Clinical trial NCT03362190
Conditions: Neovascular Age-related Macular Degeneration
Keywords: Zimura (previous name) ARC1905 Lucentis ranibizumab Wet AMD avacincaptad pegol complement factor C5 inhibitor
Sponsor: Ophthotech Corporation
Start date: 2017-10-11; Completion date: 2018-10-18
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the safety of intravitreal Zimura™ (complement factor C5 inhibitor) administered in combination with Lucentis® 0.5 mg in treatment naïve subjects with neovascular age related macular degeneration (NVAMD)

Detailed description:

Arms: arm 1: Avacincaptad Pegol dosage 1 + Lucentis 0.5 mg arm 2: Avacincaptad Pegol dosage 2 + Lucentis 0.5 mg arm 3: Avacincaptad Pegol dosage 3 + Lucentis 0.5 mg arm 4: Avacincaptad Pegol dosage 4 + Lucentis 0.5 mg
Interventions: intervention 1: Avacincaptad Pegol intervention 2: Lucentis
Intervention descriptions: intervention 1: Avacincaptad Pegol in combination with Lucentis intervention 2: Avacincaptad Pegol in combination with Lucentis

Protocol documents:
Prot_002.pdf: 
NCT Number 
 
NCT03362190 
 
Official Study Title: 
A Phase 2A Open-label Trial to Assess the Safety of 
ZIMURA™ (Anti-C5) Administered in Combination 
With LUCENTIS® 0.5 mg in Treatment Naive 
Subjects With Neovascular Age Related Macular 
Degeneration   
 
Document: 
Protocol 
 
Date of Document: 
09-Aug-2017 


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A PHASE 2A OPEN-LABEL TRIAL TO ASSESS THE SAFETY OF 
ZIMURA™ (ANTI-C5) ADMINISTERED IN COMBINATION WITH 
LUCENTIS® 0.5 MG IN TREATMENT NAÏVE SUBJECTS WITH 
NEOVASCULAR AGE RELATED MACULAR DEGENERATION  
 
 
PROTOCOL NO:  OPH2007 
 
 
 
Version Date:  
9 August 2017 
 
 
 
SPONSOR: 
OPHTHOTECH CORP. 
One Penn Plaza – 19th Floor 
New York, NY 10119 
 
FOR MEDICAL EMERGENCIES REFER TO THE 
“SAFETY CONTACT LIST” PROVIDED SEPARATELY 
                                               Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without written authorization 
from Ophthotech Corp., except to the extent necessary to obtain informed consent from persons receiving the 
investigational drug or their legal guardians, or for discussions with local regulatory authorities, institutional 
review boards (IRB), or persons participating in the conduct of the trial. 


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TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ...................................................................... 4 
2 
SUMMARY OF PROTOCOL OPH2007 ............................................................... 6 
3 
STUDY ASSESSMENTS ..................................................................................... 9 
4 
INTRODUCTION ................................................................................................ 13 
4.1 
Age-Related Macular Degeneration (AMD) ............................................ 13 
4.2 
The Complement Pathway and AMD ...................................................... 14 
4.3 
VEGF Inhibition and Complement .......................................................... 15 
4.4 
Zimura™ ................................................................................................. 16 
4.5 
Clinical Data ............................................................................................ 17 
4.6 
Trial Rationale ......................................................................................... 20 
5 
TRIAL OBJECTIVES .......................................................................................... 23 
5.1 
Objectives ............................................................................................... 23 
5.2 
Endpoints ................................................................................................ 23 
6 
TRIAL DESIGN .................................................................................................. 24 
7 
PROCEDURES .................................................................................................. 26 
7.1 
Procedures for Refraction and Vision Testing ......................................... 26 
7.2 
Tonometry ............................................................................................... 26 
7.3 
Ophthalmologic Examination .................................................................. 26 
7.4 
Fundus Photography and Fluorescein Angiography ............................... 27 
7.5 
Spectral Domain Optical Coherence Tomography (SD-OCT) ................. 27 
7.6 
Laboratory Tests ..................................................................................... 27 
7.7 
Vital Signs and Physical Examination ..................................................... 28 
7.8 
12- Lead Electrocardiogram (ECG) ........................................................ 28 
8 
SUBJECT POPULATION ................................................................................... 29 
8.1 
Sample Size ............................................................................................ 29 
8.2 
Inclusion Criteria ..................................................................................... 29 
8.3 
Exclusion Criteria .................................................................................... 30 
9 
TRIAL MEDICATION .......................................................................................... 33 
9.1 
Drug Supply ............................................................................................ 33 
9.2 
Dose and Administration ......................................................................... 34 
9.3 
Previous or Concomitant Therapy .......................................................... 37 
10 TRIAL CONDUCT .............................................................................................. 39 
10.1 
Subject Enrollment .................................................................................. 39 
10.2 
Trial Assessments – Cohort 1 ................................................................. 39 
10.3 
Trial Assessments – Cohort 2 ................................................................. 49 


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10.4 
Trial Assessments – Cohort 3 ................................................................. 57 
10.5 
Trial Assessments – Cohort 4 ................................................................. 65 
10.6 
Withdrawal from Trial .............................................................................. 76 
10.7 
Trial Discontinuation ............................................................................... 76 
11 STATISTICAL METHODS .................................................................................. 77 
11.1 
Experimental Design ............................................................................... 77 
11.2 
Randomization ........................................................................................ 78 
11.3 
Endpoints ................................................................................................ 78 
11.4 
Number of Subjects ................................................................................ 79 
12 ADVERSE EVENTS ........................................................................................... 80 
12.1 
Definition of Adverse Events ................................................................... 80 
12.2 
Assessment and Reporting of Adverse Events ....................................... 80 
12.3 
Definition of Serious Adverse Events ...................................................... 82 
12.4 
Assessment and Reporting of Serious Adverse Events .......................... 83 
12.5 
Exposure in Utero ................................................................................... 83 
13 RESPONSIBILITIES .......................................................................................... 85 
13.1 
Emergency Equipment............................................................................ 85 
13.2 
Case Report Forms and Trial Documentation ......................................... 85 
13.3 
Drug Accountability/Storage Conditions.................................................. 86 
13.4 
Protocol Compliance ............................................................................... 86 
13.5 
Ethical Aspects ....................................................................................... 86 
13.6 
Institutional Review Board (IRB) or Ethics Committee (EC) Approval and 
Informed Consent ................................................................................... 87 
13.7 
Clinical Trial Insurance............................................................................ 87 
13.8 
Trial Report and Publications .................................................................. 87 
14 MONITORING .................................................................................................... 88 
15 REFERENCES ................................................................................................... 89 
16 SIGNATURE PAGE ........................................................................................... 95 
17 APPENDICES .................................................................................................... 96 
 
 
 
 
 
 
 
 
 
 
 
 


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1 GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CATT 
Comparison of AMD Treatments Trials 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
CHF 
Compliment Factor H 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
DA 
Disc Area 
EC 
Ethics Committee 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FP 
Color Fundus Photography 
GA 
Geographic Atrophy 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GLD 
Greatest Linear Diameter 
hERG 
Human Ether-à-Go-Go-Related Gene 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
idT 
Deoxythymidine Nucleotide 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 
ICG 
Indocyanine Green Angiography 
 
IPCV 
Idiopathic Polypoidal Choroidal Vasculopathy 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
MAC 
Membrane Attack Complex 
NLP 
No Light Perception 
NV 
Neovascular 
NVAMD 
Neovascular Age-Related Macular Degeneration 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OU 
Both Eyes 
PED 
Pigment Epithelial Detachment 
PEG 
Polyethylene Glycol 
RAP 
Retinal Angiomatous Proliferation 
RC 
Reading Committee  
RNA 
Ribonucleic Acid  
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SD-OCT 
Spectral Domain Optical Coherence Tomography 


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GLOSSARY OF ABBREVIATIONS CONT.  
 
SE 
Study Eye 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
TN 
Treatment Naïve 
ULN 
Upper Limit of Normal 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


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2 SUMMARY OF PROTOCOL OPH2007 
SYNOPSIS 
TITLE: 
A Phase 2A Open-Label Trial to Assess the Safety of Zimura™ (Anti-
C5) Administered in Combination With Lucentis® 0.5 mg in Treatment 
Naïve Subjects with Neovascular Age Related Macular Degeneration  
OBJECTIVES: 
To assess the safety of intravitreal Zimura™ administered in 
combination with Lucentis® 0.5 mg in treatment naïve subjects with 
neovascular age related macular degeneration (NVAMD)  
STUDY DESIGN: 
 
 
 
 
There will be 4 dosing cohorts in this trial. Approximately 60 subjects 
will be enrolled; 10 subjects in cohorts 1 and 2 and 20 subjects in 
cohorts 3 and 4.     
Cohort 1  
Administered Day 1 – Month 5, in the following sequence, 2 days 
apart: 
 
D0: Lucentis® 0.5 mg/eye  
 
D2: Zimura™ 4 mg/eye (administered as two injections 
of Zimura 2 mg)  
Cohort 2 
Administered Day 1 – Month 5, in the following sequence: 
 
Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye 
on the same day  
Cohort 3 
Induction Phase: Administered Day 1 – Month 2, in the following 
sequence, 14 days apart: 
 
D0: Lucentis® 0.5 mg/eye followed by Zimura™ 2 
mg/eye on the same day 
 
D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered Month 3 – Month 5, in the 
following sequence: 
 
Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye 
on the same day 
Cohort 4 
Induction Phase: Administered Day 1 – Month 2, in the following 
sequence, 14 days apart: 
 
D0: Lucentis® 0.5 mg/eye followed by Zimura™ 2 
mg/eye on the same day 


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SYNOPSIS 
 
D14: Zimura™ 2 mg/eye 
Maintenance Phase: Administered Month 3 – Month 5, in the 
following sequence, 2 days apart: 
 
D0: Zimura™ 2 mg/eye 
 
D2: Lucentis® 0.5 mg/eye followed by Zimura™ 2 
mg/eye on the same day 
All subjects will have a final follow-up visit at Month 6. 
The first 10 subjects will be enrolled into Cohort 1 according to the 
procedures noted below. 
The first three subjects will be assigned to Cohort 1 (Lucentis® 0.5 mg 
and Zimura™4 mg). Once the 3rd subject completes a safety period of 
one week after the first dose of Zimura™ 4 mg without the occurrence 
of a dose limiting toxicity as defined in Section 9.2.3 Dose Limiting 
Toxicity, full enrollment of Cohort 1 may commence.  
If a DLT occurs in one or more of the first 3 subjects assigned to 
Cohort 1, then the Ophthotech medical team will evaluate all available 
data and either discontinue Cohort 1 or enroll an additional three 
subjects (for a total of 6 subjects) in Cohort 1.  If the three additional 
subjects are enrolled, and no additional DLT occurs once the second 
set of 3 subjects in Cohort 1 has reached one week after the first 
dose of Zimura™ 4 mg/eye, full enrollment of Cohort 1 may 
commence.  If one or more DLTs occur in the second set of 3 
subjects, a discussion of safety data will be held among the 
Ophthotech medical team to review the observed toxicities and 
determine whether Cohort 1 may proceed. 
Once Cohort 1 has been fully enrolled, or if enrollment has been 
stopped due to one or more DLTs, then enrollment in the remaining 3 
cohorts may commence. Subjects will be randomized in a 1:2:2 ratio 
to Cohort 2, Cohort 3, or Cohort 4.  
 
 ENDPOINTS: 
Safety Endpoints: 
Safety 
endpoints 
include 
adverse 
events, 
vital 
signs, 
electrocardiography readings (ECG), ophthalmic variables [visual 
acuity, 
intraocular 
pressure 
(IOP), 
ophthalmic 
examination, 
stereoscopic fundus photography, fluorescein angiography (FA), 
spectral domain optical coherence tomography (SD-OCT)], and 
laboratory variables. 
 
PLANNED SAMPLE SIZE: Approximately 60 subjects will be enrolled: 


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SYNOPSIS 
Cohorts 1 and 2: 10 subjects per cohort 
Cohorts 3 and 4: 20 subjects per cohort 
 
SUBJECT SELECTION: 
Subjects of either gender aged 50 years or above diagnosed with 
NVAMD. 
 
TEST DRUG DOSAGE: 
Subjects randomized to Cohort 1 will receive 12 injections of Zimura™ 
2 mg/eye, and 6 injections of Lucentis® 0.5 mg/eye. 
 
Subjects randomized to Cohort 2 will receive 6 injections of Zimura™ 
2 mg/eye, and 6 injections of Lucentis® 0.5 mg/eye. 
 
Subjects randomized to Cohort 3 will receive 9 injections of Zimura™ 
2 mg/eye, and 6 injections of Lucentis® 0.5 mg/eye. 
 
Subjects randomized to Cohort 4 will receive 12 injections of Zimura™ 
2 mg/eye, and 6 injections of Lucentis® 0.5 mg/eye. 
 
 
FORMULATION: 
Zimura™  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lucentis®  0.5 mg (ranibizumab) 
Lucentis® 0.5 mg is a preservative-free colorless to pale yellow sterile 
solution, presented in a single-use glass vial or as a pre-filled syringe 
designed to deliver 0.05 mL (50 µL) of 10 mg/mL Lucentis® 0.5 mg 
aqueous solution with 10 mM histidine HCl, 10% α, α-trehalose 
dihydrate, 0.01% polysorbate 20, pH 5.5. 
Lucentis® 0.5 mg should be used without further dilution and 
administered in accordance with the package insert. 
 










