomized 
EBT  
 
 
 
Controlled 
120 enrolled 
 
Begink et al.  
4 x 6Gy 
37 Treated 
Less severe vision loss-52% vs 32% 
1998  
 
 
 
Randomized No complications 
(f/u 1 yr) 
 
 
 
Controlled 
EBT  
 
 
 
(72 enrolled) 
 
Yonemoto et al. 
8 Gy  
21 Treated 
36% Lesion control at 21 mos 
2000  
 
14Gy  
27 Treated 
89% Lesion control at 21 mos 
(f/u mean 16 mos)  
 
 
 
No complications; VA stable 
Proton Beam  
 
 
 
 
No control 
 

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Total # Subjects Treated 
 
1062 
 
 
1.2 
TREATMENT OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION 
The current treatment options for treatment of exudative age-related macular 
degeneration include thermal laser photocoagulation, photodynamic therapy alone 
or in combination with intravitreal Kenalog, intravitreal Macugen, intravitreal 
Lucentis (ranibizumab) and intravitreal Avastin (bevacizumab).   
 
1.3 
RANIBIZUMAB AND BEVACIZUMAB FOR EXUDATIVE AGE-RELATED 
MACULAR DEGENERATION 
Among the various treatments, the treatment of choice for patients with exudative 
age-related macular degeneration involving the fovea, the central macula, is anti-
VEGF therapy, either ranibizumab (Lucentis) or bevacizumab (Avastin).  The 
visual outcome of intravitreal anti-VEGF therapy is much better than that observed 
with other therapies.4,5  Both drugs are used in equal frequency by clinicians to 
treat exudative AMD (PAT Survey by American Society of Retinal Specialists 
2009).  Although the relative efficacy of ranibizuamab and bevacizumab in treating 
exudative AMD is being investigated in several large multi-center prospective 
studies, most studies have shown that both drugs are effective and safe in 
treating eyes with exudative AMD.4,5,44 
 
1.4 
NONCLINICAL EXPERIENCE WITH RANIBIZUMAB AND BEVACIZUMAB 
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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The intravitreal dose of Bevacizumab (Avastin) most commonly used clinically is 
1.25mg in 0.05ml.  This dose was derived from consideration of the molecular 
weight and binding affinity differences between ranibizumab and bevacizumab.  
Bevacizumab 1.25mg is estimated to be roughly equivalent to ranibizumab 0.3 to 
0.5mg in terms of number and affinity of the binding sites that are delivered to the 
eye.32  The intravitreal half-life of bevacizumab is estimated to be twice that of 
ranibizumab due to the increased size of the moleculte (149kD versus 48kD) as 
well as the presence of the Fc portion.  Pharmacokinetics of intravitreal 
bevacizumab have been studied in rabbits and cynomolgus macaques monkeys 
and found to be 4.3 days.33-34  In both species, the drug was found to penetrate 
the full thickness of the retina into the choroidal layer.35-37   
 
1.4.2 Nonclinical Toxicology 
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). 
Electrophysiologic studies in rabbits done at 3 hours to 4 weeks following 
intravitreal injection of 2.5mg of bevacizumab  showed no evidence of retinal 
toxicity.37      
 
1.4.3 Stability Studies 
The stability of ranibizumab alone and in combination with verteporfin was 
assessed in vitro.  The combination of ranibizumab and verteporfin in a 
5% dextrose solution at concentrations of 500 g/mL and 1.4 g/mL, respectively, 
resulted in ranibizumab degradation and a decrease in ranibizumab capacity to 
bind VEGF.  The ranibizumab degradation products have not been fully 
characterized.  Although it is currently unknown if such degradation also occurs in 
vivo, sequential administration of verteporfin followed by ranibizumab with an 
intervening washout period will decrease the likelihood of loss of ranibizumab 
activity and degradation.   
The stability of bevacizumab stored at 4 degrees C after aseptically aliquoting into 
multidose vials was studied.  The drug was found to remain stable up to 6 months 
and remain stable if aseptic precautions are taken.38 
 

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1.5 
CLINICAL EXPERIENCE WITH RANIBIZUMAB AND BEVACIZUMAB 
Ranibizumab has been FDA-approved for treatment of exudative AMD as monotherapy. 
Please refer to the Ranibizumab Investigator Brochure or Lucentis Package Insert for 
additional details regarding clinical safety experience with ranibizumab.  It is being 
clinically evaluated in several studies to study its effect in treating diabetic macular 
edema and retinal vein occlusion.  
Bevacizumab was FDA-approved for systemic intravenous administration to treat patients 
with metastatic cancer (please refer to package insert for Avastin attached).  Intravitreal 
bevacizumab has been used off-label successfully by clinicians since 2005 to treat eyes 
with exudative AMD and other causes of choroidal neovascularization.39,40  It has been 
used successfully to treat macular edema and ocular neovascularization from retinal vein 
occlusion or diabetic retinopathy.41-43  There are several large multi-center randomized 
clinical trials that are on-going to compare the efficacy of bevacizumab to ranibizumab in 
treating eyes with exudative AMD (e.g. CATT trial).  The results are pending but 
retrospective non-randomized studies showed no difference in visual acuity in eyes with 
exudative AMD treated with ranibizumab versus bevacizumab.44  No safety concerns 
have been noted in patients treated with intravitreous bevacizumab.45  A recent survey of 
practicing retinal specialists showed that bevacizumab is used in equal frequency as 
ranibizumab in treating patients with exudative AMD (PAT survery, 2009). 
 
