Conditions: Geographic Atrophy Macular Degeneration
Keywords: Geographic Atrophy (GA) Age-related Macular Degeneration AMD Complement C5 inhibitor avacincaptad pegol IZERVAY
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 448
Healthy volunteers: no

Brief summary:
The objectives of this study was to evaluate the safety and efficacy of avacincaptad pegol intravitreal administration in participants with geographic atrophy secondary to age-related macular degeneration (AMD)

Detailed description:
Participants were randomized in a 1:1 ratio to the following monthly treatment groups:

* Avacincaptad pegol 2 mg
* Sham

At Month 12, the participants in the avacincaptad pegol 2mg treatment group were re-randomized to receive the study drug either on a monthly basis or on an every other month basis

The participants initially randomized to sham treatment continued with monthly sham administration through Month 23

All participants had a final follow up visit at Month 24

Arms:
arm 1: Participants received avacincaptad pegol (ACP) 2 milligram (mg)/eye via intravitreal (IVT) injections monthly through Month 11 (Year 1). At month 12, participants were re-randomized to receive ACP 2 mg/eye via IVT injections monthly from month12 through month 23 (Year 2). arm 2: Participants received sham injections; through Month 11 (Year 1). At month 12, participants continued to receive monthly sham administration from month 12 through month 23 (Year 2). arm 3: Participants who received ACP 2mg monthly through Month 11 (Year 1) were re-randomized at month 12, to receive ACP 2 mg/eye via IVT injections every other month at months 13, 15, 17, 19, 21, and 23 and sham injections at months 12, 14, 16,18, 20, and 22.

Interventions: intervention 1: Avacincaptad Pegol intervention 2: Sham
Intervention descriptions: intervention 1: Avacincaptad Pegol Intravitreal Injection intervention 2: Sham Administration (includes placement of the blunt opening of an empty, needleless syringe barrel on the conjunctiva in the inferotemporal quadrant of the eyeball to simulate the pressure of an injection)

Protocol document:
SAP_002.pdf: 
Official Study Title: A Phase 3 Multicenter, Randomized, Double-Masked, 
Sham-Controlled Clinical Trial to Assess the Safety and Efficacy of 
Intravitreal Administration of Zimura™ (Complement C5 Inhibitor) in Patients 
with Geographic Atrophy Secondary to Age-Related Macular Degeneration 
NCT#: NCT04435366 
Document: Statistical Analysis Plan 
Document Date: 07 April 2022 


Signature Page for ISEE2008_SAP
Study ISEE2008 v4.0
Signature Page for ISEE2008_SAP
Study ISEE2008 v4.0
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STATISTICAL ANALYSIS PLAN 
 
SPONSOR:  
IVERIC BIO, INC. 
PROTOCOL 
TITLE: 
A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
SHAM CONTROLLED CLINICAL TRIAL TO ASSESS THE SAFETY 
AND EFFICACY OF INTRAVITREAL ADMINISTRATION OF 
ZIMURA™ (COMPLEMENT C5 INHIBITOR) IN PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED 
MACULAR DEGENERATION 
STUDY CODE: 
ISEE2008 (GATHER2) 
VERSION: 
4.0 
DATE: 
07APR2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 Outcome ....................................................................................................................... 6 
 
 
 
 
2.1.4 
Safety Outcomes ..................................................................................................................................... 7 
2.2 
STUDY DESIGN AND SAMPLE SIZE ..................................................................................................................... 7 
2.3 
RANDOMIZATION ............................................................................................................................................. 8 
3 
GENERAL ANALYSIS DEFINITIONS .................................................................................................................. 10 
3.1 
STUDY PERIOD AND VISIT WINDOW DEFINITIONS .......................................................................................... 10 
3.2 
DEFINITION OF POPULATIONS ........................................................................................................................ 11 
3.2.1 
Intention-To-Treat (ITT) Population ...................................................................................................... 11 
3.2.2 
Per-protocol (PP) Population ................................................................................................................. 11 
3.2.3 
Safety Population .................................................................................................................................. 11 
3.3 
DEFINITION OF SUBGROUPS ........................................................................................................................... 11 
3.4 
DATA HANDLING CONVENTIONS .................................................................................................................... 11 
3.4.1 
General Conventions ............................................................................................................................. 11 
3.4.2 
Visit Windows........................................................................................................................................ 12 
3.4.3 
Procedures for Minimizing the Occurrence of Missing Data ................................................................. 12 
3.4.4 
Handling Missing Data in Efficacy analyses .......................................................................................... 13 
3.4.5 
Handling Missing Data in Descriptive Analyses .................................................................................... 13 
3.4.6 
Handling Missing or Partially Missing Dates ......................................................................................... 13 
 
 
4 
STUDY SUBJECTS ........................................................................................................................................... 15 
4.1 
DISPOSITION OF SUBJECTS ............................................................................................................................. 15 
4.2 
TREATMENT MISALLOCATIONS ...................................................................................................................... 15 
4.3 
PROTOCOL VIOLATIONS.................................................................................................................................. 16 
4.4 
INCLUSION AND EXCLUSION CRITERIA ............................................................................................................ 16 
5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................................................ 16 
6 
PRIOR AND CONCOMITANT MEDICATION ..................................................................................................... 17 
7 
EFFICACY EVALUATION ................................................................................................................................. 18 
7.1 
CONTROL OF ALPHA ....................................................................................................................................... 18 
7.2 
ANALYSIS OF PRIMARY EFFICACY OUTCOME .................................................................................................. 18 
 
 
7.4 
SENSITIVITY ANALYSES .................................................................................................................................... 22 
7.4.1 
Sensitivity Analyses for Missing Data .................................................................................................... 22 
7.4.2 
Sensitivity Analysis for Stratification Error ............................................................................................ 23 
7.4.3 
Sensitivity Analysis for Observed GA Measurement ............................................................................. 24 
 
 
 
 
7.6 
SUBSET ANALYSES ........................................................................................................................................... 24 
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8 
SAFETY EVALUATION .................................................................................................................................... 25 
8.1 
EXTENT OF EXPOSURE .................................................................................................................................... 25 
8.2 
ADVERSE EVENTS ............................................................................................................................................ 25 
8.3 
SERIOUS ADVERSE EVENTS AND DEATHS ........................................................................................................ 27 
8.4 
VITAL SIGNS .................................................................................................................................................... 27 
8.5 
OPHTHALMIC VARIABLES................................................................................................................................ 27 
8.6 
CLINICAL LABORATORY DETERMINATION ...................................................................................................... 28 
8.7 
ECG ................................................................................................................................................................. 31 
REFERENCES ........................................................................................................................................................... 32 
APPENDICES ........................................................................................................................................................... 33 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
Abbreviation 
Term 
 
 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration  
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
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 
GGT 
Gamma-glutamyl Transferase 
ICH 
International Conference on Harmonization 
DSMB 
Data Safety Monitoring Board 
IOP 
Intraocular Pressure 
ITT 
Intention-to-Treat 
LLN 
Lower Limit Normal 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
NA 
Not Available / Not Applicable 
OU 
Oculus Uterque (Both Eyes) 
PSC 
Posterior Subcapsular Cataract 
REML 
Restricted Maximum Likelihood 
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Study Eye 
SGOT/AST 
Aspartate Aminotransferase 
SGPT/ALT 
Alanine Aminotransferase 
ULN 
Upper Limit Normal 
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VA 
Visual Acuity 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 
 
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INTRODUCTION  
This Statistical Analysis Plan describes the statistical methodology and data handling for the clinical 
trial with Protocol Number: ISEE2008 (GATHER2), Version Date: 18 December 2020.  
The trial consists of a total treatment period of 24 months. This SAP covers all analyses to be 
performed on 1 year data.  By pre-specification, this study will obtain evidence regarding the effect 
of Zimura on the mean rate of growth (slope) estimated based on geographic atrophy (GA) area 
measured by fundus autofluorescence (FAF) in at least 3 time points over 12 months, when 
compared with Sham (square root treansformation). Details of an analysis at 18 and 24 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. 
STUDY DESIGN AND OBJECTIVES  
STUDY OBJECTIVES  
The objectives of this study are to evaluate the safety and efficacy of Zimura intravitreal 
administration in patients with geographic atrophy secondary to age-related macular degeneration 
(AMD). 
Primary Efficacy Outcome 
The primary efficacy outcome is the mean rate of growth (slope) estimated based on GA area 
measured by FAF in at least 3 time points: Baseline, Month 6, and Month 12 (square root 
transformation). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Safety Outcomes 
The following safety outcomes will be evaluated: 
• Adverse events (AEs) 
• Serious adverse events (SAEs) 
• Vital signs (pulse, systolic and diastolic blood pressure) 
• Ophthalmic variables (ophthalmic examination, best corrected visual acuity (BCVA), low 
luminance BCVA (LLBCVA), intraocular pressure (IOP)) 
• Electrocardiography (ECG) (12-lead) 
• Laboratory variables (blood: hematology, renal function, hepatic function, and electrolytes; 
urinalysis) 
STUDY DESIGN AND SAMPLE SIZE 
Approximately 400 patients will be randomized at Day 1 in a 1:1 ratio to the following monthly 
treatment groups: 
• Zimura 2 mg 
• Sham 
Patients receiving monthly Zimura 2 mg will be re-randomized at Month 12 in a 1:1 ratio to the 
following treatment groups: 
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• Zimura 2 mg administered monthly from Month 12 – Month 23 
• Sham administered at Months 12, 14, 16, 18, 20, and 22, and Zimura 2mg administered 
every other month at Months 13, 15, 17, 19, 21, and 23 
All patients who were initially randomized to Sham (at Day 1) will continue with monthly Sham 
injections through Month 23. 
All patients will have a final follow-up visit at Month 24. 
The trial consists of a total treatment period of 24 months. This SAP covers all analyses to be 
performed on 1 year (12 months) data. 
The sample size for this study is based on the 12-month results of the OPH2003 (GATHER1) 
pivotal international, multicenter, randomized, double masked, sham-controlled clinical trial that 
was performed to evaluate the safety and efficacy of Zimura in patients with geographic atrophy 
secondary to AMD. The prespecified primary endpoint, mean change in GA growth over 12 months, 
equivalent to the mean rate of GA growth used in this study, was measured by 
fundus autofluorescence (FAF) based on readings at three time points (Baseline, Month 6, and 
Month 12) and was calculated using the square root transformation of the GA area. The FAF images 
were assessed by an independent masked reading center. The reduction in the mean rate of GA 
growth over 12 months was 0.11 mm (p = 0.0072) for the Zimura 2 mg group compared to the 
Sham control group.  
A total of approximately 400 patients will be randomized in the GATHER2 trial. The effect of 
treatment will be assessed on the square root transformation of the mean rate of GA growth (slope) 
estimated based on GA area measured in at least 3 time points over 12 months, where the analysis 
of variance will include the stratification factors.  Suppose the standard deviation for the primary 
endpoint in GATHER2 is as assumed in the design of the GATHER1 trial, (which is 7% higher 
than was actually observed in that trial.) If the 2 mg dose of Zimura truly provides a 0.11 mm 
reduction in the mean rate of GA growth over 12 months, then the trial will have 97% power to 
detect that effect when using a test statistic having (one-sided) 2.5% false positive error rate. 
Furthermore, the trial will have nearly 90% power to achieving an even more robust significance 
level at two-sided p<0.01.  Statistical significance at the traditional level of two-sided p=0.05 would 
be achieved with an estimated 0.057 reduction in the mean rate of GA growth over 12 months.  Note 
that the power of the trial will be slightly lower when using an alpha-level that would be adjusted 
by (two-sided) 0.001 for each DSMB meeting at which any data are reviewed.   
RANDOMIZATION 
Patients will be centrally allocated to one of the two treatment groups by a dynamic minimization 
procedure using clinical site in a 1:1 ratio stratified by factors known to be of prognostic 
importance in AMD: 
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• Baseline visual acuity < 50 ETDRS letters (20/100 Snellen equivalent) vs. ≥ 50 ETDRS 
letters 
• Size of Baseline GA (< 4 disc areas vs. ≥ 4 disc areas) 
• Pattern of FAF at the junctional zone of GA (none/focal vs. banded/diffuse) 
Patients initially randomized to Zimura 2 mg at Day 1 will be re-randomized at Month 12 in 1:1 
ratio to Zimura 2 mg monthly vs every other month using the same minimization procedure as for 
the initial randomization (i.e., using the same factors at Baseline). 
Randomization will be performed using an IRT system based on the stratification information above 
to randomize each subject and assign a treatment arm. 
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DEFINITION OF POPULATIONS  
The analysis and reporting of the data from this study will be performed using the following analysis 
populations: 
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. Subjects will be analyzed in the treatment group assigned at randomization.  
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. 
Safety Population  
The safety population will include all subjects who received at least one dose of study drug. Subjects 
who have ever received an injection of Zimura during this trial will be analyzed in the Zimura group. 
DEFINITION OF SUBGROUPS 
The mean rate of growth (slope) estimated based on GA area measured by FAF in at least 3 time points: 
Baseline, Month 6, and Month 12 (square root transformation) will be displayed within the following 
subgroups: 
• Size of Baseline geographic atrophy (< 4 disc area vs. ≥ 4 disc area) 
• Baseline visual acuity < 50 ETDRS letters (20/100 Snellen equivalent) vs. ≥ 50 ETDRS letters 
• Pattern of Fundus Auto Fluorescence (FAF) at the junctional zone of GA (None/focal vs. 
banded/diffuse) 
• Age (<65 vs. 65 ~ 74 vs. 75 ~ 84 vs. ≥85)  
• Gender (Male vs. Female) 
• Race (American Indian/Alaska Native vs. Black or African American vs. Asian vs. Native 
Hawaiian/Pacific Islander vs. White vs. Other) 
• Ethnicity (Hispanic or Latino vs. Not Hispanic or Latino) 
DATA HANDLING CONVENTIONS 
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 and Sham) and 
overall.  
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Descriptive statistics will be tabulated as follows:  
• Categorical data will be summarized in contingency tables presenting frequencies and 
percentages.  
• Continuous data will be summarized using number of non-missing values (n), mean, standard 
deviation, median, minimum, 1st quartile (Q1), 3rd quartile (Q3), and maximum values. 
Listings with individual subjects’ data will be provided for all CRF (including derived data) and central 
laboratory data or other external data. Data collected 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, etc.).  
Visit Windows  
The scheduled visits will be used in the analyses over time.  
Missing scheduled follow-up visits will be substituted by an unscheduled or early withdrawal visit 
occurring within each follow-up visit window, if there is only one unscheduled or early withdrawal visit 
occurring within the window. If there are multiple unscheduled or early withdrawal visits occurring 
within the window, the closest one within the visit window will be used. If no unscheduled or early 
withdrawal visit occurred within the window, the visit will be considered as missing. The details are 
tabulated in Appendix 1. 
Procedures for Minimizing the Occurrence of Missing Data 
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.  Among these approaches are the following: 
• The study protocol properly distinguishes between reasons for nonadherence (that is, for not 
receiving randomized therapy and hence for being “off study treatment”) versus nonretention 
(that is, for not obtaining outcome information and hence for being “off study”). There are 
only 2 valid reasons a patient can be off study: withdrawal of consent or the achievement of all 
required efficacy and safety end point information 
• The term ‘withdrawal of consent’ is used only when the patient no longer wishes to participate 
in the trial and no longer authorizes the investigators to make efforts to continue to obtain their 
outcome data 
• Patients are educated during the informed consent process about the continued scientific 
relevance of their data even if they discontinue treatment, as well as the deleterious effect that 
missing data has on trial integrity and credibility 
• To enable proper ITT analyses, all patients will be followed until death or trial completion,  
even if off they discontinue study treatment or initiate other treatment 
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• Creative and effective procedures are being implemented during enrollment and follow-up to 
enhance achieving targeted levels of retention. 
• 
An oversight process by the sponsor is in place during trial conduct to ensure the achievement 
of performance standards, including targeted levels of data capture. 
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 Mixed 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 7.4. 
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. 
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 conservatively 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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STUDY SUBJECTS  
DISPOSITION OF SUBJECTS 
Efforts will be made to clearly record reasons for study and/or treatment discontinuations. 
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 ‘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 population by treatment arm and overall. The primary reason for non-completion of the study 
will be summarized.   
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:  
• 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 populations. 
• 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. 
                                                 
