Conditions: Polypoidal Choroidal Vasculopathy
Keywords: polypoidal choroidal vasculopathy choroidal neovascularization ranibizumab Lucentis
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: yes

Brief summary:
This Phase I/II study will investigate the safety and tolerability of intravitreally administered 0.5mg and 1.0 or 2.0mg Ranibizumab in three monthly doses followed by a 9 month period of criteria-based, as-needed retreatment and 12 month of drug safety follow up in subjects with exudative polypoidal choroidal vasculopathy (PCV) for a total of 24 months.

Detailed description:
Twenty eyes will be randomized will receive 3 consecutive monthly intravitreal 1.0 or 2.0 mg/0.5mg (3:1 ratio) Ranibizumab injection with the first injection occuring at Day 0 and second and third injection occuring at month 1 and month 2 respectively. Retreatment with intravitreal Ranibizumab or other therapies will be at the investigators discretion but guidelines for recommended retreatment.

Arms:
arm 1: Intraocular injection of 1.0 or 2.0 mg/0.05 cc ranibizumab.

Photodynamic therapy with visudyne or laser photocoagulation or intravitreal steroids may be considered as monotherapy or in combination with Ranibizumab at the investigator's discretion if rescue criteria are met arm 2: Intraocular injection of 0.5 mg/0.05 cc ranibizumab.

Photodynamic therapy with visudyne or laser photocoagulation or intravitreal steroids may be considered as monotherapy or in combination with Ranibizumab at the investigator's discretion if rescue criteria are met

Interventions: intervention 1: ranibizumab 0.5 or 2.0 mg/0.05 cc
Intervention descriptions: intervention 1: ranibizumab (3:1 ratio of 2mg:0.5 mg ranibizumab) administered in three initial monthly doses followed by a 9 month period of criteria-based, as-needed retreatment and 12 month off drug safety follow up.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Protocol:  FVF4916s Final 
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15 November 2010 
 
PROTOCOL 
STUDY TITLE: 
Treatment of Polypoidal Choroidal Vasculopathy with 
High Dose Ranibizumab (Lucentis):A Phase I Safety 
Study 
STUDY NUBMER 
FVF4916s 
STUDY DRUG 
Recombinant humanized anti-VEGF monoclonal 
antibody fragment (rhuFab V2 [ranibizumab] 
{Lucentis}) 
 
SPONSOR 
Southeast Retina Center, P.C. 
3685 Wheeler Rd. 
Augusta, GA 30909  
IND: 
100099 
INVESTIGATOR 
Dennis M. Marcus, M.D.  
SUB-
INVESTIGATORS 
Harinderjit Singh, M.D. 
DATE FINAL: 
 15 November 2010 
 
 


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TABLE OF CONTENTS 
 
                                  
1. 
BACKGROUND ...........................................................................................  
 
1.1 
Pathophysiology ................................................................................  
 
1.2 
Treatment ..........................................................................................  
 
1.3 
Ranibizumab .....................................................................................  
1.4 
Nonclinical Experience with Ranibizumab .........................................  
 
1.4.1 
Nonclinical Pharmacokinetics ..............................................  
 
1.4.2 
Nonclinical Toxicology .........................................................  
 
1.4.3 
Stability Studies ...................................................................  
 
1.5 
Clinical Experience with Ranibizumab ...............................................  
 
1.5.1 
Study FVF1770g ..................................................................  
 
1.5.2 
Study FVF2128g ..................................................................  
 
1.5.3 
Study FVF2425g ..................................................................  
 
1.5.4 
Study FVF2428g ..................................................................  
 
1.5.5 
Study FVF2508g ..................................................................  
 
1.5.6 
Study FVF2587g ..................................................................  
 
1.5.7 
Study FVF2598g ..................................................................  
 
1.5.8 
Study FVF3192g ..................................................................  
 
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) 
 
                    
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...........................................  
 
4.6  
Subject Discontinuation .....................................................................  
 
4.7  
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 …………………………………………………. 
5.0 ASSESSMENT OF SAFETY .......................................................................  
 
5.1 
Adverse Events .................................................................................  
 
5.2 
Baseline Medical Conditions .............................................................  
5.3 
Evaluations ........................................................................................  
5.4 
Vital Signs 
5.5 
Procedures for Recording and Reporting Adverse Events ................  
 
5.5.1 
Recording Adverse Events ..................................................  
 
5.5.2 
Serious Adverse Events .......................................................  
 
5.5.3 
Special Reporting Situations …………………………………… 
 
5.5.4 
Type and Duration of Follow-up After Adverse Events ........  
 
5.5.5 
Regulatory Reporting Requirements for Principal Investigators 
Holding Their Own INDs ………………………………………………… 
 
 
5.5.5.1  MedWatch 3500A Reporting Guidelines .................  
 
 
 
 


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TABLE OF CONTENTS (cont’d) 
 
                    
 
 
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 
Study Drug Accountability  ................................................................  
 
6.6 
Disclosure of Data ……………………………………………….. ..........  
6.7 
Retention of Records  ........................................................................  
  
 
REFERENCES ....................................................................................................  
 
 
 
APPENDICES 
Appendix A: 
Study Flowchart………………………………………………………. 
    
Appendix B: 
Injection Procedures for All Subjects………………………….. 
Appendix C: 
MedWatch Form FDA 3500A………………………….. ............... ..  
Appendix D: 
Analysis of Similar Events …………………………………………... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
BACKGROUND 
1.1 
PATHOPHYSIOLOGY 
Polypoidal choroidal vasculopathy (PCV) is a type of choroidal neovascularization 
(CNV) that has occult characteristics on fluorescein angiography but demonstrates 
saccular dilations and polypoidal interconnecting vascular channels on indocyanine 
green angiography.  PCV results in serosanguinous pigment epithelial detachments 
(PED) and neurosensory retinal detachments secondary to leakage and bleeding from 
the choroidal vascular lesions. PCV is a distinct clinical syndrome and the aneurysmal 
dilatations may be visible clinically as reddish-orange.  PCV was originally recognized 
as a “uveal bleeding syndrome” often presenting with multiple recurrent hemorrhagic 
PED’s in middle-aged, pigmented females.  With time and recognition, a broader 
concept of PCV has occurred, including a broad range of ages, races including a 
propensity for Asians as well as African Americans, and both sexes (Yannuzzi 1997).   
While debated, the pathogenesis of the vascular abnormality in PCV has been 
proposed to be a likely variant of CNV (Uyama 1999), although others propose PCV 
as inner choroidal vessel abnormalities that are distinct from CNV (Yuzawa 2005).   
Within the expanding spectrum of PCV, there is some overlap in elderly patients 
initially classified as age-related macular degeneration (AMD).  PCV may be 
differentiated from AMD in that PCV is more commonly observed in the peripapillary 
region, without associated drusen, and in non-white patients (Yannuzzi 1999).  While 
the natural course of PCV is somewhat more favorable than AMD-associated CNV, 
active polypoidal lesions often cause subfoveal hemorrhagic PED’s, subretinal 
fluid/exudates and fibrosis resulting in visual loss.   
 
