Conditions: Geographic Atrophy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 637
Healthy volunteers: no

Brief summary:
This is a 24-month, Phase III, multicenter, randomized, double-masked, sham-injection controlled study to assess the efficacy and safety of multiple IVT injections of APL-2 in subjects with GA secondary to AMD.

Detailed description:

Arms:
arm 1: A single dose of 15 mg APL-2/0.1 mL will be administered via intravitreal injection in this study. Subjects will receive an injection every month arm 2: A single dose of 15 mg APL-2/0.1 mL will be administered via intravitreal injection in this study. Subjects will receive an injection every other month arm 3: Sham Procedure monthly for 24 months arm 4: Sham Procedure every other month for 24 months

Interventions: intervention 1: APL-2 intervention 2: APL-2 intervention 3: Sham Procedure intervention 4: Sham Procedure
Intervention descriptions: intervention 1: Complement (C3) Inhibitor intervention 2: Complement (C3) Inhibitor intervention 3: Subjects will receive a Sham procedure every month intervention 4: Subjects will receive a Sham procedure every other month

Protocol document:
Prot_000.pdf: 
 
 
PEGCETACOPLAN (APL-2) 
PROTOCOL APL2-304 
A PHASE 3, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, SHAM-CONTROLLED STUDY TO 
COMPARE THE EFFICACY AND SAFETY OF 
INTRAVITREAL PEGCETACOPLAN THERAPY WITH 
SHAM INJECTIONS IN PATIENTS WITH 
GEOGRAPHIC ATROPHY (GA) SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION (AMD) 
 
US IND No.: 124784 
EudraCT No.: 2018-001435-52 
Phase: 3 
Version: Amendment 5 
Date: 12 August 2020  
Confidentiality Statement 
This document is confidential. It contains proprietary information of Apellis Pharmaceuticals, 
Inc. Any viewing or disclosure of such information that is not authorized in writing by Apellis 
Pharmaceuticals, Inc, is strictly prohibited. Such information may be used solely for the purpose 
of reviewing or performing this study. 
Apellis Pharmaceuticals, Inc
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
INVESTIGATOR AGREEMENT 
Long Title:  
A Phase 3, Multi-Center, Randomized, Double-
Masked, Sham-Controlled Study to Compare the 
Efficacy and Safety of Intravitreal Pegcetacoplan 
Therapy with Sham Injections in Patients with 
Geographic Atrophy (GA) Secondary to Age-
Related Macular Degeneration (AMD) 
Short Title:  
Oaks 
Protocol Number, Version, and Date: 
APL2-304 / Amendment 5 / 12 August 2020  
Study Phase:  
Phase 3  
Sponsor Name and Address:  
Apellis Pharmaceuticals, Inc 
 
100 5th Ave 
 
Waltham, MA 02451 
 
USA  
Investigational Test Article:  
Pegcetacoplan intravitreal injection (also known as 
APL-2) 
US IND Number: 
124784 
EudraCT Number: 
2018-001435-52 
Indication Studied: 
Geographic atrophy secondary to age-related 
macular degeneration 
Investigator Agreement: 
I have read the clinical study described herein, 
recognize its confidentiality, and agree to conduct 
the described trial in compliance with Good Clinical 
Practice (GCP), the ethical principles contained 
within the Declaration of Helsinki, this protocol, 
and all applicable regulatory requirements.  
 
 
Principal Investigator:  
 
Name: ____________________________________ 
 
 
Signature: _________________________________  
 
 
Date: ______/______/______ (DD/MMM/YYYY) 
 
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 5: Summary of Changes From the Previous Version  
Amendment Date: 12 August 2020 
Updates to the protocol implemented in this amendment are provided in the table below.  
Description of change 
Section(s) affected by change 
Nonsubstantial changes that did not impact content of the document have 
been made for clarity. 
Entire document 
Updated company address 
Investigator Agreement and Sponsor 
Information 
Changed APL-2 to International Nonproprietary Name: pegcetacoplan, 
updated related abbreviations and protocol title 
Entire document 
Added the descriptor “maximum” when referencing reading speed 
Synopsis, Section 5.1.2, 
Section 5.1.5, Section 12.7.2, 
Section 12.7.3 
Removed the 6-month follow-up period and updated the study length 
from 30 months to 24 months and made it a 30- or 60-day follow-up 
period based on treatment group because that length of time is deemed 
sufficient to evaluate the safety of pegcetacoplan based on its half-life in 
the vitreous. Additionally, there is an option for subjects to enroll in a 
separate extension study (Study APL2-GA-305) during which longer-
term safety and efficacy will be collected. 
Synopsis, Section 8, 
Section 8.1.3.2.1, Section 11.8 
Inclusion criterion 6c was updated from “Reliability test ratio must be 
≤20%” to “Fixation losses must be ≤20%” on the basis of regulatory 
feedback provided to the microperimetry device manufacturer 
Synopsis, Section 6.1.1 
Updated the text regarding the sample size to both simplify and reduce 
redundancies 
Synopsis, Section 12.5 
Previous Section 4.1.3.1, Pharmacokinetics, moved to Section 4.1.3.2 to 
follow Section 4.1.3.1, Toxicology 
Section 4.1.3.1, Section 4.1.3.2 
Updated the formulation information 
Section 4.1.2, Section 7.3.3.1 
Revised number of injections for each treatment arm because the 
injections at Month 24 will no longer be administered 
Section 7.3.1 (Table 1), Section 8 
Updated the text regarding endophthalmitis for clarity 
Section 7.5.3 
Updated Study Schema 
Section 8 
Revised Study Procedures based on the removal of the Month 24 
injection and the 6-month follow-up period 
Section 8 
Revised the language regarding genotyping samples to indicate that these 
samples will be collected only for subjects who consent to the analysis 
Section 9.7 
Updated the language within the Adverse Events definition section to be 
consistent with the new Apellis standard language 
Section 11.1 
Updated the language within the Recording Adverse Events section to be 
consistent with the new Apellis standard language 
Section 11.2 
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
Removed the section on Treatment and Follow-up of Adverse Events 
because the information contained within it is now included in other 
revised sections to align with new Apellis standard language 
Section 11.3 
Updated the language within the Reporting Adverse Events section to be 
consistent with the new Apellis standard language 
Section 11.3 
Updated the language within the Serious Adverse Events section to be 
consistent with the new Apellis standard language 
Section 11.4 
Removed the section on Unexpected Adverse Events or Unexpected 
Suspected Adverse Reactions because the information contained within it 
is now included in other revised sections to align with new Apellis 
standard language 
previously Section 11.6 
Updated the language within the Pregnancy section to be consistent with 
the new Apellis standard language 
Section 11.6 
Removed APL-2 investigator’s brochure from references 
Section 15 
Updated Footnote G and M 
Appendix A, Appendix B, 
Appendix C, Appendix D, and 
Appendix K 
Deleted follow-up visits from Schedules of Activities 
Appendix B and Appendix D, and 
Table B and Table D of Appendix K 
Deleted pegcetacoplan and sham administration and postinjection 
assessment from Visit 20 of the Schedule of Activities for monthly and 
every-other-month treatment groups Month 13 to Month 24 
Appendix B and Appendix D and 
Tables B and D of Appendix K 
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
1. 
TABLE OF CONTENTS  
 
INVESTIGATOR AGREEMENT...................................................................................................2 
SPONSOR INFORMATION ..........................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
1. 
TABLE OF CONTENTS .............................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
2. 
SYNOPSIS .................................................................................................................12 
3. 
ABBREVIATIONS ....................................................................................................20 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Background .................................................................................................................23 
4.1.1. 
Age-Related Macular Degeneration .....................................................................23 
4.1.2. 
Pegcetacoplan .......................................................................................................23 
4.1.3. 
Nonclinical Data ...................................................................................................24 
 
 
 
 
4.1.4. 
Clinical Data .........................................................................................................27 
4.1.5. 
Rationale ...............................................................................................................28 
4.1.5.1. 
Rationale for Pegcetacoplan for Treatment of Geographic 
Atrophy .....................................................................................................28 
4.1.6. 
Dose Selection ......................................................................................................28 
4.2. 
Risk/Benefit ................................................................................................................28 
5. 
STUDY OBJECTIVES ..............................................................................................30 
5.1.1. 
Primary Objective .................................................................................................30 
5.1.2. 
Key Secondary Objectives ....................................................................................30 
5.1.3. 
Secondary Objectives ...........................................................................................30 
5.1.4. 
Safety Objectives ..................................................................................................30 
5.1.5. 
Exploratory Objectives .........................................................................................31 
6. 
PATIENT POPULATION ..........................................................................................32 
6.1.1. 
Inclusion Criteria ..................................................................................................32 
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12 August 2020 
6.1.2. 
Exclusion Criteria .................................................................................................33 
6.2. 
Women of Childbearing Potential ..............................................................................34 
6.3. 
Women of Nonchildbearing Potential ........................................................................34 
6.4. 
Approved Methods of Contraception .........................................................................34 
6.5. 
Discontinuation of Subjects ........................................................................................35 
7. 
TREATMENT OF SUBJECTS ..................................................................................36 
7.1. 
Allocation to Treatment ..............................................................................................36 
7.2. 
Masking and Minimization of Bias ............................................................................36 
7.2.1. 
Unmasking ............................................................................................................37 
7.3. 
Dosage and Administration ........................................................................................37 
7.3.1. 
Dose Levels and Treatment Arms ........................................................................37 
7.3.2. 
Treatment Administration .....................................................................................37 
7.3.3. 
Drug Supplies .......................................................................................................38 
7.3.3.1. 
Identity of Investigational Product ...........................................................38 
7.3.3.2. 
Storage ......................................................................................................38 
7.3.3.3. 
Accountability ...........................................................................................38 
7.3.4. 
Intravitreal Pegcetacoplan Administration ...........................................................39 
7.4. 
Sham Injection Administration ...................................................................................39 
7.5. 
Concomitant Therapies ...............................................................................................39 
7.5.1. 
Treatment of New Exudation Related to Active Choroidal 
Neovascularization in the Study Eye and/or Fellow Eye ...............................39 
7.5.2. 
Prohibited Therapies .............................................................................................40 
7.5.3. 
Endophthalmitis Treatment ..................................................................................40 
8. 
STUDY PROCEDURES ............................................................................................42 
8.1. 
Study Visit Schedule ...................................................................................................43 
8.1.1. 
Screening Period—Within 28 Days Prior to Randomization/ Treatment 
(Day –28 to –1) ...............................................................................................43 
8.1.1.1. 
Visit 1—All Subjects ................................................................................43 
8.1.2. 
Randomization/ Initial Treatment—Day 1—Within 28 Days of 
Screening ........................................................................................................44 
8.1.2.1. 
Visit 2—All Groups ..................................................................................44 
8.1.3. 
Treatment Phase—24 Months ..............................................................................44 
8.1.3.1. 
Months 1-12 ..............................................................................................44 
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8.1.3.2. 
Months 13-24 ............................................................................................45 
8.1.4. 
Early Termination Visit ........................................................................................46 
8.1.5. 
Unscheduled Visits ...............................................................................................46 
9. 
ASSESSMENTS.........................................................................................................47 
9.1. 
Informed Consent .......................................................................................................47 
9.2. 
Demographic Information/ Medical/ Surgical History ...............................................47 
9.3. 
Ocular History/ Ocular Procedures .............................................................................47 
9.4. 
Vital Signs ..................................................................................................................47 
9.5. 
Physical Examination .................................................................................................47 
9.6. 
Laboratory Analysis of Blood and Urine ....................................................................47 
9.7. 
Genotyping Samples ...................................................................................................48 
9.8. 
Urine Pregnancy Test .................................................................................................48 
9.9. 
Patient-Reported Outcomes ........................................................................................49 
9.9.1. 
The National Eye Institute Visual Functioning Questionnaire 25-Item 
Version (NEI-VFQ) ........................................................................................49 
9.9.2. 
The Functional Reading Independence (FRI) Index ............................................49 
9.10. 
Best Corrected Visual Acuity and Low Luminance Best Corrected Visual 
Acuity ...................................................................................................................49 
9.11. 
Minnesota Low-Vision Reading (MNREAD) Test or Radner Reading Charts 
(in select countries) ...............................................................................................50 
9.12. 
Home-Based Functional Digital Applications (optional, select sites) ........................50 
9.13. 
Complete Ophthalmic Exam .......................................................................................50 
9.14. 
Ocular Imaging and Microperimetry ..........................................................................50 
9.15. 
Postinjection Assessment............................................................................................51 
9.16. 
Blood Volume for Study Assessments .......................................................................52 
9.17. 
Samples for Clinical Repository (Optional, Select Sites) ...........................................52 
9.17.1. 
Approval by the Institutional Review Board or Ethics Committee ................53 
9.17.2. 
Sample Collection ...........................................................................................53 
9.17.3. 
Confidentiality and Data Ownership ..............................................................53 
9.17.4. 
Consent to Participate in the Clinical Repository ...........................................54 
9.17.5. 
Withdrawal From the Clinical Repository ......................................................54 
9.17.6. 
Monitoring and Oversight...............................................................................54 
10. 
SAFETY EVALUATIONS ........................................................................................55 
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10.1. 
Data Monitoring Committee .......................................................................................55 
11. 
ADVERSE EVENTS..................................................................................................56 
11.1. 
Definition ....................................................................................................................56 
11.2. 
Recording Adverse Events .........................................................................................56 
11.3. 
Reporting Adverse Events ..........................................................................................57 
11.3.1. 
Relationship of Events to Study Treatment ....................................................57 
11.3.2. 
Severity of Events ...........................................................................................57 
11.4. 
Serious Adverse Events ..............................................................................................58 
11.5. 
Treatment and Follow-up of Adverse Events .............................................................58 
11.6. 
Pregnancy ...................................................................................................................59 
11.7. 
Disease Progression ....................................................................................................59 
11.8. 
Withdrawal .................................................................................................................59 
12. 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS ....................60 
12.1. 
Data Collection ...........................................................................................................60 
12.2. 
Clinical Data Management .........................................................................................60 
12.3. 
Statistical Analysis Process ........................................................................................60 
12.4. 
Planned Interim Analysis and Data Safety Monitoring Committee ...........................60 
12.5. 
Sample Size Calculation and Power Considerations ..................................................61 
12.6. 
Statistical Analysis Sets ..............................................................................................61 
12.7. 
Efficacy Analyses .......................................................................................................62 
12.7.1. 
Primary Efficacy Analysis ..............................................................................62 
12.7.2. 
Secondary Efficacy Analysis ..........................................................................63 
12.7.3. 
Exploratory Efficacy Analysis ........................................................................64 
12.8. 
Safety Analyses ..........................................................................................................64 
12.8.1. 
Anti-Therapeutic Antibodies ..........................................................................65 
12.8.2. 
Death ...............................................................................................................65 
12.8.3. 
Ocular Assessments ........................................................................................65 
12.9. 
Handling of Missing Data ...........................................................................................65 
12.10. Visit Windows ............................................................................................................65 
13. 
ETHICS ......................................................................................................................66 
13.1. 
Ethical Conduct of the Study ......................................................................................66 
13.2. 
Institutional Review Board/Ethic Committee .............................................................66 
13.3. 
Subject Information and Consent ...............................................................................66 
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APL2-304 Protocol Amendment 5 
12 August 2020 
14. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................67 
14.1. 
Direct Access to Source Data/Documents ..................................................................67 
14.2. 
Quality Control and Quality Assurance ......................................................................67 
14.3. 
Monitoring ..................................................................................................................67 
14.4. 
Data Handling and Record Keeping ...........................................................................67 
14.5. 
Protocol Amendments ................................................................................................68 
14.6. 
Report Format .............................................................................................................68 
14.7. 
Finance and Insurance ................................................................................................68 
14.8. 
Publication Policy .......................................................................................................68 
14.9. 
ClinicalTrials.gov .......................................................................................................69 
14.10. Termination of Study ..................................................................................................69 
15. 
REFERENCES ...........................................................................................................70 
16. 
APPENDICES ............................................................................................................72 
APPENDIX A: VISIT SCHEDULE—Monthly Group—Screening, Day 1 through 
Month 12 ...............................................................................................................72 
APPENDIX B: VISIT SCHEDULE—Monthly Group—Month 13 to Month 24 ..................75 
APPENDIX C: VISIT SCHEDULE—Every-Other-Month Group—Screening, Day 1 
Through Month 12 ................................................................................................78 
APPENDIX D: VISIT SCHEDULE—Every-Other-Month Group—Month 13 to 
Month 24 ...............................................................................................................81 
APPENDIX E: NATIONAL EYE INSTITUTE VISUAL FUNCTIONING 
QUESTIONNAIRE 25-ITEM VERSION ............................................................84 
APPENDIX F: FUNCTIONAL READING INDEPENDENCE INDEX (FRI) ...................101 
APPENDIX G: MINNESOTA LOW-VISION READING TEST (MNREAD) AND 
RADNER READING CARDS...........................................................................102 
APPENDIX H: GRADING SCALE FOR ASSESSMENT OF ANTERIOR 
CHAMBER FLARE OR CELLS .......................................................................103 
APPENDIX I: GRADING SCALE FOR ASSESSMENT OF VITREOUS CELLS ............105 
APPENDIX J: AMENDMENT HISTORY ...........................................................................106 
APPENDIX K: PROTOCOL CHANGES TO BE FOLLOWED DURING COVID-
19 RESTRICTIONS ...........................................................................................118 
 
 
 
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APL2-304 Protocol Amendment 5 
12 August 2020 
 
LIST OF TABLES 
Table 1:  Treatment Arms with Approximate Number of Subjects ...............................................37 
Table 2:  Laboratory Sampling and Analysis ................................................................................48 
Table 3:  Total Study Blood Volume .............................................................................................52 
Table 4:  Power to Detect a Difference Among 3 Groups With an Equal Size of 
200 Subjects ................................................................................................................61 
 
LIST OF FIGURES 
Figure 1:  Study Schema ................................................................................................................42 
 
 
 