1 The ETDRS lines in order, from largest to smallest, are 20/800, 20/640, 20/500, 20/400, 20/320, 20/250, 20/200, 20/160, 
20/125, 20/100, 20/80, 20/63, 20/50, 20/40, 20/32, 20/25, 20/20, 20/16, 20/13, 20/10. 
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• 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 Zimura group. 
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 and 
significant 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. 
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. 
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. 
The variables to be summarized are: 
• Gender, ethnicity, race, iris color, age, current smoking status 
• Prior ocular history, both eyes (by MedDRA preferred term, including number and percentage 
of all subjects with at least one prior ocular history) 
• Medical history (excluding ocular history) (by body system and preferred term, with number 
and percentage for both; including number and percentage of all subjects with at least one prior 
medical history) 
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• Prior surgeries/procedures (by body system and preferred term, with number and percentage for 
both; including number and percentage of all subjects with at least one prior surgery/procedure) 
• Vital signs (height, weight, pulse, blood pressure) 
• ECOG performance status 
• Pregnancy test 
• Visual acuity (ETDRS and Snellen equivalent), both eyes 
• Low luminance visual acuity (ETDRS and Snellen equivalent), both eyes 
• Tonometry, both eyes 
• ECG 
• Ophthalmic exam, both eyes (motility, lids/lacrimal/lashes, conjunctiva/sclera, cornea, anterior 
chamber activity: cells, iris, pupils, lens status, vitreous haze, vitreous hemorrhage, posterior 
vitreous detachment, optic nerve, macula, retinal vessels, peripheral retina) 
• 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) 
• Fluorescein angiography (FA) imaging assessment, both eyes 
o Evidence of CNV 
PRIOR AND CONCOMITANT MEDICATION  
All prior and concomitant medications will be summarized separately by WHO Drug code (version 
2020 v1) 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. 
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EFFICACY EVALUATION 
All efficacy analyses will be conducted for the ITT population. The primary endpoint will also be 
conducted for the PP population in a supportive manner. 
The primary analysis will use the ITT population and will be based on a Mixed Model for Repeated 
Measures (MMRM) 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 7.4.1) will be performed to assess the potential magnitude and direction of the 
impact of missing data.  
CONTROL OF ALPHA 
The overall (one-sided) false positive error rate in this trial is 0.025.  
An alpha-level adjustment will be made in the assessment of statistical significance at the time of the 
final analysis, equal to (two-sided) 0.001 for each DSMB meeting for any look at the data.  There will 
not be formal interim analyses for early termination for benefit and, in turn, the DSMB will not make 
recommendations for early termination even if emerging data would provide strongly favorable 
evidence for benefit.  Rather, the principal justification for the DSMB to have access to emerging data 
on efficacy as well as safety data during DSMB meetings is to enable the DSMB to more effectively 
safeguard interests of study participants through a properly informed assessment of benefit-to-risk. 
 
ANALYSIS OF PRIMARY EFFICACY OUTCOME 
The primary efficacy endpoint is the mean rate of growth (slope) estimated based on GA area measured 
by FAF in at least 3 time points: Baseline, Month 6, and Month 12 (square root transformation). 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. 
Primary Estimand 
In alignment with the primary objective of the study, the main estimand to be used for the evaluation of 
the primary outcome is described as: 
The difference in the mean rate of growth (slope) estimated based on GA area measured by FAF in at 
least 3 time points: Baseline, Month 6, and Month 12 (square root transformation) between treatment 
conditions (Zimura versus Sham) in the target patient population, regardless of any non-adherence to 
or interruption of study treatment, and regardless of initiation of alternative treatment. 
The following 5 attributes define the main estimand for primary endpoint evaluation: 
A. Population: 
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Population defined through inclusion/exclusion criteria to reflect the targeted patient population. 
Analysis will be performed on all randomized patients who received at least one dose of study 
drug. 
B. Treatment: 
Zimura 2 mg versus Sham. 
C. Primary variable: 
Mean rate of growth (slope) of the square root of GA area over 12 months. 
D. Intercurrent events (ICE’s) and strategies: 
1. Treatment changes (i.e., interruptions, non-adherence, dose changes, discontinuation): 
“treatment policy” – i.e., treatment changes will be ignored and all data collected will 
contribute to the analysis regardless of whether or not these follow such ICE’s. 
2. COVID-19: “treatment policy” – i.e., impact of COVID-19 pandemic will be ignored and 
all data collected will contribute to the analysis regardless of whether or not these follow 
such ICE’s. 
E. Population-level summary: 
Difference between groups in mean rate of growth (slope) of the square root of GA area over 12 
months. 
The primary estimator is described as follows. 
A mixed model for repeated measures (MMRM) will be applied to all available data, using as response 
variable the square root of GA area measured by FAF in at least 3 time points: Baseline, Month 6, and 
Month 12. The MMRM will be used to assess the difference between the treatment groups in terms of 
the rate of growth of the square root of GA area (slope) over 12 months. Previous trial OPH2003 
(GATHER1) showed the change in the square root of geographic atrophy to be remarkably linear over 
time. As a result, a linear model is not only convenient and easily interpretable, but it is also appropriate 
given the natural history of the disease. A model will be fitted by using restricted maximum likelihood 
(REML) and include Baseline VA (< 50 letters vs. ≥ 50 letters), and pattern of FAF at the junctional 
zone of GA (none/focal vs. banded/diffuse) as used in the randomization as covariates. For the model, 
fixed effects will include time, treatment, Baseline VA (< 50 letters vs. ≥ 50 letters), pattern of FAF at 
the junctional zone of GA (none/focal vs. banded/diffuse), treatment by time interaction, Baseline VA 
(< 50 letters vs. ≥ 50 letters) by time interaction, and pattern of FAF at the junctional zone of GA 
(none/focal vs. banded/diffuse) by time interaction. The model will include an unstructured modelling 
of within-subject correlations. If this analysis fails to converge, alternative structures (e.g., 
heterogeneous autoregressive, heterogeneous compound symmetry, autoregressive, or compound 
symmetry, in this order) will be considered. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The test of difference between the two arms in the mean rate of growth 
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(slope) of the square root of GA area over 12 months will be assessed by testing the appropriate contrast 
of the model parameter estimates. 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
   
 
   
  
    
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SENSITIVITY ANALYSES 
Sensitivity Analyses for Missing Data 
For the analyses of the primary outcome, the MMRM 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.  
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 average of observed means from the active arm and the sham arm will be imputed to all 
patients with missing data; 
3. the observed mean from the sham arm will be imputed to all patients with missing data. 
4. 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); 
These four sensitivity analyses make different assumptions about missing data, and are likely to be 
increasingly biased against a true treatment effect. A robust treatment effect would be expected to 
remain statistically significant in analyses 1 to 3, since these are likely to be much less biased than 
analysis 4 under the assumption of a true treatment effect.  
To check the sensitivity of the results of the primary efficacy analysis (using the primary estimator as 
described in section 7.2) to the MAR assumption, MI based on models compatible with Missing Not At 
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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 (i.e., a specified shift in the size of GA), than 
for the observed responses (implying that the missing values are more likely corresponding to smaller 
changes vs. Baseline than the observed ones). Increasing values of the shiftwill be explored to 
investigate the sensitivity of the results. This approach can be applied to data with arbitrary missing 
data patterns. The “tipping point” is the value of the shift that causes statistical significance to be lost. 
For a robust treatment effect, the tipping point would be considered an implausible value of the shift 
used in the missing data imputation. 
2. The “pattern-mixture-model imputation” approach: missing values at Month 12 visit will be imputed 
by using the pattern-mixture-model restrictions. Pattern-mixture models provide a general and flexible 
framework for sensitivity analyses that allows formulating assumptions regarding missing data in a 
transparent and clinically interpretable manner. In particular, Complete-Case Missing Value (CCMV) 
and Neighbouring-Case Missing Value (NCMV) restrictions will be applied. 
Of note, these imputation techniques are known to induce potential bias, hence they will be used only 
for sensitivity purposes. 
Sensitivity Analysis for Stratification Error 
On Monday November 16, 2020 the Duke Reading Center notified that an error occurred at the reading 
center in the reporting of fundus autofluorescence (FAF) results used as stratification factors for 
randomization of eligible patients into GATHER2 (ISEE2008) clinical trial. 
As a result, 38 patients randomized with Baseline geographic atrophy size between 4 to 10 mm2 were 
placed in a stratum that included participants with size ≥ 10 mm2 rather than being placed in stratum 
that included participants with size < 10 mm2. 
To assess the impact of this stratification error, two sensitivity analyses will be done by performing 
analyses that stratify by 3-level covariates for the Baseline geographic atrophy size. The first analysis 
will stratify by: < 4 mm2 vs. ≥ 4 to < 10 mm2 vs. ≥ 10 mm2, and the second analysis will stratify by: 
patients randomized prior to November 16, 2020 vs. < 4 mm2 vs. ≥ 4 mm2. 
Since November 16th, patients have been stratified correctly as indicated in the protocol based on their 
baseline geographic atrophy size: < 4 disc areas (10 mm2) vs > 4 disc areas (10 mm2). The minimization 
procedure was not modified after November 16, 2020, because implementing any changes to this 
procedure would have meant putting the trial on hold while the changes were being implemented and 
validated. Furthermore, an inspection by the randomization center of the balance with respect to 
baseline geographic atrophy size achieved on November 16, 2021 provided reassurance that the 
minimization algorithm could continue unchanged. 
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Sensitivity Analysis for Observed GA Measurement 
The sensitivity of the results from the analyses of observed (non-square root transformed) area of GA 
over 12 months will be conducted using the same analysis model as specified in section 7.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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).   
 