The stimuli that prod are unknown.  However, there is evidence suggesting that 
angiogenic factors, such as vascular endothelial growth factor (VEGF), play a role in 
the pathogenesis of AMD-related CNV and in all forms of ocular neovascularization 
(see section 1.3).   Systemic hypertension is associated with PCV.   
 


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1.2 
TREATMENT OF PCV 
Observation for asymptomatic, non-exudative PCV is recommended. The efficacy of 
any treatment modality for active, exudative PCV has not been established as large 
controlled trials have not been performed.  Anecdotal evidence in case series 
indicates that PCV may respond to thermal laser (often ICG-guided) photocoagulation 
(Uyama 1999, Yannuzzi 1990, Nishijima 2004 ) or photodynamic therapy (PDT) with 
Visudyne (Spaide 2002, Chan 2004, Silva 2005, Nazimul 2005).  Other therapies for 
CNV such as periocular steroids (Okubo 2005), submacular surgery (Matsuoka 2004) 
and transpupillary thermotherapy (TTT) (Vedantham 2005) have been published as 
single case reports indicating possible benefit for PCV.  Other CNV therapies such as 
intravitreal steroids, radiotherapy, and translocation surgery have not been the focus 
of published reports in PCV patients. 
 
1.3 
RANIBIZUMAB AND PCV 
There is well-established evidence suggesting that angiogenic factors, such as 
vascular endothelial growth factor (VEGF), play a major role in the pathogenesis 
of AMD-related CNV and in all forms of ocular neovascularization.  Anti-VEGF therapy 
with aptamers (Gragoudas 2004) and with antibodies (Brown 2006, Rosenfeld 2006) 
has been demonstrated to be beneficial therapy for neovascular AMD. Surgically-
excised PCV lesions demonstrate strong VEGF expression thus indicating a likely role 
for VEGF in PCV proliferation and exudation (Matsuoka 2004, Terasaki 2002).  In 
addition, a significant increase of aqueous humor VEGF was found in eyes with 
exudative PCV (Tong 2006).  This rationale has led to investigation of intravitreal anti-
VEGF therapy for exudative PCV.   
 
Gomi and coworkers (Gomi 2008) assessed the short-term efficacy of intravitreal 
bevacizumab (Avastin, Genentech Inc., San Francisco, CA) for 11 Asian eyes with 
PCV. One or two bevacizumab injections resulted in decreased OCT thickness at 1 
month.  This anatomical effect was lost at 3 months.  Lesion size improved in one eye 
but residual or enlarged lesions were observed in the other 10 eyes.  There were no 


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significant short-term effects on visual acuity.  The authors proposed that a single 
bevacizumab injection is insufficient and that repeated bevacizumab injections or 
alternative anti-VEGF agents with greater retinal penetration or VEGF affinity may be 
required (Gomi 2008).   Song and coworkers (Song 2009) similarly evaluated a single 
intravitreal bevacizumab injection in 19 Asian eyes and observed improvement at 3 
months in both OCT retinal thickness and visual acuity.  Fluorescein angiographic 
leakage was reduced at 3 months and partial polyp regression occurred in more than 
50% of eyes.  ICG angiography demonstrated no changes in the choroidal branching 
vessels suggesting that bevacizumab may not penetrate deeply enough to effect the 
more mature choroidal vascular abnormalities (Song 2009). Lai and coworkers (Lai 
2008) treated 15 Asian PCV eyes with three monthly bevacizumab injections with or 
without PDT.  At 3 months, visual acuity and OCT thickness improved.  Persistent 
polyps were present in all eyes but subsequent PDT did lead to lesion regression in 
some eyes.  The authors concluded that bevacizumab monotherapy has limited effect 
on lesion regression and proposed that combination bevacizumab with PDT may be 
optimal (Lai 2008).   Lee and coworkers (Lee 2008) treated 8 Asian PCV eyes with 
bevacizumab alone and 4 Asian PCV eyes with combination bevacizumab and PDT. 
With mean followup of 17 weeks visual acuity, OCT thickness, and angiographic 
leakage improved.  Partial or complete lesion regression occurred in most eyes.  The 
authors proposed that bevacizumab monotherapy may be adequate therapy for less 
advanced lesions (Lee 2008).   
 
There are just two published reports evaluating ranibizumab (Lucentis, Genentech 
Inc., SanFrancisco, CA) for PCV.  Reche-Frutos and coworkers (Reche-Frutos 2008) 
noted that 3 monthly ranibizumab injections improved visual acuity and OCT thickness 
at 3 months follow-up in a Hispanic population.   Polyp regression was observed in 9 
of 13 eyes.  The authors proposed that in comparison to bevacizumab, ranibizumab’s 
deeper penetration may be responsible for the favorable polyp regression rate 
(Reche-Frutos 2008).  Kokame and coworkers (Kokame 2009) treated 12 Asian PCV 
eyes with continuous monthly ranibizumab.  Six month results indicated improved 
subretinal fluid, macular edema, and hemorrhage in the majority of eyes.  One third of 


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eyes demonstrated decrease lesion size but branching choroidal vessels were 
unchanged.  A press release from QLT Inc. (QLT Inc. 2009) reported results from the 
EVEREST prospective, randomized study evaluating ranibizumab monotherapy 
versus PDT monotherapy versus ranibizumab/PDT combination therapy for 61 eyes 
with Asian PCV.  At 6 months the ranibizumab monotherapy, PDT monotherapy, and 
ranibizumab/PDT combination groups gained 9.2, 7.5, and 10.9 letters, respectively.  
Complete polyp regression occurred in 29%, 71% and 78% of eyes in the ranibizumab 
monotherapy, PDT monotherapy, and ranibizumab/PDT combination groups, 
respectively (QLT Inc. 2009).  
 
The above data evaluating anti-VEGF therapy for PCV is limited by a relatively small 
number of treated eyes, short follow-up and absence of comparison groups.  
However, given the encouraging results of the above limited data along with the 
known favorable results of anti-VEGF therapy for neovascular AMD, as well as the 
overlap between exudative AMD and PCV, further evaluation of anti-VEGF therapy for 
PCV is needed.  In addition, evaluation of anti-VEGF therapy for PCV has primarily 
occurred in an Asian population and little or no data exist for African-American and 
Caucasian populations.  In fact, African-Americans are hardly represented in 
neovascular AMD anti-VEGF trials.   Ethnic differences in PCV may well affect 
treatment responses due to genetic makeup, variances in the natural history of 
disease, and living environments.   
 