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APL2-304 Protocol Amendment 5 
12 August 2020 
2. 
SYNOPSIS 
Study Title 
A Phase 3, Multicenter, Randomized, Double-Masked, Sham-Controlled Study to Compare the Efficacy and Safety 
of Intravitreal Pegcetacoplan Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary 
to Age-Related Macular Degeneration (AMD) 
Protocol Number, Version, and Date 
APL2-304/ Amendment 5/ 12 August 2020 
Investigational Product, Dose, and Route of Administration 
• 
Pegcetacoplan (also known as APL-2) 
• 
15 mg/0.1 mL 
• 
Intravitreal (IVT) Injection 
Study Arms 
Arm 
Abbreviation 
Randomization 
Pegcetacoplan 15 mg/0.1 mL monthly for 24 months 
PM 
2 
Pegcetacoplan 15 mg/0.1 mL every other month for 24 months 
PEOM 
2 
Sham monthly for 24 months 
SM 
1 
Sham every other month for 24 months 
SEOM 
1 
Study Phase and Type 
Phase 3, multicenter, randomized, double-masked, sham-injection controlled 
Number of Subjects and Sites 
• 
Approximately 600 subjects 
• 
Approximately 100 sites 
Objectives  
Primary   
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA secondary to AMD 
assessed by change in the total area of GA lesions from baseline as measured by FAF. 
Key Secondary 
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA secondary to AMD with 
respect to: 
• 
Monocular maximum reading speed (study eye), as assessed by Minnesota Low-Vision Reading Test 
(MNREAD) or Radner Reading Charts (in select countries) 
• 
Functional Reading Independence (FRI) index score 
• 
Normal luminance best corrected visual acuity score (NL-BCVA) in the study eye  
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Secondary: 
• 
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA secondary 
to AMD with respect to: 
o 
Low luminance best corrected visual acuity score (LL-BCVA) in the study eye  
o 
Low luminance deficit (LLD) in the study eye 
o 
Total area of GA lesion(s) in the study eye 
o 
Monocular critical print size (study eye), as assessed by MNREAD or Radner Reading Charts 
(in select countries)  
o 
National Eye Institute Visual Functioning Questionnaire 25 Item Version (NEI VFQ-25) 
distance activity subscale score (in select countries) 
o 
Macular functional response as assessed by mesopic microperimetry  
Safety: 
• 
To evaluate the safety and tolerability of pegcetacoplan compared to sham injection in patients with 
GA secondary to AMD as indicated by: 
o 
Incidence and severity of ocular and systemic treatment-emergent adverse events 
o 
Incidence of anti-therapeutic antibodies directed against pegcetacoplan 
o 
Incidence of new active CNV in the study eye 
Exploratory 
• 
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA secondary 
to AMD as indicated by: 
o 
NEI VFQ-25 composite score  
o 
NEI VFQ-25 near activity subscale score (in select countries) 
o 
Comparison between study eye and fellow eye in change in GA lesion size  
o 
To evaluate the binocular maximum reading speed as assessed by MNREAD or Radner 
Reading Charts (in select countries) 
o 
To evaluate the binocular critical print size as assessed by MNREAD or Radner Reading 
Charts (in select countries) 
• 
To evaluate the relationship between genetic polymorphisms associated with AMD with GA 
progression and response to pegcetacoplan 
• 
To evaluate the incidence of new onset of subclinical CNV in the study eye  
• 
To assess sensitivity and specificity of a digital reading speed application to detect disease progression 
/ regression (optional, select sites) 
• 
To assess sensitivity and specificity of a digital visual function application to detect disease 
progression / regression (optional, select sites) 
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Inclusion Criteria 
The study eye must meet all inclusion criteria. If both eyes meet the inclusion criteria, the eye with the worst visual 
acuity at the screening visit will be designated as the study eye. If both eyes have the same visual acuity, the right 
eye will be selected as the study eye. 
Ocular-specific inclusion criteria apply to the study eye only, unless otherwise specified. 
1. Age ≥60 years. 
2. Normal Luminance best corrected visual acuity of 24 letters or better using Early Treatment Diabetic 
Retinopathy Study (ETDRS) charts (approximately 20/320 Snellen equivalent). 
3. Clinical diagnosis of GA of the macula secondary to AMD as determined by the investigator and confirmed 
by the reading center. 
4. The GA lesion must meet the following criteria as determined by the central reading center’s assessment of 
fundus autofluorescence (FAF) imaging at screening: 
a. 
Total GA area must be ≥2.5 and ≤17.5 mm2 (1 and 7 disk areas [DA] respectively) 
b. If GA is multifocal, at least 1 focal lesion must be ≥1.25 mm2 (0.5 DA), with the overall aggregate area 
of GA as specified above in 4a. 
c. 
The entire GA lesion must be completely visualized on the macula centered image and must be able to 
be imaged in its entirety and not contiguous with any areas of peripapillary atrophy. 
d. Presence of any pattern of hyperautofluorescence in the junctional zone of GA. Absence of 
hyperautofluorescence (ie, pattern = none) is exclusionary.1 
5. Adequate clarity of ocular media, adequate pupillary dilation, and fixation to permit the collection of good 
quality images as determined by the investigator.  
6. Meets the following criteria related to microperimetry:  
a. 
Able to detect fixation target. 
b. Total elapsed time to complete the 10-2 68-point exam is ≤30 minutes in duration.  
c. 
Fixation losses must be ≤20%.  
d. Subject is willing and able to undertake microperimetry assessment in the opinion of the investigator.  
7. Female subjects must be: 
a. 
Women of non–childbearing potential (WONCBP), or 
b. Women of childbearing potential (WOCBP) with a negative serum pregnancy test at screening and 
must agree to use protocol defined methods of contraception for the duration of the study and refrain 
from breastfeeding for the duration of the study. 
8. Males with female partners of childbearing potential must agree to use protocol defined methods of 
contraception and agree to refrain from donating sperm for the duration of the study. 
9. Willing and able to give informed consent and to comply with the study procedures and assessments.  
Exclusion Criteria 
Ocular specific exclusion criteria apply to the study eye only, unless otherwise specified. 
1. GA secondary to a condition other than AMD such as Stargardt disease, cone rod dystrophy, or toxic 
maculopathies like plaquenil maculopathy in either eye. 
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2. Spherical equivalent of the refractive error demonstrating > 6 diopters of myopia or an axial length 
>26 mm. 
3. Any history or active choroidal neovascularization (CNV), associated with AMD or any other cause, 
including any evidence of retinal pigment epithelium rips or evidence of neovascularization anywhere 
based on SD-OCT imaging and/or fluorescein angiography as assessed by the reading center. 
4. Presence of an active ocular disease that in the opinion of the investigator compromises or confounds visual 
function, including but not limited to, uveitis, other macular diseases (eg, clinically significant epiretinal 
membrane [ERM], full thickness macular hole or uncontrolled glaucoma/ocular hypertension). Benign 
conditions in the opinion of the investigator such as peripheral retina dystrophy are not exclusionary. 
5. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization.  
6. History of laser therapy in the macular region. 
7. Aphakia or absence of the posterior capsule. Note: YAG laser posterior capsulotomy for posterior capsule 
opacification done at least 60 days prior to screening is not exclusionary. 
8. Any ocular condition other than GA secondary to AMD that may require surgery or medical intervention 
during the study period or, in the opinion of the investigator, could compromise visual function during the 
study period.  
9. Any contraindication to IVT injection including current ocular or periocular infection.  
10. History of prior intravitreal injection. 
11. Unable to perform microperimetry reliably in the opinion of the investigator. 
12. Prior participation in another interventional clinical study for intravitreal therapies in either eye (including 
subjects receiving sham).  
13. Prior participation in another interventional clinical study for geographic atrophy in either eye including 
investigational oral medication and placebo. 
14. Participation in any systemic experimental treatment or any other systemic investigational new drug within 
6 weeks or 5 half-lives of the active ingredient (whichever is longer) prior to the start of study treatment. 
Note: clinical trials solely involving observation, over-the-counter vitamins, supplements, or diets are not 
exclusionary.  
15. Medical or psychiatric conditions that, in the opinion of the investigator, make consistent follow-up over 
the 24-month treatment period unlikely, or would make the subject an unsafe study candidate. 
16. Any screening laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of the 
investigator is clinically significant and not suitable for study participation. 
17. Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to pegcetacoplan or any of 
the excipients in pegcetacoplan solution.  
Study Design 
This is a 24-month, Phase 3, multicenter, randomized, double-masked, sham-injection controlled study to assess the 
efficacy and safety of multiple IVT injections of pegcetacoplan in subjects with GA secondary to AMD. 
The study will randomize approximately 600 subjects across approximately 100 multinational sites. Subjects will be 
screened within 28 days before receiving pegcetacoplan or sham injection. Upon entry into the study, subjects will 
be assigned a screening number. Subjects who meet all inclusion and none of the exclusion criteria will return to the 
clinic for randomization and treatment on Visit 2 (Day 1). At this visit, subjects will be randomized 2:2:1:1 to 
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receive pegcetacoplan monthly, pegcetacoplan every other month, sham injection monthly, or sham injection every 
other month, respectively. Randomization will be stratified according to GA lesion area at screening (< 7.5 mm2; ≥ 
7.5 mm2), and presence of CNV in the fellow eye. 
All subjects will be assessed monthly during the first 12 months regardless of treatment regimen. From Month 12 to 
Month 24, subjects will follow the outlined visit schedule (Appendix A to Appendix D) based on treatment 
assignment (ie, subjects in the monthly groups will be assessed monthly while subjects in the every-other-month 
[EOM] groups will be assessed every other month). The last visit in the study will be at Month 24, approximately 30 
days (monthly treatment group) or 60 days (EOM treatment group) after the last visit at which investigational 
product is administered.  At the end of the 24-month study period, subjects will have the option to enroll into a 
separate open-label study.  
Subjects who discontinue study treatment can continue participation in the study and should be encouraged to return 
to the clinical site for as many follow-up visits as they can (with the exception of pegcetacoplan/sham 
administration). Subjects who wish to fully withdraw from the study before Month 24, should be encouraged to 
complete the early termination visit. 
Endpoints and statistical analysis: 
Endpoints 
Primary Efficacy Endpoint 
• 
Change from baseline to Month 12 in total area of GA lesion(s) in the study eye (in mm2) based on 
fundus autofluorescence (FAF).  
Key Secondary Efficacy Endpoints 
• 
Change from baseline in monocular maximum reading speed (study eye), as assessed by MNREAD or 
Radner Reading Charts at Month 24 (in select countries) 
• 
Change from baseline in Functional Reading Independence (FRI) index score, at Month 24. 
• 
Change from baseline in normal luminance best corrected visual acuity score (NL-BCVA) at Month 24 
as assessed by ETDRS chart.  
Secondary Efficacy Endpoints 
• 
Change from baseline in low luminance best corrected visual acuity score (LL-BCVA) at Month 12 
and Month 24 as assessed by ETDRS chart.  
• 
Change from baseline in low luminance deficit (LLD) at Month 12 and Month 24. 
• 
Change from baseline at each planned assessment in the total area of GA lesion(s) in the study eye (in 
mm2) as assessed by FAF. 
• 
Change from baseline in monocular critical print size (study eye), as assessed by MNREAD or Radner 
Reading Charts, at Month 12 and Month 24 (in select countries).  
• 
Change from baseline in the National Eye Institute Visual Functioning Questionnaire 25-Item Version 
(NEI VFQ-25) distance activity subscale score at Month 12 and Month 24 (in select sites).  
• 
Number of scotomatous points assessed by mesopic microperimetry for the evaluation of the macular 
functional response.  
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• 
Change in macular sensitivity as assessed by mesopic microperimetry for the evaluation of the macular 
functional response. 
Exploratory Endpoints   
• 
Change from baseline in NEI VFQ-25 composite score at Month 12 and Month 24.  
• 
Change from baseline in NEI VFQ-25 near activity subscale score at Month 12 and Month 24 (in 
select countries). 
• 
Comparison between study eye and fellow eye in change in GA lesion size from baseline to Month 12 
and Month 24.  
• 
Binocular maximum reading speed as assessed by MNREAD or Radner Reading Charts over time (in 
select countries).  
• 
Binocular critical print size as assessed by MNREAD or Radner Reading Charts over time (in select 
countries). 
• 
Relationship between genetic polymorphisms associated with AMD with GA progression and response 
to pegcetacoplan. 
• 
Incidence of new onset of subclinical CNV in the study eye.  
• 
Assess sensitivity and specificity of a digital reading speed application to detect disease progression / 
regression (optional, select sites). 
• 
Assess sensitivity and specificity of a digital visual function application to detect disease progression / 
regression (optional, select sites). 
Safety Endpoints 
• 
Incidence and severity of ocular and systemic treatment-emergent adverse events.  
• 
Incidence of anti-therapeutic antibodies directed against pegcetacoplan. 
• 
Incidence of new active CNV in the study eye. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Month 12 in the total area of GA lesion(s) in eyes 
injected with pegcetacoplan, either monthly (PM) or every-other month (PEOM), or sham injections. GA lesion area 
(mm2) as measured by a quantified central reading center based on FAF images. The primary analysis will be the 
comparison of pegcetacoplan, either monthly (PM) or every-other month (PEOM) versus the combined 2 sham arms 
(the 2 sham arms will be combined into a single ‘control’ group). 
The null and alternative hypotheses for the primary efficacy analysis are: 
H0: µS = µPM   vs  
HA:  µS ≠ µPM , and 
H0: µS = µPEOM  vs  
HA:  µS ≠ µPEOM  
Note: here µ indicates each group’s respective mean change from baseline to Month 12 in GA lesion area for the 
comparison of the primary endpoint. 
A mixed effect model for longitudinal data will be used to analyze the change from baseline in GA lesion area. The 
model will include treatment, and presence of CNV in the fellow eye as fixed effects; baseline GA lesion area (at 
screening), time (in months) as a factor; as well as the time × treatment interaction term. All available data up to 12 
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months will be included in the model for the primary analysis. The mean change from baseline to 12 months will be 
estimated from the model (ie, least square [LS] mean) and compared between each of the pegcetacoplan arms to the 
sham control. For other time point of interest, LS mean change from baseline will be estimated and compared 
between treatments. Unstructured variance covariance will be used, 
For the analysis of final study data, a similar model including data up to 24 months will be used and LS means at 
time points of interest will be estimated and compared between treatment. 
This study is expected to have an approximately 5 DMC data reviews. Allocating an alpha level of 0.0001 for each 
DMC data review, the alpha level remains for the efficacy analysis at 0.0495 to maintain an overall study alpha of 
0.05. 
The hypothesis testing strategy for the primary and secondary efficacy endpoints will be based on the Gate-keeping 
multiple testing procedures controlling for the study wide type I error strongly at 2-sided 0.0495 as follows:  
Step 1. The mean GA lesion growth at 12 months will be compared between the PM group and the Control at 
the α level of 0.0495. If the null hypotheses of no difference between groups in this step is rejected, the testing 
proceeds to Step 2 and Step 3. If it’s not rejected, the testing procedure stops at this step.  
Step 2. The mean GA lesion growth at 12 months will be compared between the PEOM group and the Control 
at the α1 level. If the null hypotheses of no difference between groups in this step is rejected, the α1 level will 
be passed down to Step 3. The actual value of α1 will be specified in the SAP and it will be defined to ensure 
an adequate power of at least 80% for the comparison in this step. 
Step 3. The mean GA lesion growth at 24 months will be compared between the PM group and the Control at 
the α level of 0.0495 if the null hypotheses are rejected at both Step 1 and Step 2; or at the α level of (0.0495 – 
α1) if Step 2 testing does not reject the null hypothesis. If the null hypothesis at this step is rejected, the α level 
used at this step will be passed down to the next step of testing. If it’s not rejected, the testing procedure stops at 
this step.  
Step 4. The prioritization and alpha allocation for the remaining secondary endpoints will be specified in the 
SAP. 
The following sensitivity and supportive analyses will be performed to evaluate the robustness of the results from 
the primary analysis method: 
• 
Analyses will be repeated using the mITT and per-protocol sets 
• 
Primary and secondary endpoints will also be summarized with no pooling of the 2 sham arms. The 
comparison for pegcetacoplan and sham injection within each dose regimen (ie, PM vs SM and PEOM 
vs SEOM) will be conducted 
• 
Multiple imputation (MI) methods and other sensitivity analyses will be explored, and details will be 
provided in the SAP 
Analysis for Key Secondary and Secondary Endpoint(s) 
The key secondary and secondary endpoints will be analyzed in the same fashion as the primary endpoint using 
mixed effect model. The binary secondary endpoints will be analyzed using Cochran-Mantel-Haenszel test stratified 
by the randomization stratification factors. Hypothesis testing for 3 key secondary endpoints will be performed in 
the order specified. The SAP will provide more details on multiplicity adjustment and the approach for alpha 
spending among the endpoints.  
Sample Size Justification 
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Subjects will be randomized in a 2:2:1:1 ratio to receive treatment with pegcetacoplan monthly, pegcetacoplan every 
other month, sham monthly, or sham every other month. The annual growth rate in GA lesion area is expected to 
have a mean of 1.47, 1.70 and 2.13 mm2/year for pegcetacoplan monthly, pegcetacoplan every-other-month, and 
sham-pooled groups, respectively, as estimated from the results of a Phase 2 trial for pegcetacoplan. The standard 
deviation of the lesion growth is estimated to be 1.50 mm2 based on the same Phase 2 trial data or 1.25 mm2 based 
on natural history data.27 ie, With a sample size of 200 subjects in each group (ie, a total enrollment of 600 subjects) 
and the observed annual growth rate in GA lesion area from Phase 2 trial for pegcetacoplan, the study will have 
99.2% power to show the difference between PM and sham group and 81.5% power to show the difference between 
PEOM and sham group using the common standard deviation of 1.5 mm2 and 2-sided alpha of 0.05. The 
approximation is calculated using PROC POWER one-way analysis of variance, SAS 9.4. The study power is likely 
larger when utilizing the longitudinal data to model the primary endpoint. The actual study power may also vary 
based on the distribution of the stratification factors (ie, lesion area at screening, presence of CNV in fellow eye), 
and site enrollment. 
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3. 
ABBREVIATIONS 
Abbreviation
Term
AE 
adverse event 
AMD 
age-related macular degeneration 
ATA 
anti-therapeutic antibodies 
BCVA 
best corrected visual acuity 
CH50 
classical pathway of complement functional test 
CNV 
choroidal neovascularization 
CRF (eCRF) 
case report form (electronic CRF) (used interchangeably) 
DA 
disk area 
DCFP 
digital color fundus photography 
DMC 
data monitoring committee 
EDC 
electronic data capture 
EOM 
every other month 
ERG 
electroretinography 
ERM 
epiretinal membrane 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
fundus autofluorescence 
FFA/FA 
fundus fluorescein angiography or fluorescein angiography 
FRI 
functional reading independence index 
FSH 
follicle-stimulating hormone 
GA 
geographic atrophy 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
IB 
investigator’s brochure 
ICF 
informed consent form  
 form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
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Abbreviation
Term
IOP 
intraocular pressure 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
IVT 
intravitreal 
IWR 
interactive web response 
LH 
luteinizing hormone 
LL-BCVA 
low luminance best corrected visual acuity 
LLD 
low luminance deficit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention to treat 
MNREAD 
Minnesota Low-Vision Reading Test 
MOP 
manual of procedures 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire 25-Item Version 
NIR 
near infrared reflectance 
NOEL 
no observable effect level 
NL-BCVA 
normal luminance best corrected visual acuity 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
PEG 
polyethylene glycol 
PEG40 
polyethylene glycol (40-kDa nominal molecular weight) 
PEOM 
pegcetacoplan every-other-month 
PI 
principal investigator 
PK 
pharmacokinetics 
PM 
pegcetacoplan monthly 
PP 
per protocol 
RPE 
retinal pigment epithelium 
SAE 
serious adverse event 
SC 
subcutaneous 
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Abbreviation
Term
SC5b-9 
soluble terminal complement complex 
SD-OCT 
spectral domain optical coherence tomography 
SEOM 
sham every-other-month 
SM 
sham monthly 
SOP 
standard operating procedures 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal elimination half-life 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
WOCBP 
women of childbearing potential 
WONCBP 
women of nonchildbearing potential 
 
 
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4. 
INTRODUCTION 
4.1. 
Background 
This study is being conducted as part of a series of studies for the clinical development of 
pegcetacoplan for advanced Age-related Macular Degeneration (AMD) (neovascular AMD and 
geographic atrophy [GA]). The trial will be conducted in compliance with this protocol, Good 
Clinical Practice (GCP), and applicable regulatory requirements. The subject population will 
comprise adult male and female subjects with GA secondary to AMD. 
4.1.1. 
Age-Related Macular Degeneration 
Age-related macular degeneration is the leading cause of severe vision loss in people over the age 
of 65 in the United States and other Western countries.2 In the United States, about 1.75 million 
people have the advanced forms of AMD.3 The early signs of AMD (drusen and pigmentary 
changes) are common in individuals over age 65 and precede the late stage forms, which are 
visually devastating. The late stage forms of AMD are classified into either macular 
neovascularization (neovascular, wet, or exudative AMD) or GA. 
Geographic Atrophy is a disease characterized by thinning and loss of the retinal pigment 
epithelium (RPE) and concurrent atrophy of photoreceptors and choriocapillaris.4,5,6  Clinically, 
GA is characterized by gradually expanding atrophy leaving islands of dead retinal cells in the 
back of the eye. Although GA can result in significant visual function deficits in reading, night 
vision, and dark adaptation, and produce dense, irreversible scotomas in the visual field, the 
initial decline in visual acuity may be relatively limited if the fovea is spared. When the fovea is 
involved, GA quickly causes blindness.  
Genetic susceptibility has become increasingly recognized as a risk factor and important 
contributor to AMD. More than 19 genetic polymorphisms have been demonstrated to influence 
AMD risk, with as many as 5 of these encoded by genes that modulate the complement system. 
Inflammatory processes, especially those mediated by complement are thought to play a key role 
in AMD.5 It is thought that these may contribute to loss of choriocapillaris, photoreceptors, and 
RPE cells.  
GA is responsible for approximately 20% of all cases of legal blindness in North America (ie, 
BCVA 20/200 or worse) with increasing incidence and prevalence owing to a higher life 
expectancy.4  While there is treatment for exudative AMD with anti-VEGF therapies, no 
approved therapy exists for GA which is usually bilateral and relentlessly progressive. It 
represents a significant unmet need as it leads to significant visual impairment and affects more 
than 5 million people worldwide.13 
An overview of available information regarding pegcetacoplan follows below. Further details 
can be found in the pegcetacoplan investigator’s brochure (IB).26 
4.1.2. 
Pegcetacoplan 
Pegcetacoplan is a PEGylated cyclic peptide inhibitor of complement C3. Pegcetacoplan is 
formed by 2 identical pentadecapeptides (combining a bioactive cyclic tridecapeptide C3-
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inhibiting moiety and a 2-amino acid linker) covalently coupled to each end of a linear 40 kDa 
polyethylene glycol (PEG) chain. There are 2 peptide moieties per molecule of pegcetacoplan. 
The peptide portion of the drug binds to complement C3 and is a broad inhibitor of the 
complement cascade, a biological process that is part of innate immunity and is involved in 
multiple inflammatory processes. The PEGylation of the molecule imparts slower clearance from 
the vitreous humor following administration.  
Pegcetacoplan Intravitreal Injection 15 mg/0.1 mL will be provided as a 150 mg/ mL sterile 
solution of pegcetacoplan in stoppered glass vials. Pegcetacoplan is a sterile, isotonic solution in 
acetate-buffer, pH 5.0, containing trehalose. The drug product is packaged in 2R clear Type I 
glass vials with 13 mm FluroTec-coated chlorobutyl grey stoppers and sealed with 13 mm 
aluminum/polypropylene flip-off type seals.  
4.1.3. 
Nonclinical Data 
This section is intended to briefly summarize information on the safety, tolerability, and PK of 
intravitreal (IVT), intravenous (IV) and subcutaneous (SC) injections of pegcetacoplan. For 
complete and detailed information, refer to the IB. 
As pegcetacoplan is only pharmacologically active in primates, the pivotal IVT toxicological 
studies have been conducted in cynomolgus monkeys. The safety and tolerability of 
IVT-administered pegcetacoplan has been assessed in a Good Laboratory Practice 
(GLP)-compliant pivotal chronic (9-month) repeat-dose study in cynomolgus monkeys. In 
addition, 2 GLP-compliant 2-month ocular bridging studies (the first comparing drug substance 
from 2 different CMOs, the second assessing the safety and tolerability profiles of 3 different 
formulations to support the Phase 3 clinical study) have been conducted in cynomolgus monkeys 
as well. . Pegcetacoplan was observed to be minimally immunogenic in the 9-month study as 
evidenced by a lack of circulating antibodies in the majority of monkeys studied. The NOEL for 
chronic (9-month) IVT dosing was concluded to be >24.8 mg/eye. The results of this 9-month 
chronic study in cynomolgus monkeys support the safety of chronic IVT injections of 
pegcetacoplan at monthly or bimonthly intervals in humans. 
PK assessments included in the chronic (9-month) study revealed serum concentrations of 
pegcetacoplan that were approximately dose-proportional 24 hours after the first IVT dose. The 
serum t1/2 of IVT-administered pegcetacoplan, determined in a separate PK assessing a 
10 mg/eye dose (in 50 µL), was 10.4 days although the pegcetacoplan levels measured in the 
serum following infrequent IVT administration are orders of magnitude lower than 
pharmacological serum levels achieved with SC or IV administration. 
Additional nonclinical studies in monkeys and rabbits, including assessments of other routes of 
administration (SC and IV), have further defined pegcetacoplan’s safety profile. . Pegcetacoplan 
has been shown to be generally tolerated through all 3 routes of administration assessed (IVT, 
SC, and IV), with no adverse effects observed in safety pharmacology studies (in vivo 
cardiopulmonary telemetry and in vitro hERG inhibition assay) and genotoxicity studies (Ames, 
in vitro aneugenicity and clastogenicity in TK6 cells, and in vivo clastogenicity in mouse 
micronuclei).  
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4.1.4. 
Clinical Data 
The initial safety and tolerability of pegcetacoplan following IVT administration in humans was 
tested in an open-label, single dose escalation, Phase I clinical study in patients with wet age-
related macular degeneration under protocol POT-CP043014 (NCT02461771). The study was 
conducted in multiple ophthalmology clinical sites in the US and Australia. A single dose of 
pegcetacoplan was administered on Day 1 to patients suffering from wet AMD currently 
receiving anti-VEGF standard of care. Three escalating doses of pegcetacoplan administered IVT 
were studied. Three subjects received 4 mg; 3 subjects received 10 mg, and 7 subjects received 
20 mg. No serious adverse events (SAEs) or drug-related adverse events (AEs) of concern were 
observed. It was concluded that administration of a single dose of pegcetacoplan IVT up to 
20 mg is safe and well tolerated.  
A Phase 2 study (Protocol POT-CP121614; NCT02503332) to assess the safety, tolerability, and 
evidence of activity of multiple intravitreal injections of pegcetacoplan in subjects with 
geographic atrophy secondary to AMD has been completed. The study was conducted at multiple 
ophthalmology clinical sites in the US, Australia, and New Zealand. Subjects were randomized 
in a 2:1:2:1 manner to either receive pegcetacoplan IVT 15 mg monthly for 12 months; sham 
IVT monthly for 12 months; pegcetacoplan IVT 15 mg every other month for 12 months; or 
sham IVT every other month for 12 months.  
This study demonstrated a statistically significant slowing of disease progression at Month 12 at 
the prespecified alpha of 0.1. Pegcetacoplan administered monthly showed a 29% (P=.008) 
reduction in the rate of GA lesion growth compared to sham and pegcetacoplan administered 
every other month showed a 20% (P=.067) reduction. Pegcetacoplan has been generally well 
tolerated. The most frequently reported AEs have been related to the injection procedure 
(intravitreal injection), which are commonly found in this type of study. An imbalance in new 
active choroidal neovascularization (CNV) in subjects treated with pegcetacoplan was observed 
and the risk of developing new exudation may be increased in subjects with a prior history of 
neovascular AMD in the fellow eye. One subject in the sham arm, 1/81 (1%) was observed to 
have developed new active study eye exudation compared with 25/165 (15%) subjects that 
received pegcetacoplan IVT injections, 26 subjects in total. Of the 25 pegcetacoplan treated 
subjects with new active CNV, 18 subjects received PM treatment and 7 subjects received 
PEOM treatment. 
Seventeen of the 25 (68%) subjects that developed new active study eye CNV had a prior history 
of neovascular AMD in the nonstudy fellow eye. No significant imbalance in history of 
neovascular AMD in the fellow eye was observed among the 3 arms to explain the imbalance in 
new exudation observed in study eyes. Visual acuity data did not demonstrate clear differences 
between subjects developing new study eye exudation compared with those that did not. 
A Phase 1b study (Protocol APL2-103; NCT 03777332) to assess the safety of pegcetacoplan in 
subjects with GA secondary to AMD and low vision is currently ongoing. This study is being 
conducted at multiple ophthalmology clinical sites across the US. Subjects receive monthly 
treatment with intravitreal pegcetacoplan for 24 months. 
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4.1.5. 
Rationale 
4.1.5.1. 
Rationale for Pegcetacoplan for Treatment of Geographic Atrophy 
The rationale for the use of a complement inhibitor in patients with AMD is based on evidence 
from both human and animal studies. Human biochemical, genetic, and clinical lines of evidence 
indicate that the complement system plays a role in the etiology of AMD. Complement 
components including C3, the membrane attack complex, and complement factor H, are present 
in drusen and basal laminar deposits in eyes from patients with AMD.7,8,9,10  Genetic variants of 
complement factor H,8,11,12,13,14 C3,15,16 complement factor I17 and other complement 
components18,19,20 have been associated with altered risks for the development of both the 
neovascular and atrophic forms of AMD. Patients with AMD also have signs of systemic 
complement activation, exhibiting higher serum levels of Complement Factor B, C3a, C5a, 
SC5b-9 (soluble terminal complement complex), C3d, and Ba compared to age-matched 
controls.21,22,23,24  
4.1.6. 
Dose Selection 
A single dose of 15 mg/0.1 mL injection administered monthly or EOM for 24 months will be 
tested in this study (see Section 7.3.1). Pegcetacoplan was well tolerated in a panel of animal 
toxicology studies. A 9-month, repeat-dose GLP study in cynomolgus monkeys was conducted 
to evaluate the safety of IVT injections of pegcetacoplan at doses up to 24.8 mg/eye at a 
frequency of 1 injection every 4 weeks. 
In this pivotal chronic toxicological study conducted in monkeys, the NOEL was established as 
>24.8 mg of pegcetacoplan delivered intravitreally every 4 weeks for 9 months using a 100 µL 
injection. The volume of the human vitreous is approximately 4 mL, which is approximately  
2.7-fold larger than the mean vitreous volume of cynomolgus monkeys, 1.5 mL.25 Based on the 
difference in vitreous volume between man and cynomolgus and the NOEL defined in 
nonhuman primates, the human equivalent dose was determined to be 67 mg/eye every 4 weeks. 
The dose (15 mg/injection) of pegcetacoplan that will be evaluated in this clinical study is 
expected to result in drug concentrations approximately 4.5-fold lower that the NOEL observed 
in cynomolgus monkeys.  
To support appropriate assessments of dose response to pegcetacoplan, pegcetacoplan is 
administered in 2 different frequencies in the study: monthly and every other month.  
Physician feedback injecting a 200 mg/mL solution in the Phase 1 (Study POT-CP043014; 
NCT02461771) trial confirmed that 150 mg/mL is the highest practical concentration that can be 
routinely administered, which set the dose of the Phase 2 trial to 15 mg (ie, 0.1 mL of a 
150 mg/mL solution). The 15-mg dose given monthly was found to be the most efficacious in the 
Phase 2 trial. The 15 mg dose given every other month demonstrated slightly less efficacy but 
offers a reduced treatment burden for patients and physicians.  
4.2. 
Risk/Benefit 
The Phase 1 (Study POT-CP043014; NCT02461771) and Phase 2 (Study POT-CP121614; 
NCT02503332) studies provide supporting evidence of a positive benefit-risk profile for the use 
of pegcetacoplan in treating patients with AMD, specifically patients with GA. These 
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preliminary results of an up to 28% reduction of GA progression rate support the evaluation of 
pegcetacoplan in a Phase 3 study.  
The reported safety data from these studies demonstrated an acceptable safety and tolerability 
profile with no clinically significant safety concerns observed. A total of 178 patients have 
received at least 1 dose (15 mg/injection) of pegcetacoplan as part of these studies. In the Phase 2 
study in patients with GA an imbalance in new exudation in subjects treated with pegcetacoplan 
was observed. Section 4.1.4 provides a summary of the study design and key results from both 
studies. 
The safety monitoring practices employed by this protocol (complete ophthalmologic exam, IOP 
monitoring, OCT, fluorescein angiography, vital signs, hematology, serum chemistry, urinalysis, 
physical exam, vital signs, and AE questioning) are adequate to protect the subjects’ safety. 
There are also risks associated with the ophthalmic procedures required for participants in this 
study. However, these are all standard procedures that are widely performed in ophthalmology. 
In the days following any IVT injection, patients are at risk of developing sterile or infectious 
intraocular inflammation (eg, endophthalmitis). In recent studies conducted with pegcetacoplan 
IVT from a single manufacturer, events of transient moderate and severe intraocular 
inflammation have been observed. Other risks of IVT injection include traumatic cataract, retinal 
detachment, increased IOP, and hemorrhage.  
The amount of blood (See Section 9.16) planned for collection from each subject over the 
24 months of the study does not pose an undue risk in this patient population. 
There is a potential health benefit for trial participants from receipt of study drug. If efficacious, 
pegcetacoplan is expected to alter the course of GA and slow its rate of progression. 
 