 
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4 INTRODUCTION 
4.1 Age-Related Macular Degeneration (AMD) 
Age-related macular degeneration is a disease characterized by progressive 
degenerative abnormalities in the macula of the eye, a small area in the central portion 
of the retina. It is characteristically a disease of individuals > 50 years of age and is the 
leading cause of visual loss in developed countries (Van Newkirk et al., 2000).  In the 
United States, it is estimated that approximately 6% of individuals 65 - 74 years of age 
and 20% of those older than 75 years of age are affected with AMD (Leibowitz et al., 
1980).   Because of the increasing life expectancy in developed and developing 
countries, the elderly sector of the general population is expected to rise at a greater 
rate in the coming decades (Ortma et al., 2014).  While 1 of 8 Americans was aged 65 
or older in 2012, it is expected that 1 of 5 will fall into this category in 2030 (US Census 
Bureau, 2012).  Using U.S. Census Bureau projections, the number of Americans over 
65 years of age will double to 80 million by the middle of this century (US Census 
Bureau, 2012).  In the absence of adequate prevention or treatment measures, the 
number of cases of AMD with visual loss is expected to grow accordingly. 
Age-related macular degeneration is classified into one of two general subgroups: the 
non-neovascular (non-exudative or dry) form of the disease and the neovascular 
(exudative or wet) form of the disease.  The non-neovascular form of AMD is more 
prevalent, accounting for approximately 90% of all AMD cases, and is often 
characterized by a slow degeneration of the macula resulting in atrophy of the central 
retina with gradual vision loss over a period of years.  By contrast, NVAMD, although 
less prevalent, commonly causes sudden, often substantial, loss of central vision and is 
responsible for most cases of severe loss of visual acuity in this disease (Vingerling, 
1995). This type of AMD results when abnormal blood vessels (neovascularization) 
proliferate under and/or within the retina.  These blood vessels leak blood and fluid into 
and under the retina, which results in rapid vision loss.  The end stage of the disease 
features scarring with irreversible destruction of the central retina.   
The current FDA approved pharmacologic therapies for NVAMD target and inhibit 
Vascular Endothelial Growth Factor (VEGF). VEGF is an endothelial cell survival factor 
and a mitogen. Endothelial cells are a key component of neovascular tissue. All 
approved anti-VEGF agents for NVAMD are administered by the intravitreal route of 
administration. These include Lucentis® (ranibizumab) and Eylea® (aflibercept) (Brown 


 
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et al., 2006; Heier et al., 2012; Rosenfeld et al., 2006). 
In addition, although not labeled by the FDA for the treatment of NVAMD, the anti-VEGF 
agent Avastin® (bevacizumab) is currently used to treat ~50% of the eyes with NVAMD 
in the United States (Parikh, et al, 2017). A multicenter, prospective, randomized trial, 
funded by the US National Eye Institute, “The Comparison of Age-Related Macular 
Degeneration Treatments Trials” (CATT) demonstrated that monthly dosing with 
Avastin® 1.25 mg (0.05 mL) was non-inferior to monthly dosing of Lucentis® for eyes 
with NVAMD (Martin et al., 2012).  
Avastin®, Lucentis®, and Eylea®, on average, all improve the visual outcome in eyes 
with NVAMD. The primary functional impact of these anti-VEGF agents is to decrease 
intraretinal and subretinal fluid associated with abnormal blood vessels. Despite 
maximal therapy with intravitreal monotherapy anti-VEGF agents, the majority of 
patients do not achieve significant visual gain (≥ 15 letters of vision), and approximately 
20% to 30% lose additional vision from baseline.  
 
4.2 The Complement Pathway and AMD 
The etiology of AMD is not completely understood.  In addition to advanced age, there 
are environmental and genetic risk factors for AMD including ocular pigmentation, 
dietary factors, a positive family history for AMD, high blood pressure, and smoking 
(Klein et al., 2004). Recent work suggests complement activation may contribute to the 
pathogenesis and progression of the disease (Bora at al., 2005, Donoso et al., 2006, 
Nozaki et al., 2006, Schnabolk G, et al., 2017) 
The complement pathway is part of the innate immune system and is a complex system 
of serum proteins that interact in a cascade. This complement cascade is activated via 
the classical (antibody-dependent), the alternative (antibody-independent) and the lectin 
pathways. Activation of the complement cascade has been implicated in drusen 
formation (Hageman et al., 2001, Anderson et al., 2002, Bok D, 2005). Additionally, 
complement components may induce up-regulation of VEGF, a well-known mediator of 
choroidal neovascularization (CNV) (Nozaki et al., 2006). Preclinical laser-induced CNV 
models have also implicated complement activation.  
Further, the choroid may serve as a nidus for the deposition of membrane attack 
complex (MAC) when compared to other tissues in the body (Chirco et al., 2016). MAC 
accumulation leads to mitochondrial damage and cellular dysfunction in RPE cells 


 
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(Georgiannakis et al. 2015). In experimental models of CNV, MAC formation has been 
shown to be important (Johnson et al., 2000). MAC is also responsible for causing 
pores in the affected cells that eventually leads to cell death. 
Inhibition of complement activation has led to a decrease in CNV formation in 
experimental mouse model (Rohrer et al., 2009; Jo et al., 2017). In a CD59 knockout 
model, mice that were deficient in MAC inhibition developed a larger CNV size when 
compared to wild type mice (Schnabolk et al., 2017). Evidence for the role of 
complement in AMD is further reinforced by genetic linkage and association studies, 
which suggest that approximately 50 to 75% of AMD cases have polymorphism in 
complement regulatory proteins compared to age-matched controls. Furthermore, 
polymorphism in genes coding for complement or complement regulatory proteins have 
demonstrated increased risk in age-related macular degeneration (Edwards et al., 2005; 
Hageman et al., 2005, Haines et al., 2005; Klein et al., 2005, Naranyan et al., 2007). 
 
4.3 VEGF Inhibition and Complement 
Avastin®, Lucentis®, and Eylea®, on average, all improve the visual outcomes in eyes 
with NVAMD. Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, 
majority of patients do not achieve significant visual gain (≥ 15 letters of vision), and 
approximately 20% to 30% lose additional vision from baseline. Further, an increase in 
dosage or regimen did not lead to additional efficacy and it appears that a “ceiling” of 
anti-VEGF effect may have been reached (Busbee et al., 2013). 
In addition, approximately one fifth of the patients who had received anti-VEGF therapy 
developed geographic atrophy (GA) within 2 years of treatment (Grunwald et al., 2014). 
The authors concluded that anti-VEGF therapy may play a role in the development of 
atrophy.  At 5 years the cumulative incidence had increased to 38%, concluding that the 
development of GA was common after 5 years of treatment (Gruwald et al., 2017). 
A meta-analysis of 13 published studies proposed that patients who are homozygous 
for complement factor H (CFH) polymorphism Y402H experience a reduced response to 
anti-VEGF treatment (Chen et al., 2015). Further, a direct relationship between VEGF 
and CFH was recently demonstrated where VEGF upregulated CFH expression and 
VEGF inhibition lead to a decrease in CFH expression in RPE cells (Keir et al., 2017). 
Mice that received anti-VEGF treatment, showed a significant decrease in VEGF and 
CFH. This led to a 200 fold increase in retinal C3 RNA and increased MAC expression, 
suggesting that VEGF inhibition may contribute to complement activation (Keir et al., 


 
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2017). Further, in patients with NVAMD, aqueous humor samples collected 48 hours 
after intravitreal injection of bevacizumab demonstrated a decrease in VEGF levels but 
an increase in C3a, C4a, and C5a levels (Keir et al. 2017). 
Taken together, these findings may potentially indicate that although VEGF inhibition 
has potent anti-permeability characteristics, it may also contribute to complement 
activation by reducing CFH expression and therefore limiting the full therapeutic 
potential of the anti-VEGF therapy in NVAMD patients. 
  
4.4 Zimura™ 
Zimura™, a PEGylated RNA aptamer, is an inhibitor of complement activation. It inhibits 
C5, a central component of the complement cascade, which plays multiple roles in 
innate immunity and inflammatory diseases. Inhibition of this key step in the 
complement cascade at the level of C5 prevents the formation of key terminal fragments 
(C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced 
their generation. The C5a fragment is an important inflammatory activator inducing 
vascular permeability, recruitment and activation of phagocytes. C5b is involved in the 
formation of MAC: C5b-9, which initiates cell lysis. By inhibiting these C5-mediated 
inflammatory and MAC activities, therapeutic benefit may be achieved in NVAMD. 
 
4.4.1 Non-Clinical Efficacy  
The preclinical data demonstrating the anti-C5 properties of Zimura™ are described in 
detail in the Investigator Brochure (IB). 
 
4.4.2 NonClinical Pharmacokinetics of Zimura™ 
Nonclinical pharmacology studies have been conducted with Zimura™, and, in some 
cases, with aptamers (Hoehlig et al., 2013).  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
The safety pharmacology studies did not reveal any effects on cardiovascular, 
respiratory or neurologic function that would raise concerns for the intended ocular 
administration. 


 
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Further information regarding the pharmacology of Zimura™ is presented in detail in the 
IB.   
 
4.4.3 Toxicology 
 
.  
 
 
   
Additional details of the results of these studies, as well as the results of the various 
intravenous toxicity studies that were previously conducted, can be found in the IB.  
 
4.5 
Clinical Data 
4.5.1 Study OPH2000 
In a phase 1 ascending dose and parallel group clinical trial the safety, tolerability, and 
pharmacokinetic profile of multiple intravitreal injections of Zimura™ in combination with 
Lucentis® 0.5 mg was evaluated in subjects with NVAMD (OPH 2000).  
Zimura™ was well-tolerated and no particular safety concerns were identified. No 
significant evidence of intraocular inflammation, retinal vasculitis, or choroidal 
vasculopathy was evident.  One patient was noted to develop a mild cataract, which 
was considered to be related to study drug by the investigator; despite this event, the 
visual acuity improved in this patient during the study.  
Visual acuity (VA) assessments were primarily safety assessments to detect any 
decrease in vision associated with the intravitreal injections. There were no safety 
issues identified through measurement of VA. Assessment of VA was focused on the 
treatment-naïve (TN) patient subgroup of 43 patients who had received 6 injections at 
doses of 0.3 mg, 1 mg or 2 mg. There was a trend towards a mean increase in VA 
(number of ETDRS letters) from Baseline at all time points for patients in the 0.3, 1 and 
2 mg dose groups in the TN subgroup who received 6 injections. At Week 24, there was 
an improvement in mean VA from Baseline of 13.6 ETDRS letters for the 0.3 mg dose 
group, 11.7 ETDRS letters for the 1 mg dose group and 15.3 ETDRS letters for the 2 
mg dose group. 


 
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Fifty-one percent (51%) of patients in the TN subgroup (n=43 patients) gained > 15 
ETDRS letters at Week 24. This included 6 patients (46%) in the 0.3 mg dose group, 7 
patients (47%) in the 1 mg dose group, and 9 patients (60%) in the 2 mg dose group 
gaining > 15 ETDRS letters of VA. 
 
4.5.2 Study OPH2001 
A separate phase 1 study was also performed in subjects diagnosed with geographic 
atrophy (GA). In this study, a total of 47 subjects were enrolled, in the 0.3 mg dose arm 
(n=24) and 1 mg dose arm (n=23). Subjects received treatment with 3 initial intravitreal 
injections of Zimura™ 0.3 mg/eye or 1 mg/eye, administered at Day 0, Week 4 and 
Week 8 with a follow up visit at Week 16. Subjects received 2 subsequent injections at 
Week 24 and Week 36 followed by a final follow up visit at Week 48. Standard safety 
assessments were performed for ophthalmic variables that included VA, IOP, 
ophthalmic examination, fundus autofluorescence (FAF), Fluorescein Angiography (FA), 
and optical coherence tomography (SD-OCT) together with AEs, vital signs and 
laboratory variables.  
Zimura™ was well tolerated and there were no AEs considered to be related to 
Zimura™. Fifteen subjects (32%) had AEs, predominantly Eye Disorder AEs in the 
study eye, assessed to be related to the injection procedure. The most frequently 
reported AEs were conjunctival hemorrhage (4 subjects, 9%), corneal edema (4 
subjects, 9%), and dry eye (3 subjects, 6%).  No other study eye AEs were reported by 
more than 2 subjects. The majority of AEs were mild or moderate in severity. There 
were 2 subjects with AEs of severe intensity: gastrointestinal inflammation and 
nasopharyngitis. 
Five subjects experienced serious adverse events (SAEs), namely device failure, pelvic 
fracture, angina pectoris, chest pain and gastrointestinal inflammation, but none were 
related to the study drugs or injection procedure. There were no discontinuations due to 
AEs. 
Vital signs and laboratory assessments did not show any particular clinically significant 
patterns or changes. Study eye ophthalmic examinations did not indicate any 
unexpected clinical findings. There were some transient findings post-injection 
(conjunctiva/sclera and cornea) that resolved prior to the next injection. Vitreous haze 
was also reported for a few subjects. Intraocular pressure (IOP) showed a small mean 
increase following injections but no indication of any cumulative increases.  


 
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VA assessments did not show any safety signals. VA measurements are not particularly 
meaningful in GA given the marked irreversible atrophy of neural and supportive tissue 
and the variable involvement of the macular region.  There was suggestion of a drug 
exposure and dose related slowing of the rate of GA growth during the period of 
increased frequency of drug exposure (i.e. monthly dosing for 3 months) from Baseline 
to Week 24, as well as a suggestion of stabilized VA, including VA under low light 
conditions. The data supported further investigation of Zimura™ in larger clinical trials. 
 
4.5.3 Study OPH2002 
The objectives of this study were to evaluate the safety and tolerability of Zimura™ 
intravitreal injection in combination with VEGF therapy in subjects with idiopathic 
polypoidal choroidal vasculopathy (IPCV). Subjects included in the study were treatment 
experienced (prior treatment with anti-VEGF monotherapy of ≥ 8 injections in the 
previous 12 months) of either gender aged 50 years or above with diagnosis of IPCV. 
Subjects received 3 monthly intravitreal injections of Zimura™ (1 mg/eye) in 
combination with intravitreal injection of anti-VEGF agent (Avastin® 1.25 mg/eye or 
Lucentis® 0.5 mg/eye or Eylea® 2 mg/eye). 
Safety endpoints included VA loss (proportion of subjects with > 15 letter loss at Month 
30, ophthalmic adverse events (AEs), systemic adverse events (AEs), change in total 
retinal thickness (SD-OCT) at Month 3, regression and/or elimination of polyps at Month 
3 compared to Screening as measured by indocyanine green angiography (ICGA) and 
laboratory values.   
A total of 4 subjects were enrolled in this clinical trial and all the subjects completed the 
study. None of the subjects had a VA loss of more than 15 ETDRS letters at Month 3. 
There were no deaths during the study. There was one SAE of endophthalmitis reported 
in 1 subject. The SAE resolved and was assessed to be related to the injection 
procedure. None of the ocular AEs were assessed to be related to Zimura™ or anti-
VEGF treatment. 
The intravitreal administration of Zimura™ in combination with an anti-VEGF agent 
(Avastin®, Eylea®, or Lucentis®) in patients with IPCV was generally well tolerated. The 
data supports further investigation of the drug in larger clinical trials. 
 


