Clinical trial NCT02686658
Conditions: Geographic Atrophy Dry Age-Related Macular Degeneration
Keywords: Geographic Atrophy (GA) Dry age-related macular degeneration AMD Zimura (previous name) Anti-inflammatory complement factor C5 inhibitor ARC1905 avacincaptad pegol
Sponsor: IVERIC bio, Inc.
Start date: 2015-12-15; Completion date: 2020-04-23
Enrollment: 286 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study were to evaluate the safety and efficacy of Zimura intravitreal (IVT) administration when administered in participants with geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD).

Detailed description:
Participants will receive monthly intravitreal injections of Zimura or Sham for 18 months.

Arms: arm 1: Participants received 1 mg of Avacincaptad Pegol in the study eye administered via IVT injection (50 µL) on Day 1 and monthly up to 18 months. arm 2: Participants received 2 mg of Avacincaptad Pegol in the study eye administered via IVT injection (100 µL) on Day 1 and monthly up to 18 months. arm 3: Participants received a Sham injection of an empty, needleless syringe administered in the study eye on Day 1 and monthly up to 18 months. arm 4: Participants received 2 mg of Avacincaptad Pegol in the study eye administered via IVT injection (100 µL) and a subsequent Sham administration on Day 1 and monthly up to 18 months. arm 5: Participants received 4 mg of Avacincaptad Pegol in the study eye administered via two consecutive IVT injections (2 x 100 µL) on Day 1 and monthly up to 18 months. arm 6: Participants received two consecutive Sham injections of empty, needleless syringes administered in the study eye on Day 1 and monthly up to 18 months.
Interventions: intervention 1: Avacincaptad Pegol intervention 2: Sham
Intervention descriptions: intervention 1: Avacincaptad Pegol 20 mg/mL solution for intravitreal (IVT) injection intervention 2: The Sham procedure included the blunt opening of an empty, needleless syringe barrel placed on the conjunctiva in the inferotemporal quadrant of the eyeball to simulate the pressure of an injection.

Protocol documents:
Prot_000.pdf: 
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 
Ophthalmol, 134(3), 411-431.  
Bok, D. (2005). Evidence for an inflammatory process in age-related macular 
degeneration gains new support. Proc Natl Acad Sci U S A, 102(20), 7053-
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Bora, N. S., Kaliappan, S., Jha, P., Xu, Q., Sohn, J. H., Dhaulakhandi, D. B., et 
al. (2006). Complement activation via alternative pathway is critical in the 
development of laser-induced choroidal neovascularization: role of factor B and 
factor H. J Immunol, 177(3), 1872-1878.  
Bora, P. S., Sohn, J. H., Cruz, J. M., Jha, P., Nishihori, H., Wang, Y., et al. 
(2005). Role of complement and complement membrane attack complex in 
laser-induced choroidal neovascularization. J Immunol, 174(1), 491-497.  
Day, J. (1993). Population Projections of the United States, by Age, Sex, Race, 
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110(Current Population Reports).  
Donoso, L. A., Kim, D., Frost, A., Callahan, A., & Hageman, G. (2006). The role 
of inflammation in the pathogenesis of age-related macular degeneration. Surv 
Ophthalmol, 51(2), 137-152. doi: 10.1016/j.survophthal.2005.12.001 
Edwards, A. O., Ritter, R., 3rd, Abel, K. J., Manning, A., Panhuysen, C., & 
Farrer, L. A. (2005). Complement factor H polymorphism and age-related 
macular degeneration. Science, 308(5720), 421-424. doi: 
10.1126/science.1110189 
Fleming, T.R., Richardson, B.A. (2004).  Some design issues in trials of 
microbicides for the prevention of HIV infection.  The Journal of Infectious 
Diseases 2004; 190:666–74 
Frederick, P. A., & Kleinman, M. E. (2014). The Immune System and AMD. 
Curr Ophthalmol Rep, 2(1), 14-19. doi: 10.1007/s40135-013-0037-x 
Grossniklaus, H. E., Miskala, P. H., Green, W. R., Bressler, S. B., Hawkins, B. 
S., Toth, C., et al. (2005). Histopathologic and ultrastructural features of 
surgically excised subfoveal choroidal neovascular lesions: submacular surgery 
trials report no. 7. Arch Ophthalmol, 123(7), 914-921. doi: 
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 
as biomarkers of immune-mediated processes at the RPE-Bruch's membrane 
interface in aging and age-related macular degeneration. Prog Retin Eye Res, 
20(6), 705-732.  
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., 
et al. (2005). Complement factor H variant increases the risk of age-related 
macular degeneration. Science, 308(5720), 419-421. doi: 
10.1126/science.1110359 
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 
macular degeneration. Ophthalmology, 122(2), 407-413. doi: 
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-
032713-120154 
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. 
Exp Eye Res, 70(4), 441-449. doi: 10.1006/exer.1999.0798 
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J. Y., Sackler, R. S., Haynes, C., et al. 
(2005). Complement factor H polymorphism in age-related macular 
degeneration. Science, 308(5720), 385-389. doi: 10.1126/science.1109557 
Leibowitz, H. M., Krueger, D. E., Maunder, L. R., Milton, R. C., Kini, M. M., 
Kahn, H. A., et al. (1980). The Framingham Eye Study monograph: An 
ophthalmological and epidemiological study of cataract, glaucoma, diabetic 
retinopathy, macular degeneration, and visual acuity in a general population of 
2631 adults, 1973-1975. Surv Ophthalmol, 24(Suppl), 335-610.  
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 
advanced AMD. PLoS Med, 3(1), e5. doi: 10.1371/journal.pmed.0030005 
Maguire, P., & Vine, A. K. (1986). Geographic atrophy of the retinal pigment 
epithelium. Am J Ophthalmol, 102(5), 621-625. 
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 
degeneration. Ophthalmology, 114(7), 1327-1331. doi: 
10.1016/j.ophtha.2006.10.035 
Nozaki, M., Raisler, B. J., Sakurai, E., Sarma, J. V., Barnum, S. R., Lambris, J. 
D., et al. (2006). Drusen complement components C3a and C5a promote 
choroidal neovascularization. Proc Natl Acad Sci U S A, 103(7), 2328-2333. 
doi: 10.1073/pnas.0408835103 
Ortma, J. M., & Velkof, V. A. (2014). An Aging Nation: The Older Population in 
the United States. Current Population Reports(May).  
Potter, J. W., & Thallemer, J. M. (1981). Geographic atrophy of the retinal 
pigment epithelium: diagnosis and vision rehabilitation. J Am Optom Assoc, 
52(6), 503-508.  
Sarks, J. P., Sarks, S. H., & Killingsworth, M. C. (1988). Evolution of geographic 
atrophy of the retinal pigment epithelium. Eye (Lond), 2 ( Pt 5), 552-577. doi: 
10.1038/eye.1988.106 
Schatz, H., & McDonald, H. R. (1989). Atrophic macular degeneration. Rate of 
spread of geographic atrophy and visual loss. Ophthalmology, 96(10), 1541-
1551.  
Seddon, J. M., Francis, P. J., George, S., Schultz, D. W., Rosner, B., & Klein, 
M. L. (2007). Association of CFH Y402H and LOC387715 A69S with 
progression of age-related macular degeneration. JAMA, 297(16), 1793-1800. 
doi: 10.1001/jama.297.16.1793 
Seddon, J. M., Gensler, G., Klein, M. L., & Milton, R. C. (2006). Evaluation of 
plasma homocysteine and risk of age-related macular degeneration. Am J 
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-
related macular degeneration: prospective assessment of C-reactive protein, 
interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol, 123(6), 
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., 
et al. (2006). Complement factor H variant Y402H is a major risk determinant 
for geographic atrophy and choroidal neovascularization in smokers and 
nonsmokers. Invest Ophthalmol Vis Sci, 47(2), 536-540. doi: 10.1167/iovs.05-
1143 
Sunness, J. S., Gonzalez-Baron, J., Applegate, C. A., Bressler, N. M., Tian, Y., 
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 
subsequent visual acuity loss from geographic atrophy in age-related macular 
degeneration. Ophthalmology, 115(9), 1480-1488, 1488 e1481-1482. doi: 
10.1016/j.ophtha.2008.03.009 
Umeda, S., Ayyagari, R., Allikmets, R., Suzuki, M. T., Karoukis, A. J., 
Ambasudhan, R., et al. (2005a). Early-onset macular degeneration with drusen 
in a cynomolgus monkey (Macaca fascicularis) pedigree: exclusion of 13 
candidate genes and loci. Invest Ophthalmol Vis Sci, 46(2), 683-691. doi: 
10.1167/iovs.04-1031 
Umeda, S., Suzuki, M. T., Okamoto, H., Ono, F., Mizota, A., Terao, K., et al. 
(2005b). Molecular composition of drusen and possible involvement of anti-
retinal autoimmunity in two different forms of macular degeneration in 
cynomolgus monkey (Macaca fascicularis). FASEB J, 19(12), 1683-1685. doi: 
10.1096/fj.04-3525fje 
Van Newkirk, M. R., Nanjan, M. B., Wang, J. J., Mitchell, P., Taylor, H. R., & 
McCarty, C. A. (2000). The prevalence of age-related maculopathy: the visual 
impairment project. Ophthalmology, 107(8), 1593-1600.  
 


