A Phase 2/3 Randomized, Double-Masked, Controlled Trial to Assess the Safety and Efficacy of Intravitreous Administration of Zimura™ (Anti-C5 Aptamer) in Patients With Geographic Atrophy Secondary to Dry Age-Related Macular Degeneration
Phase: PHASE2
Conditions: Geographic Atrophy, Dry Age-Related Macular Degeneration
Sponsor: IVERIC bio, Inc.

Official Study Title: A Phase 2/3 Randomized, Double-Masked, Controlled 
Trial to Assess the Safety and Efficacy of Intravitreous Administration of 
Zimura™ (Anti-C5 Aptamer) in Subjects with Geographic Atrophy 
Secondary to Dry Age-Related Macular Degeneration 
NCT#: NCT02686658 
Document: Protocol 
Document Date: 28 March 2018 

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 RANDOMIZED, DOUBLE-MASKED, CONTROLLED TRIAL 
TO ASSESS THE SAFETY AND EFFICACY OF INTRAVITREOUS 
ADMINISTRATION OF ZIMURA™ (ANTI-C5 APTAMER) IN SUBJECTS 
WITH GEOGRAPHIC ATROPHY SECONDARY TO DRY AGE-RELATED 
MACULAR DEGENERATION  
 
 
PROTOCOL NO:  OPH2003 
AMENDMENT C 
 
 
 
 
Version Date: 28 March 2018 
 
 
SPONSOR: 
OPHTHOTECH CORP. 
One Penn Plaza – 19th Floor 
New York, NY 10119 
 
FOR MEDICAL EMERGENCIES REFER TO THE 
“SAFETY CONTACT LIST” PROVIDED SEPARATELY 
 
 
 
EudraCT No. 2015-003991-56 
 
 
 
 
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 OPH2003 ............................................................... 5 
3 
STUDY ASSESSMENTS ..................................................................................... 7 
4 
INTRODUCTION .................................................................................................. 9 
4.1 
Age-Related Macular Degeneration .......................................................... 9 
4.2 
AMD and the Complement Pathway ....................................................... 10 
4.3 
Clinical Data ............................................................................................ 12 
4.4 
Trial Rationale ......................................................................................... 14 
5 
TRIAL OBJECTIVES .......................................................................................... 16 
5.1 
Objectives ............................................................................................... 16 
5.2 
Endpoints ................................................................................................ 16 
6 
TRIAL DESIGN .................................................................................................. 16 
7 
PROCEDURES .................................................................................................. 17 
7.1 
Refraction and Visual Acuity, 
 and Low Luminance Visual 
Acuity ...................................................................................................... 17 
7.2 
Tonometry ............................................................................................... 17 
7.3 
Ophthalmologic Examination .................................................................. 18 
7.4 
Fundus Photography, Fluorescein Angiography, and Fundus 
Autofluorescence .................................................................................... 18 
7.5 
Optical Coherence Tomography (SD-OCT) ............................................ 19 
7.6 
Laboratory Tests ..................................................................................... 19 
7.7 
Vital Signs, Physical Examination and Performance Status (ECOG) ..... 19 
7.8 
12-Lead Electrocardiogram ..................................................................... 20 
7.9 
 ........................................................... 20 
8 
SUBJECT POPULATION ................................................................................... 20 
8.1 
Sample Size ............................................................................................ 20 
8.2 
Inclusion Criteria ..................................................................................... 20 
8.3 
Exclusion Criteria .................................................................................... 21 
9 
TRIAL MEDICATION .......................................................................................... 23 
9.1 
Drug Supply ............................................................................................ 23 
9.2 
Previous or Concomitant Therapy .......................................................... 26 
10 TRIAL CONDUCT .............................................................................................. 26 
10.1 
Subject Enrollment .................................................................................. 26 
10.2 
Trial Assessments .................................................................................. 27 
10.3 
Withdrawal from Trial .............................................................................. 44 
10.4 
Trial Discontinuation ............................................................................... 45 
11 STATISTICAL METHODS .................................................................................. 45 

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11.1 
Study Design .......................................................................................... 45 
11.2 
Endpoints ................................................................................................ 46 
11.3 
Determination of Sample Size and Statistical Rationale ......................... 47 
11.4 
Randomization Procedure ...................................................................... 49 
11.5 
Masking Procedures ............................................................................... 49 
11.6 
Analytical Considerations ........................................................................ 51 
12 ADVERSE EVENTS ........................................................................................... 52 
12.1 
Definition of Adverse Events ................................................................... 52 
12.2 
Assessment and Reporting of Adverse Events ....................................... 53 
12.3 
Definition of Serious Adverse Events ...................................................... 54 
12.4 
Assessment and Reporting of Serious Adverse Events .......................... 56 
12.5 
Independent Data Monitoring Committee ............................................... 56 
12.6 
Exposure in Utero ................................................................................... 56 
12.7 
Abnormal Laboratory Results ................................................................. 57 
13 RESPONSIBILITIES .......................................................................................... 57 
13.1 
Emergency Equipment............................................................................ 57 
13.2 
Case Report Forms and Trial Documentation ......................................... 57 
13.3 
Drug Accountability/Storage Conditions.................................................. 58 
13.4 
Protocol Compliance ............................................................................... 58 
13.5 
Ethical Aspects ....................................................................................... 58 
13.6 
Institutional Review Board (IRB) or Ethics Committee (EC) Approval and 
Informed Consent ................................................................................... 59 
13.7 
Clinical Trial Insurance............................................................................ 59 
13.8 
Trial Report and Publications .................................................................. 59 
14 MONITORING .................................................................................................... 60 
15 REFERENCES ................................................................................................... 61 
16 SIGNATURE PAGE ........................................................................................... 65 
17 APPENDICES .................................................................................................... 66 
 
 
 
 
 
 
 
 
 
 
 
 

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1 GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate Aminotransferase 
BCVA 
Best Corrected Visual Acuity  
BUN 
Blood Urea Nitrogen 
C  
Complement Factor 
CFH  
Complement Factor H  
CNV 
Choroidal Neovascularization 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CRP  
C-reactive protein  
DNA 
Deoxyribonucleic Acid 
DSMB  
Data Safety Monitoring Board  
EC 
Ethics Committee 
EC 
Endothelial Cell 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
FE 
Fellow Eye 
GA 
Geographic Atrophy  
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl-Transferase 
hERG  
human Ether-à-Go-Go-Related Gene  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IL-6 
Interleukin-6  
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
ITT 
Intent to Treat Population  
MAC 
Membrane Attack Complex 
MMRM  
Mixed Model Repeated Measures  
NLP 
No Light Perception 
NV 
Neovascular 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OU 
Both eyes 
RC 
Reading Center 
REML  
restricted maximum likelihood  
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SE 
Study Eye 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 

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2 SUMMARY OF PROTOCOL OPH2003 
 
SYNOPSIS 
TITLE: 
 Randomized, Double-Masked, Controlled Trial to Assess 
the Safety and Efficacy of Intravitreous Administration of Zimura™ 
(Anti-C5 Aptamer) in Subjects with Geographic Atrophy Secondary to 
Dry Age-Related Macular Degeneration  
OBJECTIVES: 
The objectives of this study are to evaluate the safety and efficacy of 
Zimura™ intravitreous administration when administered in subjects 
with geographic atrophy secondary to dry age-related macular 
degeneration (AMD). 
TRIAL DESIGN: 
 
In Part 1, approximately 77 subjects will be randomized in a 1:1:1 
ratio to the following dose groups: 
 
• 
Zimura™ 1 mg/eye 
 
• 
Zimura™ 2 mg/eye 
 
• 
Sham 
Commencing with Amendment C, no new subjects will be enrolled in 
Part 1 of this trial as recruitment has been completed for Part 1. 
 