 
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4.6 Trial Rationale 
There is widespread acceptance that the therapeutic benefit of anti-VEGF monotherapy 
is primarily a result of its potent anti-permeability effects. Studies have shown that 
VEGF is the most potent inducer of permeability in biologic systems (Dvorak et al., 
1995).  Multiple investigations of currently available anti-VEGF agents (Lucentis®, 
Avastin® and Eylea®) suggest that they are essentially similar with respect to their safety 
and efficacy profiles (Brown et al., 2006; Martin et al., 2012; Rosenfeld et al., 2006; 
Schmidt-Erfurth et al., 2014).  Furthermore, the “ceiling” of anti-VEGF mediated 
therapeutic benefit in NVAMD appears to have been reached as attempts at improving 
visual outcomes by altering the dose and regimen of anti-VEGF therapy have been 
unsuccessful (Busbee et al., 2013; Schmidt-Erfurth et al., 2014). Despite maximal 
therapy with intravitreal monotherapy anti-VEGF agents, the majority of patients do not 
achieve significant visual gain (≥ 15 ETDRS Letters) or achieve visual acuity of 20/40 or 
better. In addition, approximately 25% of the patients lose additional vision (Martin et al., 
2012). Further, less than monthly regimen results in worse visual outcomes in the real 
world setting and over time patients in general lose vision with anti-VEGF monotherapy 
(Rakic et al. 2013, Rasmussen et al., 2013; Rofagha et al, 2013).  Approximately one 
fifth of patients who had received anti-VEGF therapy developed GA within 2 years of 
treatment (Grunwald et al., 2014). The authors concluded that anti-VEGF therapy may 
play a role in the development of atrophy.  At 5 years, the cumulative incidence was 
38%, concluding that the development of GA was common after 5 years of anti-VEGF 
treatment (Grunwald et al., 2017). 
As indicated earlier, there is mounting evidence that both the wet and dry forms of AMD 
may involve multiple complement pathway proteins. Preclinical laser-induced choroidal 
neovascularization (CNV) models have implicated complement activation as well. 
Complement activation has also induced the up-regulation of key mediators of 
angiogenesis such as VEGF (Nozaki et al., 2006). Evidence for the role of complement 
in AMD is further reinforced by genetic linkage and association studies that suggest that 
approximately 50 to 75% of AMD cases have polymorphism in complement regulatory 
proteins compared to age-matched controls. Furthermore, polymorphism in gene coding 
for complement or complement regulatory proteins have demonstrated increased risk in 
AMD (Haines et al., 2005, Edwards et al., 2005, Klein et al., 2005, Hageman et al., 
2005, Naranyan et al., 2007). A meta-analysis of 13 published studies proposed that 
patients who are homozygous for CFH polymorphism Y402H experience a reduced 
response to anti-VEGF treatment (Chen et al., 2015).  


 
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A direct potential relationship between VEGF and CFH was recently demonstrated 
indicating that VEGF inhibition may lead to a decrease in CFH expression in RPE cells 
(Keir et al. 2017). Mice that received anti-VEGF treatment, showed a significant 
decrease in VEGF and CHF.  This led to a 200 fold increase in retinal C3 RNA and 
increased MAC expression suggesting that VEGF inhibition may contribute to 
complement activation (Keir et al., 2017). Further, in patients with neovascular AMD, 
aqueous humor samples collected 48 hours after intravitreal injection of bevacizumab 
demonstrated a decrease in VEGF levels but an increase in C3a, C4a, and C5a levels. 
The totality of pre-clinical and genetic related evidence implicates the role of 
complement activation in AMD. Further, the inhibition of anti-VEGF may contribute 
further to complement activation by decreasing CFH in RPE cells. Taken together, 
these findings may potentially indicate that although anti-VEGF treatment has potent 
anti-permeability characteristics it may also activate the complement cascade by 
reducing CFH expression and therefore limit the full therapeutic potential of anti-VEGF 
in NVAMD patients. Hence, a combination treatment which inhibits both VEGF and 
complement may improve visual outcome and therefore targeting the complement 
pathway may result in a new therapeutic class in NVAMD. 
Zimura™ is currently being developed by Ophthotech Corporation for the treatment of 
complement mediated retinal diseases including dry AMD, NVAMD. Zimura™ is a 
PEGylated RNA aptamer and an inhibitor of complement activation.  Zimura™ inhibits 
C5, a central component of the complement cascade, which plays multiple roles in 
innate immunity and inflammatory diseases. Inhibition of this key step in the 
complement cascade at the level of C5 prevents the formation of key terminal fragments 
(C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced 
their generation. The C5a fragment is an important inflammatory activator inducing 
vascular permeability, recruitment and activation of phagocytes. C5b is involved in the 
formation of MAC that initiates cell lysis. By inhibiting these C5-mediated inflammatory 
and MAC activities, additional therapeutic benefit may be achieved in NVAMD patients 
receiving anti-VEGF monotherapy. 
As a dose-response relationship trend in VA gain was evident in Study OPH2000, a 
higher dose of Zimura 4 mg will be evaluated in this study.  Additionally, it has been 
shown that biweekly intravitreal injections in patients with wet AMD are well tolerated 
(Rosenfeld et al., 2006, and Stewart et al. 2011). Further, biweekly dosing may increase 
the trough levels binding activity. Therefore, this study will also evaluate the biweekly 


 
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administration of Zimura 2 mg for an induction period of 3 months. 
 


 
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5 TRIAL OBJECTIVES 
5.1 Objectives 
To assess the safety of intravitreal Zimura™ administered in combination with Lucentis® 
in treatment naïve subjects with NVAMD. 
 
5.2 Endpoints 
Safety endpoints include: 
 Adverse events (AEs) 
 Vital signs (respiration, heart rate, systolic and diastolic blood pressure, etc.) 
 ECG recordings 
 Ophthalmic variables (visual acuity, IOP, ophthalmologic examination, 
stereoscopic fundus photography, fluorescein angiography, and spectral domain 
optical coherence tomography) 
 Laboratory variables (blood:  hematology, renal function, hepatic function, and 
electrolytes; urine: urinalysis) 
 
 


 
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6 TRIAL DESIGN 
There will be 4 dosing cohorts on this trial. Approximately 60 subjects will be enrolled; 
10 subjects in cohorts 1 and 2 and 20 subjects in cohorts 3 and 4.   
Cohort 1 
Administered Day 1 – Month 5, in the following sequence, 2 days apart: 
 D0: Lucentis® 0.5 mg/eye  
 D2: Zimura™ 4 mg/eye (administered as two injections of Zimura 2 
mg/eye)  
Cohort 2 
Administered Day 1 – Month 5, in the following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day  
Cohort 3 
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days 
apart: 
 D0: Lucentis® 0.5 mg/eye  followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day 
Cohort 4 
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days 
apart: 
 D0: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence, 2 
days apart: 
 D0: Zimura™ 2 mg/eye  


 
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 D2: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 
 
All subjects will have a final follow-up visit at Month 6. 
The first 10 subjects will be enrolled into Cohort 1 according to the procedures noted 
below. 
The first three subjects will be assigned to Cohort 1 (Lucentis® 0.5 mg and Zimura™ 4 
mg). Once the 3rd subject completes a safety period of one week after the first dose of 
Zimura™ 4 mg without the occurrence of a dose limiting toxicity as defined in Section 
9.2.3 Dose Limiting Toxicity, full enrollment of Cohort 1 may commence.  
If a DLT occurs in one or more of the first 3 subjects assigned to Cohort 1, then the 
Ophthotech medical team will evaluate all available data and either discontinue Cohort 
1 or enroll an additional three subjects (for a total of 6 subjects) in Cohort 1.  If the three 
additional subjects are enrolled, and no additional DLT occurs once the second set of 3 
subjects in Cohort 1 has reached one week after the first dose of Zimura™ 4 mg/eye, 
full enrollment of Cohort 1 may commence.  If one or more DLTs occur in the second 
set of 3 subjects, a discussion of safety data will be held among the Ophthotech medical 
team to review the observed toxicities and determine whether Cohort 1 may proceed. 
Once Cohort 1 has been fully enrolled, or if enrollment has been stopped due to one or 
more DLTs, then enrollment in the remaining 3 cohorts may commence. Subjects will be 
randomized in a 1:2:2 ratio to Cohort 2, Cohort 3, or Cohort 4.  
 
 
 
 


 
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7 PROCEDURES 
7.1 Procedures for Refraction and Vision Testing 
Refraction and Vision Testing will be performed at all time-points specified in Sections 
10.2 – 10.5 “Trial Assessments”.   
For ETDRS testing, retroilluminated modified Ferris-Bailey ETDRS (Early Treatment 
Diabetic Retinopathy Study) charts are used starting at 4 meters (see Appendix 17.3). 
When protocol refraction and best-corrected visual acuity measurement is required by 
the trial protocol, this will be performed only by certified visual acuity examiners. The 
examiner will be supplied with the previous protocol refraction only.   
 
7.2 Tonometry  
Tonometry will be performed at all time-points specified Sections 10.2 – 10.5 “Trial 
Assessments”.  On days when two injections are given tonometry should be repeated 
after the first injection, to confirm perfusion of the optic nerve and return of IOP to ≤ 21 
mmHg or within 5 mmHg of pre-injection before the second injection is 
administered.  After the second injection, and also on days when only one injection is 
administered, IOP must return to < 30 mmHg before the subject leaves the clinic.  For 
the post-injection tonometry, proper care should be taken to minimize the risk of 
contamination. 
Goldmann applanation tonometry must be performed at Screening, Day 1, and Month 
6/Early Withdrawal.  Tono-Pen may be used at all other time-points, but Goldmann 
applanation tonometry must be used to verify IOP for a post-injection reading of ≥ 30 
mmHg occurring more than 30 minutes post-injection, or for a reading of ≥ 30 mmHg at 
any other time. 
 
7.3 Ophthalmologic Examination 
The following examinations will be performed at all time-points specified in Sections 
10.2 – 10.5 “Trial Assessments”. 
 Inspection of the eyelids 
 Examination of the extra-ocular muscle movement  
 Inspection of the cornea 
 Examination of the anterior chamber for inflammation (Appendix 17.1) 


 
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 Examination of the pupils 
 Examination of the iris 
 Inspection of the lens 
 Inspection of the vitreous body (Appendix 17.2) 
 Inspection of the retina and optic disc 
 
7.4 Fundus Photography and Fluorescein Angiography 
Color fundus photography (FP) and fluorescein angiography (FA) will be performed at 
all time-points specified in Sections 10.2 – 10.5 “Trial Assessments”.   
The Sponsor will provide the Principal Investigator with instructions for the FP and FA 
as well as the submission process to the Reading Committee (RC). 
 
7.5 Spectral Domain Optical Coherence Tomography (SD-OCT) 
Spectral Domain optical coherence tomography (SD-OCT) will be performed at all time-
points specified in Sections 10.2 – 10.5 “Trial Assessments”.   
The Sponsor will provide the Principal Investigator with instructions for the SD-OCT as 
well as the submission process to the RC. 
 
7.6 Laboratory Tests 
The following laboratory tests will be performed as specified in Sections 10.2 – 10.5 
“Trial Assessments”: 
 Hematology: hemoglobin, platelet count, WBC and differential 
 Renal Function: serum creatinine and BUN 
 Hepatic function: serum bilirubin, alkaline phosphatase, GGT, SGOT/AST and 
SGPT/ALT 
 Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and phosphate 
 Complete Urinalysis (including specific gravity, protein, and blood)  
 Serum pregnancy test (for women of child-bearing potential) 
If the Investigator judges a laboratory value outside of the normal range as clinically 
significant, the Investigator will repeat the laboratory determination as judged 


 
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appropriate to ensure the validity of the abnormal result. If any clinically significant 
abnormal results are noted, the tests are to be repeated until the results are normal, are 
no longer considered clinically significant by the investigator, or an explanation for the 
change is obtained. 
 
7.7 
Vital Signs and Physical Examination 
A physical examination will be performed at Screening and at the Investigator’s 
discretion thereafter.  Assessment of vital signs will be performed at all time points 
specified in Sections 10.2 – 10.5 “Trial Assessments”.   
 
7.8 
12- Lead Electrocardiogram (ECG) 
A 12-Lead ECG will be performed at all time points specified in Sections 10.2 – 10.5 
“Trial Assessments”.  
 
 
 


 
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8 SUBJECT POPULATION 
8.1 Sample Size 
Approximately 60 subjects will be enrolled; 10 subjects in cohorts 1 and 2, and 20 
subjects in cohorts 3 and 4. 
 
8.2 Inclusion Criteria 
Subjects must meet the following criteria to be eligible to participate in this study: 
Ophthalmic Inclusion Criteria 
The following inclusion criteria apply to the study eye: 
 
  
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
General Inclusion Criteria 
8.2.1.7 
Subjects of either gender aged  50 years. 
8.2.1.8 
Performance Status  2 according to Eastern Cooperative Oncology Group 
(ECOG) / World Health Organization (WHO) scale (Appendix 17.6) 
8.2.1.9 
Normal electrocardiogram (ECG) or clinically non-significant changes. 
8.2.1.10 Women must be using two forms of effective contraception, be post-
menopausal for at least 12 months prior to trial entry, or surgically sterile; if of 
child-bearing potential, a serum pregnancy test must be performed within 14 


 
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days prior to the first injection with a negative result.  The two forms of 
effective contraception must be implemented during the trial and for at least 
60 days following the last dose of test medication. 
8.2.1.11 Provide written informed consent. 
8.2.1.12 Ability to return for all trial visits. 
 
8.3 Exclusion Criteria 
Subjects will not be eligible for the trial if any of the following criteria are present in the 
study eye or systemically: 
Ophthalmic Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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General Exclusion Criteria 
8.3.1.16 Any of the following underlying diseases including: 
 
History or evidence of severe cardiac disease (e.g., NYHA Functional 
Class III or IV - see Appendix 17.5), history or clinical evidence of 
unstable angina, acute coronary syndrome, myocardial infarction or 
revascularization within last 6 months, ventricular tachyarrhythmia 
requiring ongoing treatment. 
 