 
2. 
OBJECTIVES 
2.1  Primary Objective 
. 
 To determine the safety and efficacy of proton beam radiation combined with 
ranibizumab (Lucentis) or bevacizumab (Avastin) in treating patients with exudative 
AMD 
 
2.2  Secondary Objectives 
 
 Evaluate best corrected visual acuity (BCVA) at months 0, 12 and 24 months. 
 Evaluate the number of subjects with > 15 letters of visual improvement. 
 Evaluate change in macular thickness as measured at baseline, 12 and 24 
months by optical coherence tomography. 
 Evaluate mean number of anti-VEGF injections needed at 12 and 24 months. 

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 Evaluate number of patients with loss of BCVA of > 3 lines at 12 and 24 
months. 
 Evaluate the number of subjects with >3 lines of vision loss (among subjects with 
radiation retinopathy or papillopathy) at 12 and 24 months compared to baseline. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a prospective, randomized, double-blinded Phase I/II study of the safety 
and efficacy of intravitreally administered ranibizumab or bevacizumab in subjects 
with exudative age-related macular degeneration when combined with proton 
beam radiation.   
Forty-five subjects will be consented and enrolled and randomized 1: 1: 1 to 
receive intravitreal anti-VEGF therapy (ranibizumab (0.5mg) or bevacizumab 
(1.25mg)) combined with sham, proton beam (16 Gy in 2 fractions) or proton 
beam radiation (24 Gy divided into 2 fractions).  The accrual will occur over a 12 
month period and subjects will be followed for 24 months.  Thus, the study will be 
completed within 36 months of initiation of the study.   
Each subject with newly diagnosed exudative AMD who received ranibizumab 
(0.5mg) or bevacizumab (1.25mg) intravitreally within 6 weeks as standard of care 
will be randomized 1: 1: 1 to sham irradiation, 16 Gy proton beam or 24 Gy proton 
beam in 2 fractions 24 hours apart. Randomization will be such that there is an 
equal number of subjects treated with ranibizumab versus bevacizumab for each 
radiation treatment group.  The subjects will be following monthly by the treating 
retinal specialist and treated with a total of three monthly injections of ranibizumab 
(0.5mg) or bevacizumab (1.25 mg).  Thereafter, each subject will be examined 
monthly with OCT as part of standard of care and repeat injection will be 
performed if there is any detectable recurrent or persistent macular edema or 
subretinal fluid noted on OCT, new retinal hemorrhage, or visual acuity is 
decreased by two lines or more.  This criteria for retreatment is similar to the 
PRONTO and SAILOR studies and has become the standard of care (PAT 
Survey Result 2009).6,44,46  Both the subject and treating ophthalmologist will be 
blinded to the treatment administered.  Each subject will be treated with the same 
anti-VEGF drug for the duration of the study.  Repeat fluorescein angiography will 
be performed annually and at the discretion of the treating retinal specialist.  

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Trial Schema is enclosed in Appendix A. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
Since synergism was noted between anti-VEGF therapy and radiation in animal and 
clinical oncology studies,8-10 it is of interest to determine whether the effect of intravitreal 
ranibizumab or bevacizumab in treating exudative macular degeneration can be further 
enhanced by radiation.  Based on our small pilot study and a pilot study combining 
bevacizumab with vitrectomy and epiretinal brachytherapy,28 we need to determine 
whether the combination of anti-VEGF therapy and proton beam radiation is safe and 
effective among patients with this condition.  The dose of radiation proposed for this 
study has been shown to be safe for treatment of exudative age-related macular 
degeneration when used alone.26  Low dose of radiation has been shown to normalize 
neovascular tissue.27  Proton beam is the safest way of administering radiation to the eye 
and can be administered in much fewer fractions than external beam radiation.25  Since 
radiation retinopathy is seen about 1 to 2 yrs following radiation exposure, the patients 
will be followed for at least 2 year as part of this protocol.  The enrolled subjects will be 
continued to be followed as part of usual care thereafter. 
 
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measures 
 
The primary outcome measures for safety and efficacy are the following: 
1.  Incidence and severity of ocular adverse events, as identified by eye examination 
(including visual acuity testing). 
 