In Part 2, approximately 200 subjects will be randomized in a 1:2:2 
ratio to the following dose groups: 
 
• 
Zimura™ 2 mg/eye + Sham 
 
• 
Zimura™ 4 mg/eye (administered as two injections of     
 
Zimura™ 2 mg/eye)  
• 
Sham + Sham 
 
Subjects will receive monthly intravitreal injections of Zimura™ and/or 
Sham for 18 months.  
ENDPOINTS: 
Primary Efficacy Endpoint: 
• 
Mean rate of change in GA over 12 months measured by 
fundus autofluorescence (FAF) at three time points: Baseline, 
Month 6, and Month 12 
Secondary Efficacy Endpoints: 
Secondary efficacy endpoints will be assessed from Baseline to 
Month 12:  
• 
The mean change in best corrected visual acuity (Early 
Treatment Diabetic Retinopathy Study [ETDRS] letters) from 
Baseline to Month 12 
 
• 
Mean change in low luminance best corrected visual acuity 

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SYNOPSIS 
(ETDRS letters) from Baseline to Month 12 
Safety Endpoints: 
• 
Adverse events (AEs) 
• 
Vital signs (pulse, systolic and diastolic blood pressure) 
• 
Ophthalmic findings (intraocular pressure [IOP], ophthalmic 
examination, fluorescein angiogram, FAF, and Optical 
Coherence Tomography [OCT]) 
• 
Electrocardiogram (ECG) (12-lead) 
• 
Laboratory variables (blood: hematology, renal function, 
hepatic function, and electrolytes; urinalysis) 
PLANNED SAMPLE SIZE: Approximately 277 subjects will be enrolled.  
SUBJECT SELECTION: 
Subjects of either gender aged 50 years or greater diagnosed with 
geographic atrophy secondary to dry AMD. 
FORMULATION: 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATIONAL 
DRUG DOSAGE: 
Subjects randomized to active drug will receive 18 doses of Zimura™ 
at a dose of 1 mg/eye, 2 mg/eye or 4 mg/eye. Commencing with 
Amendment C, no new subjects will be enrolled in Part 1 of this trial. 

 
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4 INTRODUCTION 
4.1 
Age-Related Macular Degeneration  
Age-related macular degeneration (AMD) is a disease characterized by progressive 
degenerative abnormalities in the macula, a small area in the central portion of the 
retina. AMD is characteristically a disease of the elderly and is the leading cause of 
blindness in individuals >50 years of age 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 increasing life expectancy in developed 
and developing countries, the elderly sector of the general population is expected to 
increase at the greatest rate in coming decades (Ortma & Velkof, 2014).  While 1 in 
8 Americans was considered to be elderly in 1994, it is expected that 1 in 5 will fall 
into this category by 2030 (Day, 1993; Hobbs, 1996).  Projections based on U.S. 
Census Bureau data suggest that the number of Americans over the age of 65 will 
more than double, increasing it to 80 million by the middle of this century (Day, 
1993).  In the absence of adequate prevention or treatment measures, the number 
of cases of AMD with visual loss is expected to grow in parallel with the aging 
population. 
AMD is classified into one of two general subgroups; the non-neovascular (“dry”) 
form of the disease and the neovascular (“wet”) form of the disease.  The non-
neovascular dry form of AMD is more prevalent, accounting for approximately 90% 
of all AMD cases. It is characterized by degeneration of the macula, and with 
continued progression over multiple years, may ultimately result in atrophy of the 
central retina associated with central vision loss.  By contrast, neovascular AMD, 
although less prevalent, is more likely to cause sudden, often substantial, loss of 
central vision (Holz et al., 2014). 
Dry AMD is a significant cause of moderate and severe loss of central vision and is 
bilateral in most patients (Maguire & Vine, 1986; Potter & Thallemer, 1981; Sarks et 
al., 1988; Schatz & McDonald, 1989; Sunness et al., 1999).  In dry AMD, thinning of 
the retinal pigment epithelial cells (RPE) in the macula develops, along with other 
age-related changes to the adjacent retinal tissue layers (Holz et al., 2014). Dry 
AMD is characterized by the presence of drusen (yellow crystalline deposits that 
develop within the macula) located under the RPE (Holz et al., 2014). When severe, 
dry AMD results in marked thinning and/or atrophy of the macula, resulting from the 
loss of the RPE and associated capillaries (choriocapillaris). This form of late stage 

 
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dry AMD is associated with thinning and loss of function of the neural retinal located 
above the affected RPE (McLeod et al., 2009). This collective phenotype in late 
stage dry AMD is termed geographic atrophy (GA). The progressive degeneration 
of light-sensitive photoreceptor cells in GA leads to severe visual loss in affected 
eyes. In addition, dry AMD can progress to the wet form of the disease (Holz et al., 
2014). 
Although dry AMD is the most common form of the disease, currently no approved 
therapy exists. The absence of treatment options for dry AMD represents an area of 
urgent unmet medical need, and a major public health concern for the rapidly 
increasing elderly population.  
 
4.2 
AMD and the Complement Pathway 
The etiology of AMD is not completely understood (Frederick & Kleinman, 2014).  In 
addition to advanced age, environmental and genetic risk factors for AMD are well 
recognized, including ocular pigmentation, dietary factors, family history for AMD, 
hypertension, and smoking (Klein et al., 2004). Research also indicates that 
inflammation is a major contributor to the pathogenesis of AMD (P.S. Bora et al., 
2005). 
Mounting evidence suggests that both the wet and dry forms of AMD may involve 
an inflammatory process (Bok, 2005; Donoso et al., 2006). Patients with AMD are 
known to have elevated systemic inflammatory biomarkers such as C-reactive 
protein (CRP), interleukin-6 (IL-6), and homocysteine (Bok, 2005; Seddon et al., 
2005). Furthermore, surgically excised choroidal neovascular tissue in patients with 
AMD contains inflammatory cells (Grossniklaus et al., 2005).   
The role for complement (C)-mediated inflammation in AMD is highlighted by 
genetic linkage and association studies, which suggest that approximately 50% of 
AMD cases have polymorphism in complement regulatory proteins compared to 
age-matched controls (Edwards et al., 2005; Hageman et al., 2005; Haines et al., 
2005; Klein et al., 2005; Narayanan et al., 2007). Furthermore, polymorphism in 
genes coding for complement or complement regulatory proteins confer an 
increased risk in age-related macular degeneration. 
The complement pathway involves a complex system of serum proteins as a part of 
the innate immune system which interacts in a cascade (Holers, 2014). The 
complement cascade is activated via the classical (antibody-dependent), the 

 
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alternative (antibody-independent), and the lectin pathways (Holers, 2014). Recent 
studies have implicated local inflammation and activation of the complement 
cascade in drusen formation (Hageman et al., 2001; Seddon et al., 2006).  
Additionally, the complement components of drusen may induce vascular 
endothelial growth factor (VEGF) up-regulation, and therefore contribute to the 
formation of neovascular AMD (Nozaki et al., 2006). Preclinical laser-induced 
choroidal neovascularization (CNV) models have also implicated complement 
activation (P.S. Bora et al., 2005). In experimental models of CNV, membrane 
attack complex (MAC: C5b-9) formation has been shown to be important (Nozaki et 
al., 2006). The MAC results in pore formation in affected cells that eventually lead 
to cell death (Holers, 2014). Inhibition of the alternate pathway of complement 
activation leads to a reduction in pro-angiogenic factors and decreased CNV 
formation in models of experimental CNV (N. S. Bora et al., 2006; Johnson et al., 
2000).  
The results from two recently completed clinical studies, with different molecules 
designed to block the complement pathways, have further substantiated the proof 
of concept for this approach in GA (Hariri et al., 2015; OPH2001). 
 