 
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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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SAP_001.pdf: 
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: Statistical Analysis Plan 
Document Date: 19 July 2019 


CONFIDENTIAL 
OPHTHOTECH – OPH2003 – SAP – V1.0– 19JUL2019     
  Page 1 of 39 
STATISTICAL ANALYSIS PLAN 
SPONSOR: 
OPHTHOTECH 
PROTOCOL 
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 
STUDY CODE: 
OPH2003 
VERSION: 
Version 1.0 
DATE: 
19 July 2019 
The undersigned certify that they have read, reviewed and approved this document. 


           
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OPHTHOTECH – OPH2003 – SAP – V1.0– 19JUL2019                                          Page 2 of 39 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................................................................. 4
1
INTRODUCTION ............................................................................................................................................... 6
2
STUDY DESIGN AND OBJECTIVES ..................................................................................................................... 6
2.1
STUDY OBJECTIVES ............................................................................................................................................ 6
2.1.1
Primary Efficacy Endpoint ....................................................................................................................... 6
2.1.2
Secondary Efficacy Endpoints .................................................................................................................. 6
2.1.3
 .............................................................................................................................. 6
2.1.4
 ............................................................................................................................ 9
2.1.5
Safety Endpoints ..................................................................................................................................... 9
2.2
STUDY DESIGN AND SAMPLE SIZE ..................................................................................................................... 9
2.3
RANDOMIZATION ................................................................................................................................................. 10
3
GENERAL ANALYSIS DEFINITIONS .................................................................................................................. 11
3.1
STUDY PERIOD AND VISIT WINDOW DEFINITIONS .......................................................................................... 11
3.2
DEFINITION OF POPULATIONS ........................................................................................................................ 13
3.2.1
Intention-To-Treat (ITT) Population ...................................................................................................... 13
3.2.2
Per-protocol (PP) Population ................................................................................................................. 13
3.2.3
Safety Population .................................................................................................................................. 13
3.3
DEFINITION OF SUBGROUPS ................................................................................................................................... 13
3.4
DATA HANDLING CONVENTIONS .................................................................................................................... 14
3.4.1
General Conventions ............................................................................................................................. 14
3.4.2
Visit Windows........................................................................................................................................ 14
3.4.3
Handling Missing Data in Efficacy analyses .......................................................................................... 14
3.4.4
Handling Missing Data in Descriptive Analyses .................................................................................... 15
3.4.5
Handling Missing or Partially Missing Dates ......................................................................................... 15
3.4.6
 ............................................................................................................................. 15
4
STUDY SUBJECTS ........................................................................................................................................... 17
4.1
DISPOSITION OF SUBJECTS ............................................................................................................................. 17
4.2
TREATMENT MISALLOCATIONS ...................................................................................................................... 17
4.3
PROTOCOL VIOLATIONS.................................................................................................................................. 17
4.4
INCLUSION AND EXCLUSION CRITERIA .............................................................................................................. 18
5
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................................................ 18
6
PRIOR AND CONCOMITANT MEDICATION ..................................................................................................... 19
7
EFFICACY EVALUATION ................................................................................................................................. 19
7.1
CONTROL OF ALPHA ............................................................................................................................................. 20
7.2
ANALYSIS OF PRIMARY EFFICACY ENDPOINT ............................................................................................................ 20
7.3
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ....................................................................................................... 22
7.4
 
 ...................................................................................................................... 24
7.5
 
 
 .................................................................................................................................... 25
7.5.1
Descriptive Summaries by Visit ............................................................................................................. 25
7.6
SENSITIVITY ANALYSES ........................................................................................................................................... 26
7.6.1
Sensitivity analyses for the primary analysis ......................................................................................... 26
7.6.2
Sensitivity analyses on the secondary endpoints .................................................................................. 26
7.7
SUBSET ANALYSES ........................................................................................................................................... 27




          
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OPHTHOTECH – OPH2003 – SAP – V1.0– 19JUL2019                                          Page 4 of 39 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
Abbreviation 
Term 
 