SUBSET ANALYSES 
The trial is not designed to have adequate power to formally test for the presence of treatment by 
covariate interactions. Thus, true treatment by covariate interactions will likely be missed, unless they 
are quite substantial. Conversely, should particular subsets of subjects seem to benefit more or less from 
therapy than the total population, this will not be taken as reliable evidence of a true treatment by 
covariate 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. In a descriptive manner, treatment effect will be presented for 
subsets created by multiple covariates. Among these covariates will be the stratification factors: 
Baseline VA (< 50 vs. ≥ 50 ETDRS letters), Baseline GA (< 4 vs. ≥ 4 disc area), Pattern of FAF at the 
junctional zone of geographic atrophy (none/focal vs. banded/diffuse) as well as age (<65 vs. 65~74 vs. 
75~84 vs. ≥85), gender (male vs. female) race (American Indian/Alaska Native vs. Black or African 
American vs. Asian vs. Native Hawaiian/Pacific Islander vs. White vs. Other), and ethnicity (Hispanic 
or Latino vs. Not Hispanic or Latino).  
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Since these analyses will be considered as exploratory, they will be conducted without any alpha-level 
adjustment. 
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. 
EXTENT OF EXPOSURE 
Exposure to study medication will be evaluated for each treatment group 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). 
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. 
Only first year AE data will be included in the following analyses. Treatment Emergent Adverse Events 
(TEAEs) from the first year will be defined as starting after the first dose of study drug until prior to 
Month 12 injection. If a Month 12 injection does not exist, the end of the first year is defined as the 
Month 12 visit (or target of 365.25 days after the first dose if no Month 12 visit) or 30 days after the 
last injection, whichever is later.  
All AEs will be coded using MedDRA (version 23.0 update) terms. 
• An overview of TEAEs will be provided. A second overview of TEAEs will be provided which 
displays the overall summary of TEAEs by the categories ‘Study Eye’, ‘Non-Study Eye’, and 
‘Non-Ocular’. In addition, the number and percentage of patients with TEAEs will be tabulated 
for each treatment group and in total by system organ class (SOC) and preferred term (PT). The 
number and percentage of the subjects who experienced at least one TEAE will be included. 
Subjects will only be counted once for each preferred term. In case that a subject experienced 
the same event more than once, the worst severity will be presented.  
• Tabular summaries of the following AEs will be provided by SOC and PT: 
• Summary of TEAEs  
• All TEAEs regardless of the relationship to study treatment 
• All TEAEs regardless of the relationship to study treatment with frequency of ≥ 5% in any 
treatment arm. 
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• TEAEs related to study treatment  
• TEAEs related to injection procedure 
• TEAEs by the maximum severity grade 
• TEAEs related to study treatment by the maximum severity grade 
• TEAEs related to injection procedure by the maximum severity grade 
• All Ocular TEAEs by study eye and fellow eye 
• Treatment related Ocular TEAEs by study eye and fellow eye 
• Injection procedure related Ocular TEAEs by study eye and fellow eye 
• Ocular TEAEs (study eye) by the maximum severity grade 
• Treatment related Ocular TEAEs (study eye) by the maximum severity grade 
• Injection procedure related Ocular TEAEs (study eye) by the maximum severity grade 
• 
TEAEs with high level term of cataract conditions by study eye and fellow eye 
• TEAEs leading to discontinuation of study drug 
• Treatment related TEAEs leading to discontinuation of study drug 
• Injection procedure related TEAEs leading to discontinuation of study drug 
• Ocular TEAEs (study eye) leading to discontinuation of study drug 
• TEAEs leading to death 
• Treatment related TEAEs leading to death 
• Injection procedure related TEAEs leading to death 
• Ocular TEAEs have been defined as TEAEs linked to the “Eye Disorders” system organ class 
and the ‘Intraocular pressure increased’ preferred term.  
• All AEs, including non-TEAEs, will be included in individual subject listings.  
• The listings will include the subject identifier, age, sex, verbatim term, preferred term, eye 
(N/A/OD/OS/OU), serious (yes/no), date of onset, relative study day of onset, 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/not resolved/fatal). 
• 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. 
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SERIOUS ADVERSE EVENTS AND DEATHS  
• Treatment-Emergent Serious adverse events (SAEs) will be summarized by system organ class 
and preferred term. The number and percentage of the subjects who experienced at least one 
SAE will be included.  
• SAE data will be evaluated for each treatment group. 
• Tabular summaries of the following SAEs will be provided: 
• All SAEs regardless of the relationship to study treatment 
• SAEs related to study treatment  
• SAEs related to injection procedure 
• Ocular SAEs (study eye) regardless of the relationship to study treatment 
• Ocular SAEs (study eye) related to study treatment 
• Ocular SAEs (study eye) related to injection procedure 
• In addition, separate listings will be created for deaths and all SAEs. List for SAEs will include 
the subject identifier, age, sex, verbatim term, preferred term, eye (N/A/OD/OS/OU), serious 
(yes/no), date of onset, relative study day of onset, 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/not 
resolved/fatal). 
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. 
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).:  
• Examination of the motility 
• Inspection of the lids/lacrimal/lashes 
• Examination of the conjunctiva/sclera  
• Inspection of the cornea 
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• Examination of the iris 
• Examination of the pupils 
• Inspection of the lens status (aphakic, pseudo-phakic, phakic; if phakic, nuclear/PSC/cortical 
0, 1, 2, 3, 4), including a listing of subjects with a change in lens status for study eye and 
(separately) for fellow eye 
• Examination for posterior vitreous detachment 
• Inspection of the optic nerve 
• Inspection of the macula  
• Examination of the retinal vessels 
The following ophthalmic examination variables will be analysed by shift table from Baseline through 
Month 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 
• Examination of anterior chamber activity: Cells (0, trace, 1+, 2+, 3+, 4+) 
• Inspection for vitreous haze (0, 1+, 2+, 3+, 4+) 
• Examination for vitreous haemorrhage 
• Examination of the peripheral retina 
Intraocular Pressure.  IOP will be summarized by visit, including all pre-injection, “IOP after first 
injection”, and “IOP after second injection” measurements for applicable visits. 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 30 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. 
CLINICAL LABORATORY DETERMINATION  
• All laboratory data will be listed and values falling outside normal ranges will be identified, 
whether they will be deemed clinically relevant or not. 
• Laboratory data will also be summarized in tables presenting values at each scheduled visit up 
through the Month 12 visit 
• Value changes from Baseline to each scheduled visit up through the Month 12 visit 
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• A summary table of all analytes with the Baseline mean and the mean change from Baseline to 
the last value observed 
• 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, carbon dioxide, calcium, and phosphate),  
• Complete urinalysis parameters (complete urinalysis including specific gravity, protein, 
blood, etc.), 
• Serum pregnancy test (if of child-bearing potential). 
Additional urine or serum pregnancy testing may be performed during the course of the study at the 
discretion of the investigator, or in accordance with local requirements or regulations. 
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 after the 
first dose of study drug, up to the laboratory data taken at the Month 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.  
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). 
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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) < 0.5xLLN or > 1.5xULN 
v. 
Eosinophile (absolute) >1.5xULN 
vi. 
Lymphocytes (absolute) < 0.5xLLN or >1.5xULN 
b. LIVER FUNCTION 
i. 
Total bilirubin > 1.5xULN 
ii. 
Alkaline phosphatase > 1.5xULN 
iii. 
ASAT (SGOT) > 3xULN 
iv. 
ALAT (SGPT) > 3xULN 
v. 
GGT > 3xULN 
c. RENAL FUNCTION 
i. 
BUN > 1.3xULN 
ii. 
Creatinine > 1.3xULN 
d. ELECTROLYTES 
i. 
Potassium < 0.9xLLN or  > 1.1xULN 
ii. 
Sodium < 0.9xLLN or  > 1.1xULN 
iii. 
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 
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iii. 
WBC count < 0.75x 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 
ECG  
ECG results will be tabulated as “normal” or “abnormal” at each visit, and will be presented in a 
normal/abnormal shift table between Baseline and each scheduled ECG visit, as well as between 
Baseline and the last ECG taken.  Descriptive statistics will be presented for continuous variables (eg, 
heart rate and RR, PR, QRS, QT, QTcB and QTcF intervals) at each visit. A by-patient listing will be 
provided for ECGs which are deemed abnormal. 
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REFERENCES 
1. 
Beunckens, C., Sotto, C., Molenberghs, G. (2008) A simulation study comparing weighted 
estimating equations with multiple imputation based estimating equations for longitudinal binary 
data. Computational Statistics & Data Analysis 52:1533-1548. 
2. 
Little, R.J.A., Rubin, D.B. (2002) Statistical Analysis with Missing Data, 2nd Edition, John Wiley 
and Sons, New York 
3. 
 
 
  
4. 
  
5. 
 
 
  
6. 
Molenberghs, G., Kenward, M. (2007) Missing Data in Clinical Studies. New York: Wiley, 2007. 
7. 
Pocock, S.J., Simon R. (1975) Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics 31:103-115. 
8. 
Schafer, J. (1997) Analysis of Incomplete Multivariate Data. Boca Raton: Chapman & Hall/CRC. 
9. 
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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Statistical Analysis Plan
Protocol ISEE2008
1
STATISTICAL ANALYSIS PLAN 
Year 2 Cumulative Data
Protocol Title: a phase 3 multicenter, randomized, double-masked, sham controlled clinical 
trial to assess the safety and efficacy of intravitreal administration of Avacincaptad Pegol
(complement c5 inhibitor) in patients with geographic atrophy secondary to age-related 
macular degeneration
Protocol Number: ISEE2008
Compound Number: ARC1905
Short Title: Gather 2 (Year 2)
Sponsor Name: Iveric Bio, Inc.
Approvers:
PPD


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Statistical Analysis Plan  
 
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Table of Contents 
Table of Contents ...........................................................................................................................2 
Version History ................................................................................................................................3 
List of Abbreviations .....................................................................................................................4 
1. 
Introduction .....................................................................................................................6 
1.1. 
Objectives and Endpoints .................................................................................................6 
1.2. 
Study Design .....................................................................................................................7 
1.3. 
Study Period and Visit Window Definition ......................................................................8 
2. 
Statistical Hypotheses .....................................................................................................9 
2.1. 
Multiplicity Adjustment ....................................................................................................9 
3. 
Analysis Sets ..................................................................................................................10 
4. 
Statistical Analyses .......................................................................................................11 
4.1. 
General Considerations ...................................................................................................11 
4.1.1. 
Visit Windows ................................................................................................................11 
4.1.2. 
Handling Missing Data in Efficacy Analyses .................................................................11 
4.1.3. 
Handling Missing Data in Descriptive Analyses ............................................................11 
4.1.4. 
Handling Missing or Partially Missing Dates .................................................................12 
4.1.5. 
 .....................................................................................................12 
4.1.6. 
Disposition of Subjects ...................................................................................................12 
4.1.7. 
Treatment Misallocation .................................................................................................13 
4.1.8. 
Protocol Deviations .........................................................................................................13 
4.1.9. 
Demographic and Baseline Characteristics ....................................................................13 
4.1.10. Prior and Concomitant Medications ...............................................................................14 
4.2. 
Efficacy Analysis ............................................................................................................15 
4.2.1. 
Mean GA growth (slope): EM, EOM vs. Sham..............................................................15 
4.2.2. 
Time to Vision Loss Analysis .........................................................................................17 
4.2.3. 
Other Secondary Endpoints ............................................................................................18 
4.3. 
Safety Analyses...............................................................................................................19 
4.3.1. 
Extent of Exposure ..........................................................................................................19 
4.3.2. 
Adverse Events ...............................................................................................................19 
4.3.3. 
Serious Adverse Events ..................................................................................................20 
4.3.4. 
Vital Signs .......................................................................................................................21 
4.3.5. 
Ophthalmic Variables .....................................................................................................21 
4.3.6. 
Clinical Laboratory .........................................................................................................22 
4.3.7. 
ECG.................................................................................................................................24 
4.4. 
Other Analyses ................................................................................................................25 
4.4.1. 
Subgroup .........................................................................................................................25 
4.5. 
Changes to Protocol-planned Analyses ..........................................................................25 
5. 
Supporting Documentation ..........................................................................................26 
5.1. 
26 
5.2. 
Statistical Analysis Plan Addendum for Cumulative Year 2 Data .................................27 
6. 
References ......................................................................................................................28 
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Version History 
 
SAP version 
Date 
Change 
Rationale 
2.0 
22 June 2023 
x 
Analysis populations and Expand 
analysis visit windows up to year 2 
 
Population at the re-randomization is 
defined. Analysis visit windows are 
defined to cover visits up to year 2 in 
the analysis data sets 
x 
Untransformed response outcome 
(growth rate of GA) without square 
root transformation will be used 
 
Untransformed data is direct and 
easy to interpret the growth of GA 
area 
x 
Remove the per-protocol analysis 
 
Intent-to-treat population is the 
primary analysis set. Per-protocol 
analysis set doesn’t provide 
additional meaningful information in 
this superiority study 
x 
Revise the MMRM model to fit the 
design for year 2 analysis 
 
With re-randomization at the end of 
year 1, the stratification factors from 
the initial randomization are no-
longer applicable to the cumulative 
data at year 2. In addition, the 
untransformed GA area will be used 
in the model. Several sensitivity 
analyses are added. 
x 
Revise analysis on fellow eye (FE) 
 
 
 
x 
Vision loss analysis 
 
 
 
The study is on the study eye (SE) 
for efficacy and safety evaluation. FE 
will not provide additional 
information 
 
Time-to-event analysis is added with 
the vision loss event defined as 
BCVA  15 letters loss from baseline 
in 2 or more consecutive visits 
1.0 
3 August 
2022 
 
Original version: a brief SAP 
addendum for year 2 analysis 
 


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Statistical Analysis Plan  
 
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List of Abbreviations  
Abbreviation 
Term 
 
 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration  
ACP 
Avacincaptad Pegol 
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
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 
GGT 
Gamma-glutamyl Transferase 
ICH 
International Conference on Harmonization 
DSMB 
Data Safety Monitoring Board 
IOP 
Intraocular Pressure 
ITT 
Intention-to-Treat 
LLN 
Lower Limit Normal 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
NA 
Not Available / Not Applicable 
OU 
Oculus Uterque (Both Eyes) 
PSC 
Posterior Subcapsular Cataract 
REML 
Restricted Maximum Likelihood 
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Study Eye 
SGOT/AST 
Aspartate Aminotransferase 
SGPT/ALT 
Alanine Aminotransferase 
ULN 
Upper Limit Normal 
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VA 
Visual Acuity 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








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Statistical Analysis Plan  
 
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2. 
Statistical Hypotheses 
The following hypothesis testing will be conducted sequentially. 
1. Hypothesis testing in EM vs. Sham for mean GA growth rate are: 
H0: ǻ = 0  
versus H1: ǻ  0, 
where ǻ = μ1 - μ2, μi is the mean growth rate (slope) of GA over 24 months for treatment EM, 
or Sham, respectively. 
2. Hypothesis testing in ACP 2mg vs Sham for time to vision loss will be conducted using 
Kaplan-Meier method with a log-rank test 
3. Hypothesis testing in EOM vs. Sham for mean GA growth: similarly, as in (1) 
4. Hypothesis testing in ACP 2mg vs Sham for mean change in best corrected visual acuity 
(BCVA in ETDRS letters) from Baseline to Month 24 
5. Hypothesis testing in ACP 2mg vs Sham for mean change in low luminance best 
corrected visual acuity (LL BCVA in ETDRS letters) from Baseline to Month 24 
6. 
 
The hypothesis testing will be evaluated according to a pre-specified hierarchical testing 
procedure to control overall type-1 error at a 5% two-sided significance level. If the primary 
analysis testing GA growth rate (ACP 2mg vs Sham) based on Year 1 data is statistically 
significant, the hypotheses tests will be performed in a sequential way as described above to 
control familywise type I error rate with 2-sided significance level of 0.05. A test will be 
performed only if all the preceding tests are statistically significant. 
2.1. 
Multiplicity Adjustment 
There will be no adjustment for the multiplicity as the hypotheses will be tested in a hieratical 
procedure on the primary endpoint and the secondary endpoints described above.  
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3. 
Analysis Sets 
For the purposes of analyses, the following analysis sets (populations) will be used and are 
defined below. 
Participant Analysis Set 
(population) 
Description 
Intent-to-treat analysis set 
(ITT)  
All randomized participants who received at least one dose of 
study drug. Participants will be analyzed in the treatment group 
assigned at randomization 
Safety analysis set (Safety) All participants who received at least one dose of study drug. 
Subjects who have ever received an injection of ACP during this 
trial will be analyzed in the ACP group. 
Re-randomized analysis 
set (Re-Rand) 
The subset of ITT population who are re-randomized at Month 
12 
In the ITT/Safety population, ACP (ARC1905 2mg) and Sham will be used as treatment groups. 
Subjects who were discontinued from the study in Year 1 will be included.  In the Re-
randomized population, ARC1905 2mg EM, ARC1905 2mg EOM, and Sham will be used as 
treatment groups. Subjects who were discontinued from the study in Year 1 will be excluded. 


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4. 
Statistical Analyses 
4.1. 
General Considerations 
Data will be analyzed using SAS 9.4 or R. In the ITT/Safety population, ACP (ARC1905 2mg), 
Sham will be used as treatment groups. Subjects who were discontinued from the study in Year 1 
will be included. In the Re-randomized population, ARC1905 2mg EM, ARC1905 2mg EOM, 
and Sham will be used as treatment groups. 
Descriptive statistics will be tabulated as follows:  
Categorical data will be summarized in contingency tables presenting frequencies and percentages.  
Continuous data will be summarized using number of non-missing values (n), mean, standard 
deviation, median, minimum, 1st quartile (Q1), 3rd quartile (Q3), and maximum values. 
Graphic display and visualization will be utilized to summarize descriptive statistics.  
4.1.1. 
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 the Supporting Document section. 
4.1.2. 
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. The Mixed Model on Repeated 
Measures fitted by Restricted Maximum Likelihood method will be used in the mean growth GA 
analysis, where the observed data will be used with no imputation. Several imputation methods 
will be used in sensitivity analyses, whenever necessary, to impute the missing data, as described 
in Section 4.2.4 sensitivity analyses. 
4.1.3. 
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. 