We previously enrolled 20 non-Asian PCV eyes and evaluated intravitreal ranibizumab 
(0.3mg and 0.5 mg) for exudative PCV.   Subjects included 16 African-Americans (12 
female, 4 male) and 3 male Caucasians. The mean age was 63.6 years and the mean 
follow-up for the present ongoing study is 18 months. Mean baseline BCVA was 
20/127 (range, 20/16-20/500) and CPT was 298 μm. Mean BCVA increased from 
baseline by 1.2 and 1.5 ETDRS lines at 12 and 24 months, respectively. Four of 14 
eyes and 3 of 12 eyes gained ≥3 lines BCVA at 12 and 24 months, respectively. Mean 
CPT decreased from baseline by 53 μm and 67 μm at 12 and 24 months, respectively. 
Eyes received a mean of 7.2 injections during a mean follow-up of 19 months. Visually 


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significant ocular adverse events included cataract progression (n=3), mild vitreous 
hemorrhage (n=2), and macular hole (n=1). No systemic drug-related adverse events 
wereobserved. 
Intravitreal ranibizumab was well tolerated in non-Asian patients with PCV; the 
majority of eyes experienced improvements in BCVA and CPT following ranibizumab 
treatment.  
 
Clinical data of intravitreal anti-VEGF therapy indicate a need for multiple injections to 
maintain a beneficial effect for AMD, as well as for diabetic macular edema (DME).  
Similarly, for PCV, data outlined above indicates a need for multiple anti-VEGF 
injections and an absence of lesion regression with anti-VEGF monotherapy.  Thus, 
dose-escalation of ranibizumab has been investigated using 1.0 and 2.0 mg doses for 
AMD and DME to assess if higher doses have greater efficacy and/or require less 
injections.  Early studies for AMD and DME indicate higher doses are likely safe and 
may improve visual and anatomic outcomes.  The HARBOR study (FVF4579g) is a 
phase III randomized trial (Genentech Inc., SanFrancisco, CA) comparing 2.0 mg to 
0.5mg ranibizumab for neovascular AMD. 
 
 Evaluation of ranibizumab at higher doses is especially needed for PCV as limited 
data indicates lesions are recalcitrant to standard dose monotherapy.  In addition, 
African Americans are underrepresented in AMD trials.  We propose to evaluate high 
dose (2.0 mg) ranibizumab in previously treated and treatment naïve PCV eyes. 
 
1.4 
NONCLINICAL EXPERIENCE WITH RANIBIZUMAB 
1.4.1 Nonclinical Pharmacokinetics 
The pharmacokinetics of ranibizumab have 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 


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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. 
 
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). 
 
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 RANIBIZUMAB 
Ranibizumab has been or is being studied in more than 5000 subjects with 
neovascular AMD in a number of Phase I, I/II, II, III, and IIIb 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 endophthalimits and retinal detatchment.  Proper aseptic injection 
technique should always be used when administering ranibizumab.  Increases in IOP 
have been noted within 60 minutes of intravitreal  injection with ranibizumab.  
Therefore, IOP as well as perfusion of the optic nerve head should be monitored and 


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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 IOP.  The most 
common adverse reactions (reported > 6% higher in ranibizumab-treated subjects 
than control subjects) were conjunctival hemorrhage, eye pain, vitreous floaters, 
increased IOP, 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 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. 
 


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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 nonserious 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, vitritis, 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% (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 


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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 Lucentis® Package Insert for 
additional details regarding clinical safety experience with ranibizumab. 
 
2. 
OBJECTIVES 
This Phase I study will investigate the safety and tolerability of intravitreally 
administered Ranibizumab in three initial monthly doses of 2.0 mg followed by a 9 
month period of criteria-based, as-needed retreatment and 12 month off drug safety 
follow up in subjects with exudative polypoidal choroidal vasculopathy (PCV) for a total 
of 24 months.  
 
2.1  
Primary Objective 
To investigate the safety and tolerability of 3 initial intravitreally administered injections 
of 2.0 mg Ranibizumab with a 9 month PRN treatement period and 12 month off drug 
safey follow up. 
 
2.2  
Secondary Objectives 
1. To investigate the changes from baseline in best corrected visual acuity (BCVA) at 
specified time points in subjects treated with 2.0mg  intravitreal Ranibizumab. 
2. To investigate the occurrence of ocular non-serious and serious adverse events 
through fluorescein and ICG angiography, fundus photography, spectral domain 
optical coherence tomography (OCT) at specified time points. 
3. To investigate the occurrence of ocular non-serious and serious adverse events 
through direct and indirect ophthalmic examinations at specified time points. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Design- 


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Phase 
I 
Safety 
Study, 
Open-Label, 
Single-Center, 
Non-Randomized, 
Uncontrolled, Consecutive Case-Series. 
 
Population and Sample- 
Random sample of 20 consecutive adults, age >18 years, with polypoidal 
choroidal vasculopathy.  Polypoidal choroidal vasculopathy (PCV) will be 
defined as CNV with occult characteristics on fluorescein angiography with 
saccular dilations and polypoidal interconnecting vascular channels on 
indocyanine green angiography and/or fluorescein angiography.  PCV may be 
defined as a distinct clinical syndrome if the  aneurysmal dilatations are visible 
clinically as reddish-orange and/or there are multiple hemorrhagic PED’s. There 
may be some overlap with AMD in elderly patients.  Elderly PCV patients may 
demonstrate drusen: however PCV may be defined in elderly patients when 
CNV is observed in peripapillary region, when drusen are not prominent, and 
when the patient is non-white, especially in African Americans (the likely major 
racial predilection for PCV in our patient population).    
 
2.0 mg  Ranibizumab cohort 
Twenty eyes will be treated; PCV eyes may be treatment naïve or received 
previous PCV therapy greater than 30 days prior to enrollment.  A maximum of 
10 eyes that completed 24 month enrollment in our study evaluating 0.3 mg or 
0.5mg Ranibizumab may be included.   Eyes will be treated with 3 monthly 
doses of 2.0 mg ranibizumab followed by 2.0mg ranibizumab on a PRN dosing 
regimen 
for 
9 
months.  
 In the year 2 off drug treatment period subjects will be contacted via telephone 
interview for review of adverse events at month 18 and month 24. 
 