History or evidence of clinically significant peripheral vascular disease, 
such as intermittent claudication or prior amputation. 
 
Stroke within 12 months of trial entry. 
 
Any major surgical procedure within one month of trial entry. 
8.3.1.17 Subjects with a clinically significant laboratory value.  Laboratory tests may be 
repeated once before randomization.  
8.3.1.18 Previous therapeutic radiation in the region of the study eye. 
8.3.1.19 Any treatment with an investigational agent in the past 60 days for any 
condition. 
8.3.1.20 Women who are pregnant or nursing. 


 
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8.3.1.21 Known serious allergies to the fluorescein dye used in angiography, povidone 
iodine, to the components of the ranibizumab formulation, or to the 
components of the Zimura™ formulation. 
 
 
 
 


 
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9 TRIAL MEDICATION 
9.1 Drug Supply  
9.1.1 Zimura™  
Zimura™ is a PEGylated RNA aptamer 
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
 
 
  
   
 
 
 


 
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9.1.2 Lucentis® 0.5 mg  
Lucentis® 0.5 mg is a recombinant humanized IgG1 kappa isotype monoclonal antibody 
fragment designed for intraocular use. Lucentis® 0.5 mg has a molecular weight of 
approximately 48 kilodaltons and is produced by an E. coli expression system in a 
nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in 
the final product. 
 
9.2 Dose and Administration 
9.2.1 Preparation 
Zimura™ and Lucentis® 0.5 mg will be injected without dilution.   
Zimura™ is supplied in a single-use glass vial as noted in Section 9.1.1 above.  
 
 
 
 
 
Lucentis® 0.5 mg injection is a preservative-free colorless to pale yellow sterile solution, 
presented in a single-use glass vial or as a pre-filled syringe designed to deliver 0.05 
mL of 10 mg/mL ranibizumab injection aqueous solution with 10 mM histidine HCl, 10% 
α, α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.  Lucentis® should be used 
without further dilution and administered in accordance with the package insert. 
 


 
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9.2.2 Treatment Regimen and Duration 
There will be 4 dosing cohorts on this trial. Approximately 60 subjects will be enrolled; 
10 subjects in cohorts 1 and 2, and 20 subjects in cohorts 3 and 4.   
Cohort 1  
Administered Day 1 – Month 5, in the following sequence, 2 days apart: 
 D0: Lucentis® 0.5 mg/eye  
 D2: Zimura™ 4 mg/eye (administered as two injections of Zimura 2 mg)  
Cohort 2 
Administered Day 1 – Month 5, in the following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day  
Cohort 3 
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days 
apart: 
 D0: Lucentis® 0.5 mg/eye  followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day 
Cohort 4 
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days 
apart: 
 D0: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence, 2 
days apart: 
 D0: Zimura™ 2 mg/eye  
 D2: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 


 
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All subjects will have a final follow-up visit at Month 6. 
The first 10 subjects will be enrolled into Cohort 1 according to the procedures noted 
below. 
The first three subjects will be assigned to Cohort 1 (Lucentis® 0.5 mg and Zimura™ 4 
mg). Once the 3rd subject completes a safety period of one week after the first dose of 
Zimura™ 4 mg without the occurrence of a dose limiting toxicity as defined in Section 
9.2.3 Dose Limiting Toxicity, full enrollment of Cohort 1 may commence.  
If a DLT occurs in one or more of the first 3 subjects assigned to Cohort 1, then the 
Ophthotech medical team will evaluate all available data and either discontinue Cohort 
1 or enroll an additional three subjects (for a total of 6 subjects) in Cohort 1.  If the three 
additional subjects are enrolled, and no additional DLT occurs once the second set of 3 
subjects in Cohort 1 has reached one week after the first dose of Zimura™ 4 mg/eye, 
full enrollment of Cohort 1 may commence.  If one or more DLTs occur in the second 
set of 3 subjects, a discussion of safety data will be held among the Ophthotech medical 
team to review the observed toxicities and determine whether Cohort 1 may proceed. 
Once Cohort 1 has been fully enrolled, or if enrollment has been stopped due to one or 
more DLTs, then enrollment in the remaining 3 cohorts may commence. Subjects will be 
randomized in a 1:2:2 ratio to Cohort 2, Cohort 3, or Cohort 4.  
 
9.2.3 Dose Limiting Toxicity 
9.2.3.1 Clinical Examination 
 Visual acuity: loss of 4 or more lines (≥ 20 letters), Baseline through Week 1.  
This will not be considered a DLT if the vision loss is due to an event deemed 
related to the injection procedure by the investigator (e.g., vitreous 
hemorrhage). 
 Clinically significant inflammation: defined as > 3+ according to the grading 
schedule as modified from the Hogan or Nussenblatt method. (Appendix 17.1 
and 17.2) 
 Tonometry: increase of intraocular pressure (IOP) from Baseline of ≥ 15 
mmHg on two separate examinations at least one day apart excluding the day 
of injection, despite pharmaceutical intervention.   


 
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 Accelerated formation of cataract (not related to the injection procedure): 
progression of one unit from Baseline to Week 1 defined by the Age-Related 
Eye Disease Study (AREDS) Lens Opacity Grading Protocol as adapted from 
the Wisconsin Cataract Grading System where the same observer is used.   
 Other severe ocular abnormalities not usually seen in subjects with NVAMD. 
9.2.3.2 SD-OCT 
Significant retinal abnormalities deemed related to study drugs by the investigator.  
 
9.2.3.3 Systemic DLT 
Grade III (severe), IV (life threatening) or V (death related to adverse event) toxicities as 
defined in the NCI Common Toxicity Criteria version 4.03,  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf 
or any significant severe toxicity deemed related to study drug by the principal 
investigator. 
 
9.2.4 Administration of Trial Drug 
The method for intravitreal administration of Zimura™ and Lucentis® 0.5 mg is described 
in detail in Appendix 17.4.  
 
9.2.5 Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all 
trial drugs are stored in a secured area, under labeled storage conditions and in 
accordance with applicable regulatory requirements. 
 
 
 
 
   
 
9.3 Previous or Concomitant Therapy 
Subjects enrolled must be treatment naïve except for oral supplements of vitamins and 
minerals.  Previous treatment for AMD in the study eye prior to Screening is not 
permitted.  


 
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Any treatment with any investigational agent for any condition in the 60 days prior to 
Screening, or treatment with an investigational agent for any condition during the trial, is 
not permitted.   
Treatment for NVAMD in the fellow eye during the study with an approved product is 
permitted at any time. If intravitreal treatment in the fellow eye is administered on 
the same day as study drug, the injection(s) in the study eye should be 
administered first (before the injection in the fellow eye). 
Although not labeled for the treatment of NVAMD, Avastin® is also allowed in the fellow 
eye at the discretion of the investigator. 
 
 


 
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10 TRIAL CONDUCT 
10.1 Subject Enrollment 
Before recruitment of subjects into the trial, written Institutional Review Board (IRB) or 
Ethics Committee (EC) approval of the protocol and informed consent must be 
obtained. 
Subjects who meet the eligibility criteria and have provided written informed consent will 
be enrolled in the trial.  If any inclusion or exclusion criteria are not met, treatment with 
trial drug should not commence without prior written approval from Ophthotech Corp. or 
its designee. 
Written informed consent must be obtained before any of the Screening procedures 
listed below are performed.  However, if a routine office procedure (e.g. FA, OCT) is 
performed to diagnose NVAMD independent of this clinical trial, and subsequently the 
subject provides informed consent for this study, these procedures performed prior to 
informed consent may be used as screening assessments for this study, provided the 
14-day period of screening evaluations is respected and provided the assessments are 
acceptable to the standards of the study.  An explanation of the trial and discussion of 
the possible risks and discomforts will be given by the investigator.   
For the Screening visit only, assessments can be broken into 2 days if necessary.  For 
all other visits, all assessments indicated must be performed on the same day.  
The RC will determine eligibility of all subjects prior to enrollment. Only those subjects 
who fulfill all eligibility criteria will be entered into the trial.  
The following assessments will be performed during the study.   
 
10.2 Trial Assessments – Cohort 1 
The following dosing days apply to subjects in Cohort 1. 
D0 
D0 = The first day of dosing at each monthly timepoint.   
D2 
D2 = The second day of dosing, 2 days after D0. 
The following evaluations, as outlined in the Study Assessments Chart (see Section 3), 
will be performed on the days specified below: 
 


 
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Note:  
 Concomitant Medications should be assessed at every study visit. 
 Adverse events (AEs) should be assessed starting at Day 1 after the first 
dose of trial drug.   
 
10.2.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed within 14 days prior to Day 1.   
 Informed consent 
 Medical history 
 Ophthalmic history (OU) 
 Physical exam/Vital signs 
 12-Lead ECG 
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 Ophthalmologic examination and Goldmann applanation tonometry (OU) 
 Color fundus photography (FP) (OU)  
 Fluorescein angiography (FA) (OU, transit SE) 
 Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 Serum pregnancy test within 14 days of first trial injection (if applicable) 
 Laboratory tests 
 Concomitant medication assessment 
 
10.2.1.1 
Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the following two criteria must be met: 
1. There is NO SIGNIFICANT ANATOMICAL CHANGE by clinical examination 
between the Screening visit and Day 1 (i.e. large subretinal hemorrhage, RPE 
rip, pigment epithelial detachment).  
 
2. VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 5 LETTERS (better or worse) of the SCREENING 
VA.   
 


 
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*OR* 
 
VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 6 – 10 LETTERS (better or worse) of the 
SCREENING VA, and repeat clinical examination, fundus photography, 
fluorescein angiography, and SD-OCT imaging – together as judged and 
documented by the investigator – still meet the inclusion criteria. 
If the patient is randomized, the repeat imaging studies must be submitted to the 
Reading Committee (RC) to be used as the new study Baseline. 
 
If the clinical examination and/or the imaging studies do not meet the inclusion 
criteria at Day 1, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is GREATER THAN 10 ETDRS LETTERS (better 
or worse) different from the SCREENING VA, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is NO LONGER WITHIN THE INCLUSION 
CRITERIA (Snellen equivalent 20/63 to 20/200), the patient must NOT be randomized. 
 
10.2.2 Day 1 (D0 Visit) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Goldmann applanation tonometry and Ophthalmologic Examination (SE) 
Injection 
 Lucentis® 0.5 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.2.3 Day 1 (D2 Visit) 


 
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Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1 
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.4 Day 9 Visit – Subjects in the DLT cohort only. The DLT cohort is defined as 
the first 3-6 subjects (depending on if DLTs are noted) enrolled in Cohort 1. 
 
Vital signs 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Ophthalmologic examination and Goldmann applanation tonometry (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
 
Laboratory tests 
 


 
Protocol OPH2007 – Confidential                                       Page 43                                                                     FINAL 9 August 2017 
10.2.5 Month 1 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.2.6 Month 1 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
 
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 44                                                                     FINAL 9 August 2017 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.7 Month 2 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.2.8 Month 2 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 45                                                                     FINAL 9 August 2017 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.9 Month 3 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  
 
Fluorescein angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
Injection 
 
Lucentis® 0.5 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 


 
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10.2.10 
Month 3 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.11 
Month 4 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Lucentis® 0.5 mg/eye  


 
Protocol OPH2007 – Confidential                                       Page 47                                                                     FINAL 9 August 2017 
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.2.12 
Month 4 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 48                                                                     FINAL 9 August 2017 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.13 
Month 5 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Lucentis® 0.5 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.2.14 
Month 5 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic examination (SE) 
Injection 
 
Zimura™ 2 mg/eye – dose 1  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 49                                                                     FINAL 9 August 2017 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – dose 2  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after each injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.15 
Month 6 (± 7 days)/Early Withdrawal  
 
Vital signs 
 
Laboratory tests 
 
12-Lead ECG 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Goldmann applanation Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  
 
Fluorescein Angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 
10.3 Trial Assessments – Cohort 2 
The following evaluations, as outlined in the Study Assessments Chart (see Section 3), 
will be performed on the days specified below: 
Note:  
 Concomitant Medications should be assessed at every study visit. 


 
Protocol OPH2007 – Confidential                                       Page 50                                                                     FINAL 9 August 2017 
 Adverse events (AEs) should be assessed starting at Day 1 after the first 
dose of trial drug.   
 
10.3.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed within 14 days prior to Day 1.   
 Informed consent 
 Medical history 
 Ophthalmic history (OU) 
 Physical exam/Vital signs 
 12-Lead ECG 
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 Ophthalmologic examination and Goldmann applanation tonometry (OU) 
 Color fundus photography (FP) (OU)  
 Fluorescein angiography (FA) (OU, transit SE) 
 Spectral domain optical coherence tomography (SD-OCT) (OU)  
 Serum pregnancy test within 14 days of first trial injection (if applicable) 
 Laboratory tests 
 Concomitant medication assessment 
 
10.3.1.1 
Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the following two criteria must be met: 
1. There is NO SIGNIFICANT ANATOMICAL CHANGE by clinical examination 
between the Screening visit and Day 1 (i.e. large subretinal hemorrhage, RPE 
rip, pigment epithelial detachment).  
 
2. VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 5 LETTERS (better or worse) of the SCREENING 
VA.   
 
*OR* 


 
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VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 6 – 10 LETTERS (better or worse) of the 
SCREENING VA, and repeat clinical examination, fundus photography, 
fluorescein angiography, and SD-OCT imaging – together as judged and 
documented by the investigator – still meet the inclusion criteria. 
If the patient is randomized, the repeat imaging studies must be submitted to the 
RC to be used as the new study baseline. 
 
If the clinical examination and/or the imaging studies do not meet the inclusion 
criteria at Day 1, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is GREATER THAN 10 ETDRS LETTERS (better 
or worse) different from the SCREENING VA, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is NO LONGER WITHIN THE INCLUSION 
CRITERIA (Snellen equivalent 20/63 to 20/200), the patient must NOT be randomized. 
 