 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration  
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CNV 
Choroidal Neovascularization 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
FP 
Fundus Photography 
GA 
Geographic Atrophy 
GEE 
Generalized Estimating Equations 
GGT 
Gamma-glutamyl Transferase 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
ITT 
Intention-to-Treat 
LLN 
Lower Limit Normal 
LOCF 
Last Observation Carried Forward 
MAR 
Missing at Random 
MCAR 
Missing Completely At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MRM 
Model for Repeated Measures 
NA 
Not Available / Not Applicable 
OU 
Oculus Uterque (Both Eyes) 
PK 
Pharmacokinetic   
PP 
Per-Protocol 
PSC 
Posterior Subcapsular Cataract 
REML 
Restricted Maximum Likelihood 
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


         
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OPHTHOTECH – OPH2003 – SAP – V1.0– 19JUL2019                                          Page 5 of 39 
 
SD 
Standard Deviation 
SE 
Study Eye 
SGOT/AST 
Aspartate Aminotransferase 
SGPT/ALT 
Alanine Aminotransferase 
ULN 
Upper Limit Normal 
VA 
Visual Acuity 
 
 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 


          
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OPHTHOTECH – OPH2003 – SAP – V1.0– 19JUL2019                                          Page 6 of 39 
 
1 
INTRODUCTION  
This Statistical Analysis Plan describes the statistical methodology and data handling for the clinical 
trial with Protocol Number: OPH2003 and Version Date: 28 March 2018.  
The trial consists of a total treatment period of 18 months. This SAP covers all analyses to be 
performed on the 1 year data. By pre-specification, a 
 screening analysis will be performed 
to assess whether the effect of Zimura on the rate of Geographic Atrophy (GA) growth is plausibly 
more efficacious (or reliably more efficacious) than that of the sham control on the rate of GA 
growth over 12 months. Details of an analysis at 18 months, if applicable, will be specified in a 
separate SAP. 
The ICH guideline E3 “Structure and Content of Clinical Study Reports” is used as a guide to the 
writing of the plan. 
2 
STUDY DESIGN AND OBJECTIVES  
2.1 
STUDY OBJECTIVES  
The objectives of this study are to evaluate the safety and efficacy of Zimura™ monotherapy 
intravitreous administration when administered in subjects with geographic atrophy secondary to 
dry age-related macular degeneration (AMD). 
2.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is mean rate of change in GA over 12 months measured by fundus 
autofluorescence (FAF) at three time points: Baseline, Month 6, and Month 12 
2.1.2 
Secondary Efficacy Endpoints 
Two secondary endpoints are pre-specified: 
x The mean change in best corrected visual acuity (Early Treatment Diabetic Retinopathy 
Study [ETDRS] letters) from Baseline to Month 12 
x The mean change in low luminance best corrected visual acuity (ETDRS letters) from 
Baseline to Month 12 
2.1.3 
 
 
 
 
 
 
 
 


        
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2.1.5 
Safety Endpoints 
The following safety endpoints will be evaluated: 
x Adverse events (AEs) 
x Serious adverse events (SAEs) 
x Vital signs (pulse, systolic and diastolic blood pressure) 
x Ophthalmic findings (Intraocular Pressure [IOP], ophthalmic examination, fluorescein 
angiograms, and FAF) 
x Electrocardiogram (ECG) (12-lead) 
x Laboratory variables (blood: hematology, renal function, hepatic function, and electrolytes; 
urinalysis) 
2.2 
STUDY DESIGN AND SAMPLE SIZE 
 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. 
In Part 1, subjects will be randomized in a 1:1:1 ratio to the following dose groups: 
x Zimura 1 mg/eye 
x Zimura 2 mg/eye 
x Sham 
In Part 2, subjects will be randomized in a 1:2:2 ratio to the following dose groups:  
x Zimura 2 mg/eye + Sham 
x Zimura 4 mg/eye (administered as two injections of Zimura 2 mg/eye) 
x Sham + Sham 
Subjects will receive monthly intravitreal injections of Zimura and/or Sham for 18 months. 


        
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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. 
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.  
2.3 
RANDOMIZATION 
Subjects will be centrally allocated to one of the three treatment groups stratified by factors known 
to be of prognostic importance in dry AMD: 
x Baseline visual acuity < 50 ETDRS letters (20/100 Snellen equivalent) vs. ≥ 50 ETDRS 
letters 
x Size of Baseline geographic atrophy (< 4 disc areas vs. ≥ 4 disc areas) 
x Pattern of FAF at the junctional zone of GA (None/focal vs. banded/diffuse) 






        
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3.2 
DEFINITION OF POPULATIONS  
The analysis and reporting of the data from this study will be performed using the following analysis 
populations: 
3.2.1 
Intention-To-Treat (ITT) Population  
The intention-to-treat population (ITT) will consist of all randomized subjects who received at least 
one dose of study drug, irrespective of the dose actually received. Subjects will be analyzed in the 
treatment group assigned at randomization. Subjects will be included in a particular analysis, for a 
particular population, if relevant data is available for analysis (e.g., the primary analysis will require 
both Baseline and at least one post-Baseline GA measurement, to calculate a change score).    
3.2.2 
Per-protocol (PP) Population  
The per-protocol population (PP) will consist of all ITT subjects without any significant violation 
of the protocol. The significant and major protocol violations will be defined prior to database lock 
in a masked fashion. 
3.2.3 
Safety Population  
The safety population will include all subjects who received at least one study drug. In the event 
that subjects receive a dose that differs from the one assigned according to the randomization 
schedule, safety analyses will be conducted according to the dose actually received rather than 
according to the dose assigned by randomization. However, subjects who have ever received an 
injection of Zimura during this trial will be analyzed in the appropriate Zimura group according to 
the actual injections received. 
3.3 
DEFINITION OF SUBGROUPS 
Forest plots will be used to display the primary efficacy results within the following subgroups: 
x Size of Baseline geographic atrophy (< 4 disc area vs. ≥ 4 disc area) 
x Baseline visual acuity < 50 ETDRS letters (20/100 Snellen equivalent) vs. ≥ 50 ETDRS 
letters 
x Pattern of Fundus Auto Fluorescence (FAF) at the junctional zone of GA (None/focal vs. 
banded/diffuse) 
x Subjects from Part 1 vs. Part 2. 