 
Trial Schema-  
Consented, enrolled patients will receive 3 consecutive monthly intravitreal 2.0 
mg/0.5 ml Ranibizumab injections with the first injection occurring at Day 0 and 


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second and third injection occurring at month 1 and 2 respectively. The first  
injection will be followed by a 1wk post treatment safety assessment.   
During the 3rd through 12th month, evaluations for retreatment will occur 
monthly (every 28-30 days). Retreatment with intravitreal 2.0 mg Ranibizumab 
or other therapies will be at the investigators discretion but guidelines for 
recommended retreatment are as follows:.  
Retreatment with 2.0 mg Ranibizumab is recommended if any of the following 
criteria are met: 
1. There is a > 5 letter visual acuity loss from the previous visit if associated 
with disease activity on OCT (intraretinal edema, subretinal fluid, pigment 
epithelial detachment with fluid etc). 
2. There is a >50 um increase in OCT CSF thickness from the previous visit. 
3.  There is persistent disease acitivity on OCT (intraretinal edema, subretinal 
fluid, pigment epithelial detachment with fluid etc). 
From Month 3-12: 
Consideration of alternative therapies, such as PDT, laser, or steroids will be at the 
investigators discretion but guidelines for alternative therapies are as follows: 
Photodynamic therapy with visudyne or laser photocoagulation or intravitreal steroids 
may be considered as monotherapy or in combination with ranibizumab 2.0mg if the 
following criteria are met: 
1.There is a >10 letter visual acuity loss from baseline or from a previous visit 
and 2 consecutive ranibizumab injections have been performed 1 and 2 months 
prior to the current visit and there is persistent acitivity on OCT (intraretinal 
edema, subretinal fluid, pigment epithelial detachment with fluid etc). 
And for PDT or Laser (not applicable to steroids) 
2. There is well defined hyperfluorescence on fluorescein angiography or ICG 
angiography that the investigator feels would be amenable to PDT or laser therapy. 
 
Timing of Intervention and Assessments  
 
Baseline/Day 0 (same day or different days):  


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Informed Consent, Medical and Ophthalmic History, Blood Pressure, Manifest 
Refraction, ETDRS Best Corrected Visual Acuity , IOP, dilated slit lamp 
examination with biomicroscopy and direct ophthalmologic exam, Routine 
Physical Exam, Fluorescein/ICG Angiography, OCT, and Fundus Photography, 
urine pregancancy test (women of childbearing potential only) Administration of 
2.0mg Intravitreal Ranibizumab #1 
 
1wk post treatment safety visit following intravitreal injection of Ranibizumab 
injection: 
Snellen visual acuity with spectacles or pinhole, intraocular pressure, dilated slit 
lamp examination with biomicroscopy and indirect ophthalmoscopy, and blood 
pressure. 
 
Month 1 & 2:  
Blood Pressure, Manifest Refraction, ETDRS Best Corrected Visual Acuity , 
IOP, dilated slit lamp examination with biomicroscopy and direct ophthalmologic 
exam, Fluorescein/ICG Angiography, OCT, and Fundus Photography.  
Intravitreal 2.0 mg Ranibizumab #2 and #3 respectively. 
 
Month(s) 3 -12: 
Blood Pressure, Manifest Refraction, ETDRS Best Corrected Visual Acuity, IOP, 
dilated slit lamp examination with biomicroscopy and direct ophthalmologic exam, 
Fluorescein/ICG Angiography (mandatory at months 3,6,9,12; optional at other visits),  
OCT, and Fundus Photography (mandatory at months 3,6,9,12; optional at other 
visits). Urine pregnancy test at month 12 for females of childbearing potential only. 
From months 3 onward, at the discretion of the Investigator, Intravitreal 2.0 mg 
Ranibizumab, observation or non-study therapy (i.e. laser, intravitreal steroids, 
PDT etc.) may be administered.  Other anti-VEGF agents including 
bevacizumab and standard dose (0.5mg) ranibizumab are excluded as optional 
therapies. 
 
Month(s) 18 & 24 


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Telephone Interview to assess for adverse events. Subjects will not be eligible 
to receive 2.0mg Ranbizumab. Alternate treatments are at the investigators discretion 
during the off drug observational period. 
Patient Accrual- 
Subject Accrual per Month:1 
Date of First Subject Enrolled: November 1, 2010 
Date of Last Subject Enrolled: July 1, 2012 
Date of Last Subject Completing Study: July 1, 2013 
 
3.2 
RATIONALE FOR STUDY DESIGN 
The route (intravitreal injections) and 2.0 mg dose employed is currently evaluated in 
the HARBOR clinical trial evaluating 2.0 mg Ranibizumab in neovascular AMD.    The 
three consecutive monthly injections will be followed by observation or therapy at the 
discretion of the investigator.  Given the variable course of PCV and unknown 
response to 2.0 mg Ranibizumab, this regimen will allow the opportunity to evaluate 
Ranibizumab’s safety and potential therapeutic efficacy, as well as to give the patient 
the opportunity to continue Ranibizumab or switch to an alternative non-anti-VEGF 
therapy.  The 1 year duration of the study is of sufficient duration to determine 
significant safety issues as well as determine potential efficacy.  The possible 
inclusion of patients completing month 24 follow up after receiving 0.3mg or 0.5 mg 
doses in our previous study, will determine significant safety issues as well as 
determine potential efficacy of the 2.0mg dose for this population, as well.   
3.3 
OUTCOME MEASURES 
3.3.1 Primary Outcome Measure 
The primary outcome measure for safety and tolerability is the following: 
Incidence and severity of ocular and systemic adverse events. Examples include 30 
letter loss, major subretinal hemorrhage,involving 75% or more of clinical macula 
(arcade 
to 
arcade), 
disease-related 
vitreous 
hemorrhage, 
injection-related 
endophthalmitis, retinal detachment, vitreous hemorrhage, study drug/procedure - 


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related uveitis, incidence and severity of other adverse events, as identified by 
physical examination, subject reporting, and changes in vital signs. 
 
Secondary Outcome Measures 
• Month 3, 6, 9, 12 best corrected visual acuity at 4 meters – rates for gain of 5,10 
and 15  or more letters 
• Month 3, 6, 9, 12 best corrected visual acuity at 4 meters-   rates for loss of 15 or 
more letters 
• Median and Average best corrected visual acuity at 4 meters- gain/loss (letters) at 
3,6,9,12 months. 
• Mean change from baseline in central foveal thickness over time up to 12 months 
as assessed on OCT 
• Mean change from baseline in macular volume overtime up to 12 months. 
• Proportion of patients with no evidence of fluid from CNV as assessed by OCT at 
12 months. 
• Mean change from baseline in the total area of CNV fluorescein angiographic 
leakage overtime up to 12 months. 
• Mean change from baseline in total area of ICG CNV lesion size (including polyps 
and deep choroidal vessels) overtime up to 12 months. 
• Fluorescein and ICG angiograms and fundus photographs will also be graded at 
each time point compared to baseline as unchanged, resolved, improved, 
worsened, or cannot determine. For the FA and ICG evaluations, “resolved” will be 
defined as no leakage and no evidence of polyps or PCV choroidal lesion; 
“improved” will be defined as decreased leakage and/or decreased size, number, 
or hyperfluorescence of polyps and/or PCV choroidal lesion; and “worsened” will 
be 
defined 
as 
increased 
leakage 
and/or 
increased 
size, 
number 
or 
hyperfluorescence of polyps and/or PCV choroidal lesion. For fundus photography 
evaluations, “resolved” will be defined as no evidence of PED, subretinal fluid, 
hemorrhage, or hard exudate; improved will be defined as a decrease in PED, 


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subretinal fluid, hemorrhage, or hard exudate; and “worsened” will be defined 
increase in PED, subretinal fluid, hemorrhage, fibrosis, or hard exudates. 
 