10.3.2 Day 1 Visit  
Pre-injection 
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Goldmann applanation tonometry and ophthalmologic examination (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™  2 mg/eye – administered 2nd  
Post 2nd Injection 


 
Protocol OPH2007 – Confidential                                       Page 52                                                                     FINAL 9 August 2017 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.3.3 Month 1 (± 7 days) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and ophthalmologic examination (SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 


 
Protocol OPH2007 – Confidential                                       Page 53                                                                     FINAL 9 August 2017 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.3.4 Month 2 (± 7 days) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 


 
Protocol OPH2007 – Confidential                                       Page 54                                                                     FINAL 9 August 2017 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.3.5 Month 3 (± 7 days) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  
 
Fluorescein angiography (FA) (OU, transit SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (OU) 
Injection  
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection. 
 
Zimura™ 2 mg/eye– administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 55                                                                     FINAL 9 August 2017 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.3.6 Month 4 (± 7 days) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.   
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 


 
Protocol OPH2007 – Confidential                                       Page 56                                                                     FINAL 9 August 2017 
10.3.7 Month 5 (± 7 days) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.3.8 Month 6 (± 7 days)/Early Withdrawal  
 
Vital signs 
 
Laboratory tests 
 
12-Lead ECG 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Goldmann applanation Tonometry and Ophthalmologic examination (OU) 


 
Protocol OPH2007 – Confidential                                       Page 57                                                                     FINAL 9 August 2017 
 
Color fundus photography (FP) (OU)  
 
Fluorescein angiography (FA) (OU, transit SE) 
 
Spectral domain optical coherence tomography (SD-OCT) (OU) 
 
10.4 Trial Assessments – Cohort 3 
The following dosing days apply to subjects in Cohort 3. 
D0 
D0 = The first day of dosing at each monthly timepoint.   
D14 
D14 = The second day of dosing, 14 days after D0. 
The following evaluations, as outlined in the Study Assessments Chart (see Section 3), 
will be performed on the days specified below: 
Note:  
 Concomitant Medications should be assessed at every study visit. 
 Adverse events (AEs) should be assessed starting at Day 1 after the first 
dose of trial drug.   
 
10.4.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed within 14 days prior to Day 1.   
 Informed consent 
 Medical history 
 Ophthalmic history (OU) 
 Physical exam/Vital signs 
 12-Lead ECG 
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 Ophthalmologic examination and Goldmann applanation tonometry (OU) 
 Color fundus photography (FP) (OU)  
 Fluorescein angiography (FA) (OU, transit SE) 


 
Protocol OPH2007 – Confidential                                       Page 58                                                                     FINAL 9 August 2017 
 Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 Serum pregnancy test within 14 days of first trial injection (if applicable) 
 Laboratory tests 
 Concomitant medication assessment 
 
10.4.1.1 
Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the following two criteria must be met: 
1. There is NO SIGNIFICANT ANATOMICAL CHANGE by clinical examination 
between the Screening visit and Day 1 (i.e. large subretinal hemorrhage, RPE 
rip, pigment epithelial detachment).  
 
2. VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 5 LETTERS (better or worse) of the SCREENING 
VA.   
 
*OR* 
 
VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 6 – 10 LETTERS (better or worse) of the 
SCREENING VA, and repeat clinical examination, fundus photography, 
fluorescein angiography, and SD-OCT imaging – together as judged and 
documented by the investigator – still meet the inclusion criteria. 
If the patient is randomized, the repeat imaging studies must be submitted to the 
RC to be used as the new study baseline. 
 
If the clinical examination and/or the imaging studies do not meet the inclusion 
criteria at Day 1, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is GREATER THAN 10 ETDRS LETTERS (better 
or worse) different from the SCREENING VA, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is NO LONGER WITHIN THE INCLUSION 
CRITERIA (Snellen equivalent 20/63 to 20/200), the patient must NOT be randomized. 
 


 
Protocol OPH2007 – Confidential                                       Page 59                                                                     FINAL 9 August 2017 
10.4.2 Day 1 (D0 Visit) – Induction Phase 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Goldmann applanation tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.3 Day 1 (D14 Visit ±1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post Injection 


 
Protocol OPH2007 – Confidential                                       Page 60                                                                     FINAL 9 August 2017 
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.4 Month 1 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 


 
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 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.5 Month 1 (D14 Visit ± 1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.6 Month 2 (±7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  


 
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 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.7 Month 2 (D14 Visit ± 1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post-injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 


 
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3-Day Post-Injection Safety Check (±1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.8 Month 3 (± 7 days) (D0 Visit) - Maintenance Phase 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  
 
Fluorescein angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 


 
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10.4.9 Month 4 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.10 
Month 5 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  


 
Protocol OPH2007 – Confidential                                       Page 65                                                                     FINAL 9 August 2017 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) - 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.4.11 
Month 6 (±7 days)/Early Withdrawal  
 
Vital signs 
 
Laboratory tests 
 
12-Lead ECG 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Goldmann applanation Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  
 
Fluorescein Angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 
10.5 Trial Assessments – Cohort 4 
The following dosing days apply to subjects in Cohort 4. 


 
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D0 
D0 = The first day of dosing at each monthly timepoint.   
D2 
D2 = The second day of dosing, 2 days after D0. 
D14 
D14 = The second day of dosing, 14 days after D0. 
The following evaluations, as outlined in the Study Assessments Chart (see Section 3), 
will be performed on the days specified below: 
Note:  
 Concomitant Medications should be assessed at every study visit. 
 Adverse events (AEs) should be assessed starting at Day 1 after the first 
dose of trial drug.   
 
10.5.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed within 14 days prior to Day 1.   
 Informed consent 
 Medical history 
 Ophthalmic history (OU) 
 Physical exam/Vital signs 
 12-Lead ECG 
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 Ophthalmologic examination and Goldmann applanation tonometry (OU) 
 Color fundus photography (FP) (OU)  
 Fluorescein angiography (FA) (OU, transit SE) 
 Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 Serum pregnancy test within 14 days of first trial injection (if applicable) 
 Laboratory tests 
 Concomitant medication assessment 
 


 
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10.5.1.1 
Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the following two criteria must be met: 
1. There is NO SIGNIFICANT ANATOMICAL CHANGE by clinical examination 
between the Screening visit and Day 1 (i.e. large subretinal hemorrhage, RPE 
rip, pigment epithelial detachment).  
 
2. VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 5 LETTERS (better or worse) of the SCREENING 
VA.   
 
*OR* 
 
VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen equivalent 
20/63 to 20/200) and WITHIN 6 – 10 LETTERS (better or worse) of the 
SCREENING VA, and repeat clinical examination, fundus photography, 
fluorescein angiography, and SD-OCT imaging – together as judged and 
documented by the investigator – still meet the inclusion criteria. 
If the patient is randomized, the repeat imaging studies must be submitted to the 
RC to be used as the new study baseline. 
 
If the clinical examination and/or the imaging studies do not meet the inclusion 
criteria at Day 1, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is GREATER THAN 10 ETDRS LETTERS (better 
or worse) different from the SCREENING VA, the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is NO LONGER WITHIN THE INCLUSION 
CRITERIA (Snellen equivalent 20/63 to 20/200), the patient must NOT be randomized. 
 
10.5.2 Day 1 (D0 Visit) – Induction Phase 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Goldmann applanation tonometry and Ophthalmologic Examination (SE) 


 
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Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.3 Day 1 (D14 Visit ± 1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 69                                                                     FINAL 9 August 2017 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.4 Month 1 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 


 
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10.5.5 Month 1 (D14 Visit ± 1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post-injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.6 Month 2 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  


 
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Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
10.5.7 Month 2 (D14 Visit ± 1 day) 
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Zimura™ 2 mg/eye  
Post-injection 
 
Indirect Ophthalmoscopy (SE) - 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.8 Month 3 (± 7 days) (D0 Visit) - Maintenance Phase 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Tonometry and Ophthalmologic examination (OU) 


 
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 
Color fundus photography (FP) (OU)  
 
Fluorescein angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
Injection 
 
Zimura™ 2 mg/eye  
Post Injection 
 
Indirect Ophthalmoscopy (SE) - 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.5.9 Month 3 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 


 
Protocol OPH2007 – Confidential                                       Page 73                                                                     FINAL 9 August 2017 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.10 
Month 4 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Zimura™ 2 mg/eye  
Post-injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 
10.5.11 
Month 4 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic Examination (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  


 
Protocol OPH2007 – Confidential                                       Page 74                                                                     FINAL 9 August 2017 
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.12 
Month 5 (± 7 days) (D0 Visit) 
Pre-Injection 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (SE) 
Injection  
 
Zimura™ 2 mg/eye  
Post-injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg 
before the subject leaves the clinic. 
 


 
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10.5.13 
Month 5 (D2 Visit)  
Pre-injection  
 Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 Tonometry and Ophthalmologic examination (SE) 
Injection 
 
Lucentis® 0.5 mg/eye – administered 1st  
 Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
 Ophthalmologic exam/Tonometry (SE) – After the injection, to confirm 
perfusion of the optic nerve and return of IOP to ≤ 21 mmHg or within 5 
mmHg of pre-injection.  
 
Zimura™ 2 mg/eye – administered 2nd  
Post 2nd Injection 
 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to assure that 
the optic nerve is perfused. 
 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be < 30 
mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day)  
 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.5.14 
Month 6 (± 7 days)/Early Withdrawal  
 
Vital signs 
 
Laboratory tests 
 
12-Lead ECG 
 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
 
Goldmann applanation Tonometry and Ophthalmologic examination (OU) 
 
Color fundus photography (FP) (OU)  


 
Protocol OPH2007 – Confidential                                       Page 76                                                                     FINAL 9 August 2017 
 
Fluorescein Angiography (FA) (OU, transit SE) 
 
Spectral Domain optical coherence tomography (SD-OCT) (OU) 
 
10.6 Withdrawal from Trial 
Subjects have the right to withdraw from the trial at any time for any reason.  The 
Investigator (after consultation with the Sponsor) or Sponsor also have the right to 
withdraw subjects from the trial in the event of concurrent illness, adverse events, 
treatment-failure after a prescribed procedure, protocol violations, cure, administrative 
or other reasons. 
Final trial assessments as outlined in the Study Assessments Chart, Section 3, should 
be performed on all subjects who withdraw.  Subjects who withdraw due to an adverse 
event should be followed until resolution of the adverse event, or an adequate 
explanation for the event is obtained. 
Subjects who withdraw for any reason should have assessments performed according 
to the Early Withdrawal schedule.  If an alternative treatment for NVAMD is initiated 
before completing the study dosing, the subject will no longer be evaluated according to 
this protocol. 
 
10.7 Trial Discontinuation 
The reason for a subject discontinuing from the trial will be recorded in the case report 
form.  A discontinuation occurs when an enrolled subject ceases participation in the 
trial, regardless of the circumstances, prior to completion of the protocol.  The 
investigator must determine the primary reason for discontinuation.  A discontinuation 
must be reported immediately to the clinical monitor or his/her designated 
representative if it is due to a serious adverse event (SAE) (see Section 12).  The final 
evaluation required by the protocol will be performed at the time of trial discontinuation.  
The investigator will record the reason for trial discontinuation, provide or arrange for 
appropriate follow-up (if required) for such subjects, and document the course of the 
subject’s condition. 
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, drug safety problems, or at the discretion of 
Ophthotech Corp. 
 
 


 
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11 STATISTICAL METHODS 
11.1 Experimental Design 
There will be 4 dosing cohorts in this trial. Approximately 60 subjects will be enrolled; 10 
subjects in cohorts 1 and 2, and 20 subjects in cohorts 3 and 4.   
Cohort 1  
Administered for a total of 6 times (Day 1 – Month 5), in the following sequence, 2 days 
apart: 
 D0: Lucentis® 0.5 mg/eye  
 D2: Zimura™ 4 mg/eye (administered as two injections of Zimura 2 mg)  
Cohort 2 
Administered for a total of 6 times (Day 1 – Month 5), in the following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day  
Cohort 3 
Induction Phase: Administered for a total of 3 times (Day 1 – Month 2), in the following 
sequence, 14 days apart: 
 D0: Lucentis® 0.5 mg/eye  followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye 
Maintenance Phase: Administered for a total of 3 times (Month 3 - Month 5), in the 
following sequence: 
 Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same day 
Cohort 4 
Induction Phase: Administered for a total of 3 times (Day 1 - Month 2), in the following 
sequence, 14 days apart: 
 D0: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 
 D14: Zimura™ 2 mg/eye  
Maintenance Phase: Administered for a total of 3 times (Month 3 - Month 5) in the 
following sequence, 2 days apart: 


 
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 D0: Zimura™ 2 mg/eye  
 D2: Lucentis® 0.5 mg/eye followed by Zimura™ 2 mg/eye on the same 
day 
All subjects will have a final follow-up visit at Month 6. 
The first 10 subjects will be enrolled into Cohort 1 according to the procedures noted 
below. 
The first three subjects will be assigned to Cohort 1 (Lucentis® 0.5 mg and Zimura™ 4 
mg). Once the 3rd subject completes a safety period of one week after the first dose of 
Zimura™ 4 mg without the occurrence of a dose limiting toxicity as defined in Section 
9.2.3 Dose Limiting Toxicity, full enrollment of Cohort 1 may commence.  
If a DLT occurs in one or more of the first 3 subjects assigned to Cohort 1, then the 
Ophthotech medical team will evaluate all available data and either discontinue Cohort 
1 or enroll an additional three subjects (for a total of 6 subjects) in Cohort 1.  If the three 
additional subjects are enrolled, and no additional DLT occurs once the second set of 3 
subjects in Cohort 1 has reached one week after the first dose of Zimura™ 4 mg/eye, 
full enrollment of Cohort 1 may commence.  If one or more DLTs occur in the second 
set of 3 subjects, a discussion of safety data will be held among the Ophthotech medical 
team to review the observed toxicities and determine whether Cohort 1 may proceed. 
Once Cohort 1 has been fully enrolled, or if enrollment has been stopped due to one or 
more DLTs, then enrollment in the remaining 3 cohorts may commence. Subjects will be 
randomized in a 1:2:2 ratio to Cohort 2, Cohort 3, or Cohort 4.  
 
11.2 Randomization 
Once all subjects have been enrolled in cohort 1, subjects will be centrally allocated to 
one of the three remaining treatment cohorts using a randomization list generated by a 
block randomization.  
 