2.  Best corrected visual acuity (BCVA) at Months 0, 12 and 24. 
 
 3.3.2 Secondary Outcome Measures 
 
 Number of subjects with > 3 lines of BCVA improvement 
 Change in macular thickness as measured at 12 and 24 months compared to 
baseline by optical coherence tomography. 
 Number of intravitreal injections with anti-VEGF drugs needed at 12 and 24 
months. 

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 Evaluate number of patients with loss of BCVA of > 3 lines at 12 and 24 
months. 
 Evaluate the number of subjects with > 3 lines of vision loss (among subjects with 
radiation retinopathy or papillopathy) at 12 and 24 months compared to baseline 
 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 
and Appendix A. 
 The potential side-effects of intravitreal anti-VEGF therapy for exudative age-
related macular degeneration have been well characterized in previous clinical 
trials and studies.4,5, 45  The only serious potential side-effect of intravitreal anti-
VEGF injection is endopthalmitis which can occur in up to 1% of patients.  This 
side-effect should not be increased by subjects treated concurrently with 
radiation.  The potential side-effects of proton beam radiation include radiation 
retinopathy and papillopathy.  The risk of serious vision loss from proton beam 
radiation using the dose and fractionation outlined in this protocol is 
negligible.26  However, the combination therapy of intravitreal anti-VEGF and 
proton beam radiation has not been investigated previously except in our small 
on-going pilot study.  Since some vascular endothelial growth factor is needed 
for normal vascular health, it is theoretically possible that inhibition of vascular 
endothelial growth factor may increase the risk of radiation retinopathy.  
However, it also is possible that anti-VEGF therapy may decrease the risk of 
visually significant radiation retinopathy since it has been used to treat 
radiation maculopathy.  This safety and efficacy study will investigate whether 
any serious adverse side-effect is observed with this combination therapy and 
whether the treatment is effective.  Enrolled subjects will be examined monthly 
for the 24 months duration of this study for any evidence of radiation 
retinopathy or papillopathy which may be visually significant. Any patient with 
retinal vascular disease or history of previous radiation exposure will be 
excluded from this study.    
 One of the secondary endpoints of this study is the incidence of loss of BCVA 
of > 3 lines at 12 and 24 months.  This severe vision loss can occur as part of 
the natural progression of exudative macular degeneration.  If this severe 
vision loss is due to radiation retinopathy, characteristic fundus and 
angiographic changes will be observed.  Thus, it will be possible to determine 

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whether the vision loss is from that natural course of the condition or from 
adverse side-effect of the treatment.  
 The incidence of endophthalmitis should be 1% or less based on previously 
published clinical data.  The incidence of radiation retinopathy using the proton 
beam radiation dose outlined in this protocol is 15% based on a recent 
published report.26  However, there should be no case of radiation retinopathy 
that is visually significant based on this previous report.  A description of 
actions that will be taken if the adverse events occur. 
 Treatment recommendations:  If visually significant radiation 
retinopathy with maculopathy is observed, subjects will be treated 
with laser therapy, intravitreal steroid therapy or anti-VEGF therapy 
as standard of care by the treating retinal specialist. 
 Supplemental clinical tests or procedures to complete diagnosis of 
the adverse even:  Fluorescein angiography as needed. 
 Contingency review and assessment of the serious adverse events: 
If visually significant radiation retinopathy or papillopathy is 
observed, the Institutional Review Board and the Radiation Safety 
Committee at the University of California, Davis will be informed of 
the adverse event.  Further enrollment in the study will be contingent 
on their recommendations.  
 The number of subjects needed to observe specific effects or to show 
statistically significant results is usually much larger than the sample size for 
this study.  Since this is a relatively small phase I/II study enrolling only 45 
subjects with 30 eyes being treated with radiation combined with antiVEGF 
therapy, the study will be too small to detect adverse side-effects that may 
occur in less than 3% of subjects.  In addition, it may be too small to determine 
whether this combination therapy is more effective than monotherapy with 
Lucentis unless the treatment effect of combination therapy is dramatically 
better than monotherapy.  This small sample size was chosen based on the 
promising results of our pilot study and the reported results of other clinical 
trials using anti-VEGF therapy combined with low dose radiation.  Thus, a 

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larger Phase III trial will be planned pending the results of this proposed study 
to obtain more safety and efficacy information of this combination therapy. 
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 
All subjects will be enrolled at the University of California, Davis, Eye Center, 
Department of Ophthalmology & Vision Science.  The subjects will be recruited 
from the retina clinic at the University of California Davis Eye Center or the 
Veteran Administration Hospital Eye Clinic at Mather, CA, and followed monthly at 
these two study sites monthly as standard of care for the duration of the study. 
 