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5. 
STUDY OBJECTIVES  
5.1.1. 
Primary Objective 
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA 
secondary to AMD assessed by change in the total area of GA lesions from baseline as measured 
by fundus autofluorescence (FAF). 
5.1.2. 
Key Secondary Objectives 
To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with GA 
secondary to AMD with respect to: 
• Monocular maximum reading speed (study eye), as assessed by Minnesota Low-
Vision Reading Test (MNREAD) or Radner Reading Charts (in select countries) 
• Functional Reading Independence (FRI) index score 
• Normal luminance best corrected visual acuity score (NL-BCVA) in the study eye  
5.1.3. 
Secondary Objectives  
• To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with 
GA secondary to AMD with respect to: 
o Low luminance best corrected visual acuity score (LL-BCVA) in the study 
eye  
o Low luminance deficit (LLD) in the study eye 
o Total area of GA lesion(s) in the study eye 
o Monocular critical print size (study eye), as assessed by MNREAD or Radner 
Reading Charts (in select countries)  
o National Eye Institute Visual Functioning Questionnaire 25-Item Version 
(NEI VFQ-25) distance activity subscale score (in select countries) 
o Macular functional response as assessed by mesopic microperimetry  
5.1.4. 
Safety Objectives 
• To evaluate the safety and tolerability of pegcetacoplan compared to sham injection 
in patients with GA secondary to AMD as indicated by: 
o Incidence and severity of ocular and systemic treatment-emergent adverse 
events 
o Incidence of anti-therapeutic antibodies directed against pegcetacoplan 
o Incidence of new active CNV in the study eye 
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5.1.5. 
Exploratory Objectives 
• To evaluate the efficacy of pegcetacoplan compared to sham injection in patients with 
GA secondary to AMD as indicated by: 
o NEI VFQ-25 composite score  
o NEI VFQ-25 near activity subscale score (in select countries) 
o Comparison between study eye and fellow eye in change in GA lesion size  
o To evaluate the binocular maximum reading speed as assessed by MNREAD 
or Radner Reading Charts (in select countries) 
o To evaluate the binocular critical print size as assessed by MNREAD or 
Radner Reading Charts (in select countries) 
• To evaluate the relationship between genetic polymorphisms associated with AMD 
with GA progression and response to pegcetacoplan 
• To evaluate the incidence of new onset of subclinical CNV in the study eye 
• To assess sensitivity and specificity of a digital reading speed application to detect 
disease progression / regression (optional, select sites) 
• To assess sensitivity and specificity of a digital visual function application to detect 
disease progression / regression (optional, select sites) 
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6. 
PATIENT POPULATION 
The study population includes approximately 600 subjects to be randomized at approximately 
100 multinational sites. To participate in the study, subjects must be diagnosed with GA of the 
macula secondary to AMD in the study eye.  
6.1.1. 
Inclusion Criteria  
The study eye must meet all inclusion criteria. If both eyes meet the inclusion criteria, the eye 
with the worst normal luminance visual acuity at the screening visit will be designated as the 
study eye. If both eyes have the same visual acuity, the right eye will be selected as the study 
eye.  
Ocular-specific inclusion criteria apply to the study eye only, unless otherwise specified. 
1. Age ≥60 years. 
2. Normal Luminance best corrected visual acuity of 24 letters or better using Early 
Treatment Diabetic Retinopathy Study (ETDRS) charts (approximately 20/320 Snellen 
equivalent). 
3. Clinical diagnosis of GA of the macula secondary to AMD as determined by the 
investigator and confirmed by the reading center. 
4. The GA lesion must meet the following criteria as determined by the central reading 
center’s assessment of FAF imaging at screening: 
a. 
Total GA area must be ≥2.5 and ≤17.5 mm2 (1 and 7 disk areas [DA] respectively). 
b. If GA is multifocal, at least 1 focal lesion must be ≥1.25 mm2 (0.5 DA), with the overall aggregate 
area of GA as specified above in 4a. 
c. 
The entire GA lesion must be completely visualized on the macula centered image and must be able to 
be imaged in its entirety and not contiguous with any areas of peripapillary atrophy. 
d. Presence of any pattern of hyperautofluorescence in the junctional zone of GA. Absence of 
hyperautofluorescence (ie, pattern = none) is exclusionary.1 
5. Adequate clarity of ocular media, adequate pupillary dilation, and fixation to permit the 
collection of good quality images as determined by the investigator.  
6. Meets the following criteria related to microperimetry:  
a. 
Able to detect fixation target. 
b. Total elapsed time to complete the 10-2 68-point exam is ≤30 minutes in duration.  
c. 
Fixation losses must be ≤20%.  
d. Subject is willing and able to undertake microperimetry assessment in the opinion of the investigator. 
7. Female subjects must be: 
a. 
Women of non–childbearing potential (WONCBP), or 
b. Women of childbearing potential (WOCBP) with a negative serum pregnancy test at screening and 
must agree to use protocol defined methods of contraception for the duration of the study and refrain 
from breastfeeding for the duration of the study. 
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8. Males with female partners of childbearing potential must agree to use protocol defined 
methods of contraception and agree to refrain from donating sperm for the duration of the 
study. 
9. Willing and able to give informed consent and to comply with the study procedures and 
assessments.  
6.1.2. 
Exclusion Criteria  
Ocular specific exclusion criteria apply to the study eye only, unless otherwise specified. 
1. GA secondary to a condition other than AMD such as Stargardt disease, cone rod 
dystrophy, or toxic maculopathies like plaquenil maculopathy in either eye. 
2. Spherical equivalent of the refractive error demonstrating > 6 diopters of myopia or an 
axial length >26 mm. 
3. Any history or active CNV, associated with AMD or any other cause, including any 
evidence of retinal pigment epithelium rips or evidence of neovascularization anywhere 
based on SD-OCT imaging and/or fluorescein angiography as assessed by the reading 
center. 
4. Presence of an active ocular disease that in the opinion of the investigator compromises 
or confounds visual function, including but not limited to, uveitis, other macular diseases 
(eg, clinically significant epiretinal membrane [ERM], full thickness macular hole) or 
uncontrolled glaucoma/ocular hypertension). Benign conditions in the opinion of the 
investigator such as peripheral retina dystrophy are not exclusionary. 
5. Intraocular surgery (including lens replacement surgery) within 3 months prior to 
randomization.  
6. History of laser therapy in the macular region. 
7. Aphakia or absence of the posterior capsule. Note: YAG laser posterior capsulotomy for 
posterior capsule opacification done at least 60 days prior to screening is not 
exclusionary. 
8. Any ocular condition other than GA secondary to AMD that may require surgery or 
medical intervention during the study period or, in the opinion of the investigator, could 
compromise visual function during the study period.  
9. Any contraindication to IVT injection including current ocular or periocular infection.  
10. History of prior intravitreal injection.  
11. Unable to perform microperimetry reliably in the opinion of the investigator. 
12. Prior participation in another interventional clinical study for intravitreal therapies in 
either eye (including subjects receiving sham). 
13. Prior participation in another interventional clinical study for geographic atrophy in either 
eye including investigational oral medication and placebo. 
14. Participation in any systemic experimental treatment or any other systemic 
investigational new drug including within 6 weeks or 5 half-lives of the active ingredient 
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(whichever is longer) prior to the start of study treatment. Note: clinical trials solely 
involving observation, over-the-counter vitamins, supplements, or diets are not 
exclusionary.  
15. Medical or psychiatric conditions that, in the opinion of the investigator, make consistent 
follow-up over the 24-month treatment period unlikely, or would make the subject an 
unsafe study candidate. 
16. Any screening laboratory value (hematology, serum chemistry or urinalysis) that in the 
opinion of the investigator is clinically significant and not suitable for study participation. 
17. Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to 
pegcetacoplan or any of the excipients in pegcetacoplan solution.  
6.2. 
Women of Childbearing Potential 
WOCBP are defined as premenopausal women physiologically capable of becoming pregnant. 
6.3. 
Women of Nonchildbearing Potential 
WONCBP are defined as women meeting any of the following criteria: 
• Older than 45 years with amenorrhea for > 2 years or older than 60 years with 
amenorrhea for > 1 year. Both confirmed by follicle-stimulating hormone (FSH) and 
LH levels. 
• Has undergone hysterectomy, 
• Has undergone bilateral oophorectomy, 
• Has undergone bilateral salpingectomy. 
6.4. 
Approved Methods of Contraception 
Approved methods of contraception include:  
• Combined (estrogen-and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device  
• Intrauterine hormone-releasing system  
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• Bilateral tubal occlusion 
• Vasectomized partner (provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomized partner has received medical assessment 
of the surgical success) 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments). Sexual abstinence is only 
accepted when it is the preferred and usual lifestyle of the subject. 
Subjects must agree to use an approved method of contraception during the study and 90 days 
after their last dose of study drug. 
6.5. 
Discontinuation of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to his/her 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from treatment with the investigational product 
(IP) with the medical monitor, when possible. 
Subjects who discontinue treatment with the IP can continue participation in the study and 
should be encouraged to return to the clinical site for as many follow-up visits as they can. In the 
event that a subject terminates early from the study, all early termination procedures should be 
performed even if they are outside the allowed study window.  
The reason for termination, date of stopping treatment with IP, all follow-up information and the 
total amount of IP administered must be recorded in the case report form (CRF) and source 
documents. 
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7. 
TREATMENT OF SUBJECTS 
7.1. 
Allocation to Treatment 
Each subject will be assigned a unique screening number after signing the informed consent. 
Subjects who complete the study screening assessments and meet all the eligibility criteria will 
be scheduled to enter the study and randomized on Day 1. As part of the screening process, the 
reading center will evaluate FAF, OCT, Digital Color Fundus Photograph (DCFP), Near Infrared 
Reflectance (NIR), and fluorescein angiography (FA) to provide an objective assessment of 
subject eligibility. Subjects will be randomized 2:2:1:1 to receive treatment with PM, PEOM, 
sham injection monthly (SM) or sham injection every other month (SEOM), respectively. 
Table 1 presents the treatment arms along with the approximate number of subjects and 
injections per arm. 
The randomization scheme will be generated and maintained by the sponsor, or designee. 
Subject randomization will be stratified by GA lesion area at screening (< 7.5 mm2; ≥ 7.5 mm2) 
and presence of CNV in the fellow eye (yes; no). Further details on the randomization 
procedures will be described in the statistical analysis plan.  
7.2. 
Masking and Minimization of Bias 
The intent of masking is to limit the occurrence of conscious and unconscious bias in the conduct 
and interpretation of the clinical study. Bias could arise from the influence that the knowledge of 
a specific treatment assignment may have on the recruitment and allocation of subjects, their 
subsequent care, the assessment of endpoints, the handling of withdrawals, and so on. The 
essential aim of masking, therefore, is to prevent identification of the treatments by the subject 
and the masked assessors associated with the conduct of the study until all such opportunities for 
bias have passed. 
This is a double-masked study. Designated masked study site staff (eg, assistant(s), visual acuity 
technicians, OCT technicians, photographers, technicians administering questionnaires, subjects, 
reading center personnel, the assigned evaluating physician(s), and the sponsor) will be masked 
to treatment assignment. However, the treating physician and any associated support staff 
involved in performing the intravitreal or sham injections will be unmasked to study treatment. 
These individuals are not allowed to discuss treatment and/or patient outcome with masked study 
staff, including the evaluating physician. The principal investigator must be masked to subjects’ 
treatment assignment. To prevent bias in treatment assignment, eligible subjects will be 
randomized using a web-based randomization system. Documentation will be put in place to 
avoid unintentional unmasking during the study. All study roles will be clearly documented on 
the site delegation of authority log and once the roles have been designated and executed, these 
roles should not be switched during the conduct of the study. In unforeseen circumstances, a site 
can contact the sponsor to switch a study staff member from the masked role to the unmasked 
role but not vice versa. 
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7.2.1. 
Unmasking  
In the event of a medical emergency where the knowledge of subject treatment by masked 
individuals (eg, the subject or his/her physician) is required, an individual investigator (or 
designee) will have the ability to unmask the treatment assignment for a specific subject and 
share that information with the appropriate parties. All documentation indicating unmasking 
must be retained with the subject’s source documentation in a secure manner. A DMC will be 
set-up to monitor patient safety and review data. The DMC will be provided unmasked safety 
data but will be masked to efficacy data unless this data is deemed medically necessary. 
Procedures for DMC unmasking will be documented in a DMC Charter.  
For regulatory reporting and if required by local regulations, the sponsor will unmask study 
treatment for all serious, unexpected adverse reactions that are considered to be related to study 
drug. Subjects who have had their treatment assignment unmasked secondary to a serious or 
unexpected AE or medical emergency will no longer receive study treatment. However, they 
should continue to complete as many of the follow-up visits as possible. 
The study unmasking for the primary analysis at 12 months will be limited to the analysis team 
and personnel only on an as-needed basis. All other personnel in the “masked” role will remain 
masked until the end of study. A document listing out the roles and responsibilities of the 
individuals participating in the unmasking analysis will be provided prior to the unmasking.  
7.3. 
Dosage and Administration 
7.3.1. 
Dose Levels and Treatment Arms 
After randomization and during the treatment phase beginning at Day 1, all subjects will receive 
a single dose of 15 mg pegcetacoplan/0.1 mL or sham injection intravitreally either monthly or 
every other month depending on treatment designation as presented in Table 1 below.  
Table 1:  Treatment Arms with Approximate Number of Subjects 
Treatment Arms 
Pegcetacoplan 15 mg/0.1 mL monthly for 24 months (n= approximately 200 subjects; 24 pegcetacoplan 
injections) 
Pegcetacoplan 15 mg/0.1 mL EOM for 24 months (n= approximately 200 subjects; 12 pegcetacoplan 
injections) 
Sham monthly for 24 months (n= approximately 100 subjects; 24 sham injections) 
Sham EOM for 24 months (n= approximately 100 subjects; 12 sham injections) 
7.3.2. 
Treatment Administration  
Only qualified study staff and those delegated the responsibility of study drug administration on 
the delegation of authority log should perform this procedure. All staff should be appropriately 
trained on all procedures prior to performing the procedures. Sites should follow the Visit 
Schedule for order of procedures and assessments.  
Administration of study treatment (pegcetacoplan or sham) can be done on a separate day from 
the assessment visit if both days fall within the visit window. If this occurs on the randomization 
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visit, then the administration of pegcetacoplan or sham should be done within 3 days of 
randomization and after approval from the medical monitor. When study treatment 
administration is on a day other than a study visit, then the only assessment that must be done on 
the day of study treatment administration is the IOP preinjection. 
If a subject falls outside the visit window for a dosing visit, the dose should be skipped and the 
subject should be scheduled on time for the next dosing visit. 
7.3.3. 
Drug Supplies 
7.3.3.1. 
Identity of Investigational Product 
Pegcetacoplan will be supplied as a liquid solution in stoppered glass vials and should be stored 
according to the label. Specific instructions for preparing pegcetacoplan for the IVT injection 
procedure will be provided in the manual of procedures. Pegcetacoplan Intravitreal Injection 
15 mg/0.1 mL (150 mg/mL) is a sterile, isotonic solution of pegcetacoplan in acetate-buffer, pH 
5.0, containing trehalose. The drug product is packaged in 2R clear Type I glass vials with 
13 mm FluroTec-coated chlorobutyl grey stoppers and sealed with 13-mm 
aluminum/polypropylene flip-off type seals.  
Sham will be provided as empty stoppered glass vials and should be stored according to the 
label.  
7.3.3.2. 
Storage  
Vials should be automatically stored as per the instructions until ready for use. Each vial should 
only be used once. Vials should not be shaken and should be protected from sunlight.  
7.3.3.3. 
Accountability 
Pegcetacoplan drug product and sham vials will be provided to a designee at the study site and 
must be stored in a pharmacy or otherwise locked and secured, at the temperature specified on 
the label. The drug product supply is accessible only to those individuals authorized by the PI. 
The sponsor will supply sufficient quantities of pegcetacoplan drug product and sham to allow 
completion of this study. The site should only use the investigational medicinal product provided 
by the sponsor for use in the study. 
Designated unmasked study staff will provide the study treatments to the subjects in accordance 
with their assigned subject numbers and the randomization schedule. During the study, the 
receipt of the drugs supplied at the clinical site and of study treatment dispensation for each 
subject will be documented in drug accountability records. These drug accountability records are 
to be kept separate from the patient medical records and other source documents. 
All used vials should be retained by the clinical site until drug accountability monitoring is 
performed and then returned to the sponsor or designee or destroyed per sponsor instructions. At 
the conclusion of the study, any unused IP returned to the sponsor or designee, or destroyed per 
sponsor instructions, and this will be documented in the drug accountability records. 
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7.3.4. 
Intravitreal Pegcetacoplan Administration 
Subjects receiving active treatment will be administered 0.1 mL IVT injection of pegcetacoplan 
according to their treatment designation using a thin wall needle. Detailed instructions on drug 
preparation, preinjection procedures, administration of pegcetacoplan, and postinjection 
procedures will be provided in the manual of procedures. 
Clinic staff involved in the injection tray assembly, anesthetic preparation, and study drug 
preparation and administration will follow appropriate aseptic techniques to minimize the risk of 
potential AEs associated with IVT injections. 
Administration of pegcetacoplan is only allowed if preinjection IOP ≤21 mm Hg. If necessary, 
antiglaucomatous medication can be given to lower the IOP. To minimize transient IOP 
elevation after IVT injection of pegcetacoplan, decompression of the eye must be performed 
before all pegcetacoplan injections. This is done by applying moderate pressure to the globe with 
cotton swabs for 30-60 seconds during anesthetic preparation.  
In addition to the procedures outlined in the protocol and manual of procedures (MOP), 
adherence to specific institutional policies associated with IVT injections will be observed. 
7.4. 
Sham Injection Administration  
The procedure for sham injection will be the same as that used for IVT injection until the actual 
injection but no actual injection will occur. The injecting physician will only touch the study eye 
with the blunt end of the syringe. No needle or medication will be injected inside the eye. 
Detailed instructions on sham injection procedures and postinjection procedures will be provided 
in the manual of procedures.  
Subjects randomized to the monthly or every-other-month sham-injection groups will receive 
sham injection monthly or every other month, respectively. The same assessments will be 
performed as for the subjects in the pegcetacoplan groups.  
7.5. 
Concomitant Therapies 
Any concomitant medications a participant is receiving at the start of the study, within 30 days 
prior to screening, or that are given for any reason during the study (except for routine 
medications given for ocular procedures required by the protocol, such as topical anesthetic) 
must be recorded in the source documents and CRF including start and stop date and time, dose, 
route, and indication. In addition, all invasive intraocular procedures from the previous 5 years 
must also be recorded in the source documents and CRF including start and stop dates. Surgical 
anesthetics, paramedical or alternative therapies (eg, acupuncture, herbal supplements) should 
also be recorded in the source documents and CRF within 30 days prior to screening. 
Metoclopramide or other agents to prevent nausea induced by fluorescein injection may be 
administered at the discretion of the PI. 
7.5.1. 
Treatment of New Exudation Related to Active Choroidal Neovascularization in 
the Study Eye and/or Fellow Eye 
The suspected onset or presence of new exudation related to active CNV secondary to AMD in 
the study eye and/or fellow eye must be documented in the source documents and CRF. If the 
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investigator suspects new exudation related to active CNV in the study eye based on fundus 
examination and/or OCT findings (eg, subretinal fluid, intraretinal fluid, cystoid macular edema, 
serous pigment epithelial detachment), a fluorescein angiography and Optical Coherence 
Tomography Angiography (OCT-A; select sites only) must also be captured following the 
imaging protocol procedure. All images, as outlined above, must be sent to the reading center. 
The reading center will provide a report indicating whether or not evidence of active, exudative 
AMD is present or absent, based on the images sent for assessment. 
The determination about initiation of anti-VEGF treatment for the exudation related to active 
CNV is the sole responsibility of the investigator. Treatment with anti-VEGF should start after 
the report is received by the site from the reading center, with the exception of cases with clear 
evidence of disease activity (eg,; subretinal hemorrhage, extensive subretinal fluid and/or edema, 
and/or presence of subretinal hyperreflective material) that, in the opinion of the investigator, 
may have a detrimental visual impact if not treated immediately.  
If it is determined that the subject requires anti-VEGF therapy, ranibizumab or aflibercept should 
be selected and administered by the injecting (unmasked) physician. Ranibizumab should be 
given monthly and aflibercept every other month after 3 monthly loading doses. The frequency 
of aflibercept can be changed to monthly if deemed necessary by the investigator, however the 
physician should refrain from using as-needed treatment (PRN) or treat and extend protocols. 
Every effort should be made to use the same anti-VEGF therapy for a subject during the course 
of the study and all treatments should be documented in the CRF. 
If anti-VEGF therapy is administered in the study eye on the same day as an pegcetacoplan (or 
sham) injection, the anti-VEGF therapy shall be administered first and the pegcetacoplan or 
sham injection shall occur at least 30 minutes after the anti-VEGF injection and only if the IOP 
is ≤21 mm Hg. Anti-glaucomatous medication can be given to lower the IOP to the appropriate 
range to allow for the pegcetacoplan injection.  
In order to avoid potential unmasking, if anti-VEGF and pegcetacoplan are given at the same 
visit, the unmasked physician must perform both procedures. If the anti-VEGF therapy is given 
on a separate day from the pegcetacoplan administration, either the masked or the unmasked 
physician may perform this injection.  
Treatment with anti-VEGF is allowed in the fellow eye. The treatments for the fellow eye can be 
administered according to the site’s standard protocol for CNV treatment. Any treatments or 
therapies administered to the fellow eye within 5 years of screening and while on study should be 
recorded as a concomitant medication. 
7.5.2. 
Prohibited Therapies  
The PI should make a determination regarding patient continuation of therapies used to treat 
concomitant medical conditions. Therapies as noted in the inclusion/exclusion criteria are 
prohibited as specified. 
7.5.3. 
Endophthalmitis Treatment 
Endophthalmitis cases must be reported as SAEs. The decision to treat a participant for 
endophthalmitis or suspected endophthalmitis will be guided by the clinical judgment of the 
investigator and in accordance with local guidelines (as applicable). A culture sample should be 
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performed prior to making a decision on treatment. The treatment method (pars plana vitrectomy 
vs intravitreal injection of antibiotics) and choice of antimicrobial agents are also at the 
discretion of the physician and should follow current standard practice patterns. The decision to 
use IVT steroids (eg, dexamethasone) for the treatment of endophthalmitis is also at the 
discretion of the physician. 
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The planned length of participation in the study for each subject is approximately 25 months 
(from the beginning of the screening period through completion of the Month 24 visit). After 
completion of the 24-month treatment period, subjects will be offered entry into a separate open-
label study. 
8.1. 
Study Visit Schedule 
Below is a condensed description of the study visits and the procedures and examinations that 
will be performed. Please refer to the Visit Schedule in Appendix A to Appendix D for a detailed 
schedule of procedures/assessments for the monthly and EOM visit schedules. Additional safety 
assessments not listed in this section or the flow chart may be performed if considered necessary 
at the discretion of the investigator. 
8.1.1. 
Screening Period—Within 28 Days Prior to Randomization/ Treatment (Day –28 
to –1) 
8.1.1.1. 
Visit 1—All Subjects  
Note: All ophthalmic procedures (including imaging) are to be performed on both eyes, except 
where specified.  
Before any study-specific procedures are performed, the purpose and nature of the study should 
be explained and the patient should read, sign, and date the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC)-approved Informed Consent Form (ICF). The 
individual obtaining consent from the patient and a witness, if applicable, should also sign and 
date the ICF. Once the patient has signed the ICF, a screening number should be assigned to the 
patient. Demographic information, significant medical/surgical history within the previous 
5 years, invasive ocular procedures within the previous 5 years, and concomitant medications 
used within 30 days prior to screening should be collected (including vitamins and all over-the-
counter as well as prescription medications). Complete smoking/ tobacco history should also be 
collected. 
Subject eligibility should then be determined by reviewing the inclusion/exclusion criteria and 
the study eye should be selected. Prior to the administration of fluorescein, blood and urine 
should be collected for safety labs (including blood for human chorionic 
gonadotropin/follicle-stimulating hormone/luteinizing hormone [HCG/FSH/LH], if applicable) 
and vital signs along with a physical examination including weight and height should be 
performed. 
A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, 
aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and intraocular 
pressure (IOP) measurement. Normal luminance BCVA should be performed prior to dilating the 
eyes. Images should be captured as outlined in the Visit Schedule (FAF, NIR, DCFP, FFA) and 
forwarded to the reading center for determination of eligibility if applicable.  
Mesopic microperimetry should be performed on both eyes post dilation of the eyes and 
forwarded to the reading center. 
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8.1.2. 
Randomization/ Initial Treatment—Day 1—Within 28 Days of Screening 
8.1.2.1. 
Visit 2—All Groups 
At this visit, all inclusion/exclusion criteria should be reviewed prior to randomization and 
dosing, including the determination of eligibility by the reading center. Subjects will be 
randomized using the Interactive Web Response (IWR) System. A complete ophthalmic exam 
including slitlamp exam of the cornea, iris, anterior chamber, lens, and aqueous reaction (cells 
and flare), dilated fundus exam of the vitreous and retina, and IOP measurement will be 
performed and imaging collected as per the Visit Schedule. 
All assessments should be performed on the same day. All study visits should be scheduled and 
projected based on the Day 1 visit date. 
Blood should be drawn for anti-pegcetacoplan antibodies.  
Prior to dilating the eyes, all functional tests should be performed (NL-BCVA, LL-BCVA, and 
MNREAD or Radner Reading Charts [in select countries]). Subjects at select sites will be trained 
on how to use the home-based digital applications for visual function and reading speed if the 
subject decides to participate in this portion. This training must occur after completion of all 
functional tests (NL-BCVA, LL-BCVA). Tests completed using the digital application at select 
sites (optional) should be completed prior to dilating the eyes but after completion of all 
functional tests and quality of life measures (NL-BCVA, LL-BCVA, MNREAD or Radner 
Reading Charts [in select countries], NEI VFQ-25, and FRI). The subject should be instructed to 
take the electronic device home and to complete the digital application weekly on the same day 
each week, if possible. The quality of life measures (NEI VFQ-25 and FRI) should be 
administered by the masked site staff.  
Imaging should be performed including FAF, SD-OCT, OCT-A (select sites), endothelial cell 
count (select sites) and NIR and sent to the reading center for evaluation.  
Study drug or sham injection should be performed by the unmasked physician as described in the 
manual of procedures and the study eye should be monitored post injection as outlined in 
Section 9.16. A follow-up phone call should be scheduled with the subject 4 ± 2 days after 
randomization Day 1 to assess for any AEs.  
8.1.3. 
Treatment Phase—24 Months  
8.1.3.1. 
 Months 1-12 
8.1.3.1.1. Visits 3-14 (Monthly and Every-Other Month Group)  
During this phase, there will be clinic visits every month. Dosing and assessments will occur 
monthly in the monthly pegcetacoplan and sham injection treatment arms. Dosing will occur 
every other month in the EOM pegcetacoplan and sham injection treatment arms, however, the 
subjects will return monthly for assessments (with no dose given).  
A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, lens, 
and aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and IOP 
measurement will be performed and imaging collected as per the Visit Schedule. 
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Blood will be drawn for safety labs, anti-pegcetacoplan antibodies, and genotyping (Month 2 
only) prior to the administration of fluorescein as per the Visit Schedule. Samples will be 
collected for the clinical repository for those subjects that consent to this portion.  
Prior to dilating the eyes, all functional tests will be performed (NL-BCVA, LL-BCVA, and 
MNREAD or Radner Reading Charts [in select countries]). Tests completed using the digital 
application at select sites (optional) will be completed prior to dilating the eyes but after 
completion of all functional tests and quality of life measures (NL-BCVA, LL-BCVA, 
MNREAD or Radner Reading Charts [in select countries], NEI VFQ-25, and FRI). At select 
sites the subject should be instructed to take the electronic device home and to complete the 
digital application weekly on the same day each week, if possible. The subject will be instructed 
to bring back the electronic device for the visits specified in the schedule of events. The quality 
of life measures (NEI VFQ-25 and FRI) will be administered by the masked site staff.  
Mesopic microperimetry should be performed on both eyes (where specified) post dilation of the 
eyes and forwarded to the reading center. 
Imaging will be performed including FAF, FFA, SD-OCT, OCT-A (select sites), endothelial cell 
count (select sites) and NIR and sent to the reading center for evaluation per the visit schedule.  
Study drug or sham injection should be performed by the unmasked physician as described in the 
manual of procedures and the study eye should be monitored post injection as outlined in 
Section 9.16. A follow-up phone call should be scheduled with the subject as outlined in the 
schedule of events.  
In the event that a subject is early terminated from the study, all early termination procedures 
should be performed even if they are outside the allowed study window.  
If the subject would like to discontinue dosing but is amenable to continuing in the study, the site 
should make every effort to have the subject complete as many follow-up visits as possible.  
8.1.3.2. 
Months 13-24  
8.1.3.2.1. Visits 15-26 (Monthly Group) and 15-20 (Every-Other-Month Group) 
During this phase, clinic visits will follow treatment designation (ie, the monthly subjects will 
return monthly for dosing and assessments and the EOM group will return EOM for dosing and 
assessments). At select sites, subjects will complete the home-based digital assessments weekly 
during this period.  
A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, lens, 
and aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and IOP 
measurement will be performed and imaging collected as per the Visit Schedule. 
Blood should be drawn for safety labs, genotyping, and anti-pegcetacoplan antibodies prior to 
the administration of fluorescein as per the Visit Schedule. Samples will be collected for the 
clinical repository for those subjects that consented to this portion.  
Prior to dilating the eyes, all functional tests should be performed (NL-BCVA, LL-BCVA, and 
MNREAD or Radner Reading Charts [in select countries]). The quality of life measures (NEI 
VFQ-25 and FRI) should be administered by the masked site staff.  
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Mesopic microperimetry should be performed on both eyes (where specified) post dilation of the 
eyes and forwarded to the reading center. 
Imaging should be performed including FAF, FFA, SD-OCT, OCT-A (select sites), endothelial 
cell count (select sites) and NIR and sent to the reading center for evaluation per the visit 
schedule.  
IVT (or sham) injection should be performed by the unmasked physician as described in the 
manual of procedures and the study eye should be monitored post injection as outlined in 
Section 9.16. 
In the event that a subject is early terminated from the study, all early termination procedures 
should be performed even if they are outside the allowed study window.  
If the subject would like to discontinue dosing but is amenable to continuing in the study, the site 
should make every effort to have the subject complete as many follow-up visits as possible.  
The completion of the 24-month study period occurs approximately 30 days (monthly treatment 
group) and approximately 60 days (EOM treatment group) after the last visit at which 
investigational product (IP) is administered. The period following last dose of IP is sufficient to 
evaluate the safety of pegcetacoplan based on its half-life in the vitreous; further details can be 
found in the pegcetacoplan IB. At the end of the 24-month study period, subjects will have the 
option to enroll in a separate open-label study. 
8.1.4. 
Early Termination Visit 
A list of all assessments to be performed at the early termination visit can be found on the Visit 
Schedule. All subjects who end the study early for any reason must complete the early 
termination visit, however all efforts should be made to have the subject return for as many 
follow-up visits as possible even if dosing does not occur. All ophthalmic procedures are to be 
performed on BOTH EYES. 
8.1.5. 
Unscheduled Visits 
If a subject returns to the clinical site before their next scheduled visit for an assessment of an 
AE or at the request of the physician, all safety assessments should be performed and any 
additional assessments as deemed medically necessary by the physician.   
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9. 
ASSESSMENTS 
The following evaluations will be performed during the study as outlined in the Visit Schedule in  
Appendix A to Appendix D. Refer to the MOP for detailed descriptions of study-related 
procedures. 
9.1. 
Informed Consent  
Written informed consent for participation must be obtained before performing any study-
specific assessments. Informed consent for all subjects should be maintained within the subject 
source documentation.  
9.2. 
Demographic Information/ Medical/ Surgical History  
Demographic information will be collected from all subjects including but not limited to date of 
birth, race/ ethnicity (where locally permitted). All significant medical conditions and surgeries 
within the past 5 years should be captured for the subject including chronic and ongoing 
conditions. Any history or current use of tobacco is to be collected. 
9.3. 
Ocular History/ Ocular Procedures  
Ocular history within the previous 5 years should be collected and recorded for all subjects. The  
history should include any significant previous ocular surgeries, procedures and/ or medications 
or treatments used for these conditions.  
9.4. 
Vital Signs 
Vital signs consist of body temperature, respiratory rate, blood pressure (systolic and diastolic), 
and heart rate measurements.  
On injection visits, vital signs will be measured prior to dosing. Vital signs should be taken with 
the patient in a seated position after resting for 5 minutes. Vital signs will be measured before 
venipuncture. 
9.5. 
Physical Examination  
A physical exam will be performed and should include but should not be limited to an evaluation 
of the eyes, ears, nose, throat, lymph nodes, head, and neurological function. A patient’s height 
and weight should also be measured at screening. If any abnormalities are noted at screening, the 
PI, or designee, should determine the clinical significance of the finding and whether this will 
pose any safety risk to the subject. Any changes from baseline should be noted and the clinical 
significance assessed. Any new, clinically significant, findings should be documented as AEs.  
9.6. 
Laboratory Analysis of Blood and Urine 
Collection of blood and urine will occur at the study site and the samples will be shipped to a 
central laboratory for analysis. All samples (including urine) should be collected prior to 
treatment and FFA/OCT-A assessments (if applicable). Procedures for the collection and 
processing of blood and urine are provided in the laboratory manual.  
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Table 2 presents the laboratory and urine analysis that will be performed.  
Table 2:  Laboratory Sampling and Analysis 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin  
Hematocrit  
Red blood cell count   
White blood cell count 
with differential  
Platelet count 
Blood urea nitrogen  
Creatinine  
Bilirubin (total, direct 
and indirect)  
Albumin  
Alkaline phosphatase  
Aspartate 
aminotransferase  
Alanine 
aminotransferase  
Creatine kinase  
Glucose 
Electrolytes (sodium, 
potassium, chloride, 
bicarbonate) 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Nitrite  
Urobilinogen 
Leukocyte esterase 
Genotyping  
Anti-pegcetacoplan Ab  
Human chorionic 
gonadotropina  
Follicle-stimulating 
hormoneb  
Luteinizing hormoneb  
 