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4.1.4. 
Handling Missing or Partially Missing Dates  
Missing or partially missing dates will not be imputed at data level. However, assumptions for 
missing or partially missing dates for important variables will be made to allow inclusion of 
appropriate data records in the analyses.  In general, the assumptions about the missing or 
partially missing dates, when needed, are made conservative to avoid overestimation of treatment 
effect and underestimation of adverse effects.  
If a medication date or time is missing or partially missing, so it cannot be determined whether it 
was taken prior or concomitantly, it will be considered both as a prior and a concomitant 
medication.  
If the partial AE onset date information does not indicate whether the AE started prior to 
treatment or after treatment, the AE will be classified as after the start of treatment. 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
4.1.6. 
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 number of subjects re-randomized and treated post-randomization, by treatment arm will 
also be presented. 
The frequency of premature discontinuations from the study treatment prior to study completion 
(Month 24) will be given by treatment arm and overall. The details of the ‘Adverse Event’, 
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’Protocol violation’, ‘Investigator decision’, ‘Sponsor Decision’, ‘Subject request’, ‘Lost to 
Follow-Up’, ‘Subject Non-Compliance’, or ’Other’ will be included in a listing. 
The frequency of premature discontinuations from the study prior to Month 24 will be given for 
the ITT population and re-randomized population, by treatment arm and overall. The primary 
reason for non-completion of the study will be summarized.   
4.1.7. 
Treatment Misallocation 
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 ACP will be included in the ACP group 
based on actual injections received. 
x Re-randomized population will be used for both efficacy and safety analysis in Year 2 with 
the treatment as re-randomized. 
4.1.8. 
Protocol Deviations 
All protocol deviations will be assessed and identified prior to database lock in a masked fashion 
to determine whether they are major by the sponsor. The final list of major protocol deviations 
will be provided prior to the database lock. 
The major protocol deviations will be summarized for the ITT population and re-randomized 
population. The details will be listed by subject and by treatment arm. 
4.1.9. 
Demographic and Baseline Characteristics 
Descriptive statistics will be provided on Baseline information including demographics and 
disease characteristics. No tests of significance will be conducted. 
Descriptive statistics with respect to subject characteristics at Baseline will be displayed for the 
ITT population and re-randomized population. When several measurements are available before 
the first administration of study drug, the Baseline value is the last available value prior to first 


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dose, except for the Baseline visual acuity score which is the mean of the Screening and Day 1(D0) 
values if both are available. 
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), study eye 
x Tonometry, study eye 
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) 
x Fundus autofluorescence (FAF) imaging assessments, study eye 
x Fluorescein angiography (FA) imaging assessment 
4.1.10. 
Prior and Concomitant Medications 
All prior and concomitant medications will be summarized separately by WHO Drug code (WHO 
Drug Dictionary, released on 1 September 2020) on the ITT population and re-randomized 
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. 


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4.2. 
Efficacy Analysis 
4.2.1. 
Mean GA growth (slope): EM, EOM vs. Sham 
4.2.1.1. 
Definition of Estimand 
The objective is to demonstrate efficacy of ACP EM or EOM versus Sham in mean GA growth 
rate (slope) after re-randomization regardless of any non-adherence to or interruption of study 
treatment, and regardless of initiation of alternative treatment. 
The following 5 attributes define the Estimand for the objective evaluation: 
A. Population: re-randomized population 
B. Interventions: 
ACP EM or EOM versus Sham. 
C. Endpoint:  
GA area over 24 months from Baseline, Month 6, Month 12, Month 18, and Month 24.   
D. Intercurrent events (ICE’s) and strategies: 
1. Treatment changes (i.e., interruptions, non-adherence, dose changes, discontinuation): 
“treatment policy” – i.e., treatment changes will be ignored, and all data collected will 
contribute to the analysis regardless of whether these follow such ICE’s. 
2. COVID-19: “treatment policy” – i.e., impact of COVID-19 pandemic will be ignored, 
and all data collected will contribute to the analysis regardless of whether these 
follow such ICE’s. 
E. Population-level summary: 
Difference between groups (EM vs. Sham, EOM vs. Sham) in mean growth rate (slope) 
of the GA area over 24 months. 
4.2.1.2. 
Statistical Method 
With a re-randomization at the end of Year 1, the initial stratification factors from the 
randomization are no longer applicable in the analysis of Year 2. Therefore, the stratifications 
factors will be removed from the MMRM model as in the primary analysis.  
The revised model is described below. 
A mixed model for repeated measures (MMRM) will be applied to all available data, using 
response variable of the GA growth area over time up to Month 24 in 5 time points: Baseline, 
Month 6, Month 12, Month 18, and Month 24. The MMRM will be used to assess the difference 
between the treatment groups in terms of the rate of growth (slope) of the GA over time of 24 
months. Time is defined as a continuous variable in number of study days since the baseline 
assessment. Treatment groups include ACP EM, ACP EOM, and Sham. A model will be fitted 


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by using restricted maximum likelihood (REML) and include time, treatment, and treatment by 
time interaction as fixed effects, subject as random effect. 
Notice that in the primary analysis at Year 1 (Month 12), the square root transformation of GA 
growth area was used. However, the mean GA growth (slope) has shown similar results with or 
without square root transformation. In addition, it is difficult to interpret the transformed data in 
context. Therefore, in the Year 2 analysis, the untransformed GA growth using observed GA 
area of measurement will be used as the primary endpoint. 
4.2.1.3. 
Sensitivity or Supportive Analyses 
The following sensitivity or supportive analyses will be performed. 
4.2.1.3.1. Miller imputation of missing data 
For the analyses of the endpoint, the Mixed-Effects Repeated Measures (MMRM) analysis does 
not require data imputation and uses only the observed data. 
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 average of observed means from the active arm and the sham arm will be imputed to 
all patients with missing data; 
3. the observed mean from the sham arm will be imputed to all patients with missing data. 
4. 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); 
These four sensitivity analyses make different assumptions about missing data and are likely to 
be increasingly biased against a true treatment effect. Therefore, they will be used only for 
sensitivity purposes. 
4.2.1.3.2. Multiple imputation with tipping point analysis 
In addition to filling a single value for the missing value at a visit as described in Miller method, 
multiple imputation with tipping point analysis will be conducted. Please refer to primary 
analysis CSR Appendix for technical details. 
4.2.1.3.3. Time (visit) as a categorical variable in the MMRM model  
Time will be replaced as a categorical variable in the MMRM model above with the visits 
(Baseline, Month 6, Month 12, Month 18, and Month 24) to assess the change from baseline over 
time. 
4.2.1.3.4. Piece-wise analysis by every 6-month interval    
The MMRM model assumes a liner growth rate of GA over time. A linear spline approximation 
by every 6-month interval is to provide more detail on the GA growth curve by time interval 
over 2 years. The MMRM model in Section 4.2.1.2 will be used to fit every 6-month interval 
data. 


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4.2.2. 
Time to Vision Loss Analysis 
In the evaluation of vision, BCVA is an important measurement tool to assess the changes over 
time. However, substantial differences in mean change of visual acuity between treatment and 
sham are difficult to demonstrate within the timeframe of a clinical trial in patients with GA. 
Nonetheless, at various time points in the study, patients can experience a significant and 
permanent drop in visual acuity. Hence, it is more appropriate to analyze vision data by using the 
time-to-event analysis to better characterize patient’s vision loss by accounting for instances of 
clinically significant vision loss in terms of change in BCVA Scores (ETDRS Letters) from 
Baseline to Month 24. In this time-to-event analysis, a vision loss event was defined as a loss of 
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measured at any two or more consecutive visits up to Month 24. These parameters were chosen 
as a 3-line BCVA loss (equivalent to doubling of visual angle) is widely recognized as a 
significant deterioration in vision and a minimum of two consecutive visits is representative of 
persistent disease progression. The framework of this analysis is formulated as the secondary 
Estimand below. 
4.2.2.1. 
Definition of the Estimand 
This secondary efficacy objective is to demonstrate that ACP 2 mg can significantly reduce the 
rate of persistent vision loss compared to Sham up to Month 24. 
The following 5 attributes define the secondary Estimand for the secondary endpoint evaluation: 
A. Population: 
Subjects with geographic atrophy secondary to dry age-related macular degeneration.  
Analysis will be performed on all randomized patients who received at least one dose of 
study drug (ITT population). 
B. Interventions: 
ACP 2mg versus Sham. 
C. Endpoint:  
Time to persistent vision loss (BCVA  15 letters loss from Baseline at 2 or more 
consecutive visits) during the study from Baseline to Month 24.   
D. Intercurrent events (ICE’s) and strategies: 
1. 
Treatment changes (i.e., interruptions, non-adherence, dose changes, 
discontinuation): “treatment policy” – i.e., treatment changes will be ignored, and all data 
collected will contribute to the analysis regardless of whether these follow such ICE’s. 
2. 
COVID-19: “treatment policy” – i.e., impact of COVID-19 pandemic will be 
ignored, and all data collected will contribute to the analysis regardless of whether these 
follow such ICE’s. 
E. Population-level summary: 
Cumulative rate of persistent vision loss  






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 Ocular TEAEs by study eye and fellow eye  
 Treatment related Ocular TEAEs by study eye and fellow eye 
 Injection procedure related Ocular TEAEs by study eye and fellow eye 
 Ocular TEAEs (study eye) by the maximum severity grade 
 Treatment related Ocular TEAEs (study eye) by the maximum severity grade 
 Injection procedure related Ocular TEAEs (study eye) by the maximum severity 
grade 
 TEAEs with high level term of cataract conditions by study eye and fellow eye 
 TEAEs leading to discontinuation of study drug 
 Treatment related TEAEs leading to discontinuation of study drug 
 Injection procedure related TEAEs leading to discontinuation of study drug 
 Ocular TEAEs (study eye) leading to discontinuation of study drug 
 TEAEs leading to death 
 Treatment related TEAEs leading to death 
 Injection procedure related TEAEs leading to death 
x All AEs, including non-TEAEs, will be included in individual subject listings.  
 The listings will include the subject identifier, age, sex, verbatim term, preferred 
term, eye (N/A/OD/OS/OU), serious (yes/no), date of onset, relative study day of 
onset, 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/not 
resolved/fatal). 
 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. 
4.3.3. 
Serious Adverse Events  
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.  
SAE data will be evaluated for each treatment group. 
Tabular summaries of the following SAEs will be provided: 
x All SAEs regardless of the relationship to study treatment 
- 
related to study treatment  
- 
related to injection procedure 
x Ocular SAEs (study eye) regardless of the relationship to study treatment 
- 
related to study treatment (SE) 
- 
related to injection procedure (SE) 


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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 injection, after first 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/not resolved/fatal). 
Vital Signs 
Descriptive statistics at each time point up through and including the Month 24 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. 
4.3.5. 
Ophthalmic Variables 
Ophthalmic Examination. The following ophthalmic examination variables will be analysed by 
shift table from Baseline to the pre-injection examination on Month 24 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 24 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 for applicable visits. 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 30 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. 
4.3.6. 
Clinical Laboratory 
All laboratory data will be listed and values falling outside normal ranges will be identified, 
whether they will be deemed clinically relevant or not. 
Laboratory data will also be summarized in tables presenting values at each scheduled visit up 
through the Month 24 visit. 
Value changes from Baseline to each scheduled visit up through the Month 24 visit. 
A summary table of all analytes with the Baseline mean and the mean change from Baseline to 
the last value observed. 
A summary table of all analytes with the Baseline median and the median change from Baseline 
to the last value observed. 
The following parameters will be summarized:  
x Hematological parameters (hemoglobin, white blood cells, platelets, neutrophils 
(absolute numbers), lymphocytes (absolute numbers), monocytes (absolute numbers), 
eosinophils (absolute numbers), basophils (absolute numbers)), 
x Renal function parameters (serum creatinine and BUN),  
x Hepatic function parameters (serum bilirubin, alkaline phosphatase, GGT, 
SGOT/AST, and SGPT/ALT), 
x Electrolytes (sodium, potassium, chloride, carbon dioxide, calcium, and phosphate),  
x Complete urinalysis parameters (complete urinalysis including specific gravity, 
protein, blood, etc.), 
x Serum pregnancy test (if of child-bearing potential). 
Additional urine or serum pregnancy testing may be performed during the study at the discretion 
of the investigator, or in accordance with local requirements or regulations. 
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 


CONFIDENTIAL 
Statistical Analysis Plan  
 
Protocol ISEE2008 
23 
collected after the first dose of study drug, up to the laboratory data taken at the Month 18 visit 
or 30 days after last dose will be included.  
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 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 18. Three Notable Laboratory Values 
tables and accompanying 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) < 0.5xLLN or > 1.5xULN 
v. 
Eosinophils (absolute) >1.5xULN 
vi. 
Lymphocytes (absolute) < 0.5xLLN 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. 
UN > 1.3xULN 
ii. 
Creatinine > 1.3xULN 
d. ELECTROLYTES 
i. 
Potassium < 0.9xLLN or > 1.1xULN 
ii. 
Sodium < 0.9xLLN or > 1.1xULN 
iii. 
Chloride < 0.9xLLN or > 1.1xULN 
iv. 
Bicarbonate < 0.9xLLN or > 1.1xULN 


CONFIDENTIAL 
Statistical Analysis Plan  
 
Protocol ISEE2008 
24 
v. 
Calcium < 0.9xLLN or > 1.1xULN 
vi. 
Phosphate < 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 < 0.75x 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. 
UN > 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. 
Bicarbonate < 0.9x Baseline or >1.1x Baseline 
v. 
Calcium < 0.9x Baseline or >1.1x Baseline 
vi. 
Phosphate < 0.9x Baseline or > 1.1x Baseline 
4.3.7. 
ECG 
ECG results will be tabulated as “normal” or “abnormal” at each visit and will be presented in a 
normal/abnormal shift table between Baseline and each scheduled ECG visit, as well as between 
Baseline and the last ECG taken.  Descriptive statistics will be presented for continuous variables 
(e.g., heart rate and RR, PR, QRS, QT, QTcB, and QTcF intervals) at each visit. A by-patient 
listing will be provided for ECGs which are deemed abnormal. 


CONFIDENTIAL 
Statistical Analysis Plan  
 
Protocol ISEE2008 
25 
4.4. 
Other Analyses 
4.4.1. 
Subgroup 
The following subgroups are defined. Analyses on subgroups are considered as exploratory.  
%DVHOLQH 9$   YV   (7'56 OHWWHUV %DVHOLQH *$   YV   GLVF DUHD 3DWWHUQ RI )$)
at the junctional zone of geographic atrophy (none/focal vs. banded/diffuse) as well as age (<65 
YV a YV a YV  JHQGHU PDOH YV IHPDOH, race (American Indian/Alaska Native vs. 
Black or African American vs. Asian vs. Native Hawaiian/Pacific Islander vs. White vs. Other), 
and ethnicity (Hispanic or Latino vs. Not Hispanic or Latino). 
4.5. 
Changes to Protocol-planned Analyses 
The following changes are made from protocol planned analyses: 
- 
Time to vision loss analysis based on BCVA was added after primary analysis on Year 1 
- 
GA growth rate without square root transformation 
- 
Piece-wise analysis by every 6-month interval on GA growth rate    
 
 
 






CONFIDENTIAL 
Statistical Analysis Plan  
 
Protocol ISEE2008 
28 
6. 
References 
1. 
Beunckens, C., Sotto, C., Molenberghs, G. (2008) A simulation study comparing weighted 
estimating equations with multiple imputation based estimating equations for longitudinal 
binary data. Computational Statistics & Data Analysis 52:1533-1548. 
2. 
Little, R.J.A., Rubin, D.B. (2002) Statistical Analysis with Missing Data, 2nd Edition, John 
Wiley and Sons, New York 
3. 
 