Forty-five subjects from two sites in the United States will be enrolled.   Eligible 
subjects who have provided informed consent.  (See Appendix A, the study flow 
chart, for screening assessments.) 
 
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 > 50 years 
 Patient-related considerations 
 Able to maintain follow-up for at least 24 months. 
• 
Women must be postmenopausal without a period for at least one year. 
• 
Diagnosed with Age-related Macular Degeneration (ARMD) with active subfoveal 
choroidal neovascular membrane (CNVM), newly diagnosed or treated with first dose 
of anti-VEGF therapy within 6 weeks of enrollment 
• 
Visual acuity 20/40 to 20/400  
• 
Lesion size < 12 Disc Area 
• 
Submacular hemorrhage less than 75% of total lesion and not involving foveal center 

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• 
Submacular fibrosis less than 25% of total lesion 
• 
Candidate for intravitreal anti-VEGF therapy 
 
4.1.3 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study:  
 
 Prior enrollment in the study 
 Pregnancy (positive pregnancy test) or lactation   
 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 
 Previous treatment with Photodynamic Therapy (PDT) or thermal laser in study eye 
 Anti-VEGF therapy within 6 weeks 
 Intravitreal or subtenon’s Kenalog within 6 months 
 Intraocular surgery within 3 months or expected in the next 6 months 
 Current or planned participation in other experimental treatments for wet AMD  
 Other concurrent retinopathy or optic neuropathy 
 Other causes of CNVM, i.e. myopic degeneration or ocular histoplasmosis (POHS)  
 Significant media opacity precluding adequate view of the fundus for exam, 
 
photography or OCT 
 History of radiation therapy to the head or study eye 
 Diabetes mellitus or hemoglobin A1c > 6 
 Head tremor or h/o claustrophobia precluding positioning for proton irradiation 
 Inability to maintain steady fixation with either eye 
 History of Malignancy treated within 5 years 
 Allergy to Fluorescein dye  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a prospective randomized double-blinded clinical trial.  All enrolled subjects 
will be randomized 1: 1 : 1 to either sham irradiation, 16 Gy proton beam or 24 Gy 
proton beam, all administered in 2 fractions 24 hours apart.  All eyes will receive 
intravitreal ranibizumab or bevacizumab as standard of care.  
 

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4.3 
STUDY TREATMENT 
4.3.1 Formulation 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile, 2-mL or 3-mL 
stoppered glass vial.  Each single-use vial is designed to deliver 0.05 mL of 10 mg/mL 
ranibizumab aqueous solution with 10 mM histidine HCI, 10%, -trehalose dihydrate, and 
0.01% polysorbate 20, pH 5.5.  Each vial contains no preservative and is suitable for 
single use only. 

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Bevacizumab, formulated as a sterile 25mg/ mL solution for intravenous administration, 
will be aseptically aliquoted in a sterile syringe by a compounding pharmacy or hospital 
in-patient pharmacy.  Each syringe will be filled to deliver 0.05mL of 1.25mg of 
bevicizumab.  The sterile solution of bevacizumab (25mg/mL) is a clear to slightly 
opalescent, colorless to pale brown, sterile, pH 6.2 solution. The 4mL intravenous 
solution is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate 
(monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg 
polysorbate 20, and Water for Injection, USP.  
Further details and molecule characterization can also be found in the package inserts for 
the drugs. 
 
4.3.2 Dosage, Administration, and Storage 
a. Dosage 
All subjects will be treated with intravitreal ranibizumab (0.5 mg) or bevacizumab 
monthly for 3 months.  Thereafter, all subjects will be examined monthly and 
treated with the same intravitreal anti-VEGF drug (repeat injection) if there is any 
detectable recurrent or persistent macular edema or subretinal fluid noted on 
OCT, new retinal hemorrhage, or visual acuity is decreased by two lines or more 
attributed to progression of macular degeneration as standard of care.  All 
subjects will also be treated with sham or proton beam radiation (16 or 24 Gy 
divided into two fractions at least 24 hrs apart) or sham radiation 2 to 6 weeks 
after the first anti-VEGF injection.  Both the patient and treating ophthalmologist 
will be blinded. 
b. Administration 
Intravitreal administration of anti-VEGF therapy will be performed by treating 
retinal specialists using a technique and protocol which has become standard of 
care.  Briefly, the eye will be anesthesized with topical lidocaine and prepped 
using topical 5% betadine solution.  A  sterile lid speculum will be used to open 
the eye.  Anti-VEGF drug will be administered 4mm behind the limbus using a TB 
syringe attached to a 30 gauge needle.  A volume of 0.05cc will be injected per 
eye per injection.  Visual acuity of at least Counting finger after injection will be 
confirmed.  If visual acuity is worse than counting finger, intraocular pressure 

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measurement and funduscopy will be promptly performed.  Paracentesis will be 
performed at the discretion of the treating ophthalmologist. 
 