 
a Serum Pregnancy Test (ie, HCG) will be performed for females of childbearing potential at screening only.  
b FSH and LH will be performed for postmenopausal females at screening only. 
The principal investigator, or designee, must review the results of the screening visit clinical 
laboratory tests (including any retest results) and confirm that these results do not show evidence 
of any medical condition that would make study participation inappropriate. The principal 
investigator, or designee, should also assess any changes from baseline at the follow-up visits 
and the final visit. Clinically significant laboratory values are to be recorded as AEs. 
9.7. 
Genotyping Samples 
The genetic marker sample will be used to evaluate the relationship between genetic 
polymorphisms associated with AMD with disease progression and response to pegcetacoplan. 
A whole-blood sample will be collected for genetic marker analysis. These samples will be 
collected only for those subjects who consent to this analysis.  
These samples will be stored as per the clinical repository guidelines outlined in Section 9.17 if 
the subject consents to this portion of the study. These samples will be stored up to 15 years after 
the date of the final closure of the associated clinical database if the patient consented to the 
clinical repository.  
9.8. 
Urine Pregnancy Test 
Urine pregnancy test will be performed in WOCBP only as outlined in the Visit Schedule in 
Appendix A to Appendix D. 
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9.9. 
Patient-Reported Outcomes 
Data will be collected via interview-administered questionnaires to assess patient-reported 
outcomes during scheduled visits as outlined in the Visit Schedule. The questionnaire should be 
administered by the masked site staff and should be performed prior to any other assessments 
being performed that day.  
Questionnaire data will be used to assess subject-reported efficacy of pegcetacoplan and changes 
in quality of life over time. Questionnaires will be translated into the appropriate language for 
each country or region. 
9.9.1. 
The National Eye Institute Visual Functioning Questionnaire 25-Item Version 
(NEI-VFQ) 
The NEI-VFQ is an interviewer-administered questionnaire designed to assess patient-reported 
visual function (Appendix E). The NEI-VFQ is to be administered by the masked staff. It is a 25-
item questionnaire with a composite score and covers 12 domains of functional health status and 
well-being (general health, general vision, ocular pain, near activities (select countries), distance 
activities (select countries), social functioning, mental health, role difficulties, dependency, 
driving, color vision, and peripheral vision). Scoring yields 12 subscales based on the 12 
domains covered in the questionnaire. These scales are scored from 0 to 100 with higher scores 
indicating better visual function. The recall period is not specified; however, it is important that 
the patient uses the same recall period each time the questionnaire is administered throughout 
their participation in the study.  
9.9.2. 
The Functional Reading Independence (FRI) Index 
The FRI will be interviewer-administered and is an individualized assessment of functional 
reading independence (Appendix F). The questionnaire has 7 items with 1 total index score. 
Higher levels on the scale represent higher functional reading independence. The recall period is 
7 days. 
9.10. 
Best Corrected Visual Acuity and Low Luminance Best Corrected 
Visual Acuity 
Best corrected visual acuity (including best corrected visual acuity under low luminance 
[LL-BCVA]) will be measured at each visit as per the visit schedule by certified study staff. The 
study staff performing visual acuity should be masked to the treatment assignment. Best 
corrected visual acuity testing will be assessed on ETDRS chart starting at a distance of 4 m, 
performed by a certified VA examiner, and should precede any examination requiring 
administration of eye drops to dilate the eye or any examination requiring contact with the eye.  
The LL-BCVA acuity will be measured by placing a neutral density trial lens causing a reduction 
of 2.0 log units in luminance. The same requirements apply to measurement of low luminance 
visual acuity as described above for best corrected visual acuity. Low luminance deficit will be 
auto-calculated.  
A Visual Acuity Specifications procedure manual and training materials will be provided to all 
sites. All examiners will require certification prior to performing this assessment as part of the 
study.  
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9.11. 
Minnesota Low-Vision Reading (MNREAD) Test or Radner Reading 
Charts (in select countries)  
MNREAD Test or Radner Reading Charts (Appendix G) should be administered first 
monocularly for both eyes and then binocularly. The Manual of Operations should be referenced 
for a list of versions that should be administered based on country. These tests should be 
administered prior to dilating the eyes. 
9.12. 
Home-Based Functional Digital Applications (optional, select sites) 
In addition to in-clinic assessments, visual function and reading speed will also be evaluated 
using applications on an electronic device. Subjects who decide to participate in this portion will 
be trained on how to use the digital applications during the Day 1 visit and will complete the 
assessments using the digital application in the clinic at Day 1, Months 1-3, Month 6, 12, 18, 
and 24. In-clinic assessments on the digital application should be completed after completion of 
all functional tests and quality of life measures prior to dilating the eyes (NL-BCVA, LL-BCVA, 
MNREAD or Radner Reading Charts [in select countries], NEI VFQ 25, and FRI). 
Subjects will also take home the electronic device to complete visual function and reading speed 
assessments weekly beginning at Day 1. Subjects should be instructed to complete the 
assessments on the same day each week and at approximately the same time of day each week, if 
possible. 
9.13. 
Complete Ophthalmic Exam 
The complete ophthalmic exam will consist of the following: 
• External examination of the eye and adnexa. 
• Routine screening for eyelids/pupil responsiveness (including ptosis, abnormal pupil 
shape, unequal pupils, abnormal reaction to light, and afferent pupillary defect). 
• Slitlamp examination (cornea, anterior chamber, iris, lens, aqueous reaction [cells and 
flare]). Please see Appendix H for grading scales.  
• Dilated fundus exam including evaluation of retina and vitreous (ie, posterior segment 
abnormalities, retinal hemorrhage/detachment, and vitreal hemorrhage density and 
vitreous cells). Vitreal hemorrhage density and vitreous cells grading scales are 
outlined in Appendix I.  
• IOP measurement—A measurement of intraocular pressure will be conducted using 
either Tono-Pen or Goldmann applanation tonometer as outlined in the MOP. This 
should be performed prior to dilating the eyes and the same method should be used 
for all measurements in the same subject throughout the study. 
9.14. 
Ocular Imaging and Microperimetry  
The following ocular images will be obtained and sent to the reading center as outlined in the 
visit schedule. A reading center manual along with training materials will be provided to all sites 
which will provide information on standardized procedures for the collection, storage, and 
transmission of all images. Prior to any images being taken at the site, site personnel must be 
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properly trained and certified and test images and systems and software must be certified and 
validated by the reading center. Only trained and certified site staff delegated the responsibility 
of image collection should perform this task. Ocular images obtained as part of this study are: 
• Digital Color Fundus Photographs  
• Fluorescein Angiography  
• Spectral Domain Optical Coherence Tomography imaging  
• Fundus Autofluorescence (Heidelberg Spectralis Instrument)  
• Near Infrared Reflectance  
• Endothelial Cell Count (Specular Microscopy): Select sites only 
• Mesopic Microperimetry of the study eye only (at screening, performed on both eyes)  
o To account for the learning curve of this test, the patient is allowed up to 3 
attempts to meet the criteria for this portion  
• Optical Coherence Tomography Angiography (OCT-A): Select sites only  
If a patient misses a visit during which ocular images should have been taken, the images should 
be collected at the next scheduled study visit. 
In the event that a subject is suspected to have new active CNV in the study eye and/or the 
fellow eye, an SD-OCT and FFA using the protocol specified procedures should be performed 
and sent to the reading center to confirm the diagnosis (Section 7.5.1). In addition, in select sites, 
OCT-A should also be captured according to the study imaging protocol and sent to the reading 
center.  
9.15. 
Postinjection Assessment 
The study eye will be assessed after the intravitreal injection of pegcetacoplan or sham to ensure 
that the injection procedure and/or the study medication have not endangered the health of the 
eye. The initial postinjection assessments should be done within 5 minutes post injection and 
include a gross assessment of vision (light perception, hand motion). If the subject passes the 
gross vision test, he/she can be released from the clinic. If the subject does not pass the gross 
vision test, IOP must be measured at that time. Additional IOP measurement must be taken 
approximately every 30 minutes thereafter until IOP ≤30 mm Hg and the subject is able to be 
released from the clinic.  
All subjects receiving an anti-VEGF (ranibizumab or aflibercept) and pegcetacoplan/sham 
injection on the same day, should have the IOP measured prior to and after the anti-VEGF 
(prepegcetacoplan). The second injection (pegcetacoplan/sham) can only be given if the  
IOP ≤21 mm Hg. Antiglaucomatous medication can be given to lower the IOP. The subject can 
only be released from the clinic if the IOP is ≤30 mm Hg. 
Any subject who develops a significant and sustained raise in IOP (>30 mm Hg) after any 
injection, should be monitored according to the investigator’s clinical judgment and may 
undergo additional procedures and measurements of IOP beyond those specified in the protocol 
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as well as IOP lowering procedures. If any concern or immediate toxicity is noted, the subject 
will remain at the site and will be treated according to the physician’s clinical judgment. 
9.16. 
Blood Volume for Study Assessments 
Table 3:  Total Study Blood Volume 
Assay 
Number of time 
points 
Approximate 
volume per time 
point * (mL) 
Approximate 
sample volume 
over course of 
study (mL)—all 
groups 
Anti-pegcetacoplan antibodies 
9 
2 
18 
*Hematology 
8 
4 
32 
**Chemistry (incl. HCG/LH) 
8 
5 
40 
FSH/LH (postmenopausal women 
only) 
- 
5 
- 
Genotyping samplea 
1 
8 
8 
Clinical repository (select sites and 
only subjects that consent to clinical 
repository) 
5 
14 
70 
Total blood volume 
 
 
168 a 
Abbreviations: HCG=human chorionic gonadotropin; FSH=follicle-stimulating hormone ; LH=luteinizing hormone 
a Represents the standard collection volume planned over the duration of the study, actual volume may vary by 
group and across sites. 
* Volume will vary slightly between regions and analyzing labs based on the standard methodology. 
** In some regions, may be included in the chemistry sample based on local methodology. 
 