4.2.1 Non-Clinical Efficacy  
Preclinical data demonstrating the anti-C5 properties of Zimura™ are described in 
detail in the Investigator’s Brochure (IB). 
 
4.2.2 Non-Clinical Pharmacokinetics of Zimura™ 
The sponsor has performed supportive non-clinical pharmacology studies with 
Zimura™, and, in some cases, with related aptamers. 
 
 
 
 
 
These safety pharmacology studies did not reveal any effects on cardiovascular, 
respiratory or neurologic function. 
Further information regarding the pharmacology of Zimura™ is presented in detail in 
the IB.   

 
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conjunctival hemorrhage (4 patients, 9%), corneal edema (4 patients, 9%), and dry 
eye (3 patients, 6%).  No other study eye AEs were reported by more than two 
patients. The majority of AEs were mild or moderate in severity. There were 2 
patients with AEs of severe intensity: gastrointestinal inflammation and 
nasopharyngitis. 
Five patients experienced serious adverse events (SAEs), namely device failure, 
pelvic fracture, angina pectoris, chest pain, gastrointestinal inflammation, but none 
were related to the study drug 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 (SE) ophthalmic examinations were 
mostly 
normal. 
There 
were 
some 
transient 
findings 
post-injection 
(conjunctiva/sclera and cornea) which resolved prior to the next injection. Vitreous 
haze was also reported for a few patients. IOP showed a small mean increase 
following injections but no indication of any cumulative increase.  Visual acuity (VA) 
assessments did not show any safety concerns. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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In another phase 1 ascending dose and parallel group trial the safety, tolerability, 
and pharmacokinetic profile of multiple intravitreous injections of Zimura™ in 
combination with Lucentis® 0.5mg was evaluated in subjects with wet AMD 
(OPH 2000). In this study, 60 patients received doses of 0.03 mg, 0.3 mg, 1 mg, or 
2 mg of Zimura™. Zimura™ was well tolerated and no particular safety concerns 
were identified.  
Further, VA assessment for the treatment naïve patients who received 6 injections 
at the dose levels of 0.3 mg, 1 mg, or 2 mg indicated a trend towards a mean 
increase in VA (number of Early Treatment Diabetic Retinopathy Study [ETDRS] 
letters) from baseline at all time points.  At Week 24, there was an overall 
improvement in VA from baseline of 13.6 letters with the greatest improvement 
seen for the 2 mg dose group (15.3 letters).  
Taken together, there is a rationale to further investigate the antagonism of C5 
component of complement cascade by Zimura™ in dry AMD subjects with GA. 
 
4.4 
Trial Rationale 
Multiple studies suggest that the activation of the complement system plays a major 
role in the pathogenesis and progression of both dry and wet AMD. These include 
genetic studies, histopathological studies, non-clinical in vivo studies, and 
evaluation of systemic biomarkers in patients at risk (Bok, 2005; Donoso et al., 
2006; Edwards et al., 2005; Grossniklaus et al., 2005; Hageman et al., 2005; 
Haines et al., 2005).  
Much of the scientific foundation implicating the complement system is derived from 
seminal studies from multiple independent labs, published in 2005 (Edwards et al., 
2005; Hageman et al., 2005; Haines et al., 2005; Klein et al., 2005; Narayanan et 
al., 2007). These studies infer that approximately 50% of the dry and wet forms of 
AMD may have underlying activation of the complement system. Further, the 
Y402H variant of the complement factor H (CFH) gene has been shown to be 

 
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strongly associated with geographic atrophy in the populations of various countries 
(United States of America, United Kingdom, Netherlands, Iceland) (Magnusson et 
al., 2006; Seddon et al., 2007; Sepp et al., 2006).  
 
Histopathologic studies confirming the presence of complement activation in AMD 
have also been published (Grossniklaus et al., 2005). In a monkey pedigree with 
macular degeneration manifested by drusen that share phenotypic features with dry 
AMD in humans, these drusen were strongly reactive with antibodies against 
complement C5 (Umeda et al., 2005a) and the membrane attack complex (MAC, 
the terminal C5b-9 complement complex) (Umeda et al., 2005b). A study of eyes 
from more than 400 human donors revealed that drusen are intensely labelled 
using antibodies against complement C5 and MAC, and multiple complement 
regulatory proteins have also been shown to be present in drusen (Anderson et al., 
2002). 
 
Therefore, preclinical models, clinical and genetic studies implicate the activation of 
the complement cascade in AMD (Bok, 2005; Donoso et al., 2006; Edwards et al., 
2005; Hageman et al., 2005; Haines et al., 2005). Inhibition of complement 
activation may potentially slow down or arrest the underlying pathobiology of 
macular degeneration.  Thus, molecules involved in regulation and inhibition of 
complement activation are prime targets for therapeutic intervention in AMD.   
Zimura™ is currently being developed by Ophthotech Corp. for the treatment of dry 
and wet AMD.  Zimura™ is a pegylated RNA aptamer.  It is a potent and specific 
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 initial activation pathway (alternate, classical, or lectin) induced 
their generation. The C5a fragment is an important inflammatory activator that 
induces vascular permeability, and both recruits and activates phagocytes. C5b is 
involved in the formation of membrane attack complex (MAC: C5b-9) which initiates 
cell lysis. By inhibiting these C5-mediated inflammatory and MAC activities, 
therapeutic benefit may be achieved in both dry and wet AMD. 

 
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5 TRIAL OBJECTIVES 
5.1 
Objectives 
The objectives of this study are to evaluate the safety and efficacy of Zimura™ 
intravitreous administration when administered in subjects with geographic atrophy 
secondary to dry age-related macular degeneration (AMD). 
 
5.2 
Endpoints 
Primary Efficacy Endpoint: 
Mean rate of change in GA over 12 months measured by FAF at three time points: 
Baseline, Month 6, and Month 12 
Secondary Efficacy Endpoints: 
• The mean change in best corrected visual acuity (ETDRS letters) from 
Baseline to Month 12 
• Mean change in low luminance best corrected visual acuity (ETDRS letters) 
from Baseline to Month 12 
Safety Endpoints: 
• AEs 
• Vital signs (pulse, systolic and diastolic blood pressure) 
• Ophthalmic variables (IOP, ophthalmic examination, FA, FAF, and OCT) 
• ECG (12-lead) 
• Laboratory variables (blood: hematology, renal function, hepatic function, 
and electrolytes; urinalysis) 
 
6 TRIAL DESIGN 
In Part 1, approximately 77 subjects will be randomized in a 1:1:1 ratio to the 
following dose groups: 
• Zimura™ 1 mg/eye 
 
• Zimura™ 2 mg/eye 
 
• Sham 
 
 
Commencing with Amendment C, no new subjects will be enrolled in Part 1 of this 
trial as recruitment has been completed for Part 1. 