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 
and bevacizumab syringes or vials should remain refrigerated.  Protect from direct 
sunlight. Ranibizumab will be stored in original carton until time of use.  
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Subjects may be treated with topical antibiotics for 1 day before and up to 7 days 
after each intravitreal injection at the discretion of the treating ophthalmologist.  
Subjects may continue to receive all medications and standard treatments 
administered for their conditions at the discretion of their treating physician.   
4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
All subjects will be instructed to contact the investigator or treating physician by 
telephone promptly for any worsening vision or eye pain to ensure that they are 
not experiencing any serious adverse side-effect from the injection.  All subjects 
will be examined monthly by the treating retinal specialist to ensure no serious 
adverse side-effect has occurred and to determine whether repeat anti-VEGF 
injection will be needed after the first three months.   As outlined in Appendix A, all 
subject will sign an informed consent and a medical release statement at 
enrollment such that copies of the eye examination,  including visual acuity, OCT, 
fundus photography and fluorescein angiography at baseline and each monthly 
follow-up visit can be obtained from the treating retinal specialist by the study 
investigators.   
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 nonserious) if possible.  The 
schedule of assessments for early termination is the same as that for the final 
visit. 
 

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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 Department of Ophthalmology & Vision Science at the University of 
California, Davis, Medical Center 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 
 Intraocular surgery in the study eye 
 Investigator determination that it is not in the best interest of the subject to 
continue participation 
 Pregnancy 
 Verteporfin PDT treatment in the study eye 
 Pegaptanib sodium injection treatment in either eye 
 SAE 
 Any other safety concerns 
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.   In addition, the subject will be treated 
for the SAE based on the standard of care for that condition.  If a subject is 
discontinued from the study for reasons other than SAE directly related to the 
treatment proposed in this proposal, an additional subject will be enrolled.  
 
4.7 
STUDY DISCONTINUATION 
This study may be terminated by The University of California, Davis, Medical 
Center at any time.  Reasons for terminating the study may include the following: 

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 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 
4.8.1 Analysis of the Conduct of the Study 
There is no formal sample size calculation in a phase I/II study.  As this is a phase 
I/II study with three treatment groups, a sample size of forty-five patients is 
chosen, to make sure that it is feasible financially to conduct the study and 
logistically to complete the study within 3 years.   
If and when the study is planned for a phase 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 forty-five subjects will be utilized 
to summarize safety data for this study. 
4.8.3 Efficacy Analyses 
a. Primary Endpoint 
All forty-five subjects enrolled in this study will be included to determine the safety and 
efficacy of proton beam radiation combined with intravitreal anti-VEGF therapy in 
treating patients with exudative AMD.  The fifteen subjects treated with anti-VEGF 
therapy and sham irradiation will be compared to fifteen subjects treated with anti-
VEGF therapy and 16 Gy of proton beam and fifteen subjects treated with anti-VEGF 
therapy and 24 Gy of proton beam.  Best corrected visual acuity (BCVA) at Months 0, 
12 and 24 will be used as a primary measure of efficacy. 
Incidence and severity of ocular adverse events, as identified by eye examination 
(including visual acuity testing) will be evaluated.  In addition, % of subjects with 
radiation retinopathy and papillopathy at 12 and 24 months will be determined.   
b. Secondary Endpoints 
 Number of subjects with > 3 lines of visual improvement 

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 Change in macular thickness as measured at baseline and 12 and 24 months 
by optical coherence tomography. 
 Number of anti-VEGF injections needed at 12 and 24 months. 
 Evaluate number of patients with loss of BCVA of > 3 lines at 12 and 24 
months. 
 Evaluate the number of subjects with > 3 lines of vision loss (among subjects with 
radiation retinopathy or papillopathy) at 12 and 24 months compared to baseline 
Subjects who prematurely withdraw from the study will be excluded from the data 
analysis unless the withdrawal was determined to be due to SAE directly related 
to the treatment proposed in this study.  If severe vision loss (>15 letters of vision 
loss) occurred due to SAE related to the treatment proposed, this information will 
be included in the data analysis.  
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.     
 
5. 
ASSESSMENT OF SAFETY 
The safety of ranibizumab or bevacizumab combined with proton beam radiation 
will be assessed through monthly examination of the subjects until month 24.     
 