9.17. 
Samples for Clinical Repository (Optional, Select Sites) 
Apellis intends to apply genomic research across the pegcetacoplan development program to 
explore how genomic variations may affect the clinical parameters associated with and response 
to pegcetacoplan. Select sites will be asked to collect additional whole-blood samples and 
derivatives thereof in a centrally administered facility for the long-term storage of human 
biologic specimens. The collection and analysis of these specimens will facilitate the rational 
design of new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for subjects in the future. Specimens for the Genetic 
Biorepository will be collected from subjects who give specific consent to participate in this 
optional research only and this will only be done at a select group of sites.  
Specimens will be used to achieve the following objectives: 
• To study the association of biomarkers with efficacy, AEs, or disease progression 
• To increase knowledge and understanding of disease biology 
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• To study drug response, including drug effects and the processes of drug absorption 
and disposition  
• To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays  
Future research may suggest other genes, gene categories, proteins, etc. as candidates for 
influencing not only response to pegcetacoplan but also susceptibility to AMD for which 
pegcetacoplan may be evaluated. Thus, this additional genomic research may involve the future 
study of additional unnamed genes or gene categories, but only as they relate to AMD disease 
susceptibility and drug action.  
9.17.1. 
Approval by the Institutional Review Board or Ethics Committee 
Collection and submission of biological samples to the clinical repository is contingent upon the 
review and approval of the exploratory research and the clinical repository portion of the N by 
each site’s IRB or IEC and, if applicable, an appropriate regulatory body. If a site has not been 
granted approval for clinical repository sampling, this section of the protocol (Section 9.17) will 
not be applicable at that site. 
9.17.2. 
Sample Collection 
The following samples will be collected for research purposes, including but not limited to research on 
dynamic (noninherited) biomarkers related to AMD and related diseases, pegcetacoplan, and signaling 
pathways related to AMD and the complement pathway: 
• Residual whole-blood clinical genotyping sample 
• 14-mL whole-blood sample collected at the specified time points 
For all samples, dates of consent and specimen collection should be recorded on the associated 
clinical repository page of the eCRF. For sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual. 
All collected specimens will be destroyed no later than 15 years after the date of final closure of 
the clinical database. The clinical repository storage period will be in accordance with the 
IRB/EC-approved ICF and applicable laws (eg, health authority requirements). 
9.17.3. 
Confidentiality and Data Ownership 
Patient medical information associated with clinical repository specimens is confidential and 
may only be disclosed to third parties as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) signed by the patient, unless required by law. 
Data derived from clinical repository specimen analysis on individual subjects will generally not 
be provided to the subjects or to study investigators unless required by law. The aggregate results 
of any research conducted using clinical repository specimens will be available in accordance 
with the effective Apellis policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of the clinical repository data will become and remain the exclusive and unburdened property of 
Apellis, including the right to sell, license, or assign the invention to another entity.  
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9.17.4. 
Consent to Participate in the Clinical Repository 
The ICF will contain a separate section or separate ICF that will address participation in the 
clinical repository. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the clinical repository. Subjects 
will be told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period. Subjects who decline to participate in the 
clinical repository can still participate in this clinical study. The investigator should document 
whether the patient has given consent to participate by completing the clinical repository 
Research Sample Informed Consent eCRF. In the event of a clinical repository participant’s 
death or loss of competence, the participant’s specimens and data will continue to be used as part 
of the clinical repository research. 
9.17.5. 
Withdrawal From the Clinical Repository 
Subjects who give consent to provide clinical repository specimens have the right to withdraw 
their specimens from the clinical repository at any time for any reason. If a patient wishes to 
withdraw consent to the testing of his or her specimens, the investigator must inform the sponsor 
in writing of the patient’s wishes using the clinical repository Patient Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the Clinical Repository Research 
Sample Withdrawal of Informed Consent eCRF. The patient will be provided with instructions 
on how to withdraw consent after the study is closed. A patient’s withdrawal from this study 
does not, by itself, constitute withdrawal of specimens from the clinical repository. Likewise, a 
patient’s withdrawal from the clinical repository does not constitute withdrawal from this portion 
of the study. 
9.17.6. 
Monitoring and Oversight 
Clinical Repository specimens will be tracked in a manner consistent with GCP by a 
quality-controlled, auditable, and appropriately validated laboratory information management 
system to ensure compliance with data confidentiality as well as adherence to authorized use of 
specimens as specified in this protocol and in the ICF. Apellis monitors and auditors will have 
direct access to appropriate parts of records relating to patient participation in the clinical 
repository for the purposes of verifying the data provided to Apellis. The site will permit 
monitoring, audits, IRB/EC review, and health authority inspections by providing direct access 
to source data and documents related to the clinical repository samples. 
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10. 
SAFETY EVALUATIONS  
Any clinically significant abnormalities persisting at the end of the study/ early withdrawal or 
end of the posttreatment phase will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached. The study includes a number of evaluations to monitor 
safety including monitoring of AEs, postinjection monitoring, laboratory and urine sampling, 
physical examination, and vital signs.  
10.1. 
Data Monitoring Committee 
An external, independent data monitoring committee (DMC) will be formed with the purpose of 
reviewing all data across the conduct of the study on an ongoing basis. The DMC will follow a 
charter that will outline the frequency of meetings and the roles and responsibilities of all 
members. The DMC will meet at the beginning of the study and approximately every 6 months 
thereafter and will perform a masked review of all relevant events on an ongoing basis. An ad 
hoc meeting of the DMC may be convened by the sponsor or the DMC chairperson at any time 
between the regularly scheduled DMC meetings and data reviews, if warranted by new safety 
information or for any other reason. The DMC will communicate their recommendations to the 
sponsor who will notify the appropriate health authorities according to local regulatory 
requirements.  
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11. 
ADVERSE EVENTS 
11.1. 
Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered drug related. An AE can, therefore be any unfavorable and unintended 
sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally associated with the use of an IP, whether or not considered related to the IP. 
Adverse events can be spontaneously reported by the subject and/or in response to an open 
question from the study personnel or revealed by observation and will be recorded during the 
study at the investigational site. All identified AEs must be recorded and described on the 
appropriate AE or SAE page of the eCRF. 
Fluctuating or nonsignificant changes in laboratory values do not necessarily qualify for AE 
recording but are still collected and recorded via the appropriate eCRF form, if applicable. If 
these changes in laboratory values are linked to a diagnosis, this diagnosis should be reported as 
an AE, especially if the diagnosis constitutes an SAE or leads to discontinuation of 
administration of IP. 
11.2. 
Recording Adverse Events 
Adverse events and SAEs will be collected from the signing of the consent form until the last 
visit or early termination visit, 30 days after the last IP administration for the monthly treatment 
groups and 60 days after the last IP administration for the EOM treatment groups. 
Any events that occur prior to dosing will be categorized as pretreatment events; events 
occurring after dosing will be recorded as treatment-emergent adverse events (TEAEs) (start date 
of dosing and, therefore, categorization of the event will be dependent on randomization 
assignment). 
For each AE, the investigator will evaluate and report the onset date (and time if applicable), 
resolution date (and time if applicable), intensity, causality, action taken, serious outcome, and 
whether or not it caused the subject to discontinue the study. 
If possible, the outcome of any AE that caused permanent discontinuation or was present at the 
end of the study should be reported, particularly if the AE was considered by the investigator to 
be related to the IP. Subjects experiencing AEs that cause interruption or discontinuation of IP, 
or those experiencing AEs that are present at the last visit or early termination visit should 
receive follow-up as appropriate. 
All SAEs must be reported to the sponsor/Apellis Safety via eCRF within 24 hours of becoming 
aware of the event, whether or not the event is deemed treatment-related. If the electronic data 
capture (EDC) system is not operational (or for paper-based study[ies]), the site must complete 
the paper SAE form and email to
immediately and also within 24 hours of 
becoming aware of the event. The reported information submitted as a paper SAE must be 
entered into the EDC system once it becomes operational. 
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Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA). If known, the diagnosis of the underlying illness or disorder should be 
recorded, rather than its individual symptoms. 
11.3. 
Reporting Adverse Events 
The sponsor has the responsibility to inform concerned health authorities, ethic committees, and 
investigators about suspected unexpected serious adverse reactions in line with GCP guidance 
and applicable regulatory requirements. 
If required, specific SAEs should be reported to the concerned ethic committees in compliance 
with local requirements  
11.3.1. 
Relationship of Events to Study Treatment 
All AEs that occur during this study will be recorded. The investigator will review each event 
and assess its relationship to study treatment (definitely related, possibly related, unlikely related, 
not related, unknown). The date and time of onset, time relationship to drug dosing, duration, and 
outcome (recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not 
recovered/not resolved, fatal, or unknown) of each event will be noted.  
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 
Definitely 
Related 
Event or laboratory test abnormality, with plausible time relationship to drug intake 
Cannot be explained by disease or other drugs 
Response to withdrawal plausible (pharmacologically, pathologically) 
Event definitive pharmacologically or phenomenologically (ie, an objective and specific 
medical disorder or a recognized pharmacological phenomenon) 
Re-challenge satisfactory, if necessary 
Possibly 
Related 
Event or laboratory test abnormality, with reasonable time relationship to drug intake 
Could also be explained by disease or other drugs 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
Related 
Event or laboratory test abnormality, with a time to drug intake that makes a relationship 
improbable (but not impossible) 
Disease or other drugs provide plausible explanations 
Not Related 
Event or laboratory test abnormality, is plausibly related to the participant’s clinical state, 
underlying disease, or the study procedure/conditions 
Time relationship to drug intake makes a relationship unreasonable 
Other obvious causes for event or laboratory test abnormality exist 
Unknown 
Report suggests an adverse event, however, cannot be judged at this time because 
information is insufficient or contradictory 
More data for proper assessment is needed, or additional data is under examination 
11.3.2. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
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Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL a. 
Severe 
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb. 
Note: An experience may be severe but may not be serious, eg, severe headache). 
Abbreviation: ADL=activities of daily living 
A semicolon indicates ‘or’ within the description of the grade. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
11.4. 
Serious Adverse Events 
An SAE is any AE or suspected adverse reaction that, in the view of either the investigator or 
sponsor, results in any of the following outcomes: death; life-threatening; inpatient 
hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity 
or substantial disruption of the ability to conduct normal life functions; or a congenital 
anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening*, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the above 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. 
*Life-threatening is defined as an AE or suspected adverse reaction, which in the view of either 
the investigator or sponsor places the subject at immediate risk of death as it occurred. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
Unexpected Adverse Event 
An AE is considered “unexpected” if it is not listed in the Reference Safety Information section 
of the IB. 
11.5. 
Treatment and Follow-up of Adverse Events 
AEs (whether serious or nonserious), including clinically significant abnormal laboratory test 
values, will be evaluated by the investigator and treated and/or followed up until the symptoms 
or value(s) return to baseline or are clinically stable. Treatment of AEs will be performed by 
appropriately trained medical personnel, either at the clinical site or at a nearby hospital 
emergency room. When appropriate, medical tests and/or examinations will be performed to 
document resolution of the event(s).  
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AEs continuing after completion of the study will be followed up by telephone or with visits per 
the discretion of the investigator. If possible, the outcome of any AE that caused discontinuation 
from the study or was present at the end of the study should be reported, particularly if the AE 
was considered by the investigator to be related to the study drug. 
11.6. 
Pregnancy  
Although pregnancy is not an AE, all pregnancies and suspected pregnancies (including a 
positive pregnancy test regardless of age or disease state) occurring with a female subject or the 
female partner of a male subject, must be followed to conclusion to determine their outcome and 
are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Apellis 
Safety within 24 hours of the investigator’s awareness using the paper Pregnancy Report Form. 
The Pregnancy Report Form shall be signed and dated by the investigator and submitted via 
email to 
. 
The investigator must follow the subject until completion of the pregnancy and must report the 
outcome of the pregnancy (eg, delivery, termination, etc.) and neonatal status up to 12 months 
postdelivery. An abnormal outcome is defined as any pregnancy that results in the birth of a 
child with persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. 
In the event of an abnormal outcome, an SAE Report Form will be required. 
11.7. 
Disease Progression 
Normal progression or worsening of the medical condition under study (eg, vision loss due to the 
progression of GA in either eye), by itself, does not necessarily constitute an AE unless the 
change can be reasonably attributed to an action of the test article and not only to its lack of 
efficacy. Disease progression that requires an intervention (eg, administration of IVT anti-VEGF 
agents for neovascular AMD) should be recorded as an AE in the eCRF.  
11.8. 
Withdrawal 
Participants may choose to discontinue from treatment or to completely withdraw from this study 
for any reason at any time without penalty or prohibition from enrolling in other clinical 
protocols. 
Participants wishing to withdraw from the study completely will be offered an early termination 
visit. This early termination visit will include the examinations outlined in Section 8.1.5. 
Participants wishing to discontinue treatment but willing to continue with other study 
procedures, will return to the clinical site for follow-up visits, as per protocol, until Month 24. 
Additional information on subject discontinuation is provided in Section 6.5. 
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12. 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS 
12.1. 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  
12.2. 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the contract research organization’s 
data management plan. Quality control and data validation procedures are applied to ensure the 
validity and accuracy of the clinical database.  
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
12.3. 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications. The SAP will also include a 
description of how missing, unused, and spurious data will be addressed.  
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SAS (SAS 
Institute, Cary, NC 27513). 
12.4. 
Planned Interim Analysis and Data Safety Monitoring Committee  
No interim analysis is planned for this study. During the study, patient safety will be monitored 
on a continuous basis by the medical monitor until the last patient completes his or her last 
scheduled study assessment. 
An independent DMC will also be established to provide an ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and 
safety of the participating patients in the study. The ongoing review of SAEs and other 
responsibilities of the DMC will be described in the DMC Charter. 
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The overall Type I (alpha) error rate for the study will be 0.05. To accommodate DMC data 
reviews, the alpha available for efficacy hypothesis testing will be reduced by 0.0001 for each 
DMC review. The study is expected to have 3-4 DMC data reviews prior to the primary analysis 
of 12-month data and 1 review afterward.  
12.5. 
Sample Size Calculation and Power Considerations  
Subjects will be randomized in a 2:2:1:1 ratio to receive treatment with pegcetacoplan monthly, 
pegcetacoplan every other month, sham monthly, or sham every other month. The annual growth 
rate in GA lesion area is expected to have a mean of 1.47, 1.70 and 2.13 mm2/year for 
pegcetacoplan monthly, pegcetacoplan every-other-month, and sham-pooled groups, 
respectively, as estimated from the results of a Phase 2 trial for pegcetacoplan. The standard 
deviation of the lesion growth is estimated to be 1.50 mm2 based on the same Phase 2 trial data 
or 1.25 mm2 based on natural history data.27 The following table provides an approximation of 
the study power for a sample size of 200 subjects in each group (ie, a total enrollment of 
600 subjects) under different alpha values and standard deviations. The approximation is 
calculated using PROC POWER one-way analysis of variance, SAS 9.4. The study power is 
likely larger when utilizing the longitudinal data to model the primary endpoint. The actual study 
power may also vary based on the distribution of the stratification factors (ie, lesion area at 
screening, presence of CNV in fellow eye), and site enrollment.   
Table 4:  Power to Detect a Difference Among 3 Groups With an Equal Size of 
200 Subjects  
Common 
standard 
deviation (mm2) 
Alpha 
(2-sided) 
Power for a true mean of 1.47, 1.70, and 2.13 mm2/year for 
PM, PEOM, and sham, respectively 
PM vs sham 
PEOM vs sham 
Overall  
(among 3 groups) 
1.25 
0.0495 
> 99.9% 
92.9% 
99.9% 
1.25 
0.0248 
99.9% 
88.2% 
99.7% 
1.40 
0.0495 
99.7% 
86.5% 
99.3% 
1.40 
0.0248 
99.3% 
79.4% 
98.6% 
1.50 
0.0495 
99.2% 
81.5% 
98.4% 
1.50 
0.0248 
98.4% 
73.1% 
97.0% 
Abbreviations: PM = pegcetacoplan monthly; PEOM = pegcetacoplan every other month. 
12.6. 
Statistical Analysis Sets  
The safety set will consist of all subjects who receive any amount of IP. 
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed in 
the treatment arm assigned at randomization with the 2 sham treatment arms being combined 
into a single ‘control’ group.  
The modified ITT (mITT) set will include all randomized subjects who receive at least 1 
injection of pegcetacoplan or sham and have baseline and at least 1 postbaseline value of GA 
lesion in the study eye as assessed by FAF. 
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The per-protocol (PP) set will include all ITT subjects who follow the protocol without any 
major deviation(s) that could impact the integrity of the data. A detailed description of the 
reasons for exclusion from the PP population will be included in the statistical analysis plan 
(SAP). 
12.7. 
Efficacy Analyses 
The primary, secondary, and exploratory efficacy analyses will be performed using the ITT set 
and presented by treatment group. 
12.7.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from baseline to Month 12 in the total area of GA 
lesion(s) in eyes injected with pegcetacoplan, either monthly (PM) or every-other month 
(PEOM), or sham injections. GA lesion area (mm2) as measured by a quantified central reading 
center based on FAF images. The primary analysis will be the comparison of pegcetacoplan, 
either monthly (PM) or every-other month (PEOM) versus the combined 2 sham arms (the 2 
sham arms will be combined into a single ‘control’ group). 
The null and alternative hypotheses for the primary efficacy analysis are: 
H0: µS = µPM   vs  HA:  µS ≠ µ PM, and 
H0: µS = µPEOM vs  HA:  µS ≠ µPEOM  
Note: here µ indicates each group’s respective mean change from baseline to Month 12 in GA 
lesion area for the comparison of the primary endpoint. 
A mixed effect model for longitudinal data will be used to analyze the change from baseline in 
GA lesion area. The model will include treatment and presence of CNV in the fellow eye as 
fixed effects; baseline GA lesion area (at screening), time (in months) as a factor; as well as the 
time × treatment interaction term. All available data up to 12 months will be included in the 
model for the primary analysis. The mean change from baseline to 12 months will be estimated 
from the model (ie, least square [LS] mean) and compared between each of the pegcetacoplan 
arms to the sham control. For other time point of interest, LS mean change from baseline will be 
estimated and compared between treatments. Unstructured variance covariance will be used. 
For the analysis of final study data, a similar model including data up to 24 months will be used 
and LS means at time points of interest will be estimated and compared between treatment. 
As indicated in an earlier section, the study is expected to have an approximately 5 DMC data 
reviews. Allocating an alpha level of 0.0001 for each DMC data review, the alpha level remains 
for the efficacy analysis at 0.0495 to maintain an overall study alpha of 0.05. 
The hypothesis testing strategy for the primary and secondary efficacy endpoints will be based 
on the Gate-keeping multiple testing procedures controlling for the study wide type I error 
strongly at 2-sided 0.0495 as follows:  
Step 1. The mean GA lesion growth at 12 months will be compared between the PM group 
and the Control at the α level of 0.0495. If the null hypotheses of no difference between 
groups in this step is rejected, the testing proceeds to Step 2 and Step 3. If it’s not rejected, 
the testing procedure stops at this step.  
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Step 2. The mean GA lesion growth at 12 months will be compared between the PEOM 
group and the Control at the α1 level. If the null hypotheses of no difference between groups 
in this step is rejected, the α1 level will be passed down to Step 3. The actual value of α1 will 
be specified in the SAP and it will be defined to ensure an adequate power of at least 80% for 
the comparison in this step. 
Step 3. The mean GA lesion growth at 24 months will be compared between the PM group 
and the Control at the α level of 0.0495 if the null hypotheses are rejected at both Step 1 and 
Step 2; or at the α level of (0.0495 – α1) if Step 2 testing does not reject the null hypothesis. 
If the null hypothesis at this step is rejected, the α level used at this step will be passed down 
to the next step of testing. If it’s not rejected, the testing procedure stops at this step.  
Step 4. The prioritization and alpha allocation for the remaining secondary endpoints will be 
specified in the SAP. 
The following sensitivity and supportive analyses will be performed to evaluate the robustness of 
the results from the primary analysis method: 
• Analyses will be repeated using the mITT and PP sets 
• Primary and secondary endpoints will also be summarized with no pooling of the 2 
sham arms. The comparison for pegcetacoplan and sham injection within each dose 
regimen (ie, PM vs SM and PEOM vs SEOM) will be conducted 
• Multiple imputation methods and other sensitivity analyses will be explored, and 
details will be provided in the SAP 
12.7.2. 
Secondary Efficacy Analysis 
The key secondary and secondary endpoints will be analyzed in the same fashion as the primary 
endpoint using mixed effect model. The binary secondary endpoints will be analyzed using 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factors. Hypothesis 
testing for 3 key secondary endpoints will be performed in the order specified. The SAP will 
provide more details on multiplicity adjustment and the approach for alpha spending among the 
endpoints.  
Key Secondary Efficacy Endpoints 
• Change from baseline in maximum monocular reading speed (study eye), as assessed 
by MNREAD or Radner Reading Charts at Month 24 (in select countries) 
• Change from baseline in FRI index score, at Month 24. 
• Change from baseline in NL-BCVA at Month 24 as assessed by ETDRS chart.  
Secondary Efficacy Endpoints 
• Change from baseline in LL-BCVA at Month 12 and Month 24 as assessed by 
ETDRS chart.  
• Change from baseline in LLD at Month 12 and Month 24. 
• Change from baseline at each planned assessment in the total area of GA lesion(s) in 
the study eye (in mm2) as assessed by FAF. 
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• Change from baseline in monocular critical print size (study eye), as assessed by 
MNREAD or Radner Reading Charts, at Month 12 and Month 24 (in select 
countries).  
• Change from baseline in the NEI VFQ-25 distance activity subscale score at Month 
12 and Month 24 (in select countries).  
• Number of scotomatous points assessed by mesopic microperimetry for the 
evaluation of the macular functional response.  
• Change in macular sensitivity as assessed by mesopic microperimetry for the 
evaluation of the macular functional response. 
12.7.3. 
Exploratory Efficacy Analysis 
Summary statistics will be provided for the following exploratory endpoints: 
• Change from baseline in NEI VFQ-25 composite score at Month 12 and Month 24.  
• Change from baseline in NEI VFQ-25 near activity subscale score at Month 12 and 
Month 24 (in select countries). 
• Comparison between study eye and fellow eye in change in GA lesion size from 
baseline to Month 12 and Month 24.  
• Binocular maximum reading speed as assessed by MNREAD or Radner Reading 
Charts over time (in select countries).  
• Binocular critical print size as assessed by MNREAD or Radner Reading Charts over 
time (in select countries). 
• Relationship between genetic polymorphisms associated with AMD with GA 
progression and response to pegcetacoplan. 
• Incidence of new onset of subclinical CNV in the study eye.  
• Assess sensitivity and specificity of a digital reading speed application to detect 
disease progression / regression (optional, select sites). 
• Assess sensitivity and specificity of a digital visual function application to detect 
disease progression / regression (optional, select sites). 
12.8. 
Safety Analyses 
Adverse events will be collected from the time of the first study drug administration until a 
subject completes the study or discontinues prematurely. Treatment-emergent adverse events are 
defined as those AEs that develop or worsen after the first dose of study medication and up to 
30 days beyond the last dose of study medication. The current version of MedDRA will be used 
to classify all AEs. Treatment-emergent adverse events will be summarized by System Organ 
Class and Preferred Term, in accordance with the MedDRA coding dictionary. The number of 
subjects reporting each AE Preferred Term will be tabulated for all TEAEs and separately for 
those considered as related to study treatment by the investigator or designee. Number of 
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subjects reporting SAEs will also be tabulated. Adverse event summaries will be presented for 
each treatment group separately.  
Adverse events will be summarized by MedDRA coding terms, and separate tabulations also will 
be produced for related AEs (those considered by the investigator as definitively drug related), 
SAEs, and discontinuations due to AEs. Vital signs data and findings from physical and 
ophthalmologic examinations will be tabulated for changes over time on study. Laboratory 
parameters will be summarized for changes across study by using descriptive statistics. Separate 
summaries will be prepared for systemic (nonocular) and ocular AEs, with events in the study 
eye and nonstudy eye summarized separately 
12.8.1. 
Anti-Therapeutic Antibodies   
Data on anti-therapeutic antibodies (ATAs) directed against pegcetacoplan will be summarized 
by the number and percentage of subjects with confirmed positive ATAs.  
12.8.2. 
Death  
Patient deaths and primary cause of death will be summarized.  
12.8.3. 
Ocular Assessments  
Descriptive summaries will be generated for ocular assessments, such as VA and IOP. 
12.9. 
Handling of Missing Data 
All efforts will be made to minimize missing data. A full description of the imputation methods 
will be provided in the SAP.  
12.10. 
Visit Windows 
Analysis visits will be derived with windows for the monthly visits to assess the primary 
endpoint. Baseline is defined as the date of randomization. If 2 or more treatment visits occur 
within a window, the closest visit to the target day will be used as that analysis visit; if 2 visits 
are equidistant from the scheduled analysis visit day, the later analysis visit will be used. 
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13. 
ETHICS 
13.1. 
Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, applicable regulations, the 
ethical principles set forth in the Declaration of Helsinki, and the ICH Harmonized Tripartite 
Guidance for Good Clinical Practice, E6, R1 (ICH GCP). 
13.2. 
Institutional Review Board/Ethic Committee 
The study protocol, any amendments to the protocol, ICF, the IB, and other study-specific 
information will be reviewed and approved by the IRB/IEC. The study will not be initiated until 
the IRB/IEC has approved the protocol or a modification thereof. All records pertaining to 
IRB/IEC submission and approval should be kept in the site’s regulatory files and sponsor’s Trial 
Master File. 
The IRB/IEC must be constituted and operate in accordance with the principles and requirements 
described in ICH Guidance E6 and national and local regulations as deemed appropriate. 
13.3. 
Subject Information and Consent 
The principal investigator, or designee, is responsible for obtaining an informed consent. A 
written informed consent, in compliance with ICH Guidance E6, must be obtained from each 
subject at the screening visit, prior to performing any study-related procedures. 
The purpose of the study, the procedures to be carried out, and the potential hazards will be 
described to the subjects in nontechnical terms. The subject will be given sufficient time to 
consider the study’s implications before deciding to participate in the study. The subject and/or 
legal guardian will be required to sign and date an ICF and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. The PI shall retain 
the original, signed informed consent for study participation in the subject’s medical record and 
shall provide the subject and/or legal guardian with a copy of the signed consent. 
If there are any changes/amendments to the approved protocol, which may directly affect the 
subject’s decision to continue participation in the study, the ICF shall be amended to incorporate 
the changes to the protocol and the subject must re-sign the IRB/IEC approved amended ICF. 
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14. 
ADMINISTRATIVE CONSIDERATIONS 
14.1. 
Direct Access to Source Data/Documents 
The principal investigator, or designee, must maintain, at all times, the primary records (ie, 
source documents) of each subject’s data for data verification. Examples of source documents 
are medical records, laboratory reports, study drug records, and printed CRF pages that are used 
as the source. 
The investigator will permit trial-related monitoring, audits, and inspections by the sponsor 
and/or its designee, IRB/IEC, and the regulatory agencies at any time during the study. The 
investigator will ensure that the auditor is allowed direct access to the source data, medical 
records, eCRFs, and the site’s regulatory file for the study and any other pertinent information.  
14.2. 
Quality Control and Quality Assurance 
This study is to be performed in full compliance with the protocol, GCP, and applicable 
regulatory requirements. The principal investigator, sponsor, and/or its designee are responsible 
for ensuring that the study staff receive appropriate training on the protocol, study procedures, 
and any other relevant information.  
Quality assurance and quality control systems are implemented and maintained using written 
Investigative site, sponsor and/or designee Standard Operating Procedures (SOPs) to ensure that 
the study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirement(s) and local laws, 
rules, regulations. 
Quality control checks will be applied at each stage of data handling (eg, edit checks) to ensure 
that all data are reliable and have been processed correctly. 
14.3. 
Monitoring 
On-site monitoring will be performed by the sponsor’s designee for the duration of the study. 
The monitor will ensure that the study is conducted, recorded, and reported in accordance with 
the protocol, SOPs, GCP, and the applicable regulatory requirements. The monitor will verify the 
accuracy and completeness of the eCRF entries, source documents, and other study-related 
records against each other. The investigator, or designee, will provide direct access to source 
data/documents for study-related monitoring. It is important that the investigator and the 
investigator site staff are available at these visits. The monitor will record the date of each visit 
together with a summary of the status and progress of the study. Proposed actions will be 
documented in writing to the investigator. 
14.4. 
Data Handling and Record Keeping 
The investigator must maintain all documentation related to this study. All essential documents 
(as defined in the ICH Guideline E6 and applicable local regulations) and the data generated in 
connection with this study, together with the original copy of the final report, will be retained for 
at least 2 years after the last approval of a marketing application in an ICH region and until there 
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are no pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the IP. These documents 
should be retained for a longer period if required by the applicable regulatory requirements or by 
an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
14.5. 
Protocol Amendments 
Any amendments to the study protocol deemed necessary as the study progresses will be 
discussed between sponsor and the investigator. The investigator will not implement any changes 
to the protocol without an agreement by the sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to 
eliminate immediate hazards to study subject or when the changes involve only logistical or 
administrative aspects of the study (eg, change in staff, telephone numbers). 
Changes resulting in amendments will be made jointly between the sponsor and the investigator 
and must be confirmed in writing. Amendment(s) will be approved and signed off in the same 
way as the protocol.  
14.6. 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure 
and Content of Clinical Study Reports). 
14.7. 
Finance and Insurance 
Finance and insurance will be addressed in a Clinical Trial Agreement between the sponsor and 
the investigator/institution. 
14.8. 
Publication Policy 
The data generated for this study are considered confidential information and are the property of 
the sponsor. All study information provided to the PI and site personnel by the sponsor shall not 
be published or disclosed to a third party without the prior written consent of the sponsor.  
Apellis will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Apellis adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Apellis. The 
purpose of the publication steering committee is to act as a noncommercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Apellis products or projects must undergo appropriate technical and 
intellectual property review, with Apellis agreement to publish prior to release of information. 
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
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commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the investigator will own (or share with other authors) the copyright 
on his/her publications. To the extent that the investigator has such sole, joint, or shared rights, 
the investigator grants the sponsor a perpetual, irrevocable, royalty-free license to make and 
distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral, or 
other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Apellis, the institution and investigator 
shall withhold submission of such publication for up to an additional 60 days to allow for filing 
of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 
14.9. 
ClinicalTrials.gov  
This study will be listed with ClinicalTrials.gov. 
14.10. 
Termination of Study 
The sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons at any time. The investigator reserves the right to discontinue dosing subjects at 
any time for safety reasons.  
 