  
 
  
 
 
.  
6. 
Molenberghs, G., Kenward, M. (2007) Missing Data in Clinical Studies. New York: 
Wiley, 2007. 
7. 
Pocock, S.J., Simon R. (1975) Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 31:103-115. 
8. 
Schafer, J. (1997) Analysis of Incomplete Multivariate Data. Boca Raton: Chapman & 
Hall/CRC. 
9. 
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. 
13. ISEE 2008 Statistical Analysis Plan – Primary Analysis, on file 
 
CCI

Prot_000.pdf: 
Official Study Title: A Phase 3 Multicenter, Randomized, Double-Masked, 
Sham-Controlled Clinical Trial to Assess the Safety and Efficacy of 
Intravitreal Administration of Zimura™ (Complement C5 Inhibitor) in Patients 
with Geographic Atrophy Secondary to Age-Related Macular Degeneration 
NCT#: NCT04435366 
Document: Protocol 
Document Date: 24 May 2021 




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                                        24May2021 Confidential 
TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ...................................................................... 4 
2 
SUMMARY OF PROTOCOL ISEE2008 ............................................................... 5 
3 
STUDY ASSESSMENTS ..................................................................................... 7 
4 
INTRODUCTION ................................................................................................ 11 
 
Age-Related Macular Degeneration ........................................................ 11 
 
AMD and the Complement Pathway ....................................................... 12 
 
Clinical Data ............................................................................................ 16 
 
Trial Rationale ......................................................................................... 24 
5 
TRIAL OBJECTIVES .......................................................................................... 26 
 
Objectives ............................................................................................... 26 
 
Endpoints ................................................................................................ 26 
6 
TRIAL DESIGN .................................................................................................. 26 
7 
PROCEDURES .................................................................................................. 27 
 
Refraction, Visual Acuity, and Low Luminance Visual Acuity .................. 27 
 
Tonometry ............................................................................................... 27 
 
Ophthalmologic Examination .................................................................. 28 
 
Fundus Photography, Fluorescein Angiography, Fundus Autofluorescence, 
and Optical Coherence Tomography (SD-OCT) ..................................... 28 
 
Laboratory Tests ..................................................................................... 28 
 
Vital Signs, Physical Examination and Performance Status (ECOG)...... 29 
 
12-Lead Electrocardiogram ..................................................................... 29 
 
8 
SUBJECT POPULATION ................................................................................... 30 
 
Sample Size ............................................................................................ 30 
 
Inclusion Criteria ..................................................................................... 30 
 
Exclusion Criteria .................................................................................... 31 
9 
TRIAL MEDICATION .......................................................................................... 33 
 
Drug Supply ............................................................................................ 33 
 
Previous or Concomitant Therapy .......................................................... 36 
10 TRIAL CONDUCT .............................................................................................. 36 
 
Subject Enrollment .................................................................................. 36 
 
Trial Assessments................................................................................... 36 
 
Development of Wet AMD During the Trial ............................................. 50 
 
Withdrawal from Trial .............................................................................. 51 
 
Trial Discontinuation ............................................................................... 51 
11 STATISTICAL METHODS .................................................................................. 53 




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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 
CFH  
Complement Factor H  
CNV 
Choroidal Neovascularization 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
EC 
Ethics Committee 
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 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
 
IPCV 
Idiopathic Polypoidal Choroidal Vasculopathy  
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
ITT 
Intent to Treat Population  
LLBCVA 
Low Luminance Best Corrected Visual Acuity 
MAC 
Membrane Attack Complex 
MMRM  
Mixed Model Repeated Measures  
NLP 
No Light Perception 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OU 
Both Eyes 
RC 
Reading Center 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SD-OCT 
Spectral-Domain Optical Coherence Tomography 
SE 
Study Eye 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
TN 
Treatment-Naïve 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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2 SUMMARY OF PROTOCOL ISEE2008 
SYNOPSIS 
TITLE: 
A Phase 3 Multicenter, Randomized, Double Masked, Sham-
Controlled Clinical Trial to Assess the Safety and Efficacy of Intravitreal 
Administration of Zimura (Complement C5 Inhibitor) in Patients with 
Geographic Atrophy Secondary to Age-Related Macular Degeneration  
OBJECTIVES: 
The objectives of this study are to evaluate the safety and efficacy of 
Zimura intravitreal administration in patients with geographic atrophy 
secondary to age-related macular degeneration (AMD) 
TRIAL DESIGN: 
 
Approximately 400 patients will be randomized at Day 1 in a 1:1 ratio 
to the following monthly treatment groups: 
 
•  Zimura 2 mg 
•  Sham 
Patients receiving monthly Zimura 2 mg will be re-randomized at 
Month 12 in a 1:1 ratio to the following treatment groups: 
 
 
• Zimura 2 mg administered monthly from Month 12 through Month 
23 
• Sham administered at Months 12, 14, 16, 18, 20, and 22, and 
Zimura 2 mg administered every other month at Months 13, 15, 17, 
19, 21, and 23 
All patients who were initially randomized to Sham (at Day 1) will 
continue with monthly Sham injections through Month 23 
All patients will have a final follow up visit at Month 24 
 
ENDPOINTS: 
Primary Efficacy Endpoint: 
• 
The mean rate of growth (slope) estimated based on GA area 
measured by FAF in at least 3 time points: Baseline, Month 6, 
and Month 12 (square root transformation) 
Safety Endpoints:  
• 
Adverse events (AEs) 
• 
Vital signs (pulse, systolic and diastolic blood pressure) 
• 
Ophthalmic findings (best corrected visual acuity [BCVA], low 
luminance BCVA, intraocular pressure [IOP], and ophthalmic 
examination) 
• 
Electrocardiogram (ECG) (12-lead) 
• 
Laboratory variables (blood: hematology, renal function, 
hepatic function and electrolytes; urinalysis) 
 
 


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PLANNED SAMPLE SIZE: Approximately 400 patients will be enrolled  
SUBJECT SELECTION: 
Patients of either gender aged 50 years or greater diagnosed with 
geographic atrophy secondary to AMD 
FORMULATION: 
 
 
 
 
 
INVESTIGATIONAL 
DRUG DOSAGE: 
Patients will receive a minimum of 18 doses and a maximum of 24 
doses of Zimura at a dose of 2 mg 




 
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 9 Ireland, Slovakia Poland, France, Czech Republic: a urine pregnancy test will be done at all monthly visits at which a serum pregnancy test is not done, for any female subject of 
childbearing potential.  
10 Italy: A urine pregnancy test will be done at Day 1 for any female subject of childbearing potential. 
 
*Month 12 assessments are divided into “End of Year 1 Assessments” (shown in the table above) and the “Beginning of the Year 2 Assessments” as shown in the Year 2 Table of 
Assessments in the next page. 
VISIT WINDOWS: It is essential that patients adhere to their prescheduled study visits within the visit window as per Section 10, Trial Conduct. 
         
 




 
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*Month 12 assessments are divided into “End of Year 1 Assessments” (shown in the table in the previous page) and the “Beginning of the Year 2 Assessments” (shown in the table   
above). 
VISIT WINDOWS: It is essential that patients adhere to their prescheduled study visits within the visit window as per Section 10, Trial Conduct. 
 
     
 
  
 


 
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4 INTRODUCTION 
 
Age-Related Macular Degeneration  
Age-related macular degeneration (AMD) is an aging disease characterized by progressive 
degenerative abnormalities in the macula, a small area in the central portion of the retina, 
responsible for central vision.  AMD is characteristically a disease of the elderly and is the 
leading cause of visual loss in individuals > 50 years of age in developed countries (Van 
Newkirk et al., 2000).  In the United States, it is estimated that approximately 11 million 
individuals are affected with AMD with a global prevalence of 170 million individuals 
(Pennington et al., 2016).  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, 
et al., 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, leading to a major public health challenge with significant socioeconomic 
implications (Mitchell et. al., 2018). 
AMD, at its early stages, presents with drusen and abnormalities of retinal pigment epithelium 
(RPE).  As the disease progresses with age to the advanced stage, it generally progresses to 
either the non-neovascular (“atrophic, dry”) form of AMD or the neovascular (“wet or 
exudative”) form of the disease (Mitchell et. al., 2018).  In the dry, atrophic form, loss of 
photoreceptors, RPE cells and associated capillaries (choriocapillaris) in the macula result in 
marked thinning and/or atrophy of retinal tissue.  This collective phenotype in the advanced 
stage of dry AMD is termed geographic atrophy (GA) (Holz et al, 2014).  Furthermore, 
development or progression of geographic atrophy over time is a common cause of vision loss 
in patients diagnosed with the wet form of advanced AMD who are treated with anti-VEGF 
therapy, indicating that in many patients regardless of having the dry or the wet form of AMD, 
the final anatomic outcome leading to loss of vision is geographic atrophy (Bhisitkul et al., 
2015; Grunwald et al., 2017; Abdelfatah et al., 2016). 
 
Geographic atrophy is a significant cause of bilateral, irreversible and severe loss of functional 
vision, with a potential loss on average of 22 letters over 5 years, and is associated with a 
major impact on functional vision, quality of life, and independence (Mitchell et al., 2018; 


 
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Sivaprasad et al., 2019; Boyer et al. 2017, AREDS Report Number 26, 2009).  The median 
time for development of central geographic atrophy from the time of diagnosis is 2.5 years with 
an expectancy of development in the fellow eye in approximately 7 years (AREDS Report 
Number 26, 2009).  
Although anti-VEGF therapy is available for treatment of wet AMD, currently no Food and Drug 
Administration (FDA) or European Medicines Agency (EMA) approved treatment is available 
for geographic atrophy (Brown et al., 2006; Rosenfeld et al, 2006; Heier et al., 2012; Martin et 
al., 2012; Boyer et al. 2017).  
The absence of treatment options for geographic atrophy secondary to AMD represents an 
area of urgent unmet medical need and a major public health concern for the rapidly increasing 
elderly population.  
 
 
AMD and the Complement Pathway 
Although the etiology of AMD is not completely understood (Frederick & Kleinman, 2014), 
recognized risk factors include advanced age, environmental and genetic factors, ocular 
pigmentation, dietary factors, family history for AMD, hypertension, and smoking (Klein et al., 
2004).  
The scientific rationale for the role of complement in AMD is derived from genetic linkage 
studies, pre-clinical in vitro studies, and the presence of complement deposition in post-mortem 
human eyes of patients diagnosed with AMD. 
The role for complement in development of AMD is highlighted by genetic linkage and 
association studies, which suggest that approximately 50% of AMD cases show 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. In individuals 
homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (Klein et 
al., 2005).  
The complement cascade, which was originally described over a century ago by Paul Ehrlich, 
represents a critical portion of the innate immune system, involving a complex system of over 
50 serum proteins (Ehrlich et al., 1899; Holers, 2014; Arbore et al., 2016; Kolev et al., 2014).  
In addition to its role in the innate immune system, recent studies indicate that complement 


 
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may also play a role in the adaptive immune system, cell and tissue development, homeostasis 
and repair (Kolev et al., 2014). 
The complement cascade is activated via the classical (antibody-dependent), the alternative 
(antibody-independent), and the lectin pathways (Holers, 2014).  The three cascades converge 
to generate the complement C3 convertase which cleaves complement C3 and leads to 
subsequent generation of complement C5 convertase which cleaves complement C5 into C5a 
and C5b, the main terminal effector components of the complement cascade, leading to cell 
death.  
 
C5a: Inflammasome Activation and Cell Degeneration 
Inflammasomes are critical components of the innate immune system (Swanson et al., 2019).  
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that 
detects a broad range of endogenous danger signals and environmental irritants, resulting in 
the formation and activation of the NLRP3 inflammasome (Swanson et al., 2019).  
Inflammasome activation leads to pyroptosis, a rapid inflammatory form of lytic programmed 
cell death (Swanson et al. 2019). It is characterized by pore formation in the plasma 
membrane, increased osmotic pressure, cell swelling and subsequent plasma membrane 
rupture and release of pro-inflammatory intracellular contents (Fink et al., 2006).  The 
extracellular release of pro-inflammatory content may further advance the spreading of 
damage in neighboring cells, leading to the progression of the pathology (Bergsbaken et al., 
2009).  
NLRP3 inflammasomes generally require two signals for activation: Signal 1 for priming and 
Signal 2 for NLRP3 assembly.  Since complement system and NLRP3 inflammasomes both 
protect the host against danger, a functional cross talk between the two would appear to be 
natural.  
Complement factor C5a is an important driver of Signal 1 priming for NLRP3 inflammasome 
activation and may regulate NLRP3 activation and assembly by increasing the generation of 
reactive oxygen species (ROS) (Arbore et al., 2016). 
Human RPE cells express both C3a and C5a receptors which bind to C3a and C5a 
respectively; however, after incubation with activated complement only C5aR (and not C3aR) 
is upregulated (Cortight et al., 2009; Brandstetter et al., 2015).  In response to lipofuscin 
toxicity, C5a leads to an increased IL-1ß secretion and a decrease in RPE cell viability, 
suggesting its role as active priming agent for inflammasomes in RPE cells (Brandstetter et al., 
2015). 


 
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The potential role of inflammasome activation in the formation of geographic atrophy is further 
substantiated by reports demonstrating the presence of NLRP3 inflammasome and 
inflammasome products IL-1ß and IL-18 inside the RPE cells of post-mortem eyes of patients 
with geographic atrophy (Tarallo et al., 2012 and Cao et al., 2016).  These findings support the 
rationale for therapeutic complement C5 inhibition in AMD, since C5 activation and C5a 
formation may serve as the link between lipofuscin accumulation, photooxidative damage and 
inflammasome formation leading to RPE degeneration in AMD (Brandstetter et al., 2015).  The 
pyroptosis resulting from inflammasome activation may be a contributing factor in the 
progression of GA in patients with AMD. 
 