 
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In Part 2, approximately 200 subjects will be randomized in a 1:2:2 ratio to the 
following dose groups: 
 
• Zimura™ 2 mg/eye + Sham 
 
• Zimura™ 4 mg/eye (administered as two injections of Zimura™ 2 mg)  
 
• Sham + Sham 
Subjects will receive monthly intravitreal injections of Zimura™ and/or Sham for 18 
months.  
 
7 PROCEDURES 
7.1 
Refraction and Visual Acuity, 
 and Low Luminance 
Visual Acuity 
Refraction, Vision Testing, Low Luminance, 
 will be performed at 
all time-points specified in Section 10.2 “Trial Assessments”.  Retroilluminated 
modified Ferris-Bailey ETDRS 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 
masked to the previous visual acuity measurement and to whether or not the 
subject has been assigned to active treatment or Sham.  The examiner will be 
supplied with the previous protocol refraction only.   
All necessary materials and instructions these assessments will be provided by 
Ophthotech Corp. 
 
These assessments should always be performed in the following order; Refraction, 
Visual Acuity, 
 and then Low Luminance. 
 
7.2 
Tonometry  
Tonometry will be performed at all time-points specified in Section 10.2 “Trial 
Assessments”.  On days when two injections are given, the second injection may 
not be administered until the IOP is ≤ 21 mmHg or within 5 mmHg of the pre-
injection IOP, at which time the IOP is recorded.  After the second injection and also 

 
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on days with only one injection, the IOP should be measured and recorded at least 
30 minutes after the injection and IOP must be < 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 and pre-injection 
on Day 1, Months 6, 12, 18, and Early Withdrawal.  Tono-Pen may be used at all 
other timepoints.  Goldmann applanation tonometry must also be used to verify 
intraocular pressure (IOP) reading of ≥ 30 mmHg occurring at any time.  
 
7.3 
Ophthalmologic Examination 
The following examinations will be performed at all time-points specified in Section 
10.2 “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) 
• 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, Fluorescein Angiography, and Fundus 
Autofluorescence 
Color stereoscopic fundus photographs, FA, and FAF will be performed at all time-
points specified in Section 10.2 “Trial Assessments”.   
A Reading Center (RC) will confirm eligibility of subjects prior to enrollment.  All 
color fundus photos, FAs, and FAFs that are collected at protocol-specified time 
points must be sent to the RC as specified in the RC procedure manual.  The RC 
will provide instructions for the color fundus photographs, FA, and FAF procedures.  
 

 
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7.5 
Optical Coherence Tomography (SD-OCT) 
Spectral Domain Optical Coherence Tomography (SD-OCT) will be performed at all 
time-points specified in Section 10.2 “Trial Assessments”.  The RC will provide 
instructions for the OCT procedures, including which OCT reports must be sent to 
the RC. 
 
7.6 
Laboratory Tests 
The following laboratory tests will be performed as specified in Section 10.2 “Trial 
Assessments”: 
• Hematology: hemoglobin, platelet count, WBC and differential 
• Renal Function: serum creatinine and blood urea nitrogen (BUN) 
• Hepatic function: serum bilirubin, alkaline phosphatase, gamma-glutamyl-
transferase (GGT), serum glutamic oxaloacetic transaminase (SGOT)/ 
aspartate aminotransferase (AST) and serum glutamic pyruvic transaminase 
(SGPT)/ alanine aminotransferase (ALT)  
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and 
phosphate 
• Complete Urinalysis (including specific gravity, protein, blood, etc.) 
• Serum pregnancy test (if of child-bearing potential) 
If a laboratory value outside of the normal range is judged as clinically significant by 
the Investigator, the Investigator should repeat the laboratory determination as 
judged appropriate to ensure the validity of the abnormal result.  If any clinically 
significant abnormal results are noted, the tests should 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, Physical Examination and Performance Status 
(ECOG) 
A physical examination will be performed at Screening and at the Investigators’ 
discretion thereafter.  Assessment of vital signs will be performed at all time-points 
specified in Section 10.2 “Trial Assessments”.   
Performance Status (Eastern Cooperative Oncology Group [ECOG]) will be 

 
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assessed at Screening in accordance with Appendix 17.4.  
 
7.8 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at all time-points specified in 
Section 10.2 “Trial Assessments”.   
 
7.9 
 
 
 
  
 
 
 
 
 
8 SUBJECT POPULATION 
8.1 
Sample Size 
Approximately 277 subjects will be enrolled. 
 
8.2 
Inclusion Criteria  
Subjects must meet the following criteria to be eligible to participate in this study. 
 
8.2.1 Ophthalmic Inclusion Criteria 
The following inclusion criteria apply to the SE: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  

 
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8.2.2 General Inclusion Criteria 
8.2.2.1 
Subjects of either gender aged  50 years. 
8.2.2.2 
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 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. 
8.2.2.3 
Provide written informed consent. 
8.2.2.4 
Ability to return for all trial visits. 
 
8.3 
Exclusion Criteria 
Subjects will not be eligible for the trial if subjects cannot attend all trial required 
visits, or if any of the following criteria are present systemically or in the SE: 
8.3.1 Ophthalmic Exclusion Criteria 
The following exclusion criteria apply to the SE: 
 
 
 
 
 
 
 
 
 

 
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8.3.2 General Exclusion Criteria 
8.3.2.1 
Any of the following underlying diseases including: 
• History or evidence of severe cardiac disease (e.g., New York Heart 
Association [NYHA] Functional Class III or IV - see Appendix 17.6), 

 
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history or clinical evidence of unstable angina, acute coronary 
syndrome, myocardial infarction or revascularization within last 
6 months, ventricular tachyarrythmias requiring ongoing treatment. 
• History or evidence of clinically significant peripheral vascular 
disease, such as intermittent claudication or prior amputation. 
• Clinically significant impaired renal (serum creatinine >2.5 mg/dl or 
status post renal transplant or receiving dialysis) or hepatic function. 
Subjects with results outside these ranges may be enrolled after 
consultation with Ophthotech Corp. 
• Stroke (within 12 months of trial entry). 
• Any major surgical procedure within 1 month of trial entry. 
8.3.2.2 
Previous therapeutic radiation in the region of the SE. 
8.3.2.3 
Any treatment with an investigational agent in the past 60 days for any 
condition. 
8.3.2.4 
Women who are pregnant or nursing. 
8.3.2.5 
Known serious allergies to the fluorescein dye used in angiography or to 
the components of the Zimura™ formulation. 
8.3.2.6 
History of systemic treatment with any anti-complement agent in the past 
or the likelihood of treatment with any systemic anti-complement agent 
during the study. 
 
9 TRIAL MEDICATION 
9.1 
Drug Supply  
9.1.1 Zimura™ 
Zimura™ is a pegylated RNA aptamer 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  

 
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9.1.2 Treatment Regimen and Duration 
Subjects randomized to active drug or Sham will receive monthly injections of 
Zimura™ or Sham for 18 months. Monthly doses should be administered at least 21 
days apart. 
 