       
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3.4 
DATA HANDLING CONVENTIONS 
3.4.1 
General Conventions 
Data will be analyzed using SAS Studio (version 3.6) or R. Descriptive analyses will be performed 
on Baseline, safety and efficacy data. All tables will be created by treatment arm (Zimura (2 mg), 
Zimura (4 mg), and Sham) and overall.  
x Descriptive statistics will be tabulated as follows:  
x Categorical data will be summarized in contingency tables presenting frequencies and 
percentages.  
x Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median, minimum, 1st quartile (Q1), 3rd quartile (Q3), and maximum 
values. 
Listings with individual subjects’ data will be provided for all CRF (including derived data) and 
central laboratory data or other external data. Data collected in the CRF that are not present in a 
table will also be listed (e.g. time and method of tonometry, comments fields, data on Fatal 
Outcomes page, Unscheduled Visit pages, etc.). 
3.4.2 
Visit Windows  
The scheduled visits will be used in the analyses over time.  
Missing scheduled follow-up visit will be substituted by an unscheduled or early withdrawal visit 
occurring within each follow-up visit window, if there is only one unscheduled or early withdrawal 
visit occurring within the window. If there are multiple unscheduled or early withdrawal visits 
occurring within the window, the closest one within the visit window will be used. If no 
unscheduled or early withdrawal visit occurred within the window, the visit will be considered as 
missing. The details are tabulated in Appendix 1. 
3.4.3 
Handling Missing Data in Efficacy analyses 
Methods that take into account the presence of missing data and that yield valid estimates under the 
assumption of data missing at random (MAR) will be used. In particular, a Model for Repeated 
Measures fitted by Restricted Maximum Likelihood method will be used in the primary analysis, 
where as-observed data will be used with no imputation. Multiple-imputation will be used in 
sensitivity analyses, whenever necessary, to impute the missing data, as described in Section 7.6.1. 
Of note, the proper approach to address missingness is the prevention of missing data. The sponsor 
will implement aggressive proactive approaches to minimize the number of patients who are not 
assessed at 12 months. 


         
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3.4.4 
Handling Missing Data in Descriptive Analyses  
When summarizing categorical variables, subjects with missing data are generally not included 
unless otherwise specified. When needed, the category of “Missing” is created and the number of 
subjects with missing data is presented. 
When summarizing continuous variables, subjects with missing data are not included in 
calculations. No imputations are made. 
3.4.5 
Handling Missing or Partially Missing Dates  
Missing or partially missing dates will not be imputed at data level. However, assumptions for 
missing or partially missing dates for important variables will be made to allow inclusion of 
appropriate data records in the analyses.  In general, the assumptions about the missing or partially 
missing dates, when needed, are made conservative to avoid overestimation of treatment effect and 
underestimation of adverse effects.  
If a medication date or time is missing or partially missing, so it cannot be determined whether it 
was taken prior or concomitantly, it will be considered both as a prior and a concomitant medication.  
If the partial AE onset date information does not indicate whether the AE started prior to treatment 
or after treatment, the AE will be classified as after the start of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 




       
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4 
STUDY SUBJECTS  
4.1 
DISPOSITION OF SUBJECTS 
The number of subjects randomized and treated, by treatment arm will be presented.  The reason 
for exclusion from one or more analysis sets will be summarized.   
The frequency of premature discontinuations from the study treatment prior to Month 12 will be 
given by treatment arm and overall. The details of the ‘Non-fatal Adverse Event’, ’Protocol 
violation’, ‘Investigator decision’, ‘Sponsor Decision’, ‘Subject request’, ‘Lost to Follow-Up’, 
‘Subject Non-Compliance’, ‘Death’, or ’Other’ will be included in a listing. 
The frequency of premature discontinuations from the study prior to Month 12 will be given for the 
ITT and PP populations by treatment arm and overall. The primary reason for non-completion of 
the study will be summarized.   
4.2 
TREATMENT MISALLOCATIONS   
For subjects with errors in treatment allocation, the following is described under which treatment 
groups they will be reported for efficacy and safety analyses:   
For example, if subjects were:  
x Randomized (regardless of error) but not treated, then they will be excluded for all 
efficacy and safety analyses. These subjects will be included in the summary of subject 
dispositions. 
x Treated but not randomized, then by definition they will be excluded from the efficacy 
analyses since randomization is missing, but will be reported under the treatment they 
actually received for all safety analyses. 
x Randomized but were administered the incorrect treatment at any time during the study, 
then they will be reported under their randomized treatment group for efficacy analyses on 
ITT population, but will be reported under the treatment they actually received for all 
safety analyses on SAFETY population (see Section 3.2.3); specifically, this implies that 
for safety analyses, a patient who ever received Zimura will be included in the applicable 
Zimura group based on actual injections received. 
4.3 
PROTOCOL VIOLATIONS  
All protocol violations will be assessed and identified prior to database lock in a masked fashion to 
determine whether they are significant, major, or neither by the sponsor. The final list of major 
protocol violations will be provided prior to the database lock. 
Subjects with significant protocol violations will be excluded from the Per-Protocol Population.  
The major protocol violations and significant protocol violations will be summarized for the ITT 
population. The details will be listed by subject and by treatment arm. 


         
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4.4 
INCLUSION AND EXCLUSION CRITERIA 
A frequency table of all inclusion and exclusion criteria not met will be provided for the ITT 
population by treatment arm and overall. A detailed listing will be provided by subject. 
5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS  
Descriptive statistics will be provided to document Baseline and on-trial comparability, including 
demographic information and treatment administration. 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. 
Descriptive statistics with respect to subject characteristics at Baseline will be displayed for the ITT 
population; if the PP and safety populations are different than the ITT population, demographic data 
will also be provided for these populations. When several measurements are available before the 
first administration of study drug, the Baseline value is the last available value prior to first dose, 
except for the Baseline visual acuity score which is the mean of the screening and Day 1 values, if 
both are available. 
x The variables to be summarized are: 
x Gender, ethnicity, race, iris color, age, current smoking status.  
x Prior ocular history, both eyes (by MedDRA preferred term, including number and 
percentage of all subjects with at least one prior ocular history) 
x Medical history (excluding ocular history) (by body system and preferred term, with number 
and percentage for both; including number and percentage of all subjects with at least one 
prior medical history) 
x Prior surgeries/procedures (by body system and preferred term, with number and percentage 
for both; including number and percentage of all subjects with at least one prior 
surgery/procedure) 
x Vital signs (height, weight, pulse, blood pressure) 
x ECOG performance status 
x Pregnancy test 
x Visual acuity (ETDRS and Snellen equivalent), both eyes 
x Low luminance ETDRS, both eyes 
x Tonometry, both eyes 
x ECG 
x Ophthalmic exam, both eyes (motility, lids/lacrimal/lashes, conjunctiva/sclera, cornea, 
anterior chamber activity: cells, iris, pupils, lens status, vitreous haze, vitreous hemorrhage, 
posterior vitreous detachment, optic nerve, macula, retinal vessels, peripheral retina) 