C5b: Membrane Attack Complex (MAC) Formation and Cell Degeneration 
One hallmark of AMD is the accumulation of lipofuscin granules inside the aging RPE cells 
(Feeney-Burns et al., 1984).  Accumulation of lipofuscin may lead to the activation of 
complement system and accumulation of membrane attack complex (MAC) in RPE cells, 
potentially contributing to their deterioration over time and resulting in photoreceptor cell loss 
and decrease in vision (Zhou et al., 2006; Zhou et al., 2009; Lenis et al., 2017).  Lipofuscin and 
MAC complex have a damaging effect on RPE cell function by impacting both lysosomes and 
mitochondria inside the cells (Georgiannakis et al., 2015).   
Photo-oxidation of lipofuscin in RPE cells activates the complement cascade in vitro and 
potentially could contribute to complement activation in the RPE-Bruchs membrane interface 
(Zhou et al., 2006; Zhou et al., 2009).  Bisretinoid pigments of lipofuscin other than A2E were 
also capable of activating the complement system in RPE cells (Zhou et al., 2009). 
As indicated above, the activation of complement cascade results in the formation of MAC.  In 
RPE cells MAC is cleared by endocytic pathway and lysosomal degradation (Georgiannakis et 
al., 2015).  Lipofuscin accumulation leads to lysosomal dysfunction in RPE cells.  This prevents 
the clearance of MAC and leads to its further accumulation, inducing cellular distress (Schutt 
et al., 2002, Bergmann et al., 2004, Georgiannakis et al., 2015).  These findings indicate that 
lipofuscin not only activates the complement system but may also prevent the clearance of 
MAC in RPE cells, creating a vicious cycle that makes RPE cells further susceptible to 
complement activation. 
The accumulation of MAC not only impacts lysosomes but also leads to mitochondrial 
perturbation in RPE cells (Georgiannakis et al., 2015).  MAC accumulation leads to a significant 
decrease in the quantitative number of mitochondria as a function of area and induces 
ultrastructural defects i.e. smaller size, rounder morphology, and fewer cristae.  These changes 


 
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potentially have a deleterious impact on the energy production and subsequently the function 
of RPE cells.  In addition, the accumulation of lipofuscin inside RPE cells impacts the 
mitochondria as well.  Mitochondria are significantly more sensitive to lipofuscin when 
compared to lysosomes and their latency decreases at a lower concentration and a shorter 
period of time (Schutt et al., 2002).  Further, accumulation of MAC leads to the complete lysis 
and destruction of RPE cells in a concentration-dependent manner (Li et al., 2010). 
Taken together, the accumulation of lipofuscin and MAC synergistically damage both 
lysosomes and mitochondria inside the RPE cells, leading to their dysfunction and death.  To 
further substantiate the role of C5 and MAC in AMD, post mortem histopathologic studies 
demonstrated their presence in the drusen and RPE cells of patients with AMD (Anderson et 
al., 2002; Bok 2005). 
These findings indicate that the activation of complement pathway, contributing to the 
formation of inflammasome and accumulation of MAC, may play an important role in 
geographic atrophy, and therefore inhibition of C5 may potentially slow progression of this 
devastating disease.  Positive efficacy results from the recently reported clinical trials 
assessing the impact of complement inhibition in geographic atrophy may further validate the 
therapeutic role of complement inhibition in GA (Liao et al., 2019; OPH2003). 
 
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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4.2.3 Toxicology 
 
 
 
    
Additional details regarding results of these studies, as well as results from the various 
intravenous toxicity studies previously conducted, can be found in the IB.  
 
 
Clinical Data 
4.3.1  Study OPH2000 
In a phase 1 ascending dose and parallel group clinical trial, the safety, tolerability, and 
pharmacokinetic profile of multiple intravitreal injections of Zimura in combination with 
Lucentis® 0.5 mg was evaluated in patients with wet AMD (OPH 2000).  
Zimura was well-tolerated and no particular safety concerns were identified.  
 
  
 
 
  
 
 
 
  There 
was a trend towards a mean increase in VA (number of ETDRS letters) from Baseline at all 
time points for patients in the 0.3, 1 and 2 mg dose groups in the TN subgroup who received 
6 injections.  At Week 24, there was an improvement in mean VA from Baseline of 
 
15.3 ETDRS 
letters for the 2 mg dose group.  
 
  
 
 
  
 
 
4.3.2  Study OPH2001 
An additional phase 1 study was performed in patients diagnosed with geographic atrophy 


 
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(GA).  
 
Patients received treatment with 3 initial intravitreal injections of Zimura 
0.3 mg or 1 mg, administered at Day 0, Week 4 and Week 8, with a follow up visit at Week 16.  
Patients received two subsequent injections at Week 24 and Week 36 followed by a final follow 
up visit at Week 48.  Standard safety assessments were performed for ophthalmic variables 
that included VA, IOP, ophthalmic examination, fundus autofluorescence (FAF), fluorescein 
angiography (FA), and spectral-domain optical coherence tomography (SD-OCT) together with 
adverse events (AEs), vital signs, and laboratory variables.  
Fifteen 
patients (32%) had AEs, predominantly Eye Disorder AEs in the study eye, reported to be 
related to the injection procedure.  The most frequently reported AEs were 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 2 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 and 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 ophthalmic examinations did not indicate any unexpected 
clinical findings.  There were some transient findings post-injection (conjunctiva/sclera and 
cornea) that resolved prior to the next injection.  Vitreous haze was also reported for a few 
patients.  Intraocular pressure (IOP) showed a small mean increase following injections but no 
indication of any cumulative increase.  
 
 
 
 
 
  
 
 
4.3.3 Study OPH2002 
The objectives of this study were to evaluate the safety and tolerability of Zimura intravitreal 
injection in combination with VEGF therapy in patients with idiopathic polypoidal choroidal 


 
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vasculopathy (IPCV).  Treatment experienced patients (prior treatment with anti-VEGF 
monotherapy of ≥ 8 injections in the previous 12 months) diagnosed with IPCV of either 
gender, aged 50 years or more were enrolled in this study.  Patients received 3 monthly 
intravitreal injections of Zimura (1 mg) in combination with intravitreal injection of anti-VEGF 
agent (Avastin® 1.25 mg or Lucentis® 0.5 mg or Eylea® 2 mg). 
 
 
 
   
A total of 4 patients were enrolled in this clinical trial and all completed the study.  None of the 
patients had a VA loss of more than 15 ETDRS letters at Month 3.  There were no deaths 
during the study.  There was one SAE of endophthalmitis reported in 1 subject.  The SAE 
resolved and was reported to be related to the injection procedure.  None of the ocular AEs 
were assessed to be related to Zimura or anti-VEGF treatment. 
The intravitreal administration of Zimura in combination with an anti-VEGF agent (Avastin®, 
Eylea®, or Lucentis®) in patients with IPCV was generally well tolerated.  
 
4.3.4 Study OPH2003 
A pivotal international, multicenter, randomized, double-masked, Sham-controlled clinical trial 
was performed to evaluate the safety and efficacy of Zimura in patients with geographic 
atrophy secondary to AMD.  
 
 
In Part 1 of the trial:  
patients were randomized to receive monthly intravitreal injections of 
Zimura 1 mg; 
Zimura 
2 mg; and 
Sham injections. 
This trial was modified (while masked) to include a 4 mg dose group and therefore part 2 was 
added.  In Part 2 of the trial: 
patients were randomized to receive monthly intravitreal 
injections of Zimura 4 mg, administered as two injections of Zimura 2 mg; 
 
 Zimura 2 mg plus a Sham injection; 
and 
 Sham injections, administered as two 
separate Sham injections.  
 
 


 
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Safety 
Zimura was generally well tolerated after 12 months of administration and there were no 
Zimura-related 
AEs, 
no 
Zimura-related 
inflammation, 
and 
no 
Zimura-related 
discontinuations.  Further, there have been no ocular serious adverse events and no cases 
of endophthalmitis reported in the study eye in this clinical trial.  During the first 12 months 
of the trial, the incidence of choroidal neovascularization (CNV) in the untreated fellow eye 
was 10 patients (3.5%); in the study eye of the Sham control group was 3 patients (2.7%); 
in the Zimura 2 mg group was 6 patients (9.0%); and in the Zimura 4 mg group was 8 
patients (9.6%).  These numbers were lower than reported in the literature for complement 
C3 inhibition (Liao et al., 2019).  The most frequently reported ocular adverse events were 
related to the injection procedure. 
 
Primary Efficacy Endpoint 
The prespecified primary efficacy endpoint, mean rate of change in GA growth over 12 months, 
was measured by fundus autofluorescence (FAF) based on readings at three time points 
(Baseline, Month 6, and Month 12) and was calculated using the square root transformation of 
the GA area.  The FAF images were assessed by an independent masked reading center.  
This trial met its prespecified primary efficacy endpoint. 
The reduction in the mean rate of GA growth over 12 months was 27.38% (p = 0.0072) for the 
Zimura 2 mg group as compared to the corresponding Sham control group, and 27.81% (p = 
0.0051) for the Zimura 4 mg group as compared to the corresponding Sham control group.  
These efficacy data for both dose groups were similar and statistically significant.  
 
 
 
 
   
 
 






 
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4.3.5. Study OPH2005 
Study OPH2005 is a multi-center, randomized, double-masked, Sham-controlled 
 
Phase 2b clinical trial designed to assess the safety and efficacy of Zimura compared to Sham 
in patients with autosomal recessive Stargardt disease.  
Patients who were between 18 and 50 years of age, diagnosed with Stargardt disease with at 
least two pathogenic mutations of ABCA4 gene and best corrected visual acuity in the study 
eye between 20/20 to 20/200 Snellen equivalent were randomized in a 1:1 ratio to Zimura or 
Sham group.  
During the induction phase, at Day 1, Month 1, and Month 2, all patients received either Zimura 
2 mg or Sham on Day 0 and Day 14; during the maintenance phase, patients received monthly 
Zimura 4 mg (administered as 2 intravitreal injections) or Sham (administered as 2 Sham 
injections).  
 
 
 
  
 
 
 
 
4.3.6 Study OPH2007  
OPH2007 was a multi-center, randomized, open-label, dose-ranging Phase 2a clinical trial 
designed to assess the safety of various Zimura dosing regimens in combination with anti-
VEGF therapy at Month 6 for the treatment of wet AMD.  
 
 
In Cohort 1, 
patients were administered monthly combination therapy consisting of Lucentis 
0.5mg followed by Zimura 4mg two days later.  
 
 
 
 


 
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In Cohort 2, 
patients were administered monthly combination therapy consisting of Lucentis 
0.5mg and Zimura 2 mg on the same day, which was the same dosing regimen as the best-
performing group from the previously completed OPH2000.  
 
 
 
 
In Cohort 3, during the induction phase (Day 1 – Month 2), 
patients were administered 
Lucentis 0.5mg followed by Zimura 2 mg on the same day followed by Zimura 2 mg fourteen 
days later.  During a subsequent maintenance phase (Month 3 – Month 5), patients were 
administered Lucentis 0.5mg followed by Zimura 2 mg on the same day.  
 
 
 
 
In Cohort 4, during the induction phase (Day 1 – Month 2) 
patients were administered 
Lucentis 0.5mg followed by Zimura 2 mg on the same day followed by Zimura 2 mg fourteen 
days later.  During a subsequent maintenance phase (Month 3 – Month 5) patients were 
administered Zimura 2 mg followed two days later by Lucentis 0.5mg and Zimura 2 mg.  
 
 
 
 
Zimura was generally well tolerated after 6 months of administration.  There was no Zimura-
related AEs and no Zimura-related discontinuations from the trial.  There was one ocular SAE 
of retinal detachment which was reported as not related to the study drugs or the injection 
procedure, and related to the normal aging process.  There were no cases of endophthalmitis.  
The most frequently reported ocular adverse events were related to the injection procedure. 
 
 
 
 
 


 
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Trial Rationale 
The scientific foundation implicating the role of complement in AMD is derived from genetic 
linkage studies, in vitro experimental studies, and post-mortem histopathologic studies 
performed by independent laboratories. 
The seminal genetic linkage studies published in 2005 (Edwards et al., 2005; Hageman et al., 
2005; Haines et al., 2005; Klein et al., 2005; Narayanan et al., 2007) 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 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).  
In vitro studies implicate the role of C5 in inflammasome priming and activation and MAC 
accumulation in RPE cells, leading to their degeneration (Brandstetter et al., 2015; 
Georgiannakis et al., 2015; Li et al., 2010).  The presence of NLRP3 inflammasome and 
inflammasome products IL-1ß and IL-18 inside the RPE cells have been demonstrated in the 
post-mortem eyes of patients with geographic atrophy (Tarallo et al., 2012 and Cao et al., 
2016).  A study of eyes from more than 400 human donors revealed that drusen are intensely 
labelled using antibodies against complement C5 and MAC while multiple complement 
regulatory proteins have also been shown to be present in drusen (Anderson et al., 2002, Bok 
2005). 
The recent pivotal Zimura clinical trial data demonstrated a significant reduction of GA growth 
in patients with AMD over 12 months for both 2 mg and 4mg dose groups (OPH2003).  Further, 
a third-party clinical trial evaluating the role of complement inhibition in GA also showed a 
significant reduction in GA growth in patients with AMD over 12 months, validating the potential 
role of complement inhibition in the treatment of GA secondary to AMD (Liao et al., 2019). 
Preclinical, clinical and genetic studies implicate the potential role of the complement cascade 
in AMD (Bok, 2005; Donoso et al., 2006; Edwards et al., 2005; Hageman et al., 2005; Haines 
et al., 2005, Liao et al., 2019, Brandstetter et al., 2015, Georgiannakis et al., 2015, Liao et al., 
2019, OPH2003).  Inhibition of complement activation may potentially slow down or arrest the 
underlying pathophysiology of macular degeneration.  Thus, molecules involved in regulation 
and inhibition of complement cascade are prime targets for therapeutic intervention in AMD.   
Zimura is currently being developed by IVERIC bio for the treatment of GA secondary to AMD 
and Stargardt disease.  Zimura is a pegylated RNA aptamer.  It is a potent and specific inhibitor 
of complement C5.  Zimura inhibits C5 cleavage, a central component of the complement 


 
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cascade, which plays multiple roles in innate immunity and cell death.  Inhibition of this critical 
step in the complement cascade prevents the formation of key terminal fragments (C5a and 
C5b) regardless of the initial activation pathway (alternate, classical, or lectin).  The C5a 
fragment plays an important role in inflammasome priming and activation leading to pyroptosis 
and cell death.  C5b is involved in the formation of membrane attack complex (MAC: C5b-9) 
which also leads to cell lysis and cell death.  By inhibiting these C5-mediated activities, one 
may slow down the progression of retinal cell degeneration and achieve therapeutic benefit in 
GA secondary AMD. 
In this pivotal clinical trial, the safety and efficacy of Zimura 2 mg will be compared to Sham 
control.  This is based on results of the first pivotal clinical trial (OPH2003), in which both 
Zimura 2 mg and Zimura 4 mg cohorts demonstrated a statistically significant reduction in the 
mean rate of GA growth over 12 months when compared to their corresponding Sham control 
cohorts with a similar efficacy, and Zimura 2 mg is administered as a single intravitreal injection 
vs 2 intravitreal injections for Zimura 4mg. 
In the first pivotal trial, treatment with Zimura 2 mg dose, led to a 27.38% reduction in the mean 
rate of GA growth over 12 months as compared to the corresponding sham control group which 
was highly statistically significant (p-value = 0.0051).  In prior clinical studies, Zimura 2 mg 
dose was generally well-tolerated with no drug-related AEs, drug-related inflammation, or 
endophthalmitis. Therefore, the sponsor believes the risk/benefit assessment is favorable.  
Currently there are no treatments available for patients with geographic atrophy. 
 