11.3 Endpoints 
Safety Endpoints: 
Safety endpoints include adverse events, vital signs, electrocardiography readings 
(ECG), ophthalmic variables [visual acuity, intraocular pressure (IOP), ophthalmic 


 
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examination, stereoscopic fundus photography, fluorescein angiography (FA), spectral 
domain optical coherence tomography (SD-OCT)], and laboratory variables. 
 
11.4 Number of Subjects 
Approximately 60 subjects will be enrolled, 10 subjects in cohorts 1,2 and 20 subjects in 
cohorts 3, 4.   
 
11.4.1 Sample Size Required 
As this study is not designed to perform formal hypothesis testing, there is no formal 
sample size calculation.  The sample size selected is based on a reasonable number of 
subjects to understand the safety variables of the proposed regimen and to improve 
upon the study design prior to performance of controlled trials that may be initiated in 
the future. 
 
11.4.2 Statistical Analyses 
No formal hypothesis testing will be performed. 
 
11.4.3 Descriptive Statistics 
Descriptive statistics will be provided to document Baseline and on-trial comparability, 
including demographic information, treatment administration, and protocol violations.   
 
11.4.4 Safety Analysis 
The safety analysis will be conducted on all subjects who had at least one 
administration of the study drug. 
Adverse events will be summarized using MedDRA terms. The incidence and severity 
of adverse events will be listed and grouped by body system.  
All laboratory data will be listed and values falling outside normal ranges will be 
identified. Summary statistics (i.e., mean, median, standard deviation, minimum, and 
maximum) will be presented for all continuous variables.  
Summary statistics will be given on the number of subjects for whom the trial medication 
had to be permanently stopped. 
 
 


 
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12 ADVERSE EVENTS 
12.1 Definition of Adverse Events 
An Adverse Event (AE) is defined as follows:  Any untoward medical occurrence in a 
patient or subject including unfavorable and unintended signs, symptoms or disease 
temporally associated with the use of a medicinal product and which does not 
necessarily have to have a causal relationship to this treatment. 
Adverse events include illnesses with onset during the trial, or exacerbations of pre-
existing illnesses. Exacerbation of pre-existing illness is defined as a significant 
increase in the severity of the illness as compared to the start of the trial, and should be 
considered when a subject requires new or additional treatment for that illness.  Lack of 
or insufficient clinical response or efficacy should not be recorded as an adverse event. 
In addition, clinically significant changes in objective findings (e.g., laboratory, ECG, X-
ray, physical examination) should also be considered as to whether they are adverse 
events.  The criteria for determining whether an objective finding should be reported as 
an adverse event are as follows: 
1. Associated with accompanying symptoms; and/or 
2. Requires medical/surgical intervention; and/or 
3. Leads to a change in trial dosing or discontinuation from the trial, significant 
additional concomitant drug treatment or other therapy; and/or 
4. Leads to any of the outcomes included in the definition of a serious adverse 
event; and/or 
5. Is considered to be an adverse event by the investigator or Sponsor. 
Any abnormal test result that is determined to be an error does not require reporting as 
an adverse event. 
 
12.2 Assessment and Reporting of Adverse Events 
Adverse events will be recorded starting after the first dose of trial drug and 
continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  An adverse event that is ongoing 
at the last follow up study visit is required to be followed up until the event resolves or 
stabilizes at a level acceptable to the investigator and/or Sponsor. 


 
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All adverse events spontaneously reported, elicited or observed by the investigators will 
be recorded. The events will be recorded in the source documents and onto the adverse 
event pages of the case report form, including date of onset and resolution, severity, 
relationship to trial treatment and determination of “serious”. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as adverse events.  However, the medical condition for which 
the procedure was performed should be reported if it meets the definition of an adverse 
event.  For example, an acute appendicitis that begins during the adverse event 
reporting period should be reported as the adverse event, and the resulting 
appendectomy should be recorded as treatment of the adverse event. 
The investigator will take all therapeutic measures necessary for resolution of the 
adverse event.  Any medication necessary for treatment of the adverse event must be 
recorded in the subject’s source documents and on the appropriate pages of the 
subject’s case report form. 
To assist with grading of adverse event severity, the following definitions are provided: 
Mild 
= Aware of sign or symptom, but easily tolerated;  
Moderate 
= Discomfort enough to cause interference with usual 
activity; 
Severe 
= Incapacitating with inability to work or do usual activity; 
Adverse events are assessed as either related to the intravitreal injection procedure 
(eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, povidone-iodine 
drops or flush, subconjunctival injection of anesthetic, intravitreal injection), termed 
“injection procedure-related”, or to study drug (Zimura™ or Lucentis® 0.5 mg). 
The relationship to the intravitreal injection procedure or to study drug will be assessed 
using the following definitions: 
Not Related 
= There is not a reasonable possibility that the adverse 
event is related to the injection procedure or to the study 
drug. 
Related  
=  There is a reasonable possibility that the adverse event 
is related to the injection procedure or to the study drug. 


 
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12.3 Definition of Serious Adverse Events 
A serious adverse event is any event that: 
1. Results in death; 
2. Is life-threatening (immediate risk of death); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 
5. Results in congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient/subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
A life-threatening adverse event is any event that places the patient/subject at 
immediate risk of death from the reaction as it occurred; i.e., it does not include a 
reaction that, had it occurred in a more severe form, might have caused death. 
Disability is a substantial disruption of a person’s ability to conduct normal life functions. 
Hospitalization is defined as any formal inpatient admission (even if less than 24 hours).  
For chronic or long-term inpatients, inpatient admission also includes transfer within the 
hospital to an acute/intensive care inpatient unit (e.g., from the psychiatric wing to a 
medical floor, from a medical floor to the coronary care unit).   
 Inpatient admission does not include the following: 
o Emergency Room/Casualty Department visits 
o Outpatient/same-day/ambulatory procedures and observation/short-stay 
units 
o Hospice facilities and Respite care (e.g., caregiver relief) 
o Rehabilitation facilities, skilled nursing facilities, nursing homes, custodial 
care facilities 


 
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 Inpatient admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for “seriousness” but is not an adverse event 
and thus is not subject to immediate reporting to the Sponsor.  For example: 
o Admission for treatment of a pre-existing condition not associated with the 
development of a new adverse event or with a worsening of the pre-
existing condition (e.g., for work-up of persistent pretreatment lab 
abnormality) 
o Social admission (e.g., subject has no place to sleep) 
o Optional admission not associated with a precipitating clinical adverse 
event (e.g., yearly physical, elective cosmetic surgery) 
 
12.4 Assessment and Reporting of Serious Adverse Events 
Serious adverse events will be recorded starting after the first dose of trial drug 
and continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  Any serious adverse event 
occurring at any other time after completion of the trial must be promptly reported if a 
causal relationship to trial drug is suspected.  
If a serious adverse event occurs, the Sponsor is to be notified within 24 hours of 
awareness of the event by the investigator.  In particular, if the serious adverse event is 
fatal or life-threatening, notification to the Sponsor must be made regardless of the 
extent of available adverse event information.  This timeframe also applies to additional 
new information (follow-up) on previously forwarded serious adverse event reports. 
 
All Serious Adverse Events must be reported to the  
Sponsor or Designee within 24 hours. 
Refer to the “Safety Contact List” provided separately 
 
12.5 Exposure in Utero 
Ophthotech Drug Safety or contracted CRO must be notified of any patient who 
becomes pregnant or their partner who becomes pregnant, while participating in a 
clinical trial.  The Investigator must immediately notify the Sponsor’s Medical Monitor of 
any pregnancy associated with study medication exposure (at least 6 half-lives after 


 
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drug administration) and record the event using sponsor provided pregnancy report 
form.  Protocol-required procedures for study discontinuation must be performed on the 
patient unless contraindicated by pregnancy.  All pregnancies must be followed to 
conclusion to determine their outcome.  Infants should be followed for a minimum of 8 
weeks. 
 
 


 
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13 RESPONSIBILITIES 
13.1 Emergency Equipment 
All participating sites should have emergency resuscitation equipment available, 
including at a minimum, an Ambu bag, IV tubing, D5W IV fluid, oxygen, and epinephrine 
1:1000, and Diphenhydramine Hydrochloride (Benadryl).  It is each center’s 
responsibility to ensure that all equipment is within specifications for the duration of the 
trial.  Each center should have written policies regarding resuscitation procedures.   
 
13.2 Case Report Forms and Trial Documentation 
The Investigator or designee will complete the appropriate case report form pages 
promptly following completion of each procedure or evaluation. 
All data recorded on case report forms will be supported by source documents.  For 
certain trial parameters, with prior written agreement by the trial sponsor and monitor, 
the case report form may be used to record source data. 
All source documents will be made available to Ophthotech Corp. clinical monitors 
during scheduled monitoring visits, to auditors during any audits requested by 
Ophthotech Corp., and to regulatory agencies during inspections. 
The investigator will maintain a Trial File containing all trial related documentation 
required by Good Clinical Practice (GCP). This Trial File will be reviewed periodically for 
completeness by Ophthotech Corp.’s clinical monitors and must be made available to 
auditors and regulatory agencies. 
All case report forms and original source documents including ocular images should be 
stored for a minimum of two years after a marketing application has been approved, or 
two years after formal discontinuation of development of the investigational drug, or five 
years after completion of the trial, whichever is longer.  Documents should not be 
destroyed without the permission of Ophthotech Corp.  In the event of the Principal 
Investigator leaving the clinical site, it is the Principal Investigator’s responsibility to 
notify Ophthotech Corp. in writing and to designate which trial material will be 
transferred at the clinical site. 
 


 
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13.3 Drug Accountability/Storage Conditions 
The investigator is responsible for the accountability of all used and unused trial 
medication and for recording and documenting the drug storage temperature at arrival 
and throughout the trial.  Drug accountability records will be reviewed during monitoring 
visits.  Adequate drug accountability records include documentation of all trial drug 
supplies received, dispensed to trial subjects, and returned to Ophthotech Corp. 
At the end of the trial, all drug supplies and documentation will be reviewed and verified 
by the trial monitors.  The sites will be instructed to destroy unused trial drug supplies 
when the trial is completed, or the site may choose to return the drug to an Ophthotech 
Corp. contracted drug management facility for destruction.  If the drug is destroyed at 
the site, the drug accountability form must be completed and sent to Ophthotech Corp. 
for archiving. 
 
13.4 Protocol Compliance 
Ophthotech Corp. will not compensate the Investigator for evaluation of cases in which 
the procedures and evaluations are conducted in a manner other than that specified by 
the protocol. 
 
13.5 Ethical Aspects 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, 
South Africa, and Scotland) and with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the individual.  
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline (May 9th 1997) and with local law if it affords greater 
protection to the subject. For studies conducted in the USA or under US IND, the 
investigator will additionally ensure adherence to the basic principles of “Good Clinical 
Practice” as outlined in the current version of 21 CFR, subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”. 
 


 
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13.6 Institutional Review Board (IRB) or Ethics Committee (EC) Approval 
and Informed Consent 
The investigator is responsible for obtaining approval of the trial protocol, informed 
consent, and any advertising used for subject recruitment from the appropriate IRB/EC 
prior to initiating the trial.  The investigator will forward the following documents prior to 
commencement of subject enrollment:  
 
IRB/EC approval documentation 
 
Approved trial subject informed consent 
 
A list of IRB/EC members, or statement of compliance 
Prior to enrollment, written informed consent must be obtained from each subject or 
his/her legally authorized representative.  The informed consent must contain all of the 
elements prescribed by the relevant regulatory authorities and must be appropriately 
signed, dated and witnessed. Any changes by the Investigator or local IRB/EC to 
the sample consent provided by the Sponsor must be approved by the Sponsor 
before initiating enrollment. 
 
13.7 Clinical Trial Insurance 
Ophthotech Corp. has insurance coverage for medicine-induced injury and other 
liabilities incurred during clinical trials with its compounds. 
 
13.8 Trial Report and Publications 
The trial will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview. No individual site or investigator may publish or present 
any results from the trial until a joint, multi-center publication of the trial results is made 
by Sponsor in conjunction with various participating investigators and appropriate sites 
contributing data and comments. Subsequently, individual investigators may request to 
publish or present results from the trial; however, approval will be at the sole discretion 
of the Sponsor. Should the foregoing language be in conflict with the language 
addressing publication in the clinical trial agreement, the language in the clinical trial 
agreement will prevail. 
 


 
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14 MONITORING 
The investigator will permit representatives of Ophthotech Corp. to review all case 
report forms, trial documentation, and subject medical records at regular intervals 
throughout the trial.  These monitoring visits are for the purpose of verifying protocol 
compliance, subject safety, and the adequacy of data collected. 