       
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x Fundus autofluorescence (FAF) imaging assessments, both eyes 
o Localization of hypo FAF (Foveal, Extrafoveal, Ungradeable or no hypo FAF 
present) 
o Localization of peripapillary atrophy (Temporal only, Nasal and temporal, 
ungradeable or not applicable) 
o Hyper FAF pattern (Fine granular-punctate spots, Branching, Fine granular-dusty, 
Trickling, Reticular, Patchy, Banded, Focal, Not determinable/NA) 
o Temporal peripapillary atrophy (N/Y/ungradable or NA) 
o Is peripapillary atrophy confluent with macular GA (N/Y/ungradable or NA) 
o Macular atrophy gradable (N/Y) and reason if not gradable 
o Area of macular atrophy (mm2) 
x Fluorescein angiogram (FA) imaging assessment, both eyes 
o Evidence of CNV 
6 
PRIOR AND CONCOMITANT MEDICATION  
x All prior and concomitant medications will be summarized separately by WHO Drug code 
(WHO Drug Dictionary version B2 enhanced March, 2016) on the ITT population. 
Medication usage will be summarized according to the 2nd level (main therapeutic level) and 
the 4th level (preferred term level) Anatomic Therapeutic Chemical (ATC) classification.  
Subjects will only be included once in the summaries within each ATC 2nd level or ATC 4th 
level category. The summaries will include the number and percentage of all Subjects with 
at least one prior or concomitant medication, respectively. 
7 
EFFICACY EVALUATION 
All efficacy analyses will be conducted for the ITT population. The primary and secondary 
endpoints will also be conducted for the PP population in a supportive manner. 
The 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  subjects randomized 
from Part 1 will be combined with the  subjects randomized to 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 only based 
on subjects randomized in Part 2.  
The primary analysis will use the ITT population and will be based on a Model for Repeated 
Measures (MRM) to compare the treatment groups. This analysis provides valid estimates as long 
as the missing data mechanism fulfills the Missing at Random (MAR) assumption. However, 
sensitivity analyses (see Section 7.6) will be performed to assess the potential magnitude and 
direction of the impact of missing data. Although Zimura 1 mg dose is not of an interest, a 


     
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descriptive analysis for a treatment effect of Zimura 1 mg dose vs. Sham control will be conducted 
in a supportive manner. 
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. The 
decision guideline for this trial is based on whether the estimated mean reduction in rate of square 
root of GA area 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%. These numbers may be adjusted based on the final 
sample size and standard deviation. 
1. If the estimated reduction in the rate of GA growth over 12 months for a dose of Zimura 
vs. Sham control 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 for a dose of Zimura 
vs. Sham control 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. 
3. If the estimated reduction in the rate of GA growth over 12 months for a dose of Zimura 
vs. Sham control 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).  
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. 
7.1 
CONTROL OF ALPHA 
The overall (one-sided) false positive error rate in this trial, accounting for the conduct of two 
pairwise comparisons (2 mg and 4 mg) with Sham control, is 0.025 for the analysis of the primary 
endpoint. The actual test of each dose vs. sham will use a Hochberg procedure for significance 
testing.  
An analysis of secondary endpoints will be carried with a descriptive intent only, without alpha-
adjustment. 
7.2 
ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is mean rate of change in GA over 12 months measured by fundus 
autofluorescence (FAF) at three time points: Baseline, Month 6, and Month 12. To eliminate the 
dependency of GA growth rates on the Baseline lesion size (Feuer et al., 2013), instead of using the 
observed GA area measurement, the square root of the GA area will be used in the analysis. 


       
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For analyses of the primary endpoint, a Mixed-Effects Repeated Measures (MMRM) model will be 
used to assess the differences between the treatment groups in rate of change of GA area over 12 
months. Two separate models will be fitted for comparing Zimura 4 mg vs. Sham control, and 
Zimura 2 mg vs. Sham control. Both models will be fitted by using restricted maximum likelihood 
(REML) and include Baseline VA (< 50 letters vs. ≥ 50 letters), size of the Baseline GA (< 4 disc 
area vs. ≥ 4 disc area), and pattern of FAF at the junctional zone of GA (none/focal vs. 
banded/diffuse) as used in the randomization as covariates. For Zimura 2 mg vs. Sham control 
model, fixed effects will include treatment, visit, part (Part 1 vs. Part 2), the Baseline VA (< 50 
letters vs. ≥ 50 letters), size of the Baseline GA (< 4 disc area vs. ≥ 4 disc area), pattern of FAF at 
the junction zone of GA (none/focal vs. banded/diffuse), treatment by visit interaction, and the 
stratification factors by visit interactions. For Zimura 4 mg vs. Sham control model, the same fixed 
effects will be used excluding part (Part 1 vs. Part 2). An unstructured (co)variance structure will 
be used to model the within-subject errors. If this analysis fails to converge, alternative structures 
(e.g., heterogeneous autoregressive or heterogeneous compound symmetry, in this order) will be 
considered. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The test of the mean rate of change over 12 months will be assessed by testing the 
appropriate contrast of the model parameter estimates.
 
 
 
 
   
 
   
 
 
   
 
   
  
  
 
 
 
   
 
   
   
 
   
 
   
  
  


        
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In addition to the analyses described above, a similar analysis will be conducted using the observed 
GA area measurement. 
The analyses described above will also be repeated in a supportive manner for the PP population. 
7.3 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
Two secondary efficacy endpoints are pre-specified: 
x Mean change in best corrected visual acuity (ETDRS letters) from Baseline to Month 12 
x Mean change in low luminance best corrected visual acuity (ETDRS letters) from Baseline 
to Month 12   
Secondary efficacy analysis will be conducted for ITT population for these pre-specified secondary 
endpoints. The analyses described above will also be repeated in a supportive manner for the PP 
population. 
Descriptive tables will be provided for secondary endpoints based on the observed data, but due 
caution will be exercised in interpreting descriptive tables because of the potential impact of missing 
data. Sensitivity analyses of the secondary endpoints will also be performed (see Section 7.6). 
Any hypothesis testing performed as part of analyzing secondary efficacy endpoints will be 
considered exploratory. 
For analyses of the secondary endpoints, a Model for Repeated Measures (MRM) will be used to 
assess the differences between the treatment groups at month 12 visit. The model will be fitted by 
using restricted maximum likelihood (REML). The model will include Baseline VA (< 50 letters 
vs. ≥ 50 letters), size of the Baseline GA (< 4 disc area vs. ≥ 4 disc area), and pattern of FAF at the 
junctional zone of GA (none/focal vs. banded/diffuse) as used in the randomization as covariates. 
Fixed effects will include treatment, visit, part (Part 1 vs. Part 2), the Baseline VA (< 50 letters vs. 
≥ 50 letters), size of the Baseline GA (< 4 disc area vs. ≥ 4 disc area), pattern of FAF at the junction 
zone of GA (none/focal vs. banded/diffuse), treatment by visit interaction, and the stratification 
factors by visit interactions for Zimura 2 mg vs. Sham control model. For Zimura 4 mg vs. Sham 
control model, the same fixed effects will be used excluding part (Part 1 vs. Part 2). An unstructured 
(co)variance structure will be used to model the within-subject errors. If this analysis fails to 
converge, alternative structures (e.g., heterogeneous autoregressive or heterogeneous compound 
symmetry, in this order) will be considered. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. Significance tests will be based on appropriate treatment 
contrasts at month 12. 