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REFERENCES 
1. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and 
impact of fundus autofluorescence patterns in age-related macular degeneration. American 
journal of ophthalmology. 2007;143(3):463-472. 
2. Rein DB, Wittenborn JS, Zhang X, et al. Forecasting age-related macular degeneration through 
the year 2050: the potential impact of new treatments. Archives of ophthalmology. 
2009;127(4):533-540. 
3. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in 
the United States. Archives of ophthalmology. 2004;122(4):564-572. 
4. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: 
clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079-1091. 
5. Sunness JS, Bressler NM, Tian Y, Alexander J, Applegate CA. Measuring geographic atrophy in 
advanced age-related macular degeneration. Investigative ophthalmology & visual science. 
1999;40(8):1761-1769. 
6. Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity 
loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. 
1999;106(9):1768-1779. 
7. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-
related macular degeneration. Proceedings of the National Academy of Sciences of the United 
States of America. 2002;99(23):14682-14687. 
8. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement 
regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. 
Proceedings of the National Academy of Sciences of the United States of America. 
2005;102(20):7227-7232. 
9. Lommatzsch A, Hermans P, Muller KD, Bornfeld N, Bird AC, Pauleikhoff D. Are low 
inflammatory reactions involved in exudative age-related macular degeneration? Morphological 
and immunhistochemical analysis of AMD associated with basal deposits. Graefe's archive for 
clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und 
experimentelle Ophthalmologie. 2008;246(6):803-810. 
10. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-
related macular degeneration contain proteins common to extracellular deposits associated with 
atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB journal : official 
publication of the Federation of American Societies for Experimental Biology. 2000;14(7):835-
846. 
11. Edwards AO, Ritter R, 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H 
polymorphism and age-related macular degeneration. Science. 2005;308(5720):421-424. 
12. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-
related macular degeneration. Science. 2005;308(5720):419-421. 
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13. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular 
degeneration. Science. 2005;308(5720):385-389. 
14. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding 
variant in CFH, strongly influences risk of age-related macular degeneration. Nature genetics. 
2006;38(9):1055-1059. 
15. Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk 
of advanced age-related macular degeneration. Nature genetics. 2013;45(11):1366-1370. 
16. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular 
degeneration. The New England journal of medicine. 2007;357(6):553-561. 
17. van de Ven JP, Nilsson SC, Tan PL, et al. A functional variant in the CFI gene confers a high risk 
of age-related macular degeneration. Nature genetics. 2013;45(7):813-817. 
18. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular 
degeneration. Nature genetics. 2013;45(4):433-439, 439e431-432. 
19. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 
(C2) genes is associated with age-related macular degeneration. Nature genetics. 2006;38(4):458-
462. 
20. Horie-Inoue K, Inoue S. Genomic aspects of age-related macular degeneration. Biochemical and 
biophysical research communications. 2014;452(2):263-275. 
21. Hecker LA, Edwards AO. Genetic control of complement activation in humans and age related 
macular degeneration. Advances in experimental medicine and biology. 2010;703:49-62. 
22. Hecker LA, Edwards AO, Ryu E, et al. Genetic control of the alternative pathway of complement 
in humans and age-related macular degeneration. Human molecular genetics. 2010;19(1):209-
215. 
23. Machalinska A, Dziedziejko V, Mozolewska-Piotrowska K, Karczewicz D, Wiszniewska B, 
Machalinski B. Elevated plasma levels of C3a complement compound in the exudative form of 
age-related macular degeneration. Ophthalmic research. 2009;42(1):54-59. 
24. Scholl HP, Charbel Issa P, Walier M, et al. Systemic complement activation in age-related 
macular degeneration. PloS one. 2008;3(7):e2593. 
25. Leeds JM, Henry SP, Bistner S, Scherrill S, Williams K, Levin AA. Pharmacokinetics of an 
antisense oligonucleotide injected intravitreally in monkeys. Drug metabolism and disposition: 
the biological fate of chemicals. 1998;26(7):670-675. 
26. Fleckenstein M, Mitchell P, Freund KB, et al. The Progression of Geographic Atrophy Secondary 
to Age-Related Macular Degeneration. Ophthalmology. 2018; 125(3):369-390. 
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G. Only subjects that sign the separate consent for the clinical repository and genotyping will have these samples collected. A 14-mL whole-blood sample will be collected at each 
of the specified visits. 
H. Blood pressure, respiratory rate, heart rate, and temperature. On dosing days, vital signs should be taken predose. 
I. Height and weight should be collected at screening. 
J. Perform assessments prior to dilating the eyes. 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly. 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA and OCT-A (select sites) images 
must be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand-motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg  in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and  post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study. 
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye. 
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than  a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
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I. Height and weight should be measured at screening. 
J. Perform assessments prior to dilating the eyes. 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly. 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified  
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
 
 
 
 
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J. Perform assessments prior to dilating the eyes. 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly. 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital application will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified  
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye. 
 T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
 
 
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I. Height and weight should be measured at screening.  
J. Perform assessments prior to dilating the eyes. 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly. 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.   
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified  
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes the gross vision test and IOP is ≤30 mm Hg. 
Note: if the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab 
or aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the investigator determines that there are any safety 
concerns, a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
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APPENDIX E: NATIONAL EYE INSTITUTE VISUAL FUNCTIONING 
QUESTIONNAIRE 25-ITEM VERSION 
 
 
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APPENDIX F: FUNCTIONAL READING INDEPENDENCE INDEX (FRI)  
Kimel M, Yu R, Leidy N. The Functional Reading Independence Index (FRI Index) - User Manual 
(Version 1.2). Evidera. 2015  
 
 
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Pegaetacoplan 
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12 August 2020
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Pegaetacoplan 
APL2-304 Protocol Amendment 5
 
12 August 2020
Apellis Pharmaceuticals, Inc
Page 130 of 164
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Pegaetacoplan 
APL2-304 Protocol Amendment 5
 
12 August 2020
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Pegaetacoplan 
APL2-304 Protocol Amendment 5
 
12 August 2020
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12 August 2020
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12 August 2020 
APPENDIX G: MINNESOTA LOW-VISION READING TEST (MNREAD) 
AND RADNER READING CARDS     
The manual of procedures should be referenced for a detailed table of countries and languages to 
determine which test will be administered. Equipment and testing procedures will also be 
described in detail in the manual of procedures for both tests.  
Minnesota Low-Vision Reading Test: 
The Minnesota Low-Vision Reading Test acuity cards are continuous-text reading-acuity cards 
used for measuring the reading acuity and speed of normal and low-vision patients. These charts 
were developed at the Minnesota Laboratory for Low-Vision Research, University of Minnesota, 
Minneapolis, Minnesota, USA.  
The MNREAD Acuity Charts will be used to measure:  
• Critical Print Size: the smallest print that the patient can read with maximum speed  
• Maximum Reading Speed: the patient’s reading speed when reading is not limited by 
print size  
Radner Reading Cards: 
The Radner Reading Cards consist of sentence optotypes, which are optimized reading test 
items, standardized by construction and statistical selection. These cards allow for accurate and 
comparable measurements of reading acuity and reading speed and measurement of critical print 
size. 
 
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APPENDIX H: GRADING SCALE FOR ASSESSMENT OF ANTERIOR 
CHAMBER FLARE OR CELLS  
AQUEOUS REACTION—FLARE  
Grade 
Description 
0 
No protein is visible in the anterior chamber when viewed by an experienced observer 
using slitlamp biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification. 
Trace 
Trace amount of protein detectable in the anterior chamber. This protein is visible only 
with careful scrutiny by an experienced observer using slitlamp biomicroscopy; a small, 
bright, focal slit-beam of white light; and high magnification. 
1+ 
Mild amount of protein detectable in the anterior chamber. This protein is immediately 
apparent to an experienced observer using slitlamp biomicroscopy and high magnification, 
but such protein is detected only with careful observation with the naked eye and a small, 
bright, focal slit-beam of white light. Note presence of any fibrin. 
2-3+ 
Moderate amount of protein detectable in the anterior chamber. These grades are similar to 
1+ but the opacity would be readily visible to the naked eye of an observer using any 
source of a focused beam of white light. This is a continuum of moderate opacification, 
with 2+ being less apparent than 3+. Note presence of any fibrin. 
4+ 
A large (severe) amount of protein is detectable in the anterior chamber. Similar to 3+, but 
the density of the protein approaches that of the lens. Additionally, frank fibrin deposition 
is frequently seen in acute circumstances. It needs to be noted that because fibrin may 
persist for a period of time after partial or complete restoration of the blood-aqueous 
barrier, it is possible to have resorbing fibrin present with lower numeric assignations for 
flare (eg, 1+ flare with fibrin). 
 
AQUEOUS REACTION—CELLS 
Grade 
Description 
0 
No cells are seen in any optical section when a large slitlamp beam is swept across the 
anterior chamber. 
Trace 
Rare (1-3) cells are observed when the slitlamp beam is swept across the anterior chamber. 
When the instrument is held stationary, not every optical section contains circulating cells. 
1+ 
3-10 cells/optical section are seen when the slitlamp beam is swept across the anterior 
chamber. When the instrument is held stationary, every optical section contains circulating 
cells. Note stage of hypopyon, if applicable. 
2+ 
10-25 cells are seen when the slitlamp beam is swept across the anterior chamber. When 
the instrument is held stationary, every optical section contains circulating cells. Note 
stage of hypopyon, if applicable. 
3+ 
25-50 cells are seen when the slitlamp beam is swept across the anterior chamber. When 
the instrument is held stationary, every optical section contains circulating cells. Keratic 
precipitates or cellular deposits on the anterior lens capsule may be present. Note stage of 
hypopyon, if applicable. 
4+ 
More than 50 cells are seen when the slitlamp beam is swept across the anterior chamber. 
When the instrument is held stationary, every optical section contains circulating cells or 
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hypopyon is noted. As for the fibrin deposition, hypopyon may persist for a period of time 
after exudation of cells into the anterior chamber has diminished or ceased entirely, 
making it possible for have 1+ circulating cells in the anterior chamber with a resolving 
hypopyon. 
 
 
 
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APPENDIX I: GRADING SCALE FOR ASSESSMENT OF VITREOUS 
CELLS  
Grade 
Description 
Cells in Retro-Illuminated Field 
0 
Clear 
0 
Trace 
Few opacities 
1-20 
1 
Scattered opacities 
21-50 
2 
Moderate opacities 
51-100 
3 
Many opacities 
101-250 
4 
Dense opacities 
≥ 251 
 
 
 
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Section revised to further define approved methods of contraception 
include:  
• 
Combined (estrogen-and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation: 
o 
Oral 
o 
Injectable 
o 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the 
surgical success) 
• 
Sexual abstinence (defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the 
study treatments). Sexual abstinence is only accepted when it is 
the preferred and usual lifestyle of the subject. 
Approved methods of contraception include: oral contraceptives, 
intrauterine device, medically acceptable barrier methods 
(diaphragm or condom), implantable or injectable contraceptives 
(like DepoProvera) or removable birth control device (like 
NuvaRing or Ortho Evra patches); and/or surgical sterilization (at 
least 6 months before dosing). Subjects practicing abstinence and 
coitus interruptus (pull out method) must agree to use an approved 
method of contraception during the study and 90 days after their last 
dose of study drug. 
Section 6.4  Approved Methods of 
Contraception 
The following section was added: 
 
A subject may withdraw from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the 
institution. The investigator or sponsor may withdraw the subject at any 
time (e.g., in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from treatment with the 
investigational product with the medical monitor when possible. 
Subjects who discontinue treatment with the investigational product can 
continue participation in the study and should be encouraged  to return to 
the clinical site for as many follow-up visits as they can. In the event that 
a subject terminates early from the study, all early termination 
procedures should be performed even if they are outside the allowed 
study window.  
The reason for termination, date of stopping treatment with 
investigational product, all follow-up information and the total amount of 
investigational product administered must be recorded in the case report 
form (CRF) and source documents. 
Section 6.5  Discontinuation of 
Subjects 
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The requirement to notify the sponsor prior to unmasking was removed: 
 
In the event of a medical emergency where the knowledge of subject 
treatment by masked individuals (e.g., the subject or his/her physician) is 
required, an individual Investigator (or designee) will have the ability to 
unmask the treatment assignment for a specific subject and share that 
information with the appropriate parties. The Investigator (or designee) 
must endeavor to notify the Sponsor prior to unmasking a subject.  
Section 7.2.1  Unmasking 
Section was revised to allow study treatment administration to occur on a 
day separate from the assessment visit: 
 
Section was revised to allow study treatment administration to occur on a 
day separate from the assessment visit: 
 
Only qualified study staff and those delegated the responsibility of study 
drug administration on the Delegation of Authority log should perform 
this procedure. All staff should be appropriately trained on all procedures 
prior to performing the procedures. Sites should follow the Visit 
Schedule for order of procedures and assessments.  
Administration of study treatment (APL-2 or Sham) can be done on a 
separate day from the assessment visit if both days fall within the visit 
window. If this occurs on the randomization visit, then the administration 
of APL-2 or Sham should be done within 3 days of randomization and 
after approval from the medical monitor. When study treatment 
administration is on a day other than  a study visit, then the only 
assessment that must be done on the day of study treatment 
administration is the pre-injection IOP.  
If a subject falls outside the visit window for a dosing visit, the dose 
should be skipped and the subject should be scheduled on time for the 
next dosing visit. 
Section 7.3.2  Treatment 
Administration 
The description of sham injection was modified as there is no 
requirement for sham to be sterile: 
 
Sham will be provided as sterile empty stoppered glass vials and should 
be stored according to the label.   
 
Section 7.3.3.1 Identity of the 
Investigational Product 
The procedure for sham injection was further described: 
 
The procedure for sham injection will be the same as that used for IVT 
injection until the actual injection but no actual injection will occur. The 
injecting physician will only touch the study eye with the blunt end of 
the syringe. No needle or medication will be injected inside the eye. 
Section 7.4  Sham Injection 
Administration 
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Detailed instructions on sham injection procedures and post-injection 
procedures will be provided in the Manual of Procedures. 
 
The end of the trial for each subject was defined: 
 
The end of the trial for each subject is defined as when the subject either 
completes their Month 24 Visit and enrolls in the open-label extension 
study or, should a subject elect not to enter the open label extension 
study, when the subject completes their exit visit at Month 30. 
 
Through the section it has also been noted that endothelial cell count 
assessment is for “select sites only”. This was previously noted in the 
schedule of events but not consistently in the body of the protocol. In 
addition FAF and NAR are no longer “study eye only”. 
 
Section 8  Study Procedures 
The following assessments were removed as they will no longer be 
conducted at the screening Visit 1: 
• 
Low luminance BCVA 
• 
Endothelial cell count 
• 
OCT A 
The following text was moved to Section 8.1.2 as training for home-
based digital applications will now be conducted at Visit 2: 
Prior to dilating the eyes, subjects at select sites will be trained on how to 
use the home based digital applications for visual function and reading 
speed if the subject decides to participate in this portion. This training 
must occur after completion of all functional tests (NL BCVA, LL
BCVA). 
Section 8.1.1  Visit 1 All Subjects 
It was clarified that: 
All assessments should be performed on the same day. All study visits 
should be scheduled and projected based on the Day 1 visit. 
 
The following text was added as home-based digital application training 
will now occur at Visit 2: 
Subjects at select sites will be trained on how to use the home-based 
digital applications for visual function and reading speed if the subject 
decides to participate in this portion. This training must occur after 
completion of all functional tests (NL-BCVA, LL-BCVA). 
 
The following assessments were added: 
• 
Endothelial cell count 
• 
OCT-A (select sites) 
 
The following text was removed as subject discontinuation is now 
covered in Section 6.5. 
In the event that a subject is early terminated from the study, all early 
termination procedures should be performed even if they are outside the 
allowed study window.  
If the subject would like to discontinue dosing but is amenable to 
Section 8.1.2 Randomization/Initial 
Treatment—Day—Within 28 Days 
of Screening 
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continuing in the study, the site should make every effort to have the 
subject complete as many follow up visits as possible. 
 
It has been noted in the text which assessments will be conducted at 
Month 27 and Month 30. 
Section 8.1.4 Follow-up Phase 
Instructions were revised to include the following: 
 
All AEs encountered during the study will be monitored and reported in 
detail in the source documents and documented on the eCRF, from 
signing of the ICF until the Exit Visit. AEs should be recorded by 
maximum severity. AEs, especially those for which the relationship to 
test drug study treatment are considered by the Investigator to be 
possibly or definitely related, should be followed up until they have 
returned to the baseline status or stabilized. If a clear explanation is 
established, it should be recorded on the eCRF. 
Section 11.2   Recording Adverse 
Events 
Instructions modified as follows: 
If any AEs are serious, special procedures will be followed. All SAEs 
will be reported to the Safety Monitor by the Investigator via fax or 
email within one calendar day of becoming aware of the event, whether 
or not the serious events are deemed drug related. SAE reporting contact 
information will be provided separately and as included in the Safety 
Monitoring Plan. All SAEs must be reported to the applicable ethics 
committee by the Investigator in accordance with their regulations. 
 