 
 
 
 
 
 
 


 
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5 TRIAL OBJECTIVES 
 
Objectives 
The objectives of this study are to evaluate the safety and efficacy of Zimura intravitreal 
administration in patients with geographic atrophy secondary to age-related macular 
degeneration (AMD). 
 
 
Endpoints 
Primary Efficacy Endpoint: 
The mean rate of growth (slope) estimated based on GA area measured by FAF in at least 3 
time points: Baseline, Month 6, and Month 12 (square root transformation) 
 
Safety Endpoints: 
• AEs 
• Vital signs (pulse, systolic and diastolic blood pressure) 
• Ophthalmic variables (BCVA, LLBCVA, IOP, and ophthalmic examination) 
• ECG (12-lead) 
• Laboratory variables (blood: hematology, renal function, hepatic function, and 
electrolytes; urinalysis) 
 
6 TRIAL DESIGN 
Approximately 400 patients will be randomized at Day 1 in a 1:1 ratio to the following monthly 
treatment groups: 
• Zimura 2 mg 
• Sham 
Patients receiving monthly Zimura 2 mg will be re-randomized at Month 12 in a 1:1 
ratio to the following treatment groups 
• Zimura 2 mg administered monthly from Month 12 - Month 23 
• Sham administered at Months 12, 14, 16,18, 20, and 22, and Zimura 2 mg 
administered every other month at Months 13, 15, 17, 19, 21, and 23 


 
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All patients who were initially randomized to Sham (at Day 1) will continue with monthly 
Sham injections through Month 23 
All patients will have a final follow up visit at Month 24 
 
7 PROCEDURES 
 
Refraction, Visual Acuity, and Low Luminance Visual Acuity 
Refraction, Vision Testing, and Low Luminance Vision testing will be performed at all time-
points specified in Section 10.2 “Trial Assessments”.  Retro-illuminated modified Ferris-Bailey 
ETDRS charts are used starting at 4 meters (see Appendix 17.3). 
 
When protocol refraction and best-corrected visual acuity measurement are required by 
the study protocol, this will be performed only by certified visual acuity examiners 
masked to the previous visual acuity measurement and masked 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 for these assessments will be provided by IVERIC bio.  
These assessments should always be performed in the following order; Refraction, Visual 
Acuity, and Low Luminance Visual Acuity. 
 
 
Tonometry  
Tonometry will be performed at all time-points specified in Section 10.2 “Trial Assessments”.  
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, pre-injection on Day 1, 
Month 6, Month12, Month18, Month 24 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.  
 
 


 
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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 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 
 
 
Fundus Photography, Fluorescein Angiography, Fundus 
Autofluorescence, and Optical Coherence Tomography (SD-OCT) 
Color stereoscopic fundus photographs, FA, FAF, and SD-OCT will be performed at all time-
points specified in Section 10.2 “Trial Assessments”.   
An independent and masked Reading Center (RC) will confirm eligibility of patients prior to 
enrollment.  All color fundus photos, FAs, FAFs, and SD-OCTs 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 photography, FA, FAF, and SD-OCT 
procedures.  During the eligibility assessment, if the FAF images were reviewed to be 
ungradable per the independent Reading Center, the FAF images must be repeated 
within 72 hours.  The eligibility decision by the Reading Center is final. 
 
 
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 


 
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(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 woman of child-bearing potential): These laboratory tests will be 
performed at the Screening, Month 6, Month 12, Month 18, and Month 24/EW visit. The total 
blood volume collected per patient for this study is approximately 35 mL.  Additionally, a serum 
or urine pregnancy test will be performed for women of childbearing potential at the visits as 
indicated in Section 3, “Study Assessments”, and in Section 10.2 “Trial Assessments” in 
specified countries. 
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. 
 
 
Vital Signs, Physical Examination and Performance Status (ECOG) 
A physical examination will be performed at Screening and at the Investigator’s discretion 
thereafter.  Assessment of vital signs will be performed at all time-points specified in Section 
10.2 “Trial Assessments”.   
Performance Status (Eastern Cooperative Oncology Group [ECOG]) will be assessed at 
Screening in accordance with Appendix 17.4.  
 
 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at all time-points specified in Section 
10.2 “Trial Assessments”.   
 
 
 
 
  
 
 




 
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contraceptives (i.e., combined oral contraceptive, patch, vaginal ring, injectable, or 
implant), intrauterine devices or intrauterine systems, abstinence as defined by 
refraining from heterosexual intercourse during the entire period of the study and 
until at least 90 days following the last dose of study medication, vasectomy, and 
tubal ligation.  
 
A woman of non-childbearing potential is defined as follows: 
• A woman who has had surgical sterilization (hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy) 
• A woman ≥ 60 years of age 
• A woman ≥ 40 and < 60 years of age who fulfills at least one of the following: 
o A cessation of menses for at least 12 months and a follicle-stimulating 
hormone (FSH) test confirming non-childbearing potential (refer to laboratory 
reference ranges for confirmatory levels) 
o A cessation of menses for at least 24 months without FSH levels confirmed 
If the patient is a woman of childbearing potential, she must have a negative serum 
pregnancy test within 14 days prior to the first injection and have no plans to donate 
ova during the duration of the trial and at least 90 days following the last dose of 
test medication. 
Ireland, Slovakia, United Kingdom, Czech Republic, Poland, France, Italy: If the 
patient is male, he should use a condom and not donate sperm during the time of 
study drug exposure and for 90 days following the last exposure of study drug. 
 
8.2.2.3 Provide written informed consent. 
8.2.2.4 Ability to return for all trial visits for the 24-month duration of the study. 
 
 
Exclusion Criteria 
Patients will not be eligible for the trial if patients cannot attend all trial required visits, or if 
any of the following criteria are present systemically or in the SE: 




 
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infarction or revascularization within last 6 months, ventricular tachyarrhythmias 
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.  
• 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, povidone 
iodine, or hypersensitivity to the active substance or any of the excipients or 
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 
 
Drug Supply  
9.1.1 Zimura 
 
 
 
  
 
 
 
 
  
 
  
 
   
 
 
 




 
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9.1.3 Administration of Study Drug 
An Interactive Randomization Technology (IRT) system will be used to assign masked study 
kits to patients 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 the appropriate 
study medication kit(s) based upon randomized treatment assignment.  Study medication kits 
will be assigned by the unique identifier (kit number) printed on the label.  
 
  
 
 
 
 
   
 
 
  
 
  
 
  
 
9.1.4 Drug Accountability  
A Drug accountability log will be provided by the Sponsor and must be maintained by the 
clinical site.  The drug accountability log must be kept current and must contain the date and 
drug units [kit number(s) dispensed (as indicated by the IRT system), subject number, date of 
dispensation and initials of the dispenser].  
At the end of the study or when indicated by the Sponsor, all unused study medication should 
be destroyed locally by the study site.  Where local laws or site procedures do not permit local 
site destruction the Sponsor will provide instructions for the return of unused medication to a 
local depot.  Sites that destroy study medication locally must be able to produce a certificate 
of destruction upon request of the Sponsor.  
 
9.1.5 Storage 
The Investigator, or an approved representative (e.g. pharmacist), will ensure that all study 
drugs are stored in a secured area, under recommended storage conditions and in accordance 


 
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with applicable regulatory requirements.  
 
 
 
   
 
 
Previous or Concomitant Therapy 
Patients enrolled must be treatment-naïve (no previous treatment for dry or wet 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.   
If wet AMD were to develop during the study, in either the Study Eye or the Fellow Eye, please 
refer to section 10.3 for guidance on the use of concomitant treatment. 
 
10 TRIAL CONDUCT 
 Subject Enrollment 
Before recruitment of patients into the trial, written Institutional Review Board (IRB) or Ethics 
Committee (EC) approval of the protocol and informed consent must be obtained. 
Patients 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 study drug 
should not commence without prior written approval from IVERIC bio or its designee. 
 
 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 patients who 
fulfill all eligibility criteria will be entered into the trial.  


 
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A trained and qualified professional will take the laboratory samples (hematology, renal 
function, hepatic function, electrolytes, complete urinalysis) as well as the serum pregnancy 
test. 
Ocular assessments performed at Baseline (Screening or Day 1), Month 6, Month 12, Month 
18, and Month 24 (and at an Early Withdrawal visit if performed) should be performed pre-
injection on both eyes (OU).  Ocular assessments at all other study visits are performed only 
on the SE. 
The following assessments will be performed during the study:   
 
10.2.1 Screening Assessments - Year 1 
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 
• Vital signs /physical examination/performance status (ECOG – see appendix 
17.4) 
• Medical history 
• Ophthalmologic history (OU) 
• 12-lead ECG 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Fluorescein angiography (OU, transit study eye) 
• Optical coherence tomography (OU)  
• 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.     


 
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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 study drug.   
• Ireland, Slovakia, Poland, France, and the Czech Republic: A urine pregnancy test 
will be performed for any woman of childbearing potential at all monthly study visits at 
which a serum pregnancy test is not done. 
 
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 - 20/320  
 
10.2.3.1 Day 1 Visit  
Pre-injection 
• 
 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Low luminance ETDRS visual acuity (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Italy: Urine pregnancy test for any women of childbearing potential.  
• Confirmation of Day 1 eligibility 
• Randomization 
• Randomized treatment:  Zimura/Sham 
 
 
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  


 
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• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.4 Month 1 + 3 Days (±1 day) 
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 


 
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10.2.3.6 Month 2 + 3 Days (±1 day) 
o Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.8 Month 3 + 3 Days (±1 day)  
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
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 
 


 
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10.2.3.11 
Month 5 (±7 days) 
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.12 
Month 5 + 3 Days (±1 day) 
o 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 
• 
 
• Vital signs 
• 12-Lead ECG 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Low luminance ETDRS visual acuity (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Optical coherence tomography (OU)  
• Fundus autofluorescence (OU) 
• Laboratory tests 
• Serum pregnancy test (if applicable) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 


 
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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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.16 
Month 7 + 3 Days (±1 day) 
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.18 
Month 8 + 3 Days (±1 day)  
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 


 
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10.2.3.19 
Month 9 (±7 days) 
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.20 
Month 9 + 3 Days (±1 day) 
o Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 


 
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• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.24 
Month 11 + 3 Days (±1 day) 
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.25 
Month 12 (±7 days) 
Pre-Injection: End of Year 1 Assessments  
• 
 
• Vital signs 
• 12-lead ECG 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Low luminance ETDRS visual acuity (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Fluorescein angiography (OU, transit study eye) 
• Optical coherence tomography (OU)  
• Fundus autofluorescence (OU) 
• Laboratory tests 
• Serum pregnancy test (if applicable) 
Beginning of the Year 2 Assessments  
• Re-randomization 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
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 


 
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10.2.3.27 
Month 13 (±7 days) 
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.28 
Month 13 + 3 days (±1 day) 
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
10.2.3.30 
Month 14 + 3 Days (±1 day)  
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 


 
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• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.32 
Month 15 + 3 days (±1 day) 
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.34 
Month 16 + 3 days (±1 day)   
• Telephone call to patient 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) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 


 
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10.2.3.36 
Month 17 + 3 Days (±1 day) 
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.37 
Month 18 (±7 days) 
Pre-Injection 
• 
 
• Vital signs 
• 12-lead ECG 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Low luminance ETDRS visual acuity (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Optical coherence tomography (OU)  
• Fundus autofluorescence (OU) 
• Laboratory tests 
• Serum pregnancy test (if applicable) 
• Assigned treatment:  Zimura/Sham  
Post-Injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
10.2.3.38 
Month 18 + 3 Days (±1 day) 
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.39 
Month 19 (±7 days)  
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  


 
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• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.40 
Month 19 + 3 days (±1 day)   
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.41 
Month 20 (±7 days)  
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.42 
Month 20 + 3 days (±1 day)   
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.43 
Month 21 (±7 days)  
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.44 
Month 21 + 3 days (±1 day)   
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 


 
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10.2.3.45 
Month 22 (±7 days)  
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment: Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.46 
Month 22 + 3 days (±1 day)   
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.47 
Month 23 (±7 days)  
Pre-Injection 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
• Optical coherence tomography (SE) 
• Assigned treatment:  Zimura/Sham  
Post-injection 
• Ophthalmic exam (SE):  Must be performed at least 30 minutes after the injection  
• Tonometry (SE):  The IOP should be recorded at least 30 minutes after the injection 
(including Sham) 
 
10.2.3.48 
Month 23 + 3 days (±1 day)   
• Telephone call to patient to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis 
 
10.2.3.49 
Month 24/Early Withdrawal  
• 
 
• Vital signs 
• 12-lead ECG 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 


 
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• Low luminance ETDRS visual acuity (OU) 
• Goldmann applanation tonometry and ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Fluorescein angiography (OU, transit study eye) 
• Optical coherence tomography (OU)  
• Fundus autofluorescence (OU) 
• Laboratory tests 
• Serum pregnancy test (if applicable) 
Adverse events are recorded 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. 
 
 Development of Wet AMD During the Trial 
If the investigator suspects the development of CNV in the study eye, or if the subject has > 5 
EDTRS letters of VA loss between the current visit and the immediate past visit, the 
diagnosis must be assessed with FP, FA and OCT and confirmed by the Duke Reading 
Center prior to initiating anti-VEGF treatment in the study eye. 
For patients who develop CNV in the study eye and the diagnosis is confirmed by the Duke 
Reading Center during the trial, the study eye should be treated with either Lucentis® 
(ranibizumab) or Eylea® (aflibercept) per their label. 
If the investigator plans to administer the anti-VEGF agent on the day of the diagnosis, the 
Duke Reading Center will confirm the diagnosis within 1 hour after receiving the images. If the 
anti-VEGF agent and Zimura/Sham are administered in the SE on the same day, Zimura/Sham 
should be administered first, and the anti-VEGF administered second. The anti-VEGF agent 
may NOT be administered after the Zimura/Sham injection until the IOP is ≤ 21 mmHg or within 
5 mmHg of the baseline IOP on that day (i.e., the “baseline” IOP is the pre-injection IOP before 
the Zimura/Sham administration on that day).  If the IOP is not ≤ 21 mmHg or within 5 mmHg 
of the baseline IOP, the IOP should continue to be monitored until it is ≤ 21 mmHg or within 5 
mmHg of the baseline IOP before proceeding to the anti-VEGF injection.  