3.4 
SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 4.5 and 
Appendix A. 
Serious adverse events of intravitreal injection such as endophthalmitis, retinal 
detachment and significant vitreous hemorrhage will be reported and monitored.  
Potential serious adverse events related to study drug such as significant uveitis, 
hypertension, thromboembolic event, or poor wound healing will be reported and 
monitored.  Serious ocular adverse events such as major subretinal hemorrhage, 
vitreous hemorrhage and 6-line loss rate will be reported and monitored.  Serious 
adverse events such as hospitalizations, surgeries, emergency room admissions and 
death will be reported and monitored.    
Given the small population studied in this Phase I trial, it will be difficult to estimate the 
adverse event occurrences.   Unmasking procedures or treatment recommendations 
related to drug or the study in particular are not necessary.  Any death in the study 
population will lead to review and assessment while withholding drug injections for 
enrolled patients until fully reviewed.  If two or more patients suffer thromboembolic 
events, drug injections will also be withheld for all enrolled patients until review and 
assessment occur.  
 
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. 
 


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4. 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
4.1.1 Subject Selection 
Twenty subjects from one site in the United States will be enrolled.   Subjects with 
active, exudative-PCV who have provided informed consent will be eligible.  Subjects 
who completed the 24 month follow up in the original FVF3671s 0.3 mg or 0.5mg PCV 
protocol may enter the extension study with 2.0 mg without necessarily demonstrating 
active exudative PCV at enrollment.  (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. Any deviation/waivers granted 
regarding inclusion/exclusion criteria will be reviewed by the principal investigator and 
fully documented.   
• Males and Females >18 years of age. Females of child bearing potential will 
undergo urine pregnancy testing and be required to use appropriate methods of 
birth control. 
• ICG and fluorescein angiographic characteristics consistent with active, leaking 
PCV with subfoveal lesions &/or subfoveal hemorrhage, lipid exudates, PED or 
fluid diagnosed within the past 6 months or diagnosed as newly active within the 
past 6 months. Subjects who completed the 24 month follow up in the original 
FVF3671s protocol may enter the extension study with 2.0 mg without necessarily 
demonstrating active exudative PCV at enrollment.     
• Best-Corrected ETDRS Visual Acuity at 4 meters between 20/20 – 20/800 
• Lesion size- no limitations 
• Lesion Characteristics- leaking lesions consistent with PCV.  No limitations on 
hemorrhage, fibrosis or atrophy. 
• No therapy (includes non foveal laser, PDT, intravitreal steroids, TTT, 
radiotherapy, or anti-VEGF therapy) or intraocular surgery within the past 30 days 
for any condition.   


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• Clear ocular media to allow for photography/angiography. 
• Ability to provide written informed consent and comply with study assessments for 
the full duration of the study 
 
4.1.3 Exclusion Criteria 
 
• Patients with features of age-related macular degeneration such as abundant 
drusen and demographic features consistent with this diagnosis. 
• Allergy to Fluorescein, ICG, Iodine, Shellfish. 
• Pregnancy (positive pregnancy test) 
• 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 
• Exclude other anti-VEGF agents as therapy options. 
• History of previous subfoveal laser. 
• Advanced glaucoma (IOP>25 or cup/disc ratio >0.8) 
• Any condition in the opinion of the investigator that would interfere with disease 
status/progression or jeopardize patients’ participation in the study. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a non-randomized, open-label study of 2.0 mg Ranibizumab. Treatment 
assignment will be determined by baseline status of treatment naive vs. previously 
treated PCV eyes. 
 
4.3 
STUDY TREATMENT 
4.3.1 Formulation 
Ranibizumab 2.0mg is formulated as a sterile solution aseptically filled in a sterile 3-
mL stoppered glass vial.  Each vial contains 0.5 mL of  40 mg/mL (2.0mg dose level) 
ranibizumab aqueous solution (pH 5.5) with 10 mM histidine HCI, 10% trehalose 


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dihydrate, and 0.01% polysorbate 20, pH 5.5.  The vial contains no preservative and is 
suitable for single use only.  Vials should be protected from direct light.   
For further details and molecule characterization, see the Investigator Brochure. 
 
4.3.2 Dosage, Administration, and Storage 
1. Dosage-      2.0 mg/0.05 ml Ranibizumab will be given monthly from Day 0 through 
Month 2, and then at the discretion of investigator no more frequent than monthly 
for months 3-12.   
2. Administration-  Intravitreal Injection will only be given at the Southeast Retina 
Center location. 
*See Appendix B for detailed pre-injection procedures. 
3. Storage- Upon receipt, study drug kits will be refrigerated at 2°C - 8°C (36°F - 
46°F).    Vials will not be used beyond the expiration date.  Ranibizumab vials will 
remain refrigerated and will not be frozen.   
 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Starting at month three (ranibizumab injection #1 at baseline, #2 at month 1, and #3 at 
month 2), treatment will occur at the discretion of the investigator.  Observation is 
permitted as well as intravitreal 2.0 mg Ranizibumab as frequent as every month for 
months 3-12. Other anti-VEGF agents, such as Avastin or Macugen®  or 0.5mg 
Ranibizumab, will not be permitted.  At the discretion of the investigator, starting at 
month 3 thermal laser, photodynamic therapy with Visudyne®, intravitreal or periocular 
steroids are permitted, if necessary.   
 
4.5 
STUDY ASSESSMENTS 
4.5.1 Assessments during the Treatment Period 
See Section 3.1 


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4.5.2 Early Termination Assessments 
Subjects who withdraw from the study prior to completion should return for an early 
termination evaluation 30 days (± 7 days) 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. 
 
4.6  
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 Southeast Retina 
Center may request the withdrawal of a subject because of protocol violations, 
administrative reasons, or any other valid and ethical reasons.   
All non serious and serious 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 
• Macugen injection treatment in study 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.   
 


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4.7 
STUDY DISCONTINUATION 
This study may be terminated by Southeast Retina Center 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 
4.8.1 Analysis of the Conduct of the Study 
There is no formal sample size calculation in this pilot study.  As this is a phase I 
study, a sample size of 20 patients is chosen, making sure that it is feasible financially 
to conduct the study and logistically to complete the study within 2-3 years.  If and 
when the study is planned for a phase II randomized control trial, appropriate 
statistical analysis will be determined.  
 
4.8.2 Safety Analyses 
All non serious and serious adverse events, angiographic assessments, physical 
examinations, vital signs, ocular examinations and visual acuity measurements from 
all 20 subjects will be utilized to summarize safety data for this pilot study. 
 