5.1 
ADVERSE EVENTS 
AEs that start on Day 0 through the last study visit will be recorded on the 
appropriate AE pages of the CRF.  Subjects discontinuing early from the study 

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should return for an early termination evaluation and will be contacted 7 days after 
their last injection or study visit to elicit for occurrence of adverse events (serious 
and nonserious). 
For this protocol, an AE is any “on study” untoward medical occurrence (e.g., sign, 
symptom, disease, syndrome, intercurrent illness) that occurs in a study subject, 
regardless of the suspected cause.  “On study” refers to Day 0 through the last 
study visit. 
Unchanged, chronic conditions are NOT AEs and should not be recorded on the 
AE pages of the CRF.  An exacerbation or worsening of a chronic condition 
should be recorded as an AE. 
Both serious and nonserious AEs should be graded on a three-point scale (mild, 
moderate, severe) and reported in detail on the appropriate AE page of the CRF.   
The suggested definitions are as follows:  
Mild: 
Discomfort noticed but no disruption of normal daily activity 
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity 
Severe: 
Incapacitating with inability to work or perform normal daily activity 
Using the following criteria, investigators also need to assess whether there is a 
reasonable possibility that study drug caused or contributed to the AE. 
 Yes (possibly or probably) 
There is a clinically plausible time sequence between onset of the AE and 
study drug administration; and/or 
There is a biologically plausible mechanism for study drug causing or 
contributing to the AE; and 
The AE may or may not be attributed to concurrent/underlying illness, other 
drugs, or procedures. 
 No 
A clinically plausible temporal sequence is inconsistent with the onset of 
the AE and study drug administration; and/or 

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A causal relationship is considered biologically implausible. 
 
5.2 
BASELINE MEDICAL CONDITIONS 
It is not necessary to complete an AE CRF page for chronic medical conditions 
present at enrollment that do not worsen in intensity or frequency during the trial.  
These medical conditions should be adequately documented on the appropriate 
page of the CRF (medical history and/or physical examination).  However, 
medical conditions present at enrollment that worsen in intensity or frequency 
during the treatment or posttreatment periods and ongoing AEs that started during 
the previous study should be reported and recorded as AEs.   
 
5.3 
EVALUATIONS 
Reviews of body systems will be performed.   
Ophthalmologic evaluations will include slitlamp 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.)   
 
5.4 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS 
 
5.4.1 Serious Adverse Events 
An AE occurring at any dose (including overdose) should be classified as 
SERIOUS if: 
 It resulted in death (i.e., the AE caused or led to death). 
 It was life threatening (i.e., the AE placed the subject at immediate risk of 
death; it does not apply to an AE that hypothetically might have caused 
death if it were more severe). 
 It required or prolonged inpatient hospitalization (i.e., the AE required at 
least a 24-hour inpatient hospitalization or prolonged a hospitalization 
beyond the expected length of stay; hospitalizations for elective 
medical/surgical procedures, scheduled treatments, or routine check-ups 
are not SAEs by this criterion). 

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 It was disabling (i.e., the AE resulted in a substantial disruption of the 
subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect (i.e., an adverse outcome in 
a child or fetus of a subject exposed to the molecule or study drug prior to 
conception or during pregnancy). 
 It does not meet any of the above serious criteria but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
SAE Reporting 
Investigators must report all SAEs to the FDA and local IRB within 48 hours of 
observing or learning of the event.  For initial SAE reports, investigators should 
record all case details that can be gathered within 48 hours on the SAE page of 
the CRF. 
 
5.4.3 Special Reporting Situations 
a. Death 
Death is an outcome of an event.  The event that resulted in the death should 
be recorded and reported on the SAE pages of the CRF. 
b. Hospitalizations for Surgical or Diagnostic Procedures 
The illness leading to the surgical or diagnostic procedure should be recorded 
as the SAE, not the procedure itself.  The procedure should be captured in the 
case narrative as part of the action taken in response to the illness. 
c. Pregnancy 
Animal reproduction studies have not been conducted with ranibizumab or 
bevacizumab.  It is also not known whether ranibizumab can cause fetal harm when 
administered to pregnant women or can affect reproduction capacity.  Any pregnancy 
occurring during study treatment should be reported and the subject removed from 
the study. 
5.4.4 Type And Duration Of Follow-Up After Adverse Events 
All reported AEs should be followed until resolution or until the subject’s 
participation in the study ends.  Subjects who have an ongoing  

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study drug–related SAE at study completion or at discontinuation from the study 
will be followed by the investigator or his or her designee until the event is 
resolved or determined to be irreversible, chronic, or stable by the investigator.   
 
5.4.5 Regulatory Reporting Requirements for Principal Investigators Holding Their Own 
INDs  
Investigators conducting studies under their own INDs are responsible for expedited 
Safety Reports and IND Annual Reports to the FDA. 
Expedited IND Safety Reports: 
 
For this Investigator Sponsored IND Study, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR § 312.32. 
 
Events meeting the following criteria should be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
Fatal or Life-Threatening, Unexpected, Drug-related SAEs 
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 related to the use of 
anti-VEGF therapy or proton beam irradiaiton. Reports are to be telephoned or faxed to 
the FDA within 7 calendar days of the Investigator’s knowledge of the event.   
 