 
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For the anti-VEGF agent administration, it is mandatory that, the same injection preparation 
and administration protocol specified for the Zimura administration be followed by an 
unmasked ophthalmologist. Please refer to Appendix 17.5 Intravitreous Administration 
Protocol; for example, the use of aseptic technique, sterile gloves, anesthesia, eye speculum 
and povidone-iodine are required.    
The subject will continue with the study treatment (Zimura or Sham) as scheduled. 
For patients who develop CNV in the fellow eye during the study, the fellow eye should be 
treated with either Lucentis® (ranibizumab) or Eylea® (aflibercept) per their label, with no 
change to study conduct regarding the study eye.  However, if the study eye is treated on 
the same day as the fellow eye, the study eye should be treated before the fellow eye. 
 
 Withdrawal from Trial 
Patients 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 patients from 
the trial in the event of concurrent illness, adverse events (including pregnancy in female 
patients), 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 patients who withdraw.  Patients 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. 
Patients who withdraw for any reason should have assessments performed according to the 
Early Withdrawal schedule.  
 
 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 


 
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Investigator will record the reason for trial discontinuation, provide or arrange for appropriate 
follow-up (if required) for such patients, 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 IVERIC bio.  
The study will be considered completed when the last subject completes the final study visit.   
 
 


 
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11 
STATISTICAL METHODS 
The following summarizes the statistical methods that will be employed in this trial designed to 
compare the effects of Zimura 2 mg dose against the Sham control arm in patients with 
geographic atrophy secondary to AMD.  
 
 Study Design 
This is a randomized, double-masked, Sham-controlled pivotal study that will obtain evidence 
regarding the effects of Zimura 2 mg in reducing the mean rate of GA growth over 12 months, 
when compared with Sham control.   
Approximately 400 patients will be randomized at Day 1 in a 1:1 ratio to the following monthly 
treatment groups: 
• Zimura 2 mg 
• Sham 
Patients receiving monthly Zimura 2 mg will be re-randomized at Month 12 in a 1:1 ratio 
to the following treatment groups: 
• Zimura 2 mg administered monthly from Month 12 - Month 23      
• Sham administered at Months 12, 14, 16,18, 20, and 22, and Zimura 2 mg administered 
every other month at Months 13, 15, 17, 19, 21, and 23 
All patients who were initially randomized to Sham (at Day 1) will continue with monthly Sham 
injections through Month 23. 
All patients will have a final follow up visit at Month 24. 
 
 Endpoints 
11.2.1 Primary Efficacy Endpoint 
Primary Efficacy Endpoint: 
• The mean rate of growth (slope) estimated based on GA area measured by FAF in at 
least 3 time points: Baseline, Month 6, and Month 12 (square root transformation) 
 
11.2.2 Safety and Tolerability Endpoints 
Safety and tolerability endpoints: 


 
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• All adverse events reported, whether or not deemed related to the injection procedure 
or study drug 
• All SAEs, whether or not deemed related to the injection procedure or study drug 
• Laboratory data (blood:  hematology, renal function, hepatic function, and electrolytes; 
urinalysis) 
• Ophthalmic variables (best corrected visual acuity, low luminance best corrected 
visual acuity, IOP, and ophthalmic examination) 
• Vital sign measurements 
• 12-lead ECG 
 
 Determination of Sample Size and Statistical Rationale 
The sample size for this study is based on recently obtained 12-month results of the OPH2003 
pivotal international, multicenter, randomized, double masked, sham-controlled clinical trial 
that was performed to evaluate the safety and efficacy of Zimura in patients with geographic 
atrophy secondary to AMD.  The prespecified primary endpoint, mean change in GA growth 
over 12 months, equivalent to the mean rate of GA growth used in this study, was measured 
by fundus autofluorescence (FAF) based on readings at three time points (Baseline, Month 6, 
and Month 12) and was calculated using the square root transformation of the GA area.  The 
FAF images were assessed by an independent masked reading center.  The reduction in the 
mean rate of GA growth over 12 months was 0.11 mm (p = 0.0072) for the Zimura 2 mg group 
compared to the Sham control group.  
In this Phase 3 trial, the primary analyses will be based on the comparison of the estimated 
reduction in the mean rate of GA growth over 12 months for Zimura 2 mg group versus the 
Sham control group.  By pre-specification, this study will obtain evidence regarding the effect 
of Zimura on the mean rate of growth (slope) estimated based on GA area measured by fundus 
autofluorescence (FAF) in at least 3 time points over 12 months, when compared with Sham 
(square root transformation).  The FAF images will be assessed by an independent masked 
reading center.  The effect of treatment on the square root transformation of the GA area will 
be assessed using a mixed model for  repeated measures model (MMRM) including 
stratification factors. 
A total of approximately 400 patients will be randomized.  If the 2 mg dose of Zimura truly 
provides a 0.11 mm reduction in the mean rate of GA growth over 12 months, then the trial will 
have 97% power to detect that effect at the two-sided significance level of 0.05. Statistical 


 
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significance at the two-sided significance level of 0.05 will be achieved for an estimated 
0.057 mm reduction in the mean rate of GA growth over 12 months. 
 
 Year 2 Data Analysis 
When the 12-month follow-up is complete for the primary analysis, the database will be locked.  
Post-12 month information will remain fully masked until completion of 24-month follow-up.  
 
 Randomization Procedure 
Patients will be centrally allocated to one of the two treatment groups by a dynamic 
minimization procedure using clinical site in a 1:1 ratio stratified by factors known to be of 
prognostic importance in 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) 
Patients initially randomized to Zimura 2 mg at Day 1 will be re-randomized at Month 12 in 1:1 
ratio to Zimura 2 mg monthly vs every other month (please see 11.1 Study Design) using the 
same minimization procedure as for the initial randomization (i.e. using the same factors at 
Baseline).  
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 patients 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.  
 
 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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To maintain masking, the IRT system will provide instructions as to which kit is to be 
administered 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.   
In the case of a rare emergency where, in the Investigator’s 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.  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 patient’s randomized 
treatment assignment.  Any unmasking information must be stored separately from the 
patient'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. 
 
11.6.1 Visual Acuity Assessments  
Since this is a double-masked study, patients 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. 
 
11.6.2 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 any other manner and are not to communicate with any 
other personnel or patients 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. 
 


 
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11.6.3 Statistical Analyses 
All statistical analyses will be performed by a statistical office independent of the study 
Sponsor.  The Sponsor and the patients will remain masked to treatments until the end of the 
study, except if safety considerations justify breaking the code for individual patients. 
 
 Analytical Considerations 
11.7.1 Analytical Plan 
A Statistical Analysis Plan (SAP) will provide the details necessary for the statistical analyses 
to be explicitly pre-specified prior to unmasking, both at Month 12 and at Month 24.  The 
methods for imputation of post-baseline, missing data will be specified in the SAP. 
 
11.7.2 Significance Levels 
The overall two-sided false positive error rate in this trial is 5%. 
 
11.7.3 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 since the lack of a well-defined sampling context would render corresponding p-
values to be uninterpretable.   
 
11.7.4 Efficacy Analysis 
The efficacy analysis will be conducted on all randomized and treated patients according to 
the intention-to-treat principle.  
For normal endpoints, treatment groups will be compared through an analysis of variance 
including stratification factors.  
For binary endpoints, treatment groups will be compared through Mantel-Haenszel or 
Cochran-Mantel-Haenszel χ² tests adjusting for stratification factors. 
 


 
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11.7.5 Subset Analyses 
The trial is not sized to test for the presence of treatment by Baseline covariate interactions.  
Thus, true treatment by Baseline covariate interactions likely will not be rigorously established, 
unless they are quite substantial.  In particular, should any subset of patients seem to benefit 
more or less from therapy than the total population, this will not be taken as reliable evidence 
of a true treatment by Baseline covariate interaction, given the likelihood that such an 
observation readily could be due to chance alone.  With these caveats in mind, exploratory 
subset analyses will be performed as descriptive evidence regarding the generalizability of trial 
results. 
 
11.7.6 Safety Analysis 
The safety analysis will be conducted on all patients who had at least one administration of 
study drug. 
Adverse events will be summarized using MedDRA terms.  The incidence and severity of 
adverse events will be listed and grouped by body system.  
All laboratory data will be listed and values falling outside normal ranges will be identified.  
Summary statistics (i.e., mean, median, standard deviation, minimum and maximum) will be 
presented for all continuous variables.  
Summary statistics will be given on the number of patients for whom the trial medication had 
to be permanently stopped. 
 
12 ADVERSE EVENTS 
 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 be considered when a patient 
requires new or additional treatment for that illness.  Lack of or insufficient clinical response or 
efficacy should not be recorded as an adverse event. 


 
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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. 
 
 Assessment and Reporting of Adverse Events 
Adverse events 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.  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 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 


 
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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 “not related” or “related”  to  one of the following: (1) the 
intravitreous injection procedure (including eyelid speculum, anesthetic drops, mydriatic drops, 
antibiotic drops, povidone-iodine, subconjunctival injection of anesthetic, intravitreous injection 
of Zimura or anti-VEGF), or (2) related to the study drug (Zimura/sham), or (3) related to anti-
VEGF treatment (if administered).  
The adverse relationship will be assessed using the definitions below. The investigator will 
choose either “not related”, or chose the most likely cause of the AE (i.e., only one of the 
relationships noted in the above paragraph may be chosen):  
 
Not Related 
= There is not a reasonable possibility that the adverse 
event is related to the intravitreous injection procedure, or 
to the study drug (Zimura/sham), or to the anti-VEGF 
treatment. 
Related  
=  There is a reasonable possibility that the adverse event is 
related to the intravitreous injection procedure or to the 
study drug (Zimura/sham), or to the anti-VEGF treatment. 
 Definition of Serious Adverse Events 
A serious adverse event is any event that: 
1. Results in death; 
2. Is life-threatening (immediate risk of death); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 


 
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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 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) 


 
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 Assessment and Reporting of Serious Adverse Events 
Serious adverse events 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.  Any serious adverse event occurring at any other time 
after completion of the trial must be promptly reported if a causal relationship to study 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 
 
 Independent Data Monitoring Committee  
An Independent Data Monitoring Committee, consisting of persons who are independent of 
the Sponsor, trial coordination center, data coordination center, regulatory agencies, IRB/EC 
and investigators, and who have no financial, scientific, or other conflict of interest with the 
clinical trial, will meet approximately every  6 months to review aggregate and individual subject 
data related to safety, data integrity and overall conduct of the trial, and provide 
recommendations to continue, modify, or terminate the trial depending upon the analyses. The 
safety data provided to the Committee will be prepared by an independent statistician. 
The Sponsor will ensure the proper conduct of the study, collection of accurate and timely data, 
and promptly report potential safety concerns to the Data Monitoring committee, and 
communicate with regulatory authorities, IRB/EC, and investigators in a manner that maintains 
integrity of the data as necessary. 
 
 Exposure in Utero 
If any trial patient becomes or is found to be pregnant while receiving study 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 


 
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inform the site of the information to be provided. 
 
 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 
 Emergency Equipment 
Each center must adhere to their policies regarding emergency equipment and resuscitation 
procedures that may be in effect at the individual site or institution. 
The sponsor recommends, if applicable for the participating sites, to 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) and to 
ensure that all equipment is within specifications for the duration of the trial.  If applicable, each 
center should follow their written policies regarding resuscitation procedures.  In addition to the 
above, any additional measures in adherence to specific site or institutional policies should be 
followed. 
 
 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 IVERIC bio clinical monitors, or its 
representatives, during scheduled monitoring visits, to auditors during any audits requested by 
IVERIC bio, 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 
IVERIC bio’s clinical monitors, or its representatives, and must be made available to auditors 
and regulatory agencies. 


 
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All case report forms and original source documents including ocular images should be stored 
for a minimum of two years after a marketing application has been approved, or two years after 
formal discontinuation of development of the investigational drug, or five years after completion 
of the trial, whichever is longer.  Documents should not be destroyed without the permission 
of IVERIC bio.  In the event of the Principal Investigator leaving the clinical site, it is the 
Principal Investigator’s responsibility to notify IVERIC bio in writing and to designate which trial 
material will be transferred at the clinical site. 
 
 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 
study.  Drug accountability records will be reviewed during monitoring visits.  Adequate drug 
accountability records include documentation of all study drug supplies received, dispensed to 
trial patients, and returned to IVERIC bio.  
At the end of the study, all drug supplies and documentation will be reviewed and verified by 
the trial monitors.  The sites will be instructed to destroy unused study drug supplies when the 
trial is completed, or the site may choose to return the drug to an IVERIC bio contracted drug 
management facility for destruction.  If the drug is destroyed at the site, the drug accountability 
form must be completed and sent to IVERIC bio for archiving. 
 
 Protocol Compliance 
IVERIC bio 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 IVERIC bio and in 
agreement with the Investigator.  Any such waiver will be documented in writing and provided 
to the Investigator by IVERIC bio.  
 
 
 Ethical Aspects 
Local Regulations/Declaration of Helsinki 


 
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The Investigator will ensure that this trial is conducted in full conformance with the principles 
of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, South Africa, and 
Scotland) and with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the individual.  The trial must fully adhere to the 
principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline (May 9th 
1997) and with local law if it affords greater protection to the subject.  For studies conducted 
in the USA or under US IND, the Investigator will additionally ensure adherence to the basic 
principles of “Good Clinical Practice” as outlined in the current version of 21 CFR, subchapter 
D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Patients”, and part 56, “Institutional Review Boards”. 
Expedited reporting will be conducted in accordance with local legislation. 
 
 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:  
o IRB/EC approval documentation 
o Approved trial patient informed consent 
o A list of IRB/EC members, or statement of compliance 
Prior to enrollment, written informed consent must be obtained from each patient 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. 
 
 Clinical Trial Insurance 
IVERIC bio has insurance coverage for medicine-induced injury and other liabilities incurred 
during clinical trials with its compounds. 
 


 
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 Trial Report and Publications 
The trial will be documented in a final report, which will contain appropriate statistical analysis 
and medical overview.  No individual site or Investigator may publish or present any results 
from the trial until a joint, multi-center publication of the trial results is made by Sponsor in 
conjunction with various participating Investigators and appropriate sites contributing data and 
comments.  Subsequently, individual Investigators may request to publish or present results 
from the trial; however, approval will be at the sole discretion of the Sponsor.  Should the 
foregoing language be in conflict with the language addressing publication in the clinical trial 
agreement, the language in the clinical trial agreement will prevail. 
 
14 MONITORING 
The Investigator will permit representatives of IVERIC bio 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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