4.8.3 Efficacy Analyses 
1. Primary Endpoint-  See Section 3.3.1 
2. Secondary Endpoints-  See Section 3.3.2 
All subjects will be used in analysis of primary and secondary outcome parameters.  
Rates for the endpoints at the suggested time points will be presented as a % of the  
patients enrolled.  Analysis of Variance will be used to assess for role of variables in 
for the endpoints.  Variables will include # Ranibizumab injections, other therapies, 
baseline acuity, age, gender, etc.  


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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 extension 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 will be assessed through the collection and analysis of 
rates of primary safety outcomes.   
 
5.1 
ADVERSE EVENTS 
All adverse events occurring from Day 0 through Month 12 or Early Withdrawal will be 
documented and assessed by the principal investigator.  Subjects discontinuing early 
from the study 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 will not be recorded.  An 
exacerbation or worsening of a chronic condition should be recorded as an AE. 


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Both serious and nonserious AEs should be graded on a three-point scale (mild, 
moderate, severe) and reported in detail in the subjects clinic record. 
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, the investigator will also 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 
• No  
The AE may or may not be attributed to concurrent/underlying illness, other 
drugs, or procedures. 
A clinically plausible temporal sequence is inconsistent with the onset of the AE 
and study drug administration; and/or 
A causal relationship is considered biologically implausible. 
 
5.2 
BASELINE MEDICAL CONDITIONS 
Chronic medical conditions present at enrollment that do not worsen in intensity or 
frequency during the trial shall not be considered as adverse events.  These medical 
conditions will be adequately documented in the clinic record section medical history 
and/or physical examination.  However, medical conditions present at enrollment that 
worsen in intensity or frequency during the treatment or post-treatment periods should 
be reported and recorded as AEs.   


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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 
VITAL SIGNS 
Blood pressure will be measured at protocol-specified study visits (see Section 3.1).   
 
5.5 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS 
5.5.1 Recording Adverse Events (see examples below) 
To improve the quality and precision of acquired AE data, investigators should 
observe the following guidelines: 
• Whenever possible, use recognized medical terms when recording AEs.  Do 
not use colloquialisms and/or abbreviations. 
• If known, record the diagnosis (i.e., disease or syndrome) rather than 
component signs and symptoms (e.g., record congestive heart failure rather 
than dyspnea, rales, and cyanosis).  However, signs and symptoms that are 
considered unrelated to an encountered syndrome or disease should be 
recorded as individual AEs (e.g., if congestive heart failure and severe 
headache are observed at the same time, each events should be recorded as 
an individual AE). 
• AEs occurring secondary to other events (e.g., sequelae) should be identified 
by the primary cause.  A “primary” AE, if clearly identifiable, generally 
represents the most accurate clinical term recorded.  If a primary serious AE 
(SAE) is recorded, events occurring secondary to the primary event should be 
described as a narrative description of the case.   


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For example: 
Orthostatic 
hypotension 
→ 
Fainting and fall to 
floor 
→ 
Head trauma 
→ Neck pain 
The primary AE is orthostatic hypotension. 
 
5.5.2 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). 
• 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. 


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SAE Reporting 
For guidelines on reporting SAEs refer to section 5.5.5 Expedited IND Safety Reports. 
 
• 
5.5.3 Special Reporting Situations 
a. Death 
Death is an outcome of an event.  The event that resulted in the death should be 
recorded and reported in the clinic record and MedWatch and IND Forms.   
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 
d. Thromboembolic events occurring in 2 or more of enrolled patients. 
 
5.5.4 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 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.   
 
5.5.5 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: 
 


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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 
ranibizumab. Reports are to be telephoned or faxed to the FDA within 7 calendar 
days of the Investigator’s knowledge of the event.  Additionally, notify Genentech 
Medical Science Liaison by telephone within 7 calendar days. 
 
An unexpected adverse event is one that is not already described in the ranibizumab 
Investigator’s Brochure (IB) 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 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, Genentech, the IRB, and all participating investigators within 15 calendar days of 


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the Investigator’s knowledge of the event.  The FDA prefers these reports 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  
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be 
faxed to:  
 
Genentech Medical Science Liaison: 
Name:  Lester Hosten  
Tel: 
  2404010969 
 
AND: 
Genentech Drug Safety at: 
(650) 225-4682 or (650) 225-5288 
 
AND: 
IRB Contact information 
RCRC IRB 
706B Ben White Blvd., West 
Austin, TX 78704 
phone: +800 688 2132 
fax: +512 685 6012  
 
 
For questions related to Safety reporting, contact your Genentech Medical Science 
Liaison. 
 


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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 but is not life-
threatening or fatal.  Investigators are required to notify the FDA, Genentech, the 
IRB, and all participating investigators by submitting the IND Safety Report within 15 
days of the Investigator’s knowledge of the event. 
 
IND Annual Reports 
All IND annual reports submitted to the FDA by the Investigator should be copied to 
Genentech.  Copies of such reports should be mailed to:  
Jim Nickas 
Director of Drug Safety 
Mailstop #84 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080-4990 
 
 
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.) 
 
Occasionally Genentech may contact the investigator for additional information, 
clarification, or current status of the subject for whom an adverse event was reported.   
 
For questions regarding SAE reporting, you may contact the Genentech Medical 
Science Liaison. 
 
6.0 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with Southeast 
Retina 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 


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• 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  
• Written documentation of IRB approval of protocol (identified by Southeast Retina 
Center (protocol number or title and date of approval) and informed consent 
document (identified by Southeast Retina 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 
• 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 Southeast 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) 
• 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) 
 


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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 possibility that the 
FDA and the Southeast Retina Center and the drug manufacturer may inspect 
the records 


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• 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 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 


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any written safety report or update provided by Southeast Retina Center (e.g., IND 
safety report, Investigator Brochure, safety amendments and updates, etc.). 
 
 
6.5 
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.  
 
6.6 
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. 
6.7 
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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REFERENCES 
Brown DM, Kaiser PK, Michels M, et al. for the ANCHOR study group. Ranibizumab versus 
Verteporfin for Neovascular Age-Related Macular Degeneration. N. Engl. J. Med. 2006; 
355:1432-1444 
Chan et al.  Photodynamic therapy with verteporfin for symptomatic polypoidal 
choroidal vasculopathy.  Ophthalmol 2004;111:1576-1584. 
Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR for the VEGF 
Inhibition Study In Ocular Neovascularization Clinical Trial Group.  Pegaptanib in 
neovascular age-related macular degeneration.  N Engl J Med 2004;351:2805-2816. 
Gomi F, Sawa MD, Sakaguchi H, et al. The efficacy of intravitreal bevacizumab for 
polypoidal choroidal vasculopathy. Br. J. Ophthalmol. 2008;92:70-73. 
Kokame GT, Yeung L, Lai JC.  Continuous anti-VEGF treatment with ranibizumab for 
polypoidal choroidal vasculopathy: an interim 6-month report.  Br. J. Ophthalmol. 2009. 
(epub) 
Lai TY, Chan WM, Liu DT, Luk FO, Lam DS. Intravitreal bevacizumab (Avastin) with or 
without photodynamic therapy for the treatment of polypoidal choroidal vasculopathy. Br. J. 
Ophthalmol. 2008;92:661-666. 
Lee SY, Kim JG, Joe SG, Chung H, Yoon YH. The therapeutic effects of bevacizumab in 
patients with polypoidal choroidal vasculopathy. Korean J. Ophthalmol. 2008;22:92-99. 
Matsuoka M, Ogata N, Otsuji T, Nishimura T, Takahashi K, Matsumura M.  
Expresssion of pigment epithelium derived factor and vascular endothelial growth 
factor in choroidal neovascular membranes and polypoidal  choroidal vasculopathy.  
Br J Ophthalmol 2004;88:809-815. 
Nazimul H, Anjli H, Sundaram N.  Role of photodynamic therapy in polypoidal 
choroidal vasculopathy.  Indian J Ophthalmol 2005;53:101-104. 