• Part 1 Subjects:  
o Subjects randomized to the Zimura™ 1 mg/eye treatment arm will 
receive Zimura™ 1 mg/eye (50 µL) intravitreal injection.  
o Subjects randomized to the Zimura 2 mg/eye treatment arm will 
receive Zimura™ 2 mg/eye (100 µL) intravitreal injection.  

 
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o Subjects randomized to the Sham treatment arm will receive Sham 
injections.  
o Commencing with Amendment C, no new subjects will be enrolled in 
Part 1 of this trial. Subjects in Part 1 who have received greater than 
or equal to 18 months of Study Drug treatment will be discontinued 
from the study after Amendment C.   
 
• Part 2 Subjects:  
o Subjects randomized to the Zimura™ 2 mg/eye treatment arm will 
receive a Zimura™ 2mg/eye injection (100 µL) and a Sham injection 
o Subjects randomized to the Zimura™ 4 mg/eye treatment arm will 
receive two injections of Zimura™ 2 mg/eye.  The injection volume for 
subjects randomized to this arm will be of (100 µL) per injection.  
o Subject’s randomized to the Sham treatment arm will receive 2 Sham 
injections.  
 
9.1.3 Administration of Trial Drug 
An (Interactive Randomization Technology) IRT system will be used to assign 
masked study kits to subjects throughout the duration of the trial. All study 
medication must be dispensed using the IRT system. At each dispensing visit the 
IRT system will allocate each study drug kit(s) using the kit number on the label of 
the study medication kit.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
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9.1.4 Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that 
all trial drugs are stored in a secured area, under recommended storage conditions 
and in accordance with applicable regulatory requirements. 
 
 
 
   
 
  
 
9.2 
Previous or Concomitant Therapy 
Subjects enrolled must be treatment-naïve (no previous treatment for AMD) in 
either eye except for oral supplements of vitamins and minerals.   
Any treatment with any investigational agent for any condition in the past 60 days, 
or treatment with an investigational agent for any condition during the trial, is not 
permitted.   
 
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. 
 

 
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10.2 Trial Assessments 
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 AMD 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, including the RC. An 
explanation of the trial and discussion of the possible risks and discomforts will be 
given by the investigator or appropriate designee.  Only those subjects who fulfill all 
eligibility criteria will be entered into the trial.  
Ocular assessments performed at Baseline (Screening or Day 1), Month 6, Month 
12, and Month 18 (and at an Early Withdrawal visit if performed) should be 
performed on both eyes (OU) pre-injection.  Ocular assessments at all other study 
visits are performed on the SE only. 
The following assessments will be performed during the study.   
 
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.  Screening 
assessments can be broken into 2 days if necessary.    
• Informed consent 
• Medical history 
• Ophthalmologic history (OU) 
• Vital Signs /Physical Examination/Performance Status (ECOG – See 
Appendix 17.4) 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Ophthalmologic Examination and Goldmann Applanation Tonometry 
(OU) 
• 12-Lead ECG 
• Color fundus photographs (OU)  
• Fluorescein Angiograms (OU, transit study eye) 
• Optical Coherence Tomography (OU)  

 
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• Fundus Autofluorescence (OU) 
• Laboratory Tests 
• Serum pregnancy test (if applicable) 
• Concomitant Medication Assessment 
 
10.2.2 On-Trial Assessments 
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) and Serious Adverse Events (SAEs) should be 
assessed starting at Day 1 after the first dose of trial drug.   
 
10.2.3 
Reconfirmation of Eligibility at Day 1  
• 
Subject will be EXCLUDED if any of the following criteria are met between 
Screening and Day 1; 
o A VA change of >= 5 letters 
OR 
o Significant anatomical changes (i.e. large subretinal hemorrhage, RPE 
rip, pigment epithelial detachment, per investigator discretion) 
OR 
o If the Snellen Equivalent is no longer between 20/25 to 20/320  
 
10.2.3.1 
Day 1 Visit  
Pre-injection 
• 
 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
 
• 
Low Luminance ETDRS Visual Acuity (OU) 
• Goldmann Applanation Tonometry and Ophthalmologic Examination (OU) 
• 
Randomization 
• 
Randomized Treatment:  Zimura™/Sham  

 
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Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.2 
Day 3 (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.3 
Month 1 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.4 
Month 1 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.5 
Month 2 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.6 
Month 2 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.7 
Month 3 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.8 
Month 3 + 3 Days (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.9 
Month 4 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.10 Month 4 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.11 Month 5 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 

 
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10.2.3.12 Month 5 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.13 Month 6 (±7 days)  
Pre-Injection 
• 
 
• 
Protocol refraction and Visual Acuity (4 meters) using ETDRS chart (OU) 
• 
 
• 
Low Luminance ETDRS Visual Acuity (OU) 
• 
Goldmann Applanation Tonometry and Ophthalmologic examination (OU) 
• 
Vital Signs 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (OU, transit study eye) 
• 
Optical Coherence Tomography (OU)  
• 
Fundus Autofluorescence (OU) 
• 
12-Lead ECG 
• 
Laboratory Tests 
• 
Serum pregnancy test (if applicable) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 

 
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10.2.3.14 Month 6 + 3 Days (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.15 Month 7 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.16 Month 7 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.17 Month 8 (±7 days)  
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  

 
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Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.18 Month 8 + 3 Days (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.19 Month 9 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.20 Month 9 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.21 Month 10 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered: (including sham) 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 

 
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10.2.3.22 Month 10 + 3 Days (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.23 Month 11 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.24 Month 11 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.25 Month 12 (±7 days) 
Pre-Injection 
• 
 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
 
• 
Low Luminance ETDRS Visual Acuity (OU) 
• 
Goldmann Applanation Tonometry and Ophthalmologic examination (OU) 

 
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• 
Vital Signs 
• 
12-Lead ECG 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (OU, transit study eye) 
• 
Optical Coherence Tomography (OU)  
• 
Fundus Autofluorescence (OU) 
• 
Laboratory Tests 
• 
Serum pregnancy test (if applicable) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.26 Month 12 + 3 days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.27 Month 13 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  

 
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Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.28 Month 13 + 3 days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.29 Month 14 (±7 days)  
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 

 
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• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.30 Month 14 + 3 Days (±1 day)  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.31 Month 15 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE)  
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 

 
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10.2.3.32 Month 15 + 3 days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.33 Month 16 (±7 days)  
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  
Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.34 Month 16 + 3 days (±1 day)   
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.35 Month 17 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Low Luminance ETDRS Visual Acuity (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Randomized Treatment:  Zimura™/Sham  

 
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Post-injection 
• 
Ophthalmologic Examination - at least 30 minutes after the last (whether first 
or second) injection (SE) 
• 
Tonometry (SE): 
• If one injection is administered (including sham): 
o The IOP should be recorded at least 30 minutes after the 
injection. 
• If two injections are administered (including sham): 
o The second injection may NOT be administered until the IOP is 
≤ 21 mm Hg or within 5 mm Hg of the baseline IOP on the day of 
injection, at which time the IOP will be recorded. 
o The IOP should be recorded at least 30 minutes after the 2nd 
injection. 
 