 
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Seddon, J. M., Francis, P. J., George, S., Schultz, D. W., Rosner, B., & Klein, M. L. 
(2007). Association of CFH Y402H and LOC387715 A69S with Progression of 
Age-related Macular Degeneration. JAMA, 297(16), 1793-1800.  
Schmidt-Erfurth, U., Kaiser, P., Korobelnik J-K., Brown, D., Chong, V., Nguyen, Q., Ho, 
A., Ogura, Y., Simader, C., Jaffe, G., Slakter, J., Yancopoulos, G., Stahl, N., Vitti, 
R., Berliner, A., Soo, Y., Anderesi, M., Sowade, O., Zeitz, O., Norenberg, C., 
Sandbrink, R., Heier, J. (2014) Ophthalmology;121:193-201. 
Schnabolk, G., Beon, M. K., Tomlinson, S., Rohrer, B. (2017). New Insights on 
Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal 
Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein 
Replacement. J Ocul Pharmacol Ther, 33(5): 400-411. 
Stewart, M.W., Rosenfeld, P., Penha, F. M., Wang, F., Yehoshua, Z., Bueno-Lopez, E., 
Lopez, P. F. (2012). Pharmacokinetic Rationale for Dosing Every 2 Weeks 


 
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Versus 4 Weeks with Intravitreal Ranibizumab, Bevacizumab, and Aflibercept 
(Vascular Endothelial Growth Factor Trap-eye). Retina, 32(3):434-57. 
Van Newkirk, M. R., Nanjan, M. B., Wang, J. J., Mitchell, P., Taylor, H. R., & McCarty, 
C. A. (2000). The Prevalence of Age-related Maculopathy: The Visual 
Impairment Project. Ophthalmology, 107(8), 1593-1600. 
Vingerling, J. R., Dielemans, I., Hofman, A., Grobbee, D. E., Hijmering, M., Kramer, C. 
F., & de Jong, P. T. (1995). The Prevalence of Age-related Maculopathy in the 
Rotterdam Study. Ophthalmology, 102(2), 205-210. 
Wang, Y., Wang, V. M., & Chan, C. C. (2011). The Role of Anti-inflammatory Agents in 
Age-related Macular Degeneration (AMD) Treatment. Eye, 25(2), 127-139. 
U.S. Census Bureau. International Database. Washington, DC. 2012 




 
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SAP_003.pdf: 
NCT Number 
 
NCT03362190 
 
Official Study Title: 
A Phase 2A Open-label Trial to Assess the Safety of 
ZIMURA™ (Anti-C5) Administered in Combination 
With LUCENTIS® 0.5 mg in Treatment Naive 
Subjects With Neovascular Age Related Macular 
Degeneration   
 
Document: 
Statistical Analysis Plan 
 
Date of Document: 
25-Sep-2018 




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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
3
1
INTRODUCTION
4
2
STUDY DESIGN AND OBJECTIVES
4
2.1
STUDY OBJECTIVE 
4
2.1.1
Safety Endpoints 
4
2.2
STUDY DESIGN 
4
2.3
SAMPLE SIZE AND RANDOMIZATION 
6
3
GENERAL ANALYSIS DEFINITIONS
6
3.1
STUDY PERIOD AND VISIT WINDOW DEFINITIONS
6
3.2
DEFINITION OF POPULATIONS
8
3.2.1
Full Analysis Population 
8
3.2.2
Safety Population 
8
3.3
DATA HANDLING CONVENTIONS 
8
3.3.1
General Conventions 
8
3.3.2
Visit Windows 
9
3.3.3
Handling Missing Data in Descriptive Analyses 
9
3.3.4
Handling Missing or Partially Missing Dates 
9
3.3.5
Visual Acuity Conventions 
10
4
STUDY SUBJECTS 
11
4.1
DISPOSITION OF SUBJECTS 
11
4.2
TREATMENT MISALLOCATIONS 
11
4.3
PROTOCOL VIOLATIONS 
11
4.4
INCLUSION AND EXCLUSION CRITERIA 
12
5
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
12
6
PRIOR AND CONCOMITANT MEDICATION 
13
7
SAFETY EVALUATION 
13
7.1
EXTENT OF EXPOSURE 
13
7.2
ETDRS VISUAL ACUITY
13
7.3
OPTICAL COHERENCE TOMOGRAPHY AND FLUORESCEIN ANGIOGRAPHY 
14
7.4
ADVERSE EVENTS 
15
7.5
SERIOUS ADVERSE EVENTS AND DEATHS 
17
7.6
VITAL SIGNS 
18
7.7
OPHTHALMIC VARIABLES 
18
7.8
CLINICAL LABORATORY DETERMINATION 
19
7.9
ECG 
21
8
ANALYSES NOT SPECIFIED IN PROTOCOL 
21
APPENDICES 
22
APPENDIX 1   DEFINITION OF VISIT WINDOWS IN REPORTING 
22


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Term
AE
Adverse Event
AMD
Age-Related Macular Degeneration 
ATC
Anatomic Therapeutic Classification
BUN
Blood Urea Nitrogen
CNV
Choroidal Neovascularization
CRF
Case Report Form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ETDRS
Early Treatment Diabetic Retinopathy Trial
FA
Fluorescein Angiography
FAS
Full Analysis Set
ICH
International Conference on Harmonization
IOP
Intraocular Pressure
MedDRA
Medical Dictionary for Regulatory Activities
OCT
Optical Coherence Tomography
RPE
Retinal Pigment Epithelium
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SE
Study Eye
SHRM
Subretinal Hyper-Reflective Material
TEAE
Treatment-Emergent Adverse Event
VA
Visual Acuity
WHO
World Health Organization


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1
INTRODUCTION
This Statistical Analysis Plan describes the statistical methodology and data handling for the clinical 
trial with Protocol Number: OPH2007.
The ICH guideline E3 “Structure and Content of Clinical Study Reports” is used as a guide to the 
writing of the plan.
2
STUDY DESIGN AND OBJECTIVES
2.1
STUDY OBJECTIVE
The objective of this study is to assess the safety of intravitreal Zimura™ administered in 
combination with Lucentis® 0.5 mg in treatment naïve subjects with neovascular age related 
macular degeneration (NVAMD)
2.1.1
Safety Endpoints
Safety endpoints include:
Adverse events (AEs)
Vital signs (respiration, heart rate, systolic and diastolic blood pressure, etc.)
ECG recordings
Ophthalmic variables (visual acuity, IOP, ophthalmologic examination, stereoscopic 
fundus photography, fluorescein angiography, and spectral domain optical coherence 
tomography)
Laboratory variables (blood: hematology, renal function, hepatic function, and 
electrolytes; urine: urinalysis)
2.2
STUDY DESIGN
OPH2007 is a Phase 2A open-label trial to assess the safety of Zimura™(ANTI-C5) administered 
in combination with Lucentis® 0.5mg in treatment naïve subjects with neovascular age related 
macular degeneration.
There will be 4 dosing cohorts on this trial. Approximately 60 subjects will be enrolled; 10 subjects 
in cohorts 1 and 2 and 20 subjects in cohorts 3 and 4.
Cohort 1
Administered Day 1 – Month 5, in the following sequence, 2 days apart:
D0: Lucentis® 0.5 mg/eye
D2: Zimura™4 mg/eye (administered as two injections of Zimura 2 mg/eye)


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Cohort 2
Administered Day 1 – Month 5, in the following sequence:
Lucentis® 0.5 mg/eye followed by Zimura™2 mg/eye on the same day
Cohort 3
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days apart:
D0: Lucentis® 0.5 mg/eye followed by Zimura™2 mg/eye on the same day
D14: Zimura™2 mg/eye
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence:
Lucentis® 0.5 mg/eye followed by Zimura™2 mg/eye on the same day
Cohort 4
Induction Phase: Administered Day 1 – Month 2, in the following sequence, 14 days apart:
D0: Lucentis® 0.5 mg/eye followed by Zimura™2 mg/eye on the same day
D14: Zimura™2 mg/eye
Maintenance Phase: Administered Month 3 – Month 5, in the following sequence, 2 days apart:
D0: Zimura™2 mg/eye
D2: Lucentis® 0.5 mg/eye followed by Zimura™2 mg/eye on the same day
All subjects will have a final follow-up visit at Month 6.
The first 10 subjects will be enrolled into Cohort 1 according to the procedures noted below.
The first three subjects will be assigned to Cohort 1 (Lucentis® 0.5 mg and Zimura™4 mg). Once 
the 3rd subject completes a safety period of one week after the first dose of Zimura™4 mg without 
the occurrence of a dose limiting toxicity as defined in the Study Protocol, Section 9.2.3 Dose 
Limiting Toxicity, full enrollment of Cohort 1 may commence.
If a DLT occurs in one or more of the first 3 subjects assigned to Cohort 1, then the Ophthotech 
medical team will evaluate all available data and either discontinue Cohort 1 or enroll an additional 
three subjects (for a total of 6 subjects) in Cohort 1. If the three additional subjects are enrolled, and 
no additional DLT occurs once the second set of 3 subjects in Cohort 1 has reached one week after 
the first dose of Zimura™4 mg/eye, full enrollment of Cohort 1 may commence. If one or more 
DLTs occur in the second set of 3 subjects, a discussion of safety data will be held among the 


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Ophthotech medical team to review the observed toxicities and determine whether Cohort 1 may 
proceed.
Once Cohort 1 has been fully enrolled, or if enrollment has been stopped due to one or more DLTs, 
then enrollment in the remaining 3 cohorts may commence. Subjects will be randomized in a 1:2:2
ratio to Cohort 2, Cohort 3, or Cohort 4.
2.3
SAMPLE SIZE AND RANDOMIZATION
As this study is not designed to perform formal hypothesis testing, there is no formal sample size 
calculation. The sample size selected is based on a reasonable number of subjects to understand 
the safety variables of the proposed regimen and to improve upon the study design prior to 
performance of controlled trials that may be initiated in the future. Approximately 60 subjects will 
be enrolled, 10 subjects each in cohorts 1, 2 and 20 subjects each in cohorts 3, 4.
Once all subjects have been enrolled in cohort 1, subjects will be centrally allocated to one of the 
three remaining treatment cohorts using a randomization list generated by a block randomization.
3
GENERAL ANALYSIS DEFINITIONS
3.1
STUDY PERIOD AND VISIT WINDOW DEFINITIONS


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3.2
DEFINITION OF POPULATIONS
The analysis and reporting of the data from this study will be performed using the following analysis 
populations:
3.2.1
Full Analysis Population
The Full Analysis Population will consist of all subjects enrolled in Cohort 1 or subjects randomized 
in Cohorts 2, 3, or 4 who did not fail screening.
3.2.2
Safety Population 
The Safety population will include all subjects in the Full Analysis Population who received at least 
one study drug.
3.3
DATA HANDLING CONVENTIONS
3.3.1
General Conventions
Data will be analysed using SAS (Version 9.4 or later) or R. Descriptive analyses will be performed 
on baseline, safety data. All tables will be created with the 4 dosing cohorts presented in columns, 
unless otherwise specified.


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Descriptive statistics will be tabulated as follows: 
Categorical data will be summarized in contingency tables presenting frequencies and 
percentages. 
Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median, minimum, 1st quartile (Q1), 3rd quartile (Q3), and maximum
values.
Listings with individual Subjects’ data will be provided for all CRF (including derived data) and 
central laboratory data or other external data. Data collected on the CRF that are not present in a 
table will also be listed (e.g. time and method of tonometry, comments fields, data on Fatal 
Outcomes page, Unscheduled Visit pages, etc.).
3.3.2
Visit Windows 
The scheduled visits will be used in the analyses over time. 
Missing scheduled follow-up visits will be substituted by an unscheduled or early withdrawal visit 
occurring within each follow-up visit window, if there is only one unscheduled or early withdrawal 
visit occurring within the window. If there are multiple unscheduled or early withdrawal visits 
occurring within the window, the closest one within the visit window will be used. If no 
unscheduled or early withdrawal visit occurred within the window, the visit will be considered as 
missing. The details are tabulated in Appendix 1.
3.3.3
Handling Missing Data in Descriptive Analyses 
When summarizing categorical variables, subjects with missing data are generally not included in 
calculations of percentages unless otherwise specified. When needed, the category of “Missing” is 
created and the number of subjects with missing data is presented.
When summarizing continuous variables, subjects with missing data are not included in 
calculations. No imputations are made.
3.3.4
Handling Missing or Partially Missing Dates 
Missing or partially missing dates will not be imputed at data level. However, assumptions for 
missing or partially missing dates for important variables will be made to allow inclusion of 
appropriate data records in the analyses. In general, the assumptions about the missing or partially 
missing dates, when needed, are made conservative to avoid overestimation of treatment effect and 
underestimation of adverse effects.
If a medication date or time is missing or partially missing, so it cannot be determined whether it 
was taken prior or concomitantly, it will be considered both as a prior and a concomitant medication.
If the partial AE onset date information does not indicate whether the AE started prior to treatment 
or after treatment, the AE will be classified as after treatment.




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4
STUDY SUBJECTS
4.1
DISPOSITION OF SUBJECTS
The number of subjects screened, assigned (if Cohort 1)/randomized (if Cohorts 2, 3, or 4), and 
treated will be presented. The reason for exclusion from one or more analysis sets will be 
summarized.  
Disposition will be summarized for the Safety Population. The frequency and percentage of 
premature discontinuations from the study prior to Month 6 will be presented by cohort and overall. 
The primary reason for non-completion of the study will be summarized. The details of the ‘Adverse 
event’, ’Protocol violation’, ‘Investigator decision’, ‘Sponsor decision’, ‘Subject request’, ‘Lost to 
follow-up’, ‘Subject non-compliance’ or ’Other’ will be included in a listing.
4.2
TREATMENT MISALLOCATIONS  
For subjects with errors in treatment allocation, the following is described under which cohorts they 
will be reported for safety analyses:  
For example, if subjects were: 
•
Assigned a cohort (regardless of error) but not treated, then they will be excluded for all safety 
analyses. 
•
For Cohorts 2, 3, and 4: Treated but not randomized, then by definition they will be reported 
under the cohort they actually followed for all safety analyses. 
4.3
PROTOCOL VIOLATIONS
All protocol violations will be assessed and identified as “major” or “significant” by the sponsor.
The final list of major protocol violations will be provided by the sponsor, and the criteria for 
significant protocol violation will be determined prior to the database lock. The significant protocol 
1 The ETDRS lines in order, from largest to smallest, are 20/800, 20/640, 20/500, 20/400, 20/320, 20/250, 20/200, 
20/160, 20/125, 20/100, 20/80, 20/63, 20/50, 20/40, 20/32, 20/25, 20/20, 20/16, 20/13, 20/10.