An unexpected adverse event is one that is not already described in the ranibizumab 
and bevacizumab package inserts.  This includes adverse events that have not been 
identified as life-threatening or causing a death as described in the IB, for example, 
elevated hepatic enzymes or hepatitis versus liver failure.  This also includes unusual 
AEs not specifically described in the IB, for example, hemorrhage versus intraocular 
bleeding.   
 
The 7-day telephone or fax report must be followed within 8 additional calendar days by a 
written IND safety report (MedWatch 3500A Form). Written IND Safety Reports should 
include an Analysis of Similar Events in accordance with regulation 21 CFR § 312.32.  
(See Appendix D for Analysis of Similar Events template).  All safety reports previously 

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filed to the IND concerning similar events should be analyzed. The significance of the 
new report in light of the previous, similar reports should be commented on.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA,  
preferably on a MedWatch 3500A Form but alternative formats are acceptable (e.g. 
summary letter). 
 
FDA Fax Number for IND Safety Reports: 
 
1 (800) 332-0178  
 
AND submitted to: 
University of California, Davis, Institutional Review Board 
 
 
Serious, Unexpected, and Drug-related SAEs (not life-threatening or fatal) 
 
A written IND Safety Report (described above) should also be produced for any 
unexpected SAE that is considered related to the use of ranibizumab or bevacizumab or 
proton beam but is not life-threatening or fatal.  Investigators are required to notify the 
FDA, the IRB, and all participating investigators by submitting the IND Safety Report 
within 15 days of the Investigator’s knowledge of the event. 
 
5.5.5.1 MedWatch 3500A Reporting Guidelines: (See Appendix C for MedWatch form) 
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: 
 
 Identification of the primary event term 
 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 

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 If a death occurred, autopsy results if available 
 
MedWatch forms can be obtained on-line at www.fda.gov/medwatch or by calling the 
FDA at 1-800-332-1088. 
 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
 
 Add to the original MedWatch 3500A report and submit it as follow-up 
 Add documents and submit as follow-up with the original MedWatch 3500A form  
 Summarize new information and fax it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted.  (Patient identifiers are important so that new information is added to the 
correct initial report.) 
 
 
 
6.0 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with The 
University of California, Davis, Medical Center or its appointed representative:  
 FDA correspondence letter assigning an IND number or an IND waiver letter 
 Original U.S. FDA Form 1572 (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal 
Investigator 
 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  

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 Written documentation of IRB approval of protocol (identified by The University 
of California, Davis, Medical Center, protocol number or title and date of 
approval) and informed consent document (identified by University of 
California, Davis, Medical Center protocol number or title and date of approval) 
 A copy of the IRB-approved informed consent document 
 Written documentation of IRB review and approval of any advertising materials 
to be used for study recruitment, if applicable 
 The informed consent document and any advertising materials must also be 
reviewed and approved by the University of California, Davis, Medical Center 
Legal Department. 
 Certified translations of IRB approval letters, pertinent correspondence, and 
approved informed consent document (when applicable) 
 Current laboratory certification of the laboratory performing the analysis as well 
as current normal laboratory ranges for all laboratory tests. 
6.2 
STUDY COMPLETION 
The following data and materials are required by The University of California, 
Davis, Medical 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) 
 Copies of protocol amendments and IRB approval/notification (if applicable) 
 A summary of the study prepared by the Principal Investigator (will accept IRB 
summary close letter) (if applicable) 
 All regulatory documents (e.g., curricula vitae for each Principal Investigator, 
U.S. FDA Form 1572) 
 
6.3      INFORMED CONSENT 
Informed consent documents will be provided to each subject.  

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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 possibility that the 
FDA and the [University of California Davis Medical 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 

Protocol:  FVF4150S  Amendment 3 
 
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4-22-08  
 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 IRB/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 IRB/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 IRB/EC any written safety report or update provided 
by [University of California Davis Medical Center] (e.g., IND safety report, 
Investigator Brochure, safety amendments and updates, etc.). 
 
6.5 
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. 

Protocol:  FVF4150S  Amendment 3 
 
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4-22-08  
 
6.6 
STUDY DRUG ACCOUNTABILITY 
Not applicable since ranibizumab and bevacizumab will be administered as 
standard of care by treating ophthalmologist.  
 
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. 