10.2.3.36 Month 17 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.3.37 Month 18 (±7 days) 
• 
 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
 
• 
Low Luminance ETDRS Visual Acuity (OU) 
• 
Goldmann Applanation Tonometry and Ophthalmologic examination (OU) 
• 
Vital Signs 
• 
12-Lead ECG 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (OU, transit study eye) 
• 
Optical Coherence Tomography (OU)  
• 
Fundus Autofluorescence (OU) 
• 
Laboratory Tests 
• 
Serum pregnancy test (if applicable) 
 
 

 
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10.2.3.38 Early Withdrawal  
• 
 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
 
• 
Low Luminance ETDRS Visual Acuity (OU) 
• 
Goldmann Applanation Tonometry and Ophthalmologic examination (OU) 
• 
Vital Signs 
• 
12-Lead ECG 
• 
Color fundus photographs (OU)  
• 
Fluorescein Angiograms (OU, transit study eye) 
• 
Optical Coherence Tomography (OU)  
• 
Fundus Autofluorescence (OU) 
• 
Laboratory Tests 
• 
Serum pregnancy test (if applicable) 
Adverse events are recorded up until 30 days after the last dose of study drug or 
until the last follow up visit of the trial, 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.  
If the subject still presents with any treatment-related toxicity, the follow-up period 
will be extended until return to baseline status or until the condition has stabilized. 
 
10.3 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.  

 
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10.4 Trial Discontinuation 
The reason for a subject discontinuing from the trial will be recorded in the source 
documentation and 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 12.3).  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. 
 
11 
STATISTICAL METHODS 
The following summarizes the statistical approaches that will be employed in this 
trial designed to compare the effects of 2 mg and 4 mg doses of Zimura™ against 
the Sham control arm, regarding geographic atrophy secondary to Dry AMD.  
  
11.1 Study Design 
This is a randomized, double-masked, Sham controlled 
 study that will 
obtain evidence regarding the effects of multiple dose levels of Zimura™ in reducing 
the rate of GA growth over 12 months, when compared with the Sham control.   
 
This 
 trial will provide evidence suggesting that a dose of Zimura™:  
• Is not plausibly more efficacious than the Sham control, and should be 
discarded in its current formulation in this indication; 
• Is plausibly more efficacious than the Sham control and should be evaluated 
definitively in a subsequent Phase 3 clinical trial; or 
• Is more efficacious than the Sham control, with strength of evidence meeting the 
standard requirement of a 0.0125 one-sided false-positive error rate, adjusting 
for the multiple comparisons of 2 mg and 4 mg doses against the Sham control.  
A confirmatory trial likely would be required for regulatory approval. 

 
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Eligible subjects that consent to participate will be randomized to Zimura™ or Sham 
control in two parts of the trial.  In Part 1, approximately 77 subjects are randomized 
to Zimura™ 1 mg vs Zimura™ 2 mg vs Sham control, in a 1:1:1 allocation.  In Part 2, 
approximately 200 subjects are randomized to Zimura™ 2 mg vs Zimura™ 4 mg vs 
Sham control, in a 1:2:2 allocation.   A total of approximately 277 subjects are to be 
randomized.  
11.2 Endpoints 
11.2.1 Primary Efficacy Endpoint 
Primary Efficacy Endpoint: 
• 
Mean rate of change in GA over 12 months measured by 
fundus autofluorescence (FAF) at three time points: Baseline, Month 6, 
Month 12 
Secondary Efficacy Endpoints: 
Secondary efficacy endpoints will be assessed from Baseline to Month 12: 
 
• Mean change in best corrected visual acuity (ETDRS letters) from Baseline 
to Month 12 
 
• Mean change in low luminance best corrected visual acuity (ETDRS letters) 
from Baseline to Month 12 
 
11.2.2 Safety and Tolerability Endpoints 
Safety and tolerability endpoints: 
• 
All adverse events reported, whether or not deemed related to the injection 
procedure or study treatment 
• 
All SAEs, whether or not deemed related to the injection procedure or study 
treatment  
• 
Laboratory data (blood:  hematology, renal function, hepatic function, and 
electrolytes; urinalysis) 
• 
Ophthalmic variables (IOP, ophthalmic examination, fluorescein angiograms, 
FAF, and OCT) 
• 
Vital sign measurements 
• 
12-lead ECG 
 

 
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11.3 Determination of Sample Size and Statistical Rationale 
 
The sample size determination for this study is based on 
 screening 
methodology presented in Fleming and Richardson (2004). The power calculations 
are based on the recently released results from a clinical trial of a complement 
inhibitor, including the estimated precision of the estimated effects on rate of GA 
growth over 12 months, and including the plausible effect size for Zimura™.   
 
A total of approximately 277 subjects will be enrolled. When follow-up is complete 
for the primary analysis based on 12-month follow-up, the data base will be locked.  
Information post-12 months will remain fully confidential until completion of 18-
month follow-up.  By pre-specification, a hierarchical analysis will be performed 
where the treatment effect on the rate of GA growth over 18 months will be 
statistically assessed if statistical significance is achieved on the rate of GA growth 
over 12 months.   
 
 the primary analyses will be based on comparisons of 
Zimura™ 2 mg vs the Sham control, and Zimura™ 4 mg vs Sham control.  For the 
comparison of Zimura™ 2 mg vs Sham control, the 26 subjects randomized to 
Zimura™ 2 mg and 26 subjects randomized to Sham control from Part 1 will be 
combined with the 40 subjects randomized to Zimura™ 2 mg and 80 subjects 
randomized to Sham control from Part 2, where the analysis will be stratified by 
Part 1 vs Part 2.  The comparison of Zimura™ 4 mg vs Sham control will be based 
on the 80 subjects randomized to each of these two arms in Part 2.  
 
The primary analysis 
 for each of the two pairwise comparisons 
of an active dose of Zimura™ vs the Sham control is formally based on a three-
category decision guideline.  To be specific, the decision guideline for this trial is 
based on whether the estimated reduction in rate of GA growth over 12 months for 
a dose of Zimura™ versus Sham control is less than 14%, is from 14% up to 24.5%, 
or is at least 24.5%.   
 
Note that these categories should not be interpreted as providing strict decision 
rules but rather as guidelines that will be factored into a broader scientific 
assessment of the benefit to risk profile of the Zimura™ dose regimen.  This broader 
assessment will include consideration of safety, of supportive efficacy endpoints, 
and of relevant information external to this trial.  Specifically, the decision guidelines 
for this trial are: 
 

 
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1. If the estimated reduction in the rate of GA growth over 12 months is less 
than 14%, then this dose of Zimura™ is not plausibly more efficacious than 
the Sham control; its utility in this indication should be reconsidered.  
2. If the estimated reduction in the rate of GA growth over 12 months is from 
14% to up to 24.5%, then this dose of Zimura™ is plausibly more efficacious 
than the Sham control and should be evaluated in a subsequent Phase 3 
clinical trial. 
In planning the design of the confirmatory Phase 3 trials, this trial (and other 
information that emerges during the conduct of this trial) will provide 
important insights through consideration of:  
a. The estimated benefit-to-risk profile of this dose of Zimura™; 
b. Possible refinements in the dose/schedule of Zimura™ 
c. Approaches to improve adherence to the Zimura™ regimen; 
d. Modifications to defining eligibility criteria to enhance enrichment; 
e. Approaches to achieving timely accrual of study participants at centers 
with established ability to provide high quality implementation of the trial 
and high quality data. 
3. If the estimated reduction in the rate of GA growth over 12 months is at least 
24.5%, then this dose of Zimura™ would be statistically significantly more 
effective than the Sham control, with strength of evidence meeting the 
standard requirement of a 0.0125 one-sided false positive error rate 
(incorporating an adjustment for multiplicity arising from comparing each 
dose with the Sham control). 
 