      
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7.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.5.1 
Descriptive Summaries by Visit 
The change in score from Baseline will be analyzed as continuous variables. The composite score 
and the scores of each sub-scales at Baseline and the changes from Baseline will be summarized 
descriptively by visit and by treatment group using the observed cases (missing values will not be 
imputed).   
The proportions (%) of subjects gaining/losing  ≥ 10 points in score for the 4 pre-specified sub-
scales, as well as the composite score, will be tabulated by visit and by treatment group using the 
observed cases (missing values will not be imputed). 
Change in mean score from Baseline over time will be plotted by visit and by treatment group.  
 


       
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7.6 
SENSITIVITY ANALYSES 
7.6.1 
Sensitivity analyses for the primary analysis 
For the analyses of the primary endpoint, the Model for Repeated Measures (MRM) analysis does 
not require data imputation and uses only the observed data. Moreover, assuming that the missing 
data are MAR, the model yields valid results that are comparable to those obtained by applying MI 
under the MAR assumption.  
To check the sensitivity of the results of the primary efficacy analysis to the MAR assumption, MI 
based on models compatible with Missing Not At Random (MNAR) missingness mechanisms will 
be used. Two approaches, using SAS’ PROC MI, will be considered: 
1. The “shift imputation” approach: for missing values at a particular visit, it will be assumed that 
their expected value is smaller (shifted) by a specified amount than for the observed responses 
(implying that the missing values are more likely corresponding to smaller changes vs. Baseline 
than the observed ones). Different values of the shift will be explored to investigate the sensitivity 
of the results. Scenarios with treatment-dependent shift values will also be explored. This approach 
can be applied to data with arbitrary missing data patterns. 
2. The “pattern-mixture-model imputation” approach: missing values at Month 12 visit will be 
imputed by using the pattern-mixture-model restrictions. In particular, Neighbouring-Case Missing 
Value (NCMV) restrictions will be applied. 
In addition to these two analyses, four analyses described by Miller et al. (2001) will be performed 
for further insight into the potential impact of missing data on the results: 
1. the observed means from the active arm and the sham arm will be imputed to patients with 
missing data in the arm they were allocated to; 
2. the observed means from the active arm and the sham arm will be imputed to patients with 
missing data in the opposite arm they were allocated to (a “cross-over” scheme); 
3. the average of observed means from the active arm and the sham arm will be imputed to 
all patients with missing data; 
4. the observed mean from the sham arm will be imputed to all patients with missing data. 
Of note, these imputation techniques are known to induce potential bias, hence they will be used 
only for sensitivity purposes. 
7.6.2 
Sensitivity analyses on the secondary endpoints 
Sensitivity analyses on the secondary endpoints will also be performed using different methods of 
data imputation for missing values at a particular visit if applicable, namely 1) the “shift imputation” 
approach; and 2) the “pattern-mixture-model imputation” approach.  
The latter approach can be applied to data with monotone missing data patterns. Hence, if necessary 
to apply the approach, the data will be transformed into the monotone patterns by considering the 


       
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longest uninterrupted sequences of the measurements for the subjects and/or excluding a few 
measurement visits from modelling, to increase the number of monotone patterns in the data. In 
case data are re-shaped, the primary analysis MRM model will be applied to the re-shaped data as 
well. 
7.7 
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: Baseline visual 
acuity (< 50 vs. ≥ 50 ETDRS letters), Baseline geographic atrophy (<4 vs. ≥ 4 disc area), Pattern of 
Fundus Auto Fluorescence at the junctional zone of geographic atrophy (none/focal vs. 
banded/diffuse).  
These analyses will be considered as supportive efficacy analyses and conducted without any alpha-
level adjustment. 
8 
SAFETY EVALUATION 
All safety analyses will be performed on the safety population. The analyses will be conducted 
according to the treatment that they actually received. However, subjects who have ever received 
an injection of Zimura will be analyzed in the Zimura group.  Missing values of safety data will not 
be imputed and safety summaries will be based on the observed cases. 
8.1 
EXTENT OF EXPOSURE 
Exposure to study medication will be evaluated for each treatment group (Zimura 4 mg, 2 mg, and 
1 mg) with respect to treatment duration (= Last injection date - First injection date + 30, in days), 
number of subjects treated at each planned visit, total injections received, using descriptive statistics 
(N, mean, standard deviation, median, minimum, Q1, Q3, maximum). 
8.2 
ADVERSE EVENTS  
Adverse events (AEs) will be recorded starting after the first dose of study drug and continuing 
until 30 days after the last dose or until the last follow-up visit required by the protocol, whichever 
comes later. AE data will be evaluated for each treatment group (Zimura 4 mg, 2 mg, and 1 mg). 
Only first year AE data will be included in the following analyses. First year will be defined as 
starting after the first dose of study drug until prior to the first injection at Month 12. If a Month 12 
injection does not exist, the end of first year is defined as the Month 12 visit (or target of 365.25 
days after the date of first dose if no Month 12 visit) or 30 days after the last injection, whichever 


        
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is later. AEs from the first year will be defined as AEs from the start of the first dose until prior to 
the first injection at Month 12 or 30 days after the last dose, within the first year as defined above. 
The safety analyses on AEs will be primarily based on the Treatment-Emergent Adverse Events 
(TEAEs), which is defined as an AE occurring after the first injection on Day 1 (day of the first 
planned dose of study drug) and up to and including 30 days after the last dose of study drug, within 
the first year as defined above. 
All AEs will be coded using MedDRA (the most recent Version 18.1) terms. 
x An overview of TEAEs will be provided. A second overview of TEAEs will be provided 
which displays the overall summary of TEAEs by the categories ‘Study Eye’, ‘Non-Study 
Eye’, and ‘Non-Ocular’. In addition, the number and percentage of patients with TEAEs 
will be tabulated for each treatment group and in total by system organ class (SOC) and 
preferred term (PT). The number and percentage of the subjects who experienced at least 
one TEAE will be included. Subjects will only be counted once for each preferred term. In 
case that a subject experienced the same event more than once, the worst severity will be 
presented.  
x Tabular summaries of the following AEs will be provided by SOC and PT: 
x Summary of TEAEs  
x All TEAEs regardless of the relationship to study treatment 
x All TEAEs regardless of the relationship to study treatment with frequency of ≥ 5% in 
any treatment arm. 
x TEAEs related to study treatment  
x TEAEs related to injection procedure 
x TEAEs by the maximum severity grade 
x TEAEs related to study treatment by the maximum severity grade 
x TEAEs related to injection procedure by the maximum severity grade 
x All Ocular TEAEs by study eye and fellow eye 
x Treatment related Ocular TEAEs by study eye and fellow eye 
x Injection procedure related Ocular TEAEs by study eye and fellow eye 
x Ocular TEAEs (study eye) by the maximum severity grade 
x Treatment related Ocular TEAEs (study eye) by the maximum severity grade 
x Injection procedure related Ocular TEAEs (study eye) by the maximum severity grade 
x 
TEAEs with high level term of cataract conditions by study eye and fellow eye 
x TEAEs leading to discontinuation of study drug 