Special procedures will be followed for reporting SAEs. All SAEs 
will be reported to the Safety Monitor by the Investigator via eCRF or 
fax/email (if eCRF is not available)  within 24 hours of becoming aware 
of the event, whether or not the event is deemed treatment-related. If the 
EDC system is not operational, the site must complete the appropriate 
paper SAE form and fax/email to the number listed on the SAE form, 
also within 24 hours of becoming aware of the event. The reported 
information submitted as a paper SAE form must be entered into the 
EDC system once it becomes operational. 
SAE reporting contact information will be provided separately and 
included in the Safety Monitoring Plan. All SAEs must be reported to the 
applicable ethics committee by the Investigator in accordance with their 
regulations. 
Section 11.5 Serious Adverse Events 
The following text was added: 
A suspected adverse reaction means any AE for which there is a 
reasonable possibility that the drug caused the AE. Reasonable 
possibility means there is evidence (such as a temporal relationship) to 
suggest a causal relationship between the drug and the AE. 
Section 11.6 Unexpected Adverse 
Events or Unexpected Suspected 
Adverse Reactions 
The analysis description was modified as follows as this will be 
conducted at all sites. This is an error correction. 
• Change from baseline at each planned assessment in the total area of 
GA lesion(s) in the study eye (in mm2) as assessed by FAF (in select 
sites)  
Section 12.7.2 Secondary Efficacy 
Analysis 
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Section 12.10 was added to describe how visit windows will be used in 
the assessment of the primary endpoint: 
 
Analysis visits will be derived with windows for the monthly visits to 
assess the primary endpoint. Baseline is defined as the date of 
randomization. If 2 or more treatment visits occur within a window, the 
closest visit to the target day will be used as that analysis visit; if 2 visits 
are equidistant from the scheduled analysis visit day, the later analysis 
visit will be used. 
Section 12.10 Visit Windows 
All study schedules were modified to align with the changes noted 
above, including removal of PK and complement profile study 
assessments. 
Appendix A, B, C, and D:  Visit 
Schedules 
 
 
 
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associated with inhibition of ovulation, oral contraceptives, intrauterine 
device, intrauterine hormone releasing system; and/or bilateral tubal 
occlusion (at least 6 months before dosing) medically acceptable barrier 
methods (diaphragm or condom), implantable or injectable 
contraceptives (like DepoProvera) or removable birth control device (like 
NuvaRing or Ortho Evra patches); and/or surgical sterilization (at least 6 
months before dosing). Subjects practicing abstinence and coitus 
interruptus (pull out method) must agree to use an approved method of 
contraception during the study and 60 90 days after their last dose of 
study drug. 
Masking language was modified to indicate that the PI is required to 
remain masked to subjects’ treatment assignments, while the treating 
physician and any associated support staff involved in IP administration 
will be unmasked. 
Section 7.2 Masking and 
Minimization of Bias 
Guidance on the treatment of new exudation related to active choroidal 
neovascularization in the study eye and/or fellow eye was modified to 
clarify that the reading center will provide a report to indicate whether or 
not there is evidence of active, exudative AMD, and the Investigator will 
then determine if anti-VEGF treatment should be initiated. The 
Investigator should wait for the reading center report before making a 
decision regarding treatment, except in cases where there is clear 
evidence of disease activity that may have a detrimental visual impact if 
not treated immediately. 
 
It was also clarified that either ranibizumab or aflibercept should be 
selected as the anti-VEGF therapy, and that the unmasked physician 
should administer anti-VEGF treatment if the treatment is administered 
on the same day as APL-2.  
 
It was also noted that any treatments of therapies administered to the 
fellow eye within 5 years of screening should be recorded as a 
concomitant medication. 
Section 7.5.1 Treatment of New 
Exudation Related to Active 
Choroidal Neovascularization in the 
Study Eye and/or Fellow Eye 
Visit Schedules A-D 
The following instruction regarding electronic devices was added: 
The subject will be instructed to bring back the electronic device for the 
visits specified in the schedule of events. 
Section 8.1.3.1 Months 1-12 
Month 6 and Month 12 were added as times of in-clinic assessment. 
It was noted that subjects will take electronic devices home at Day 1 
instead of at Screening. 
Section 9.12 Home-Based 
Functional Digital Applications (in 
select sites/countries) 
Visit Schedules A-D. 
Clarified that: 
In the event that a subject is suspected to have new active CNV in the 
study eye and/or the fellow eye, an SD-OCT and FA using the protocol 
specified procedures should be performed and sent to the Reading Center 
to confirm the diagnosis. In addition, in selected sites, OCT-A should 
also be captured according to the study imaging protocol and sent to the 
Reading Center.  
Section 9.14 Ocular Imaging 
It was clarified that if the subject does not pass the gross vision test, IOP 
must be measured at that time. Additional IOP measurement must be 
taken approximately every 30 minutes thereafter until IOP ≤ 30 mm Hg 
Section 9.15 Post-Injection 
Assessment; Visit Schedule 
Footnote “O” (all Visit Schedules) 
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and the subject is able to be released from the clinic. 
It was clarified that anti-VEGF treatment will be either ranibizumab or 
aflibercept, and that IOP should be measured before and after the anti-
VEGF injection, but prior to administration of APL-2. 
Blood volume for study assessments was updated based on the lab 
manual. 
Section 9.16 Blood Volume for 
Study Assessments 
It was clarified that 1514 mL whole blood sample will be collected at the 
specified time points for research samples. 
Section 9.17.2 Sample Collection 
Visit Schedules A-D 
The screening urine pregnancy test was removed as a serum pregnancy 
test will be performed for screening. 
 
Footnotes “M” (All Visit Schedules) was modified to indicate that 
“Beginning at Day 1 Screening, subjects will complete the functional 
assessments weekly at home.” 
Visit Schedules A and C 
 
Week 24 blood draw for clinical repository was added (error correction). 
 
Visit Schedule C 
The full version of the NEI VFQ-25 has been included in Appendix E. 
Appendix E. 
An amendment history appendix was added to show changes enacted by 
previous amendments. 
Appendix J 
 
 
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“Endothelial cell count” was removed as an assessment that will be 
provided to the reading center for objective assessment of subject 
eligibility. 
 
“Optical Coherence Tomography Angiography (OCT-A, selected sites 
only)” was added as an assessment that will be provided to the reading 
center for objective assessment of subject eligibility.  
Section 7.1 Allocation to Treatment 
Section 8.1. Study Visit Schedule 
Section 8.1.2 Randomization/Initial 
Treatment 
“Country” and “microperimetry eligibility (yes; no)” were removed as a 
stratification factor. 
Section 7.1 Allocation to Treatment 
 
References to “DSMB” updated to “DMC”. 
Section 7.2.1 Unmasking 
Section 10.1 Data Monitoring 
Committee 
Reference to preparing APL-2 for injection was removed from the 
paragraph describing sham. 
Section 7.3.3.1 Identity of the 
Investigational Product 
Text was updated to indicate that:  
 
The suspected onset or presence of new active choroidal 
neovascularization (CNV) secondary to AMD in the study eye and/or 
fellow eye must be documented in the source document and CRF.  
Section 7.5.1 Treatment of New 
Active Choroidal 
Neovascularization in the Study Eye 
and/or Fellow Eye 
Section 9.15 Ocular Imaging 
Optical Coherence Tomography Angiography (OCT-A) was added as a 
monitoring assessment for select sites to confirm the diagnosis of new 
active CNV. 
Section 7.5.1 Treatment of New 
Active Choroidal 
Neovascularization in the Study Eye 
and/or Fellow Eye 
Section 9.15 Ocular Imaging 
Text corrected as follows: 
 
The treatment method (pars plana vitrectomy vs intravitreal injection of 
antibiotics vitreous tap) and choice of antimicrobial agents are also at the 
discretion of the physician and should follow current standard practice 
patterns.  
Section 7.5.3 Endophthalmitis 
Treatment 
Content in these sections was combined. 
Section 7.5.1 Treatment of New 
Active Choroidal 
Neovascularization in the Study Eye 
and/or Fellow Eye 
 
Section 7.5.2 
Treatment of 
Neovascular AMD in the Fellow Eye 
References to “biobanking” have been replaced by references to the 
“genetic biorepository” and the “clinical repository”.  
Section 8. STUDY DESIGN 
Section 9.7 Genotyping Samples 
Section 9.17 Blood Volume for 
Study Assessments 
Protocol updated to specify that microperimetry should be conducted on 
both eyes. 
Section 8 STUDY DESIGN 
Noted that blood draws will be conducted for genotyping. 
Section 8.1.3.2 Months 13-24 
Noted that OCT-A may be conducted, if applicable as per instructions of 
the protocol. 
Section 9.6 Laboratory Analysis of 
Blood and Urine 
Text was modified to clarify that the study staff performing visual acuity 
Section 9.11 Best-corrected Visual 
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should be masked to the treatment assignment only; the protocol 
previously stated that staff should also be blinded to the study eye. 
Acuity and Low Luminance Best-
corrected Visual Acuity 
Blood volume for genetic biorepository was updated. 
Section 9.17 Blood Volume for 
Study Assessments 
The following samples were removed: 
• 
All residual serum and whole blood samples 
collected during the course of the study for PK 
analysis, genotyping and anti APL 2 antibody 
formation  
• 
Residual serum PK sample  
• 
Residual serum Anti Therapeutic Antibodies 
(ATA) sample 
 
It was noted that the 15 mL whole blood sample will be collected at 
Month 2, baseline, Month 12 and Month 24 of the study 
Section 9.18.2 Sample Collection 
It was clarified that the DMC will meet at the beginning of the study and 
every 6 months thereafter. 
Section 10.1 Data Monitoring 
Committee 
Reference to “possibly related” AEs was removed as there is no 
“possibly related” AE categorization for this study. 
 
Resolution outcome possibilities were updated to accurately align with 
the SAE report forms that will be used for this study. 
Section 11.2 Recording Adverse 
Events 
 
Section 11.4.1 Relationship of 
Events to Study Treatment 
Clarified that: 
All SAEs will be reported to the Safety Monitor by the Investigator via 
fax or email within one working calendar day of becoming aware of the 
event, whether or not the serious events are deemed drug-related. 
Section 11.5 Serious Adverse Events 
Section reorganized, modified, and updated to depict protocol 
specifications for data management and statistical considerations more 
clearly, accurately, and thoroughly. 
Section 12. DATA MANAGEMENT 
AND STATISTICAL 
CONSIDERATIONS 
Footnote was updated to indicate that: All assessments should be 
performed on the same day, with the exception of screening. 
 
The blood draw for the clinical repository was removed at baseline, 
Month 1, Month 8, Month 18, and Month 27. 
 
OCT-A was added at screening, Month 6, Month 12, Month 18, and 
Month 24 for select sites. Footnote “R” was added to note that in 
addition to the time points indicated on the study schedule, OCT-A 
should be performed at the time of any suspected new active CNV. If 
new active CNV is confirmed in the study eye, OCT-A should be 
repeated every 2 months for the study eye. 
All Study Schedules (Appendices: 
A, B, C, and D) 
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APPENDIX K: PROTOCOL CHANGES TO BE FOLLOWED DURING 
COVID-19 RESTRICTIONS 
OVERVIEW  
In response to the COVID-19 crisis, to ensure the safety of study subjects and Investigative Sites 
as well as proper conduct of the study, TEMPORARY changes to the protocol have been 
implemented. These changes should be followed only during COVID-19 restrictions and include 
extended IP administration windows, changes to masking rules, rescreening instructions, and a 
revised schedule of assessments.  
Where feasible, sites could continue to follow the full schedule of assessments (based on their 
treatment group assignment). 
EXTENDED IP ADMINISTRATION WINDOWS 
In order to allow more flexibility to sites and subjects, and to potentially mitigate missed IP 
administration, an extended IP administration window can be followed. The extended window 
can ONLY be used in situations related to COVID-19 restrictions and after medical monitor 
approval. Footnote “T” of each COVID-19 assessment table below reflects these extended IP 
options. 
Per protocol, the study window is as followed: 
• Monthly treatment group: +/–8 days for the entire study duration 
• EOM treatment group: +/–8 days for the first study year and +/–16 days for the 
second study year 
During COVID-19 restrictions, the IP administration window can be extended to the following: 
• Monthly treatment group: –8 days to +15 days. Note, interval for consecutives 
injection must be at least 14 days. 
• EOM treatment group: –8 days to +30 days for the first study year and –16 days to 
+30 days for the second study year 
MASKING RULES 
Due to current COVID-19 restrictions, clinical sites might encounter difficulties maintaining 
appropriate clinic staffing to satisfy the approved masking rules for the APL2-304 (Oaks) study. 
Based on this, and in an attempt to minimize the amount of missed data and IP administrations, 
Apellis is implementing a temporary adjustment to the study masking rules.  
This temporary change must be approved by the Apellis Medical Director prior to 
implementation and must be documented via a temporary and modified Delegation of Authority 
Log. Each masked assessment performed by an unmasked staff and vice versa (even with Apellis 
approval and following the below guidelines) should be documented.  
The principal investigator (PI) is responsible for the overall safety oversight of the study site data 
and s/he will not be allowed to switch into an unmasked role. Every masked individual that 
performs IP administration and/or postinjection assessment (all unmasked assessment) as a 
temporary measure, will permanently be considered an unmasked individual and will not be 
able to perform masked assessments once these exemptions are lifted. 
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RESCREENING PROCEDURE 
Prior to the implementation of these temporary changes, sites continuing to screen patients have 
been encouraged to complete the screening and baseline assessments in their entirety. However, 
if a subject was deemed a screen failure for not being able to meet the original screening window 
(Day –28 to Day –1 [+/–2 days]) due to COVID-19 related restrictions, a rescreening visit is 
allowed and should be followed according to the 2 scenarios below.  
Subjects Who Completed Screening and Were Considered Eligible by Reading Center and 
Investigator  
Subjects who were screened prior to 30 March 2020 and completed all screening assessments (as 
described in the Schedule of Assessments Appendix A [every month treatment group] and 
Appendix C [every-other-month [EOM] treatment group]) and considered eligible by the reading 
center and investigator and are able to return to the clinic within 90 days of initial screening, will 
receive a new subject ID number and undergo an abbreviated screening, prior to randomization, 
that includes the following assessments:   
• Informed consent/Assign new screening number  
• NL-BCVA assessment  
• Slitlamp examination  
• Dilated indirect ophthalmoscopy  
• IOP measurement  
• SD-OCT*   
• Concomitant medication/concomitant ocular procedures collection  
• AE collection  
*SD-OCT images collected at this visit will not be used by the reading center to determine 
eligibility but should be used by the investigator to detect any potential new exclusion criterion.  
If the investigator deems it necessary, additional assessments can be performed if there is a 
concern that the subject might now meet an exclusion criterion that was not the case during the 
original screening (eg, fundus fluorescein angiography to exclude the presence of CNV).  
Subjects With Incomplete Screening Assessment  
Subjects that signed the informed consent but were not able to complete all screening 
assessments due to COVID-19-related restrictions are not eligible for the abbreviated screening. 
These subjects can be rescreened but must follow the standard screening schedule of 
assessment (as described in the Schedule of Assessments Appendix A [every month treatment 
group] and Appendix C [EOM treatment group]). These subjects will also receive a new 
screening ID number.  
MINIMUM SCHEDULE OF ASSESSMENT 
Schedule of Assessments  
Where feasible, sites could continue to follow the full schedule of assessments (based on their 
treatment group assignment). The minimum assessment tables, only to be followed during this 
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12 August 2020 
COVID-19 effort and if determined necessary to use based on the investigator’s clinical 
judgment, are provided below to reduce the time required for each study visit. Subjects in the 
EOM treatment group do not need to be seen for the non-IP administration visits. Assessments 
not performed (even those that have been removed in the minimum assessment table) should be 
documented.  
Subjects that are not able to come into the clinic for a study visit due to COVID-19-related 
restrictions, including visits for the EOM group that do not include IP administration, should 
be contacted via the phone for the collection of adverse events (including SAEs) and 
concomitant medications. All SAEs are still required to be reported to Apellis within 24 
hours of site awareness, even if reported via phone call. All communications via phone call 
should also be documented in the source documentation and in the respective CRF page. In 
addition, these subjects should be instructed to self-monitor their vision at home and report any 
changes in vision or their overall health via phone call. The site must inform the Sponsor of any 
subjects lost to follow-up.  
It is critical that local, country, and regional governance regarding COVID-19 is followed along 
with your best clinical judgment when managing this situation. All visits or assessments missed 
as a result of COVID-19 will be captured in the Case Report Forms. 
The Schedule of Assessments tables shown below supersede those sent on 30 March 2020. These 
changes were previously communicated to the sites via a memorandum.  
 
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
J. Perform assessments prior to dilating the eyes.  
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly.  
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA and OCT-A (select sites) images 
must be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and  post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than  a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 15 days after medical monitor approval. Note, interval for consecutive injections must be at least 14 days. 
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
J. Perform assessments prior to dilating the eyes.  
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly.  
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is 
specified  and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for 
specifics on image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be 
obtained at a specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A 
(selected sites) images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and  post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than  a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 15 days after medical monitor approval. Note, interval for consecutive injections must be at least 14 days. 
Apellis Pharmaceuticals, Inc
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly.  
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital application will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the in the clinic 
at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at home. Subjects 
should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is 
specified  and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for 
specifics on image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be 
obtained at a specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A 
(selected sites) images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and  post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 30 days after medical monitor approval. 
 
Apellis Pharmaceuticals, Inc
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Pegcetacoplan 
APL2-304 Protocol Amendment 5 
12 August 2020 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly.  
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is 
specified  and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for 
specifics on image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be 
obtained at a specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A 
(selected sites) images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, 
the tonometry should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the 
IOP. If IOP is >30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes the gross vision test and IOP is 
≤30 mm Hg. Note: if the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with 
ranibizumab or aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the investigator determines that there are any safety 
concerns, a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than  a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –16 days to + 30 days after medical monitor approval. 
 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
APL2-304 
A Phase III, Multi-Center, Randomized, Double-Masked, Sham-Controlled 
Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy with 
Sham Injections in Patients with Geographic Atrophy (GA) Secondary to 
Age-Related Macular Degeneration (AMD)
PROTOCOL IDENTIFIER: OAKS
Study Sponsor:
Apellis Pharmaceuticals, Inc.
100 5th Ave  
Waltham, MA 02451
Author:
Protocol:
Amendment 5, Version 1.0, 12 August 2020
SAP Version #:
2.0
SAP Date:
10 August 2021
Status:
Final
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PPD


Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 10 August 2021 
 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
1.0 
07/23/2021 
New Document 
2.0 
08/10/2021 
• Changed the thresholds for censoring 
COVID-19 impacted data in the 
supplementary analyses for the primary 
and key secondary endpoints. 
• Added an additional covariance matrix to 
the MMRM models if the statistical 
modeling fails to converge with the first 
two covariance matrices 
• Fixed an error in the sample code and text 
for maximum reading speed calculation. 
• Fixed an error in Figure 2 with extraneous 
text boxes included. 
• Provided further details on the analysis of 
suspected, confirmed, and exudative 
AMD’s. 
 
 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 10 August 2021 
 
APPROVAL SIGNATURES 
  
Apellis Pharmaceuticals, Inc. 
 Date (dd-Mmm-yyyy) 
  
Apellis Pharmaceuticals, Inc. 
 Date (dd-Mmm-yyyy) 
Apellis Ireland Limited 
 Date (dd-Mmm-yyyy) 
Apellis Pharmaceuticals, Inc  
 Date (dd-Mmm-yyyy) 
 
 
DocuSign Envelope ID: 4DCAEAF1-DCE2-4D46-BD9C-599424AFAE81
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PPD
PPD
PPD
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 10 August 2021 
Apellis Pharmaceuticals, Inc  
 