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violations will be summarized for the Safety population, and the details will be presented in a listing 
by subject and cohort. 
4.4
INCLUSION AND EXCLUSION CRITERIA
A detailed listing of inclusion/exclusion criteria not met will be provided by subject for the Safety 
Population.
5
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics will be provided to document baseline demographic information. This 
information may be used to informally assess similarity of the randomized groups at baseline, 
although no formal comparison will be conducted. 
Descriptive statistics with respect to subject characteristics at baseline will be displayed for the 
Safety population. When several measurements are available before the first administration of study 
drug, the baseline value is the last available value prior to first dose, except for the baseline visual 
acuity score and baseline intraocular pressure which are the mean of the screening and Day 1 pre-
injection values.
The variables to be summarized are:
Gender, Ethnicity, Race, Iris color, Age, Current smoking status, Study Eye, Region
Prior ocular history, both eyes (by MedDRA preferred term, including number and 
percentage of all Subjects with at least one prior ocular history)
Medical history (excluding ocular history) (by body system and preferred term, with number 
and percentage for both; including number and percentage of all subjects with at least one 
prior medical history)
Prior surgeries/procedures (by body system and preferred term, with number and percentage
for both; including number and percentage of all Subjects with at least one prior 
surgery/procedure)
Vital signs (Height, Weight, Pulse, Blood pressure, Respiratory Rate)
ECOG performance status
Visual acuity, both eyes
Tonometry, both eyes
ECG
Ophthalmic exam, both eyes (Motility, Lids/Lacrimal/Lashes, Conjunctiva/Sclera, Cornea, 
Anterior chamber activity: cells, Iris, Pupils, Lens Status, Vitreous haze, Vitreous 
hemorrhage, Posterior vitreous detachment, Optic nerve, Macula, Retinal vessels, Peripheral 
retina)


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Imaging Assessments, study eye
o
Fluorescein Angiography:
-
CNV location (extrafoveal, juxtafoveal, subfoveal)
-
CNV type (predominantly classic, minimally classic, occult)
-
Area of choroidal neovascularization (CNV) (defined as classic CNV + 
occult CNV + RPE staining in mm2)
-
Area of total lesion (mm2)
o
Optical Coherence Tomography (OCT)
-
SHRM within the center 1mm (yes/no)
-
SHRM (µm)
-
RPE elevation
-
Central subfield thickness (µm)
6
PRIOR AND CONCOMITANT MEDICATION
All prior and concomitant medications will be summarized separately by WHO Drug code (Version
3, SEP 2017) on the Safety population. Medication usage will be summarized according to the 2nd
level (main therapeutic level) and the 4th level (preferred term level) Anatomic Therapeutic 
Chemical (ATC) classification. Subjects will only be included once in the summaries within each 
ATC 2nd level or ATC 4th level category. The summaries will include the number and percentage 
of all subjects with at least one concomitant medication, respectively.
7
SAFETY EVALUATION
All safety analyses will be performed on the Safety population. Missing values of safety data will 
not be imputed and safety summaries will be based on the observed cases.
7.1
EXTENT OF EXPOSURE
Exposure to each study medication will be evaluated for each cohort and overall with respect to 
treatment duration (= Last injection date – First injection date + 31, in days), number of subjects 
treated at each planned visit, total injections received, using descriptive statistics (N, mean, standard 
deviation, median, minimum, Q1, Q3, maximum).
7.2
ETDRS VISUAL ACUITY
ETDRS Visual acuity values and changes from baseline will be presented in a summary table by 
visit and cohort for the Safety Population.
The principal visual acuity outcome measure will be the mean change in visual acuity (MCVA)
from Baseline to Month 6.
Supportive measures will be the percentage of subjects gaining 5,


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10,
,
20 letters, and 
Baseline to Month 6. Additionally, 
the number and percentage of subjects meeting each of the following criteria at Month 6 will be 
summarized: ETDRS Snellen Equivalent of 20/25 or better, ETDRS Snellen Equivalent of 20/40 
or better, and ETDRS Snellen Equivalent of 20/125 or worse. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3
OPTICAL COHERENCE TOMOGRAPHY AND FLUORESCEIN ANGIOGRAPHY
Descriptive analysis will be conducted on the following supportive imaging endpoints:




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An overview of TEAEs will be provided. A second overview of TEAEs will be provided which 
displays the overall summary of TEAEs by the categories ‘Study Eye’, ‘Non-Study Eye’, and ‘Non-
Ocular’. In addition, the number and percentage of patients with TEAEs will be tabulated for each 
treatment group and in total by system organ class (SOC) and preferred term (PT). The number and 
percentage of the subjects who experienced at least one TEAE will be included. Subjects will only 
be counted once for each preferred term. In case that a subject experienced the same event more 
than once, the worst severity will be presented. 
Tabular summaries of the following AEs will be provided by SOC and PT:
All TEAEs regardless of the relationship to study drugs
frequency based on total subjects
TEAEs related to study drugs
TEAEs related to injection procedure
TEAEs by the maximum severity grade
Systemic TEAEs
Systemic TEAEs related to study drugs
Systemic TEAEs related to injection procedure
TEAEs related to study drugs by the maximum severity grade
TEAEs related to injection procedure by the maximum severity grade
All Ocular TEAEs by study eye
All Ocular TEAEs by fellow eye
Study drug related Ocular TEAEs by study eye
Study drug related Ocular TEAEs by fellow eye
Injection procedure related Ocular TEAEs by study eye
Injection procedure related Ocular TEAEs by fellow eye
Ocular TEAEs (study eye) by the maximum severity grade
Study drug related Ocular TEAEs (study eye) by the maximum severity grade
Injection procedure related Ocular TEAEs (study eye) by the maximum severity grade
TEAEs leading to discontinuation of study drug
Study drug related TEAEs leading to discontinuation of study drug
Injection procedure related TEAEs leading to discontinuation of study drug


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Ocular TEAEs (study eye) leading to discontinuation of study drug
TEAEs leading to death
Study drug related TEAEs leading to death
Injection procedure related TEAEs leading to death
Ocular TEAEs has been defined as TEAEs linked to the “Eye Disorders” system organ class and 
the ‘Intraocular pressure increased’ preferred term. 
All AEs, including non-TEAEs, will be included in individual subject listings. 
The listings will include the subject identifier, age, sex, verbatim term, preferred term, eye 
(N/A/OD/OS/OU), serious (yes/no), date of onset, relative study day of onset, duration of the event 
(or continuing), severity (mild/moderate/severe), causality (relationship to study drug/injection 
procedure), action taken (study drug permanently discontinued: yes/no), treatment (yes/no), and 
outcome (resolved /unresolved / fatal).
The same listings will be provided separately for severe AEs, AEs leading to permanent 
discontinuation of the study drug, and for AEs leading to death.
7.5
SERIOUS ADVERSE EVENTS AND DEATHS
Treatment-Emergent Serious adverse events (SAEs) will be summarized by system organ class and 
preferred term. The number and percentage of the subjects who experienced at least one SAE will 
be included. 
Tabular summaries of the following SAEs will be provided:
All SAEs regardless of the relationship to study drug
SAEs related to study drug
SAEs related to injection procedure
Ocular SAEs (study eye) regardless of the relationship to study drug
Ocular SAEs (study eye) related to study drug
Ocular SAEs (study eye) related to injection procedure
In addition, separate listings will be created for deaths and all SAEs. List for SAEs will include the 
subject identifier, age, sex, verbatim term, preferred term, eye (N/A/OD/OS/OU), serious (yes/no), 
date of onset, relative study day of onset, duration of the event (or continuing), severity 
(mild/moderate/severe), causality (relationship to study drug/injection procedure), action taken 
(study 
drug 
permanently 
discontinued: 
yes/no), 
treatment 
(yes/no), 
and 
outcome 
(resolved/unresolved/fatal).


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7.6
VITAL SIGNS 
Descriptive statistics at each time point up through and including the Month 6 visit will be used to 
display the changes from Baseline for pulse, respiratory rate, and blood pressure (systolic and 
diastolic). Mean change of pulse, respiratory rate, and blood pressure (systolic and diastolic) from 
Baseline to the last measurement will be provided.
7.7
OPHTHALMIC VARIABLES
Ophthalmic Examination. The following ophthalmic examination variables will be analysed by 
shift table from Baseline to the pre-injection examination on Month 6 and from Baseline to the 
last visit (pre-injection) available (normal/abnormal, unless otherwise specified below).:
Examination of the motility
Inspection of the lids/lacrimal/lashes
Examination of the conjunctiva/sclera 
Inspection of the cornea
Examination of the iris
Examination of the pupils
Inspection of the lens status (aphakic, pseudo-phakic, phakic; if phakic, 
nuclear/PSC/cortical 0, 1, 2, 3, 4), including a listing of subjects with a change in lens 
status for study eye and (separately) for fellow eye
Examination of the posterior vitreous detachment
Inspection of the optic nerve
Inspection of the macula 
Examination of the retinal vessels
The following ophthalmic examination variables will be analysed by shift table from Baseline 
through Month 6 and for the last visit available, on a monthly basis (normal/abnormal, unless 
otherwise specified below), and from pre-injection to post-injection at each monthly injection
Examination of the anterior chamber activity: Cells (0, trace, 1+, 2+, 3+, 4+)
Inspection of vitreous haze (0, 1+, 2+, 3+, 4+)
Examination of vitreous haemorrhage
Examination of peripheral retina


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Intraocular Pressure.
The Baseline intraocular pressure within an eye will be determined as the average of the Screening 
and Day 1 (also called Baseline in the protocol) pre-injection measurements. Non-integer values 
for the average will be rounded up prior to subsequent calculations of change from baseline. 
IOP will be summarized by visit, including all pre-injection, “IOP after first injection” and “IOP
after second injection” measurements. An additional tabular summary of the percentage of subjects 
in categories of IOP will be presented by cohort, visit, and injection time (pre-injection, IOP after 
first injection, IOP after second injection). 
“IOP after first/second injection” is defined as the IOP measurement that is closest in time to the 
protocol-specified post-injection timepoint (but at least 25 minutes post-injection). If there are two 
closest measurements equidistant to this timepoint, then the measurement after the protocol-
specified timepoint will be used. 
Mean IOP over time of all scheduled measurements (pre-injection, IOP after first injection, and IOP 
after second injection) will be plotted.
7.8
CLINICAL LABORATORY DETERMINATION
All laboratory data will be listed and values falling outside normal ranges will be identified, whether 
they will be deemed clinically relevant or not.
Laboratory data will also be summarized in tables presenting values at each 
scheduled visit up through the Month 6 visit (mean, SD, median, minimum, Q1, Q3, 
maximum, N)
Value changes from Baseline to each scheduled visit up through the Month 6 visit 
(mean, SD, median, minimum, Q1, Q3, maximum, N)
for the following parameters: Hematological parameters (Hemoglobin, White blood cells, Platelets, 
Neutrophils (absolute numbers), Lymphocytes (absolute numbers), Monocytes (absolute numbers),
Eosinophils (absolute numbers), Basophils (absolute numbers)), Biochemical parameters (Sodium, 
Potassium, Chloride, Bicarbonate, Calcium, Phosphorus Inorganic, Creatinine, Urea Nitrogen, 
Total bilirubin, GGT, Alkaline phosphatase, SGOT/AST, SGPT/ALT).
The incidence of subjects with “Notable Laboratory Values” after the first dose of study drug will 
be evaluated using the criteria for Notable Laboratory Values given below. 
By-subject listings of all notable laboratory values will also be provided; for each subject who has 
an analyte with a notable value, all values of that particular analyte taken during the study will be 
presented in the listing, and the notable value, and any values outside of normal limits, will be 
identified.  
For this “Notable Laboratory Values” analysis, all laboratory values after randomization will be 
taken in account, i.e., any values obtained after Day 1, at unscheduled visits, as well as values from 


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the regularly scheduled laboratory visit at Month 6. Three Notable Laboratory Values tables and 
accompanying by-subject listings will be presented: (1) notable abnormalities for subjects with 
normal Baseline results, (2) notable abnormalities for subjects with abnormal Baseline results and 
(3) notable abnormalities without regard to Baseline abnormalities (i.e., normal or abnormal 
Baseline results). The table without regard to Baseline abnormalities will be a composite of the 
previous two tables (normal Baseline, abnormal Baseline).
Lab analytes and primary criteria used for Notable Laboratory Values:
a.
HEMATOLOGY
i.
Hemoglobin < 0.75x baseline
ii.
Platelets < 75 or > 750 (10^9/L)
iii.
WBC count < 2.5 or > 17.5 (10^9/L)
iv.
Neutrophils (absolute) < 0.5x LLN or > 1.5xULN
v.
Eosinophils (absolute) > 1.5xULN
vi.
Lymphocytes (absolute) < 0.5x LLN or > 1.5xULN
b. LIVER FUNCTION
i.
Total bilirubin > 1.5xULN
ii.
Alkaline phosphatase > 1.5xULN
iii.
ASAT (SGOT) > 3xULN
iv.
ALAT (SGPT) > 3xULN
v.
GGT > 3xULN
c.
RENAL FUNCTION
i.
BUN > 1.3XULN
ii.
Creatinine > 1.3xULN
d. ELECTROLYTES
i.
Potassium < 0.9xLLN or > 1.1xULN
ii.
Sodium < 0.9xLLN or > 1.1xULN
iii.
Calcium < 0.9xLLN or > 1.1xULN
Notable abnormalities for subjects with abnormal Baseline results are subject to the primary criteria 
above and the following secondary criteria:
a.
HEMATOLOGY
i.
Hemoglobin < 0.75x baseline (same as primary criterion)


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ii.
Platelets < 0.75x baseline or > 1.25x baseline
iii.
WBC count < 0.75 baseline or > 1.25x baseline
iv.
Neutrophils (absolute) < 0.5x baseline or > 1.5x baseline
v.
Eosinophils (absolute) > 1.5x baseline
vi.
Lymphocytes (absolute) < 0.5x baseline or > 1.5x baseline
b. LIVER FUNCTION
i.
Total bilirubin > 1.5x baseline
ii.
Alkaline phosphatase > 1.5x baseline
iii.
ASAT (SGOT) > 1.5x baseline
iv.
ALAT (SGPT) > 1.5x baseline
v.
GGT > 1.5x baseline
c.
RENAL FUNCTION
i.
BUN > 1.3x baseline
ii.
Creatinine > 1.3x baseline
d. ELECTROLYTES
i.
Potassium < 0.9x baseline or > 1.1x baseline
ii.
Sodium < 0.9x
baseline or > 1.1x baseline
iii.
Calcium < 0.9x baseline or > 1.1x baseline
7.9
ECG 
ECG results will be tabulated at Baseline as “normal”, “abnormal, not clinically significant” or 
“abnormal, clinically significant”. At follow-up visits, ECG results will be tabulated as “no change 
from Baseline”, “NOT clinically significant change from Baseline” or “clinically significant change 
from Baseline”. A by-patient listing will be provided for ECGs which are deemed clinically 
significant.
8
ANALYSES NOT SPECIFIED IN PROTOCOL
Analysis of ETDRS visual acuity may be conducted on a per-protocol population defined by the 
subjects who did not have a significant protocol violation (Section 4.3). Any hypothesis testing 
performed as part of this analysis will be considered exploratory. 


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APPENDICES


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