Protocol:  FVF4150S  Amendment 3 
 
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14. Churei H, Ohkubo K, Nakajo M, Hokotate H, Baba Y, Ideue J. et al.  External-beam radiation 
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24. Yonemoto LT, Slater JD, Blacharski P, Slater JM.  Proton radiation therapy of age-related 
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25. Yonemoto LT, Slater JD, Blacharski P, et al.  Dose response in the treatment of subfoveal 
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26. Zambarakji HJ, Lane AM, Ezra E, Gauthier D, Goitein M, Adams JA, et al.  Proton beam 
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27. Hori K, Saito S, Tamai M.  Effect of irradiation on neovascularization in rat skinfold chambers:  
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28. Avila MP, Farah ME, Santos A, et al.  Twelve-month short-term safety and visual-acuity results 
from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab 
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30. Park SS, Walsh SM, Gragoudas ES.  Visual field deficits associated with proton beam irradiation 
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32. Stewart MW.  Predicted biologic activity of intravitreal bevacizumab.  Retina.  2007; 27: 1196-
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33. Bakri SJ, Synder MR, Reid JM, Pulido JS, Singh RJ.  Pharmacokinetics of intravitreal 
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34. Miyake T, Sawada O, Kakinoki M, et al.  Pharmacokinetics of bevacizumab and its effect on 
vascular endothelial growth factor after intravitreal injection of bevacizumab in macaque eyes.  
Invest Ophthalmol Vis Sci. 2010; 51: 1606-1608. 
35. Heiduschka P, Fietz H, Hofmeister S, et al.  Penetration of bevacizumab through the retina after 
intravitreal injection in the monkey.  Invest Ophthalmol Vis Sci.  2007; 48: 2814-2823. 
36. Nomoto H, Shiraga F, Kuno N, et al.  Pharmacokinetics of bevacizumab after topical, 
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37. Shahar J, Avery RL, Heilweil G, et al.  Electrophysiologic and retinal penetration studies following 
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38. Chen YH, Wu PC, Shiea J, Lo LH, Wu YC, Kuo HK.  Evaluation of the sterility, stability, and 
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39. Chan WM, Lai TY, Liu DT, Lam DS.  Intravitreal bevacizumab (Avastin) for myopic choroidal 
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40. Chang LK, Spaide RF, Brue C, Freund KB, Klancnik JM, Jr., Slakter JS.  Bevacizumab treatment 
for subfoveal choroidal neovascularization from causes other than age-related macular 
degeneration.  Arch Ophthalmol.  2008; 126: 941-945. 
41. Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM.  Intravitreal bevacizumab (avastin) 
in the treatment of neovascular glaucoma.  Am J Ophthalmol.  2006; 142: 1054-1056. 
42. Avery RL, Pearlman J, Pieramici DJ, et al.  Intravitreal bevacizumab (Avastin) in the treatment of 
proliferative diabetic retinopathy.  Ophthalology 2006; 113: 1695-1705. 
43. Iturralde D, Spaide RF, Meyerle CB, et al.  Intravitreal bevacizumab (avastin) treatment of 
macular edema in central retinal vein occlusion:  A short-term study.  Retina.  2006;  26: 279-284.   
44. Fong DS, Custis P, Howes J, Hse JW.  Intravitreal bevacizumab and ranibizumab for age-related 
macular degeneration:  a multi-center, retrospective study.  Ophthalmology.  2010; 117: 298-302. 
45. Fung AE, Rosenfeld PJ, Reichel E.  The international intravitreal bevacizumab safety survery: 
using the internet to assess drug safety worldwide.  Br J Ophthalmol.  2006; 90: 1344-1349. 
46. Lalwani GA, Rosenfeld PJ, Fung AE, et al.  A variable-dosing regimen with intravitreal 
ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study.  Am 
J Ophthalmol.  2009; 148: 1-3. 
 
 
 
 
 
 
 
 

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APPENDIX A 
Study Flowchart  
 
 
Base-
line 
1-6 
wks 
1 
m 
2 
m 
3 
m 
4 
m 
5 
m 
6 
m 
7 
m 
8 
m 
9 
m 
10 
m 
11 
m 
12 
m 
13 
m 
14 
m 
15 
m 
16 
m 
17 
m 
18 
m 
19 
m 
20 
m 
21 
m 
22 
m 
23 
m 
24 
m 
Informed  
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical  
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthal 
Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus 
Photos 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Fluores 
Angio 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
OCT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Axial 
Length 
Ultra-
sonography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-VEGF 
Injection 
X 
 
X 
X 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
? 
Mask 
Fitting* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proton 
Beam or 
Sham*  
(2 Tx) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 16 or 24 Gy of proton beam or sham will be administered in 2 fractions 24 hours apart. 
Anti-VEGF therapy, either Ranibizumab (0.5 mg) or bevacizumab (1.25mg) repeat injection will be performed if there is any detectable recurrent or 
persistent macular edema or subretinal fluid noted on OCT, new retinal hemorrhage, or visual acuity is decreased by two lines or more. 
Procedures highlighted in bold will be performed by the investigators at the University of California Davis.  The remaining procedures will be done by the 
treating ophthalmologists as standard of care at the University of California Davis Eye Center or the Mather VA Hospital Eye Clinic. 
 

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APPENDIX C: MedWatch Form FDA 3500A