        
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x Treatment related TEAEs leading to discontinuation of study drug 
x Injection procedure related TEAEs leading to discontinuation of study drug 
x Ocular TEAEs (study eye) leading to discontinuation of study drug 
x TEAEs leading to death 
x Treatment related TEAEs leading to death 
x Injection procedure related TEAEs leading to death 
x Ocular TEAEs have been defined as TEAEs linked to the “Eye Disorders” system organ 
class and the ‘Intraocular pressure increased’ preferred term.  
x All AEs, including non-TEAEs, will be included in individual subject listings.  
x The listings will include the subject identifier, age, sex, verbatim term, preferred term, eye 
(N/A/OD/OS/OU), serious (yes/no), date of onset, relative study day of onset, onset before 
injection, after first injection or after second injection, duration of the event (or continuing), 
severity (mild/moderate/severe), causality (relationship to study medication/injection 
procedure), action taken (study drug permanently discontinued: yes/no), treatment (yes/no), 
and outcome (resolved /unresolved / fatal). 
x The same listings will be provided separately for severe AEs, AEs leading to permanent 
discontinuation of the study treatment, and for AEs leading to death. 
8.3 
SERIOUS ADVERSE EVENTS AND DEATHS  
x Treatment-Emergent Serious adverse events (SAEs) will be summarized by system organ 
class and preferred term. The number and percentage of the subjects who experienced at 
least one SAE will be included.  
x SAE data will be evaluated for each treatment group (Zimura 4 mg, 2 mg, and 1 mg). 
x Tabular summaries of the following SAEs will be provided: 
x All SAEs regardless of the relationship to study treatment 
x SAEs related to study treatment  
x SAEs related to injection procedure 
x Ocular SAEs (study eye) regardless of the relationship to study treatment 
x Ocular SAEs (study eye) related to study treatment 
x Ocular SAEs (study eye) related to injection procedure 
x In addition, separate listings will be created for deaths and all SAEs. List for SAEs will 
include the subject identifier, age, sex, verbatim term, preferred term, eye 
(N/A/OD/OS/OU), serious (yes/no), date of onset, relative study day of onset, onset before 


        
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injection, after first injection or after second injection, duration of the event (or continuing), 
severity (mild/moderate/severe), causality (relationship to study medication/injection 
procedure), action taken (study drug permanently discontinued: yes/no), treatment (yes/no), 
and outcome (resolved/unresolved/fatal). 
8.4 
VITAL SIGNS  
Descriptive statistics at each time point up through and including the month 12 visit will be used 
to display the changes from Baseline for pulse and blood pressure (systolic and diastolic). Mean 
change of pulse and blood pressure (systolic and diastolic) from Baseline to the last measurement 
will be provided. 
8.5 
OPHTHALMIC VARIABLES  
Ophthalmic Examination. The following ophthalmic examination variables will be analysed by 
shift table from Baseline to the pre-injection examination on Month 12 or last visit available 
whichever comes later (normal/abnormal, unless otherwise specified below).:  
x Examination of the motility 
x Inspection of the lids/lacrimal/lashes 
x Examination of the conjunctiva/sclera  
x Inspection of the cornea 
x Examination of the iris 
x Examination of the pupils 
x Inspection of the lens status (aphakic, pseudo-phakic, phakic; if phakic, 
nuclear/PSC/cortical 0, 1, 2, 3, 4), including a listing of subjects with a change in lens 
status for study eye and (separately) for fellow eye 
x Examination of the posterior vitreous detachment 
x Inspection of the optic nerve 
x Inspection of the macula  
x Examination of the retinal vessels 
The following ophthalmic examination variables will be analysed by shift table from Baseline 
through Month 12 or last visit available whichever comes later, on a monthly basis 
(normal/abnormal, unless otherwise specified below), and from pre-injection to post-injection at 
each monthly injection 
x Examination of the anterior chamber activity: Cells (0, trace, 1+, 2+, 3+, 4+) 
x Inspection of the vitreous haze (0, 1+, 2+, 3+, 4+) 
x Examination of the vitreous haemorrhage 


        
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x Examination of peripheral retina 
Intraocular Pressure.  IOP will be summarized by visit, including all pre-injection, “IOP after first 
injection” and “IOP after second injection” measurements. An additional tabular summary of the 
percentage of subjects in categories of IOP will be presented by treatment group, visit, and injection 
time (pre-injection, IOP after first injection, IOP after second injection).   
“IOP after injection” is defined as the IOP measurement that is closest in time to the protocol-
specified post-injection timepoint (but at least 25 minutes post-injection). If there are two closest 
measurements equidistant to this timepoint, then the measurement after the protocol-specified 
timepoint will be used.  
Mean IOP over time of all scheduled measurements (pre-injection, IOP after first injection, and IOP 
after second injection) will be plotted. 
8.6 
CLINICAL LABORATORY DETERMINATION  
x All laboratory data will be listed and values falling outside normal ranges will be identified, 
whether they will be deemed clinically relevant or not. 
x Laboratory data will also be summarized in tables presenting values at each scheduled visit 
up through the month 12 visit 
x Value changes from Baseline to each scheduled visit up through the month 12 visit 
x A summary table of all analytes with the Baseline mean and the mean change from Baseline 
to the last value observed 
x A summary table of all analytes with the Baseline median and the median change from 
Baseline to the last value observed 
for the following parameters: hematological parameters (hemoglobin, white blood cells, platelets, 
neutrophils (absolute numbers), lymphocytes (absolute numbers), monocytes (absolute numbers), 
eosinophils (absolute numbers), basophils (absolute numbers), renal function parameters (serum 
creatinine and BUN), hepatic function parameters (serum bilirubin, alkaline phosphatase, GGT, 
SGOT/AST and SGPT/ALT), electrolytes (sodium, potassium, chloride, bicarbonate, calcium and 
phosphate), urinalysis parameters (complete urinalysis including specific gravity, protein, blood, 
etc.). 
The incidence of subjects with “Notable Laboratory Values” after the first dose of study drug  will 
be evaluated using the criteria for Notable Laboratory Values given below. Only data collected in 
the first year after the first dose of study drug, up to the laboratory data taken at the Month 12 visit 
(before Month 12 treatment is administered) will be included; if there is no Month 12 visit, data 
will be included up to a target of 365.25 days after date of first dose, or 30 days after the last dose 
of study drug, whichever is later.  