The operating characteristics for this three-category decision guideline are: 
 
1. The false-positive error rate of the screening procedure is low.  In particular, 
if a given dose of Zimura™ truly provides no improvement in the rate of GA 
growth over 12 months, then there is only a 10% chance of bringing that 
dose forward to a Phase 3 trial and only a 1.25% chance of reaching the 
false positive conclusion that that dose regimen provides a statistically 
significant improvement in efficacy relative to a Sham control.   Given that 
there will be two pairwise comparisons, if both doses of Zimura™ truly 
provide no improvement in the rate of GA growth over 12 months, then the 
probability of achieving a false positive conclusion for further study for at 
least one dose regimen likely would be in the range of 15% to 17% (when 
one takes into account the positive correlation between these two 

 
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assessments), and the probability of reaching a conclusion that at least one 
dose regimen provides a statistically significant improvement in efficacy 
relative to a Sham control is only 2.5%.   
2. The false-negative error rate is low.  If a given dose of Zimura™ truly 
provides a 28% reduction in the rate of GA growth over 12 months, then 
there is only a 10% chance that that dose of Zimura™ would be discarded, 
and thus a 90% chance that it would be evaluated in a subsequent 
confirmatory Phase 3 trial. Given that there will be two pairwise comparisons, 
if both doses of Zimura™ truly provide a 28% reduction in the rate of GA 
growth over 12 months, then it is likely (when one takes into account the 
positive correlation between these two assessments) that there is at least a 
95% chance that at least one dose would be evaluated in a subsequent 
confirmatory Phase 3 trial.  If a given dose of Zimura™ truly provides a 28% 
reduction in the rate of GA growth over 12 months, there is a 63% chance 
that that regimen will have a statistically significant improvement in efficacy 
(at one-sided p<0.0125) relative to the Sham control.  
 
11.4 Randomization Procedure 
Subjects will be centrally allocated to one of the three treatment groups stratified by 
factors known to be of prognostic importance in dry AMD: 
• Baseline visual acuity < 50 ETDRS letters (20/100 Snellen equivalent) vs > 
50 ETDRS letters  
• Size of baseline geographic atrophy (< 4 disc areas vs >4 disc areas) 
• Pattern of Fundus Auto Fluorescence (FAF) at the junctional zone of GA 
(None/focal vs banded/diffuse) 
Randomization will be performed using an IRT system based on the stratification 
information above to randomize each subject and assign a treatment arm.  
The IRT system will be used to assign masked study kits to subjects throughout the 
duration of the trial. All study medication must be dispensed using the IRT system. 
At each dispensing visit the IRT system will allocate each study drug kit(s) using the 
kit number on the label of the study medication kit.  
 
11.5 Masking Procedures 
It is the responsibility of the Principal Investigator to ensure that the physician 
assessing adverse events, the VA examiner, all masked study personnel, and the 
subject remain masked to the subject’s treatment assignment. 
 

 
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For subjects receiving both Zimura™ and Sham injections, the Zimura™ injection 
must be administered first. To maintain masking, the IRT system will provide 
instructions as to which kit is to be administered first at each dispensing visit. These 
instructions are located on the IRT confirmation of drug assignments, which is 
provided for each dispensing visit. This information must be communicated to the 
unmasked injector and stored with subject’s study documentation.   
 
Within each study drug kit there is a dosing label which indicates the amount of 
medication to be administered to the subject, based upon the randomized treatment 
arm of the subject. This dosing label may only be seen by unmasked study 
personnel.  
 
In the case of a rare emergency where, in the Investigators opinion, unmasking the 
treatment is necessary to evaluate a further course of action, the Investigator 
should access the IRT and follow the instructions to initiate unmasking. Every effort 
should be made to contact the sponsor prior to unmasking a subject. Any 
unmasking should be reported to the unmasked contact at the sponsor 
immediately.  
 
In the event of an unmasking, the Investigator will be informed of the subjects 
randomized treatment assignment. Any unmasking information must be stored 
separately from the subject's study files in a secure location to ensure the treatment 
assignment remains masked to other site, CRO and sponsor personnel as required.  
The IRT system will generate an email notification that does not contain unmasking 
information, which will be sent to the Investigator and appropriate Sponsor 
personnel. 
 
 
11.5.1 Visual Acuity Assessments  
Since this is a double-masked study, subjects and staff at the investigational site, 
particularly the visual acuity examiners, will be masked to study treatment.  All VA 
assessments will be performed by the trial refractionist/ophthalmologist, who will be 
masked to the subject’s treatment as well as previous visual acuity assessments. 
The trial refractionist/ophthalmologist will be supplied only with the subject’s most 
recent protocol refraction. 
 
11.5.2 Injections 
Each clinical site is required to have a minimum of two ophthalmologists – the 
unmasked injector and the masked assessor.  The unmasked injector will perform 
the Zimura™/Sham injection as well as the post-injection ophthalmic exam and 
tonometry measurements. The unmasked injector and designated unmasked 
assistants (if needed) are not permitted to be involved in the conduct of the study in 

 
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any other manner and are not to communicate with any other personnel or subjects 
regarding the treatment assignment.  The masked assessor will perform all other 
physician assessments including the relationship of all adverse events to study 
drug, including those noted by the unmasked injector. 
 
11.5.3 Statistical Analyses 
All statistical analyses will be performed by a statistical office independent of the 
study Sponsor. The Sponsor and the subjects will remain masked to treatments 
until the end of the study, except if safety considerations justify breaking the code 
for individual subjects. 
 
11.6 Analytical Considerations 
11.6.1 Analytical Plan 
A Statistical Analysis Plan (SAP) will provide the details necessary for the statistical 
analyses to be explicitly pre-specified prior to unmasking.   The methods for 
imputation of post-baseline, missing data will be specified in the Statistical Analysis 
Plan. 
 
11.6.2 Significance Levels 
The overall (one-sided) false positive error rate in this trial, accounting for the 
conduct of two pairwise comparisons with Sham control, is 0.025 for the analysis of 
the primary endpoint. 
 
11.6.3 Descriptive Statistics 
Descriptive statistics will be provided on demographic information, treatment 
administration, baseline characteristics, and protocol deviations, as well as for 
selected endpoints at relevant time points. No tests of significance will be carried 
out to compare treatment groups on baseline data because any observed 
differences between them must be attributed to chance.   
 
11.6.4 Efficacy Analysis 
The efficacy analysis will be conducted on all randomized and treated subjects 
according to the intention-to-treat principle.  
For normal endpoints, treatment groups will be compared through an analysis of 
variance including stratification factors.  

 
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For binary endpoints, treatment groups will be compared through Mantel-Haenszel 
or Cochran-Mantel-Haenszel ² tests adjusting for strata as above. 
 