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Nishijima et al. Laser photocoagulation of indocyanine green angiographically 
identified feeder vessels to idiopathic polypoidal choroidal vasculopathy.  Am J 
Ophthalmol 2004;137:770-773. 
Okubo et al.  Visual improvement following trans-tenon’s retrobulbar triamcinolone 
acetonide infusion for polypoidal choroidal vasculopathy.  Graefes Arch Clin Exp 
Ophthalmol 2005;243:837-839. 
QLT, Inc. 6-Month results from EVEREST study evaluating Visudyne therapy in patients with 
polypoidal choroidal vasculopathy. Press Release, December 9, 2009, Vancouver, Canada. 
 
Reche-Frutos J, Calvo-Gonzalez C, Donate-Lopez J, et. al.  Short-term anatomic effect of  
ranibizumab for polypoidal choroidal vasculopathy. Eur J Ophthalmol. 2008;18:645-648. 
 
Rosenfeld PJ, Brown DM, Heier JS, et.al. for the MARINA Study Group.  Ranibizumab for 
Neovascular Age-Related Macular Degeneration. NEJM 2006;355:1419-1431. 
 
Silva et al.  Polypoidal choroidal vasculopathy and photodynamic therapy with 
verteporfin.  Graefe’s Arch Clin Exp Ophthalmol 2005. 
Spaide et al. Treatment of polypoidal choroidal vasculopathy with photodynamic 
therapy.  Retina 2002;22:529-535. 
Song JH, Byeon SH, Lee SC, Koh HJ, Kwon OW. Short-term safety and efficacy of a single 
intravitreal bevacizumab injection  for the management of polypoidal choroidal vasculopathy. 
Ophthalmologica 2009;223:85-92. 
Terasaki H, Miyake Y, Nakamura M, et al. Polypoidal choroidal 
vasculopathy treated with macular translocation: clinical 
pathological correlation. Br. J. Ophthalmol. 2002;86:321–327. 
Tong JP, Chan WM, Liu TL et. al. Aqueous humor levels of vascular endothelial growth 
factor and pigment epithelium-derived factor in polypoidal choroidal vasculopathy and 
choroidal neovascularization. Am. J. Ophthalmol. 2006;141:456-462. 
Uyama M, Matsubara T, Fukushima I, Matsunaga H, Iwashita K, Nagai Y, et al.  
Idiopathic polypoidal  choroidal vasculopathy in Japanese patients.  Arch Ophthalmol 
1999;117:1035-1042. 


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Vedantham et al.  Treatment of polypoidal choroidal vasculopathy with transpupillary 
thermotherapy: an interventional case report.  Eye 2005;19:914-915. 
Yannuzzi LA et al.  Idiopathic polypoidal choroidal vasculopathy (IPCV).  Retina 
1990;10:1-8 
Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB, Orlock DA.  The 
expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy.  Arch 
Ophthalmol 1997;115:478-485. 
Yannuzzi LA, Wong DWK, Sforzolini BS, Goldbaum M, Tang KC, Spaide RF, et al.  
Polypoidal choroidal vasculopathy and neovascularized age-related macular 
degeneration.  Arch Ophthalmol 1999;117:1503-1510. 
Yuzawa M, Mori R, Kawamura A. The origins of polypoidal choroidal vasculopathy. 
Brit J Ophthalmol 2005;89:602-607. 
 


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APPENDIX A 
Study Flowchart  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: 
aRanibizumab injections for months 3-11, to be determined based on investigator’s discretion. 
b Ocular Exam includes IOP. Study eye only at safety assessments 
c Safety Assessment post Injection to be performed 1 week after ranibizumab injection 
e Refraction not required at 1 wk safety follow-up. 
f F/A/ICG/photos performed at months 3,6,9 and 12 but may be performed monthly at investigator discretion
 
Screen
Baseline 
(Day 0) 
1 wk Safety 
Follow-up c 
after first dose only 
Month 1
Month 2 Months 
3 – 11 
Month 12 
Month 18 & 24 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical Examination and 
Medical History   
X 
 
 
 
 
 
 
 
Vitals  
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Testing 
X 
 
 
 
 
 
X 
 
Ocular Exam b 
X 
 
X 
X 
X 
X 
X 
 
OCT SD  
X 
X 
 
X 
X 
X 
X 
 
FA/ICG 
X 
X 
 
X 
X 
Xf 
Xf 
 
Fundus photos 
X 
X 
 
X 
X 
Xf  
Xf  
 
Ranibizumab Injection 
 
X 
 
X 
X 
(X)a 
 
 
AE and ConMed Review 
 
X 
X 
X 
X 
X 
X 
x 
ETDRS Refraction & Visual 
Acuity (4 m)e 
X 
X 
X 
X 
X 
X 
X 
 


 
 
 
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APPENDIX B  
Pre-Injection Procedures for All Patients 
The following procedures will be used to minimize the risk of potential adverse 
events associated with intravitreal injections (e.g., endophthalmitis).  Aseptic 
technique will be observed by clinic staff involved in the injection tray assembly, 
anesthetic preparation, and study drug (ranibizumab) preparation and 
administration.  In addition to the procedures outlined below, any additional safety 
measures in adherence to specific institutional policies associated with intravitreal 
injections will be observed. 
The following procedures (except where noted) will be conducted by the physician 
performing the intravitreal injection of study drug.  Patients will self-administer 
antimicrobials (e.g., ofloxacin ophthalmic solution [Ocuflox®], gatifloxacin ophthalmic 
solution [Zymar®], moxifloxacin ophthalmic solution [Vigamox®], or 
trimethoprim-polymyxin B ophthalmic solution [Polytrim®]) four times daily for 3 days 
prior to treatment. 
At the discretion of the investigator, the sites may use either ophthalmic drops 
or lidocaine injection for study eye anesthesia. 
If using propacaine- or tetracaine-based ophthalmic drops for anesthesia, the 
injecting physician or technician (if applicable) assembles the supplies and prepares 
a sterile field.  Supplies include 10% povidone iodine swabs, sterile surgical gloves, 
4 × 4 sterile pads, a pack of sterile cotton-tipped applicators, eyelid speculum, sterile 
ophthalmic drape, 5% povidone iodine ophthalmic solution, ophthalmic antimicrobial 
solution (e.g., ofloxacin ophthalmic solution, trimethoprim-polymyxin B ophthalmic 
solution, moxifloxacin ophthalmic solution, or gatifloxacin ophthalmic solution  
single-use vial), and injection supplies.  Note:  The use of generic formulations or 
next-generation formulations of the antimicrobials listed above is permitted.  
Procedure for Propacaine- or Tetracaine-Based Anesthesia: 
• Instill two drops proparacaine or tetracaine-based ophthalmic drops into the 
study eye, followed by two drops of antimicrobial solution (e.g., ofloxacin 
ophthalmic solution, trimethoprim-polymyxin B ophthalmic solution, moxifloxacin 
ophthalmic solution, or gatifloxacin ophthalmic solution single-use vial). 