      
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By-subject listings of all notable laboratory values will also be provided; for each subject who has 
an analyte with a notable value, all values of that particular analyte taken during the study will be 
presented in the listing, and the notable value, and any values outside of normal limits, will be 
identified.   
For this “Notable Laboratory Values” analysis, all laboratory values after randomization will be 
taken in account, i.e., any values obtained after Day 1, at unscheduled visits, as well as values from 
the regularly scheduled laboratory visit at Month 12.  Three Notable Laboratory Values tables and 
accompanying by-subject listings will be presented:  (1) notable abnormalities for subjects with 
normal Baseline results, (2) notable abnormalities for subjects with abnormal Baseline results and 
(3) notable abnormalities without regard to Baseline abnormalities (i.e., normal or abnormal 
Baseline results).  The table without regard to Baseline abnormalities will be a composite of the 
previous two tables (normal Baseline, abnormal Baseline). 
Lab analytes and primary criteria used for Notable Laboratory Values:  
a. HEMATOLOGY 
i. 
Hemoglobin < 0.75x Baseline 
ii. 
Platelets < 75 or > 750 (10^9/L) 
iii. 
WBC count < 2.5 or > 17.5 (10^9/L) 
iv. 
Neutrophils (absolute) < 0.5x LLN or > 1.5xULN 
v. 
Eosinophils (absolute) > 1.5xULN 
vi. 
Lymphocytes (absolute) < 0.5x LLN or > 1.5xULN 
b. LIVER FUNCTION 
i. 
Total bilirubin > 1.5xULN 
ii. 
Alkaline phosphatase > 1.5xULN 
iii. 
ASAT (SGOT) > 3xULN 
iv. 
ALAT (SGPT) > 3xULN 
v. 
GGT > 3xULN 
c. RENAL FUNCTION 
i. 
BUN > 1.3xULN 
ii. 
Creatinine > 1.3xULN 
d. ELECTROLYTES 
i. 
Potassium < 0.9xLLN or  > 1.1xULN 
ii. 
Sodium < 0.9xLLN or  > 1.1xULN 


      
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iii. 
Chloride < 0.9xLLN or  > 1.1xULN 
iv. 
Carbon dioxide < 0.9xLLN or  > 1.1xULN 
v. 
Calcium < 0.9xLLN or  > 1.1xULN 
vi. 
Phosphorus < 0.9xLLN or  > 1.1xULN 
Notable abnormalities for subjects with abnormal Baseline results are subject to the primary criteria 
above and the following secondary criteria: 
a. HEMATOLOGY 
i. 
Hemoglobin < 0.75x Baseline (same as primary criterion) 
ii. 
Platelets < 0.75x Baseline or  > 1.25x Baseline 
iii. 
WBC count < 0.75 Baseline or > 1.25x Baseline 
iv. 
Neutrophils (absolute) < 0.5x Baseline or > 1.5x Baseline 
v. 
Eosinophils (absolute) > 1.5x Baseline 
vi. 
Lymphocytes (absolute) < 0.5x Baseline or >1.5x Baseline 
b. LIVER FUNCTION 
i. 
Total bilirubin > 1.5x Baseline 
ii. 
Alkaline phosphatase > 1.5x Baseline 
iii. 
ASAT (SGOT) > 1.5x Baseline 
iv. 
ALAT (SGPT) > 1.5x Baseline 
v. 
GGT > 1.5x Baseline 
c. RENAL FUNCTION 
i. 
BUN > 1.3x Baseline 
ii. 
Creatinine > 1.3x Baseline 
d. ELECTROLYTES 
i. 
Potassium < 0.9x Baseline or  > 1.1x Baseline 
ii. 
Sodium < 0.9x Baseline or  > 1.1x Baseline 
iii. 
Chloride < 0.9x Baseline or  > 1.1x Baseline 
iv. 
Carbon dioxide < 0.9x Baseline or  >1.1x Baseline 
v. 
Calcium < 0.9x Baseline or  >1.1x Baseline 
vi. 
Phosphorus < 0.9x Baseline or  > 1.1x Baseline 


       
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8.7 
ECG  
ECG results will be tabulated at Baseline as “normal”, “abnormal, not clinically significant” or 
“abnormal, clinically significant”.   At follow-up visits, ECG results will be tabulated as “no change 
from Baseline”, “NOT clinically significant change from Baseline” or “clinically significant change 
from Baseline”. A by-patient listing will be provided for ECGs which are deemed clinically 
significant. 
Continuous data (heart rate; PR, QRS, QT and QTc intervals) will be summarized using mean, 
standard deviation, median, minimum and maximum values at each scheduled visit, and change 
from Baseline at each visit. 


         
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Beunckens, C., Sotto, C., Molenberghs, G. (2008) A simulation study comparing weighted 
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2. 
Little, R.J.A., Rubin, D.B. (2002) Statistical Analysis with Missing Data, 2nd Edition, John 
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Molenberghs, G., Kenward, M. (2007) Missing Data in Clinical Studies. New York: Wiley, 
2007. 
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Pocock, S.J., Simon R. (1975) Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 31:103-115. 
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Schafer, J. (1997) Analysis of Incomplete Multivariate Data. Boca Raton: Chapman & 
Hall/CRC. 
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Verbeke, G., Molenberghs, G. (2000) Linear Mixed Models for Longitudinal Data. New 
York: Springer-Verlag. 
10. Fleming, T.R., Richardson, B.A. (2004). Some design issues in trials of microbicides for the 
prevention of HIV infection. Journal of Infectious Diseases 190:666-74. 
11. Feuer, W. (2013) Square Root Transformation of Geographic Atrophy Area Measurements 
to Eliminate Dependence of Growth Rates on Baseline Lesion Measurements: A Reanalysis 
of Age-Related Eye Disease Study Report No. 26. JAMA Ophthalmology 131, January 
2013. 
12. Miller, M.E., Morgan, T.M., Espelan, M.A., Emerson, S.S. (2001) Group comparisons 
involving missing data in clinical trials: a comparison of estimates and power (size) for 
some simple approaches. Statistics in Medicine 20:2383-2397. 
 
 
 


      
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APPENDICES 


          
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