11.6.5 Subset Analyses 
The trial is not sized to test for the presence of treatment by subset interactions. 
Thus, true treatment by subset interactions will likely be missed, unless they are 
quite substantial. Conversely, should any particular subset of subjects seem to 
benefit more or less from therapy than the total population, this will not be taken as 
evidence of a true treatment by subset interaction, given the likelihood that such an 
observation could be due to chance alone. With these caveats in mind, exploratory 
subset analyses will be performed to identify any major effect that might be worth 
testing in future trials. Clinically meaningful subsets will be looked at, including 
stratification factors.  
 
11.6.6 Safety Analysis 
The safety analysis will be conducted on all subjects who had at least one 
administration of trial 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. 
 
12 ADVERSE EVENTS 
12.1 Definition of Adverse Events 
An 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 

 
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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. 
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 whether the event 
qualifies as a “serious” adverse event (Section 12.3). 
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 

 
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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 intravitreous injection 
procedure (eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, 
povidone-iodine drops or flush, subconjunctival injection of anesthetic, intravitreous 
injection), termed “injection procedure-related”, or to study drug (Zimura™). 
The relationship to the intravitreous 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. 
 
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; 

 
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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 inpatient admission.  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 
• 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 

 
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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 by the site 
to the Sponsor or Designee within 24 hours. 
Refer to the “Safety Contact List” provided separately 
 
12.5 Independent Data Monitoring Committee  
An Independent Data Monitoring Committee will review subject safety data during 
the course of the trial.   
 
12.6 Exposure in Utero 
If any trial subject becomes or is found to be pregnant while receiving trial drug, the 
investigator must contact the Sponsor.  This must be done irrespective of whether 
an adverse event has occurred and within 24 hours of awareness of the pregnancy.  
The Sponsor will inform the site of the information to be provided. 
 

 
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12.7 Abnormal Laboratory Results 
If a clinically significant laboratory value occurs, the investigator will repeat the 
laboratory determination as judged appropriate until the abnormality is resolved, is 
no longer considered clinically significant by the investigator, or an explanation for 
the change is obtained.  
 
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 will complete the appropriate case report form pages within 3   
business days 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, 
or its representatives, 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, or its 
representatives, 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.  

 
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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. 
 
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. 
Under certain circumstances, individual protocol criteria may be waived by 
Ophthotech Corp. and in agreement with the investigator.  Any such waiver will be 
documented in writing and provided to the investigator by Ophthotech Corp. 
 
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 

 
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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”. 
 
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 

 
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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. 
 
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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15   REFERENCES
Anderson, D. H., Mullins, R. F., Hageman, G. S., & Johnson, L. V. (2002). A 
role for local inflammation in the formation of drusen in the aging eye. Am J 
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10.1001/archopht.123.7.914 
Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., 
Hardisty, L. I., et al. (2005). A common haplotype in the complement regulatory 
gene factor H (HF1/CFH) predisposes individuals to age-related macular 
degeneration. Proc Natl Acad Sci U S A, 102(20), 7227-7232. doi: 
10.1073/pnas.0501536102 

 
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Hageman, G. S., Luthert, P. J., Victor Chong, N. H., Johnson, L. V., Anderson, 
D. H., & Mullins, R. F. (2001). An integrated hypothesis that considers drusen 
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et al. (2005). Complement factor H variant increases the risk of age-related 
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Hariri, A., Nittala, M. G., & Sadda, S. R. (2015). Outer retinal tubulation as a 
predictor of the enlargement amount of geographic atrophy in age-related 
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10.1016/j.ophtha.2014.08.035 
Hobbs, F. B. (1996). The elderly population.   Retrieved 10 Oct 2015, 2015 
Holers, V. M. (2014). Complement and its receptors: new insights into human 
disease. Annu Rev Immunol, 32, 433-459. doi: 10.1146/annurev-immunol-
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Holz, F. G., Strauss, E. C., Schmitz-Valckenberg, S., & van Lookeren 
Campagne, M. (2014). Geographic atrophy: clinical features and potential 
therapeutic approaches. Ophthalmology, 121(5), 1079-1091. doi: 
10.1016/j.ophtha.2013.11.023 
Johnson, L. V., Ozaki, S., Staples, M. K., Erickson, P. A., & Anderson, D. H. 
(2000). A potential role for immune complex pathogenesis in drusen formation. 
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(2005). Complement factor H polymorphism in age-related macular 
degeneration. Science, 308(5720), 385-389. doi: 10.1126/science.1109557 
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Magnusson, K. P., Duan, S., Sigurdsson, H., Petursson, H., Yang, Z., Zhao, Y., 
et al. (2006). CFH Y402H confers similar risk of soft drusen and both forms of 
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Maguire, P., & Vine, A. K. (1986). Geographic atrophy of the retinal pigment 
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McLeod, D. S., Grebe, R., Bhutto, I., Merges, C., Baba, T., & Lutty, G. A. 
(2009). Relationship between RPE and choriocapillaris in age-related macular 

 
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degeneration. Invest Ophthalmol Vis Sci, 50(10), 4982-4991. doi: 
10.1167/iovs.09-3639  
Narayanan, R., Butani, V., Boyer, D. S., Atilano, S. R., Resende, G. P., Kim, D. 
S., et al. (2007). Complement factor H polymorphism in age-related macular 
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10.1016/j.ophtha.2006.10.035 
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D., et al. (2006). Drusen complement components C3a and C5a promote 
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Seddon, J. M., Gensler, G., Klein, M. L., & Milton, R. C. (2006). Evaluation of 
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Ophthalmol, 141(1), 201-203. doi: 10.1016/j.ajo.2005.07.059 
Seddon, J. M., George, S., Rosner, B., & Rifai, N. (2005). Progression of age-
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774-782. doi: 10.1001/archopht.123.6.774 
Sepp, T., Khan, J. C., Thurlby, D. A., Shahid, H., Clayton, D. G., Moore, A. T., 
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Hawkins, B., et al. (1999). Enlargement of atrophy and visual acuity loss in the 

 
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geographic atrophy form of age-related macular degeneration. Ophthalmology, 
106(9), 1768-1779. doi: 10.1016/S0161-6420(99)90340-8 
Sunness, J. S., Rubin, G. S., Broman, A., Applegate, C. A., Bressler, N. M., & 
Hawkins, B. S. (2008). Low luminance visual dysfunction as a predictor of 
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Umeda, S., Ayyagari, R., Allikmets, R., Suzuki, M. T., Karoukis, A. J., 
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16 SIGNATURE PAGE 
Signatures confirm that this protocol OPH2003 Amendment C has been carefully read and 
fully understood, and that there is agreement to comply with the conduct and terms of the 
trial specified herein in compliance with Good Clinical Practice and all other regulatory 
requirements.  
PROTOCOL OPH2003:  “
 Randomized, Double-Masked, Controlled Trial to 
Assess the Safety and Efficacy of Intravitreous Administration of Zimura™ (Anti-C5 Aptamer) 
in Subjects with Geographic Atrophy Secondary to Dry Age-Related Macular Degeneration” 
 
Trial Sponsor:  
Ophthotech Corporation 
 
 
Principal 
Investigator: __________________________      _____________________________ 
 
                       Name (Print) 
 
     (Signature) 
 
 
 
 
 
 
 
 
     _____________________________ 
 
 
 
 
 
 
 
     (Date) 
 
 
 
 
 
 
 

 
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17 APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 

 
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