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• Wait 90 seconds. 
• Instill two more drops of proparacaine- or tetracaine-based ophthalmic drops into 
the study eye 
• Disinfect the periocular skin and eyelid of the study eye in preparation for 
injection.  Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine 
swabs, starting with the eyelid and lashes and continuing with the surrounding 
periocular skin.  Ensure that the eyelid margins and lashes are swabbed, 
and proceed in a systematic fashion, from medial to temporal aspects. 
• The physician will glove, place sterile ophthalmic drape to isolate the field, 
and place the speculum underneath the eyelid of the study eye. 
• Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva. 
• Wait 90 seconds. 
• Saturate a sterile, cotton-tipped applicator with proparacaine- or tetracaine-based 
drops and hold the swab against the planned intravitreal injection site for 
10 seconds 
• Use a sterile 4 × 4 pad in a single wipe to absorb excess liquid and to dry the 
periocular skin. 
• 
Instruct patient to direct gaze away from syringe prior to ranibizumab injection. 
Procedure for Lidocaine-Based Anesthesia 
If using lidocaine injection for anesthesia, physician or technician (if 
applicable) assembles the supplies and prepares a sterile field.  Supplies 
include 10% povidone iodine swabs, sterile surgical gloves, 4 × 4 sterile pads, 
a pack of sterile cotton-tipped applicators, eyelid speculum, sterile ophthalmic 
drape, 0.5% proparacaine hydrochloride, 5% povidone iodine ophthalmic 
solution, 1% lidocaine for injection, ophthalmic antimicrobial solution (e.g., 
ofloxacin ophthalmic solution, trimethoprim-polymyxin B ophthalmic solution, 
moxifloxacin ophthalmic solution, or gatifloxacin ophthalmic solution single-
use vial), and injection supplies.   
Note:  The use of generic formulations or next-generation formulations of 
the antimicrobials listed above is permitted.  
• Instill two drops of 0.5% proparacaine hydrochloride into the study eye, followed 
by two drops of antimicrobial solution (e.g., ofloxacin ophthalmic solution, 
trimethoprim-polymyxin B ophthalmic solution, moxifloxacin ophthalmic solution, 
or gatifloxacin ophthalmic solution single-use vial). 


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• Disinfect the periocular skin and eyelid of the study eye in preparation for 
injection.  Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine 
swabs, starting with the eyelid and lashes and continuing with the surrounding 
periocular skin.  Ensure that the eyelid margins and lashes are swabbed, 
and proceed in a systematic fashion, from medial to temporal aspects. 
• The physician will glove, place sterile ophthalmic drape to isolate the field, 
and place the speculum underneath the eyelid of the study eye. 
• Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva. 
• Wait 90 seconds. 
• Saturate a sterile, cotton-tipped applicator with 0.5% proparacaine hydrochloride 
drops and hold the swab against the planned intravitreal injection site for 
10 seconds in preparation for the subconjunctival injection of 1% lidocaine 
hydrochloride ophthalmic solution for injection (without epinephrine). 
• Inject 1% lidocaine (without epinephrine) subconjunctivally. 
• Use a sterile 4 × 4 pad in a single wipe to absorb excess liquid and to dry 
the periocular skin. 
• Instruct patient to direct gaze away from syringe prior to ranibizumab injection. 
 


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APPENDIX C  
Preparation and Administration of Ranibizumab Injection 
The injecting physician will prepare the ranibizumab injection as outlined below.   
Vials of ranibizumab in aqueous solution should remain refrigerated at 2°C−8°C (36°F−46°F) until just prior to use.  DO 
NOT FREEZE vials.  Protect from direct light.  Do not use beyond the expiration date.  Dose solutions should be prepared 
immediately before dosing.  Dose solutions are for single use only. 
After preparing the study eye as outlined in Appendix B, withdraw 0.2-mL ranibizumab dose solution through a 5-μm filter 
needle.  Remove the filter needle, replace it with a 30-gauge, 1/2-inch Precision Glide® needle, and expel excess 
ranibizumab so that the syringe contains 0.05 mL of solution.  Insert the syringe through an area 3.5 to 4.0 mm 
posterior to the limbus, avoiding the horizontal meridian, and aiming toward the center of the globe.  The injection 
volume should be delivered slowly.  The needle should then be removed slowly to ensure that all drug solution is in the 
eye.  The scleral site for subsequent intravitreal injections should be rotated.  Refer to Appendix D for detailed post-
injection procedures. 
All injection materials (i.e., syringes, needles) will be discarded in a sharps container immediately following each 
ranibizumab injection.  The ranibizumab drug kit (including the used vial) will be sealed by the injecting physician or 
technician with the “Do Not Tamper” seal provided in the drug kit.  
A patient’s study eye will be monitored with a finger count test within 15 minutes of the ranibizumab injection by the 
physician.  A measurement of IOP in the study eye will be obtained 30 (±5) minutes post-injection.  If the IOP is increased 
≥ 10 mmHg compared with the pre-injection IOP, then measure the IOP again at 60 (±10) minutes.  The following table 
provides specific instructions for the preparation and administration ranibizumab in aqueous solution. 
 
 


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APPENDIX D 
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 
 
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  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. 
Based on review of available data, Southeast Retina Center believes there is a reasonable 
possibility of a cause-and-effect relationship between administration of Ranizibumab and the 
occurrence of _____________( insert AE). 


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Additional information on risk factors and/or treatment of the AE may be provided if warranted. 
 
 
 
 
Or 
Based on review of available data, the Southeast Retina Center does not believe that there is 
a reasonable possibility of a cause-and-effect relationship between administration of 
Ranizibumab and the occurrence of ___________(insert AE). 
Explain if warranted.  Do not speculate. 
 
 
 
 
 
Or 
Based on review of available data, the Southeast Retina Center cannot establish or exclude 
the possibility of a cause-and-effect relationship between administration of Ranizibumab 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 Southeast 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.