 Date (dd-Mmm-yyyy) 
DocuSign Envelope ID: 4DCAEAF1-DCE2-4D46-BD9C-599424AFAE81
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan 
 10 August 2021 
TABLE OF CONTENTS 
REVISION HISTORY ................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................ 5 
LIST OF TABLES ..................................................................................................................... 10 
LIST OF FIGURES ................................................................................................................... 10 
ABBREVIATIONS .................................................................................................................. 11 
1.
INTRODUCTION .................................................................................................. 13 
2.
OBJECTIVES AND ENDPOINTS ......................................................................... 14 
2.1. 
Objectives............................................................................................................... 14 
2.1.1. 
Primary Objective ............................................................................................. 14 
2.1.2. 
Key Secondary Objectives ................................................................................ 14 
2.1.3. 
Secondary Objectives ........................................................................................ 14 
2.1.4. 
Safety Objectives .............................................................................................. 14 
2.1.5. 
Exploratory Objectives ..................................................................................... 15 
2.2. 
Endpoints ............................................................................................................... 15 
2.2.1. 
Primary Endpoint .............................................................................................. 15 
2.2.2. 
Key Secondary Endpoints ................................................................................. 15 
2.2.3. 
Secondary Endpoints ........................................................................................ 15 
2.2.4. 
Exploratory Endpoints ...................................................................................... 16 
2.2.5. 
Safety Endpoints ............................................................................................... 17 
2.2.6. 
Exploratory Endpoints Closely Related to the Primary Efficacy Endpoint ......... 17 
3.
STUDY DESIGN ................................................................................................... 18 
3.1. 
General Description ................................................................................................ 18 
3.2. 
Randomization........................................................................................................ 19 
3.3. 
Masking.................................................................................................................. 19 
3.4. 
Sample Size and Power Considerations................................................................... 19 
3.5. 
Analysis Timing and Unmasking ............................................................................ 20 
3.6. 
Definition of 12-Month Data in the Month 12 Dataset ............................................ 21 
4.
STATISTICAL ANALYSIS SETS ......................................................................... 22 
4.1. 
Screened Set ........................................................................................................... 22 
4.2. 
Intent-to-Treat Set .................................................................................................. 22 
4.3. 
Modified Intent-to-Treat Set ................................................................................... 22 
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APL2-304 Statistical Analysis Plan 
 10 August 2021 
4.4. 
Safety Set ............................................................................................................... 22 
4.5. 
Per-Protocol Sets .................................................................................................... 22 
4.6. 
Genotyping Set ....................................................................................................... 23 
5.
STUDY SUBJECTS ............................................................................................... 24 
5.1. 
Disposition of Subjects ........................................................................................... 24 
5.2. 
Demographic and Other Baseline Characteristics .................................................... 25 
5.3. 
Medical ocular and non-ocular History ................................................................... 28 
5.4. 
Prior and Concomitant Medications ........................................................................ 28 
5.5. 
Concomitant Procedures ......................................................................................... 28 
5.6. 
Exposure to Investigational Product ........................................................................ 29 
5.7. 
Protocol Deviations ................................................................................................ 30 
6.
EFFICACY ANALYSES ....................................................................................... 32 
6.1. 
Estimands ............................................................................................................... 32 
6.2. 
Analyses of Primary Efficacy Endpoint .................................................................. 36 
6.2.1. 
Type I Error Management ................................................................................. 36 
6.2.2. 
Main Analysis of Primary Efficacy Endpoint .................................................... 36 
6.2.3. 
Sensitivity Analyses of Primary Efficacy Endpoint ........................................... 37 
6.2.3.1. 
Missing Data Analyses Based on Multiple Imputation ........................... 37 
6.2.3.2. 
Other Sensitivity Analyses .................................................................... 39 
6.2.4. 
Supplemental Analyses of the Primary Efficacy Endpoint ................................. 39 
6.2.4.1. 
COVID-19 Adjusted Estimand .............................................................. 39 
6.2.4.2. 
Per Protocol Set ..................................................................................... 40 
6.2.4.3. 
Rate of Change Analyses ....................................................................... 40 
6.2.5. 
Subgroup Analyses of Primary Efficacy Endpoint ............................................. 41 
6.2.6. 
Full 24 Month Analyses .................................................................................... 42 
6.2.7. 
Exploratory Endpoints Closely Related to the Primary Efficacy Endpoint ......... 42 
6.2.7.1. 
Change in Square Root of GA Area ....................................................... 42 
6.2.7.2. 
Percent Change in GA Area and Square Root of GA Area ..................... 43 
6.3. 
Analyses of Key Secondary Efficacy Endpoints ...................................................... 43 
6.3.1. 
Type I Error Management ................................................................................. 43
6.3.2. 
Main Analyses of Key Secondary Efficacy Endpoints ....................................... 47 
6.3.2.1. 
Mean Threshold Sensitivity of All Points .............................................. 47 
6.3.2.2. 
Monocular Maximum Reading Speed .................................................... 47 
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 10 August 2021 
6.3.2.3. 
Mean FRI Index Score........................................................................... 48 
6.3.2.4. 
NL-BCVA Score ................................................................................... 49 
6.3.3. 
Sensitivity Analyses of Key Secondary Efficacy Endpoints .............................. 49 
6.3.4. 
Supplementary Analyses of Key Secondary Efficacy Endpoints ........................ 50 
6.3.5. 
Subgroup Analyses of Key Secondary Efficacy Endpoints ................................ 50 
6.4. 
Analyses of Other Secondary Efficacy Endpoints ................................................... 50 
6.4.1. 
Low Luminance Best-Corrected Visual Acuity (LL-BCVA) ............................. 51 
6.4.2. 
Total Area of GA lesion(s) at each planned assessment ..................................... 51 
6.4.3. 
Monocular critical print size.............................................................................. 51 
6.4.4. 
NEI VFQ-25 Distance Activity Subscale Score ................................................. 52 
6.4.5. 
Macular Functional Response based on Microperimetry ................................... 52 
6.5. 
Multiplicity Adjustment .......................................................................................... 53 
6.6. 
Analyses of Exploratory Endpoints ......................................................................... 53 
6.6.1. 
Other Microperimetry Endpoints ....................................................................... 53 
6.6.2. 
NEI VFQ-25 and NEI VFQ-39 Additional Analyses ......................................... 54 
6.6.3. 
Binocular Maximum Reading Speed and Critical Print Size .............................. 54 
6.6.4. 
GA Lesion (s) Study Eye to Fellow Eye Comparisons ....................................... 55 
6.6.5. 
Digital Reading Index and Visual Function Application .................................... 55 
6.6.6. 
Genetic Polymorphisms .................................................................................... 55 
6.6.7. 
Dry AMD Analysis ........................................................................................... 56 
6.6.8. 
Analyses of Other Ophthalmology Efficacy Imaging Data ................................ 56 
7.
SAFETY ANALYSES ........................................................................................... 57 
7.1. 
Adverse Events ....................................................................................................... 57 
7.1.1. 
TEAEs of New Onset Exudative AMD ............................................................. 58 
7.2. 
Clinical Laboratory Data......................................................................................... 59 
7.3. 
Vital Signs .............................................................................................................. 61 
7.4. 
Physical Examination Findings ............................................................................... 61 
7.5. 
Complete Ophthalmic Exam ................................................................................... 61 
7.6. 
NL-BCVA .............................................................................................................. 62 
7.7. 
Other Ophthalmology Imaging Assessments ........................................................... 62 
7.8. 
Immunogenicity ...................................................................................................... 64 
7.9. 
Death ...................................................................................................................... 64 
7.10. 
Other Safety Data ................................................................................................... 64 
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APL2-304 Statistical Analysis Plan 
 10 August 2021 
8.
PHARMACOKINETICS ANALYSIS .................................................................... 65 
9.
PHARMACODYNAMIC ANALYSES .................................................................. 66 
10.
OTHER ANALYSES ............................................................................................. 67 
11.
INTERIM ANALYSIS ........................................................................................... 68 
12.
DATA MONITORING COMMITTEE ................................................................... 69 
13.
DATA HANDLING CONVENTIONS ................................................................... 70 
13.1. 
General Data Reporting Conventions ...................................................................... 70 
13.2. 
Definition of Baseline ............................................................................................. 70 
13.3. 
Definition of Relative Study Days .......................................................................... 70 
13.4. 
Definition of Visit Windows ................................................................................... 70 
13.4.1. 
All Assessments Except Microperimetry ..................................................... 70 
13.4.2. 
Microperimetry Assessments ...................................................................... 72 
13.5. 
Derived Efficacy Endpoints .................................................................................... 73 
13.5.1. 
GA Lesion Size ........................................................................................... 73 
13.5.2. 
MNRead Reading Chart .............................................................................. 73 
13.5.2.1. 
Reading Speed....................................................................................... 73 
13.5.2.2. 
Maximum reading speed ....................................................................... 73 
13.5.2.3. 
Critical Print Size .................................................................................. 73 
13.5.2.4. 
Reading acuity....................................................................................... 74 
13.5.3. 
Radner Reading Chart ................................................................................. 74 
13.5.3.1. 
Reading Speed....................................................................................... 74 
13.5.3.2. 
Maximum Reading Speed...................................................................... 74 
13.5.3.3. 
Critical Print Size .................................................................................. 74 
13.5.3.4. 
Reading Acuity ..................................................................................... 75 
13.5.4. 
Mean FRI Index Score and FRI Level ......................................................... 75 
13.5.5. 
NL-BCVA and LL-BCVA .......................................................................... 75 
13.5.5.1. 
BCVA Letter Score ............................................................................... 75 
13.5.5.2. 
Conversion of BCVA Letter Score to Snellen Equivalent ...................... 75 
13.5.6. 
Low Luminance Deficit............................................................................... 75 
13.5.7. 
NEI VFQ-25 scores ..................................................................................... 76 
13.5.7.1. 
NEI VFQ-25 Distance Activity Subscale Score ..................................... 76 
13.5.7.2. 
NEI VFQ-25 Near Activity Subscale Score ........................................... 76 
13.5.7.3. 
NEI VFQ-25 Driving Subscale Score .................................................... 76 
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13.5.7.4. 
NEI VFQ-25 Composite Scores ............................................................. 76 
13.5.8. 
NEI VFQ-39 Scores .................................................................................... 76 
13.5.8.1. 
NEI VFQ-39 Distance Activity Subscale Score ..................................... 76 
13.5.8.2. 
NEI VFQ-39 Near Activity Subscale Score ........................................... 76 
13.5.8.3. 
NEI VFQ-39 Composite score ............................................................... 76 
13.5.9. 
Microperimetry ........................................................................................... 77 
13.6. 
Repeated or Unscheduled Assessments of Safety Parameters .................................. 77 
13.7. 
Handling of Missing, Unused, and Spurious Data ................................................... 77 
13.7.1. 
Missing Date of Investigational Product ...................................................... 77 
13.7.2. 
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ................................................................................ 77 
13.7.2.1. 
Incomplete Start Date ............................................................................ 77 
13.7.2.2. 
Incomplete Stop Date ............................................................................ 78 
13.7.2.3. 
Missing Day and Month ........................................................................ 78 
13.7.3. 
Missing Date Information for Adverse Events ............................................. 79 
13.7.3.1. 
Incomplete Start Date ............................................................................ 79 
13.7.3.2. 
Incomplete Stop Date ............................................................................ 79 
13.7.4. 
Missing Severity Assessment for Adverse Events........................................ 79 
13.7.5. 
Missing Relationship to Investigational Product for Adverse Events ........... 79 
13.7.6. 
Character Values of Clinical Laboratory Variables ...................................... 79 
14.
ANALYSIS SOFTWARE ...................................................................................... 81 
15.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL .................................... 82 
16.
REFERENCES ....................................................................................................... 83 
17.
APPENDIX ............................................................................................................ 84 
APPENDIX 1. 
SCHEDULE OF ACTIVITIES ................................................................... 85 
1.1. 
Protocol Changes to be followed during COVID-19 Restrictions ............................ 98 
1.2. 
Sample of SAS Code ............................................................................................ 113 
1.2.1. 
Mixed Effect Model for Repeated Measure ..................................................... 113 
1.2.2. 
Multiple Imputation ........................................................................................ 114 
1.2.3. 
Rate of Change Models ................................................................................... 117 
1.2.4. 
Sample Code for Maximum Reading Speed and Critical Print Size ................. 120 
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LIST OF TABLES 
Table 1: 
Power to Detect a Difference among Three Groups with an Equal Size of 
200 Subjects ........................................................................................................... 20 
Table 2: 
Estimands of Study ................................................................................................. 34 
Table 3: 
Criteria for Potentially Clinically Significant Laboratory Tests ............................... 60 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs ........................................ 61 
Table 5: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: All Assessments Except Microperimetry: Monthly 
Regimen ................................................................................................................. 71 
Table 6: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: All Assessments Except Microperimetry: Every Other 
Month Regimen ...................................................................................................... 72 
Table 7: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: Microperimetry Assessments ................................................... 72 
Table 8: 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables ................................................................................................................ 80 
Table 9: 
Visit Schedule - Monthly Group- Screening, Day 1 through Month 12 ................... 86 
Table 10: Visit Schedule - Monthly Group- Month 13 to Month 24 ........................................ 89 
Table 11: Visit Schedule - Every-Other-Month Group Screening, Day 1 Through 
Month 12 ................................................................................................................ 92 
Table 12: Visit Schedule - Every-Other-Month Group Month 13 to Month 24 ........................ 95 
Table 13 (TRACKED): 
COVID-19 VISIT SCHEDULE—Monthly Group—
Screening, Day 1 Through Month 12 .................................................................... 101 
Table 14 (TRACKED): 
COVID-19 VISIT SCHEDULE—Monthly Group—Month 
13 to Month 24 ..................................................................................................... 104 
Table 15 (TRACKED): 
COVID-19 VISIT SCHEDULE—Every-Other-Month 
Group—Screening, Day 1 Through Month 12....................................................... 107 
Table 16 (TRACKED): 
COVID-19 VISIT SCHEDULE—Every-Other-Month 
Group—Month 13 to Month 24 ............................................................................ 110 
LIST OF FIGURES 
Figure 1: 
Study Schema ......................................................................................................... 18 
Figure 2: 
APL2-303 and APL2-304 Hypothesis Testing and Type I Error Control ................. 45 
Figure 3: 
APL2-304 Hypothesis Testing and Type I Error Control If There is No α 
Remaining in APL2-303 to Allow Pooling Secondary Functional Endpoints .......... 46 
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ABBREVIATIONS 
ADA 
Anti-drug Antibodies 
ADY 
Analysis Study Day 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMD 
Age-related Macular Degeneration 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Class 
BCVA/NL-BCVA 
(Normal luminance) Best Corrected Visual Acuity 
BCEA 
Bivariate contour ellipse area 
BUN 
Blood Urea Nitrogen 
CMH 
Cochran Mantel Haenszel 
CNV 
Choroidal Neovascularization 
CRO 
Contract Research Organization 
cRORA 
Complete retinal pigment epithelium and outer retinal atrophy 
CSR 
Clinical Study Report 
DA 
Disk Areas 
DCFP 
Digital Color Fundus Photography 
DLS 
Double-layer sign 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EOM 
Every Other Month 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FFA/FA 
Fundus Fluorescein Angiography or Fluorescein Angiography 
FRI 
Functional Reading Independence 
GA 
Geographic Atrophy 
IOP 
Intra Ocular Pressure 
iRORA 
Incomplete retinal pigment epithelium and outer retinal atrophy 
ITT 
Intent-to-Treat 
IVT 
Intravitreal 
kg 
Kilogram 
LOV 
Last Observed Value 
LL-BCVA 
Low Luminance Best Corrected Visual Acuity 
LLD 
Low Luminance Deficit 
LS 
Least Square 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
mmHg 
Millimeter of Mercury 
MMRM 
Mixed effect Model for Repeated Measure 
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MNAR 
Missing Not At Random 
MNRead 
Minnesota Reading Chart 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire 25 Item 
Version 
NEI VFQ-39 
National Eye Institute Visual Functioning Questionnaire 39 Item 
Version 
NIR 
Near Infrared Reflectance 
OCT 
Optical Coherence Tomography 
OCT-A 
Optical Coherence Tomography Angiography 
PCS 
Potentially Clinically Significant 
PDV 
Protocol Deviation 
PEG 
Polyethylene glycol  
PEOM 
Pegcetacoplan Every-Other-Month 
PM 
Pegcetacoplan Monthly 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SEOM 
Sham Every-Other-Month 
SI 
International System of Units 
SM 
Sham Monthly 
SNP 
Single Nucleotide Polymorphism 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
µL 
Micro liter 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WPM 
Words per Minute 
 
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1. 
INTRODUCTION  
This study is being conducted as part of a series of studies for the clinical development of 
pegcetacoplan (also known as APL-2) for geographic atrophy [GA] secondary to age-related 
macular degeneration (AMD). This statistical analysis plan (SAP) provides a technical and 
detailed elaboration of the statistical analyses of efficacy and safety data supplementing what is 
described in the final study protocol, version 1.0, amendment 5, dated 12 August 2020.  
The primary study analysis will be based on complete data from the first 12 months of the study 
and performed after all subjects have completed the Month 12 visit in the study or discontinued 
early, and all corresponding data have been entered into the database, reviewed, cleaned, and 
finalized as the Month 12 dataset. Analysis will include testing of hypotheses of the primary 
efficacy endpoint at Month 12. Key secondary, secondary, and exploratory endpoints will be 
evaluated based on data in the Month 12 datasets in a descriptive manner. An analysis of the 
safety data in the Month 12 dataset will also be performed. 
The final study analysis will be based on data after all subjects have either completed the Month 
24 visit in the study or discontinued the study early, and all data from the study are in the 
database and the database is reviewed, cleaned, and locked as the final dataset. Analysis will 
include testing of hypotheses of the key secondary endpoints at Month 24 as described in 
Section 6.3.1. A cumulative analysis of all data through the end of the study will be produced 
based on the final dataset. 
See Section 3.5 for further details on analysis timing. 
The analyses specified in this document supersede the analysis plan described in the study 
protocol (protocol version 1.0, amendment 5 dated 12 August 2020).  
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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of pegcetacoplan compared to 
sham in subjects with GA secondary to AMD assessed by change in the total area of GA lesions 
in the study eye from baseline as measured by Fundus Autofluorescence (FAF). 
2.1.2. 
Key Secondary Objectives 
The key secondary objectives are to evaluate the efficacy of pegcetacoplan compared to sham in 
subjects with GA secondary to AMD with respect to: 
• Monocular maximum reading speed (study eye), as assessed by Minnesota Reading 
(MNRead) or Radner Reading Charts (in select countries) 
• Functional Reading Independence (FRI) Index score (subject-level assessment) 
• Normal luminance best-corrected visual acuity (NL-BCVA) score in the study eye 
2.1.3. 
Secondary Objectives 
To evaluate the efficacy of pegcetacoplan compared to sham in subjects with GA secondary to 
AMD with respect to: 
• Low luminance best corrected visual acuity (LL-BCVA) score in the study eye 
• Low luminance deficit (LLD) in the study eye 
• Total area of GA lesion(s) in the study eye  
• Monocular critical print size (study eye), as assessed by MNRead or Radner Reading 
Charts (in select countries) 
• National Eye Institute Visual Functioning Questionnaire 25 Item Version (NEI VFQ-
25) distance activity subscale score (in select countries) 
• Macular functional response (study eye) as assessed by mesopic microperimetry  
2.1.4. 
Safety Objectives  
To evaluate the safety and tolerability of pegcetacoplan compared to sham injection in subjects 
with GA secondary to AMD as indicated by:  
• Incidence and severity of ocular and systemic treatment-emergent adverse events 
(TEAEs)  
• Incidence of anti-drug antibodies (ADA) directed against pegcetacoplan peptide or 
polyethylene glycol (PEG)  
• Incidence of new active choroidal neovascularization (CNV) in the study eye  
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2.1.5. 
Exploratory Objectives 
• To evaluate the efficacy of pegcetacoplan compared to sham in subjects with GA 
secondary to AMD as indicated by: 
o NEI VFQ-25 composite score  
o NEI VFQ-25 near activity subscale score (in select countries) 
o Comparison between study eye and fellow eye of change in GA lesion size 
o To evaluate the binocular reading speed as assessed by MNRead or Radner 
Reading Charts (in select countries) 
o To evaluate the binocular critical print size as assessed by MNRead or Radner 
Reading Charts (in select countries) 
o To evaluate the relationship between genetic polymorphisms associated with 
AMD with GA progression and response to pegcetacoplan 
• To evaluate the incidence of new onset of subclinical CNV in the study eye. 
• To assess sensitivity and specificity of a digital reading speed application to detect 
disease progression / regression (optional, select sites) 
• To assess sensitivity and specificity of a digital visual function application to detect 
disease progression / regression (optional, select sites) 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint is the change from baseline to Month 12 in total area of GA lesion(s) in 
the study eye (in mm2) based on FAF. 
2.2.2. 
Key Secondary Endpoints 
The key secondary endpoints include: 
• Change from baseline in the mean threshold sensitivity of all points (study eye) 
assessed by mesopic microperimetry at Month 24. 
• Change from baseline in monocular maximum reading speed (study eye), at Month 
24 as assessed by MNRead or Radner reading charts (in select countries). 
• Change from baseline in mean FRI Index score (subject-level assessment) at Month 
24  
• Change from baseline in NL-BCVA score (study eye) at Month 24 as assessed by 
Early Treatment Diabetic Retinopathy Study (ETDRS) chart. 
2.2.3. 
Secondary Endpoints 
Other secondary endpoints include: 
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• Change from baseline in LL-BCVA score (study eye) over time as assessed by 
ETDRS chart. 
• Change from baseline in the total area of GA lesion(s) in the study eye (in mm2) as 
assessed by FAF over time other than Month 12. 
• Change from baseline in monocular critical print size (study eye), as assessed by 
MNRead or Radner reading charts (in select countries) over time. 
• Change from baseline in the NEI VFQ-25 distance activity subscale score (in select 
sites) (subject level assessment) over time. 
• Change from baseline in the number of scotomatous points assessed by mesopic 
microperimetry over time  
• Change from baseline in the mean threshold sensitivity within 500 microns outside 
the GA lesion, (perilesional points) assessed by mesopic microperimetry over time. 
2.2.4. 
Exploratory Endpoints 
• Additional microperimetry endpoints including: 
− Change from baseline in fixation stability (95% bivariate contour ellipse area 
(BCEA)) over time. 
− Change from baseline in the mean threshold sensitivity of points beyond 500 
microns outside the atrophy border (paralesional points) over time. 
− Change from baseline in the mean threshold sensitivity of points beyond the GA 
lesion (extralesional points) over time. 
− Number of points with clinically significant progression over time, defined as a 
decrease of more than 4 dB. 
• Additional NEI-VFQ endpoints including: 
− Change from baseline in the NEI VFQ-39 distance activity subscale score (in 
select sites) over time. 
− Change from baseline in NEI VFQ-25 composite score over time. 
− Change from baseline in NEI VFQ-39 composite score over time. 
− Change from baseline in NEI VFQ-25 near activity subscale score (in select 
countries) over time. 
− Change from baseline in NEI VFQ-39 near activity subscale score (in select 
countries) over time. 
− Change from baseline in NEI VFQ-25 driving subscale score (in select countries) 
over time as well as the number and percentage of subjects with worse driving 
outcomes for subjects who are currently driving at baseline. 
• Difference between study eye and fellow eye in change in GA lesion size from 
baseline over time in subjects with bilateral GA. 
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• Change from baseline in binocular maximum reading speed as assessed by MNRead 
or Radner Reading Charts (in select countries) over time. 
• Change from baseline in binocular critical print size as assessed by MNRead or 
Radner Reading Charts (in select countries) over time. 
• Change from baseline in digital reading index (in select sites) over time as measured 
by the Spotlight instrument.  
• Change from baseline in digital visual function (metamorphopsia) (in select sites) 
over time as measured by the Alleye instrument. 
• Progression from incomplete retinal pigment epithelium and outer retinal atrophy 
(iRORA) to complete retinal pigment epithelium and outer retinal atrophy (cRORA). 
• Progression from large drusen to iRORA or cRORA. 
• Other efficacy imaging endpoints including change in the distance of the atrophy 
junction to the fovea, and non-subfoveal atrophy to subfoveal atrophy conversion. 
2.2.5. 
Safety Endpoints 
• Incidence and severity of ocular and systemic treatment-emergent adverse events.  
• Incidence of ADA directed against pegcetacoplan peptide or PEG. 
• Incidence of new active CNV in the study eye. 
• Incidence of new onset of subclinical CNV in the study eye. 
• Incidence of subjects who lost letters based on NL-BCVA categories (≥15, ≥15 -< 30, 
≥30 ETDRS letters). 
• Change/shift from baseline in clinical labs and incidence of abnormal lab values.  
• Change from baseline in vital signs and incidence of abnormal vital sign results. 
• Shift from baseline in ocular examination assessments including slit-lamp 
examination and indirect ophthalmoscopy. 
• Change from baseline in Intra Ocular Pressure (IOP) and incidence of IOP above 
specified thresholds. 
• Change/shift from baseline in ocular imaging assessments (including specular 
microscopy; select sites). 
2.2.6. 
Exploratory Endpoints Closely Related to the Primary Efficacy Endpoint 
• Change from baseline in square root of the total area of GA lesion(s) in the study eye 
(in mm) based on FAF over time. 
• Percent change in total area of GA lesion(s) in the study eye (in mm2) based on FAF 
over time. 
• Percent change in square root of the total area of GA lesion(s) in the study eye (in 
mm) based on FAF over time. 
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3. 
STUDY DESIGN 
3.1. 
General Description 
This is a Phase 3, multicenter, randomized, double-masked, sham-injection controlled study to 
assess the efficacy and safety of multiple intravitreal (IVT) injections of pegcetacoplan (also 
known as APL-2) in subjects with GA secondary to AMD. 
The study will randomize approximately 600 subjects across approximately 100 multinational 
sites. Subjects will be screened within 28 days before receiving pegcetacoplan or Sham injection. 
Upon providing written informed consent and entry into the study, subjects will be assigned a 
screening number. Subjects who meet all inclusion and none of the exclusion criteria will return 
to the clinic for randomization and treatment on Visit 2 (Day 1). At this visit, subjects will be 
randomized 2:2:1:1 to receive pegcetacoplan Monthly (PM), pegcetacoplan Every-Other-Month 
(PEOM), Sham injection Monthly (SM) or Sham-injection Every-Other-Month (SEOM), 
respectively. Randomization will be stratified according to GA lesion area at screening (< 7.5 
mm2; ≥ 7.5 mm2), and presence of CNV in the fellow eye.  
The planned length of participation in the study for each subject is approximately 24 months 
(from the beginning of the screening period through Month 24 visit). After the COVID-19 
pandemic started, Apellis added a rescreening procedure where the screening period was 
extended to up to 90 days (applicable only to subjects that fully qualified for the trial during a 
complete screening prior to March 30, 2020). The total length of participation in this study can 
be up to 27 months for subjects that were screened using this updated procedure. The schedules 
of assessments are presented in Appendices A, B, C, and D of Study Protocol Amendment 5, 
Version 1.0 dated 12 August 2020 and are also available in Appendix 1. 
A study schematic diagram is shown in Figure 1.  
Figure 1: 
Study Schema 
 
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3.2. 
Randomization 
Subjects will be randomized 2:2:1:1 using a web-based randomization system to receive 
treatment with PM, PEOM, SM or SEOM, respectively.  
The randomization scheme will be maintained by the Sponsor, or designee. Subject 
randomization will be stratified by GA lesion area at screening based on assessment from the 
reading center (< 7.5 mm2; ≥ 7.5 mm2) and presence of CNV in the fellow eye (yes; no).  
3.3. 
Masking 
This is a double-masked study. Designated masked study site staff (e.g., assistant(s), VA 
technicians, optical coherence tomography (OCT) technicians, photographers, technicians 
administering questionnaires, subjects, Reading Center personnel, the assigned evaluating 
physician(s), and the Sponsor) will be masked to treatment assignment. However, the treating 
physician and any associated support staff involved in performing the intravitreal or sham 
injections will be unmasked to study treatment. These individuals are only responsible for 
administering the study drug and are not involved in assessing adverse events. In addition, the 
unmasked individuals are not allowed to discuss treatment and/or subject outcomes with masked 
study staff, including the evaluating physician. The Principal Investigator must be masked to 
subjects’ treatment assignment. To prevent bias in treatment assignment, eligible subjects will be 
randomized using a web-based randomization system. Processes and plans will be put in place to 
avoid unintentional unmasking during the study. All study roles will be clearly documented on 
the site delegation of authority log and once the roles have been designated and executed, these 
roles should not be switched during the conduct of the study. In unforeseen circumstances, a site 
can contact the Sponsor to switch a study staff member from the masked role to the unmasked 
role but not vice versa. Details on unmasking at the Month 12 reporting are in Section 3.5. 
While the actual study treatment (pegcetacoplan vs. sham) is masked, the treatment frequency 
(monthly vs. every other month) for each individual subject is known. 
3.4. 
Sample Size and Power Considerations 
A total of approximately 600 subjects will be randomized in a 2:2:1:1 ratio to receive treatment 
with PM, PEOM, SM, or SEOM. The annual growth rate in GA lesion area is expected to have a 
mean of 1.47, 1.70 and 2.13 mm2/year for PM, PEOM and Sham-Pooled (Sham) groups, 
respectively, as estimated from the results of a Phase 2 trial of pegcetacoplan. The standard 
deviation of the lesion growth is estimated to be 1.50 mm2 based on the same Phase 2 trial data 
or 1.25 mm2 based on natural history data (Holekamp N, 2019).  
The power of the study for the primary endpoint is presented in Table 1 for sample size of 200 in 
each treatment arm. The approximation is calculated using PROC POWER ONEWAYANOVA, 
Statistical Analysis System (SAS) 9.4. The study power for the primary endpoint is likely larger 
when utilizing the longitudinal data to model the primary endpoint. The actual study power for 
the primary endpoint may also vary based on the distribution of the stratification factors (i.e., 
lesion area at screening, presence of CNV in fellow eye). Study power was not calculated for key 
secondary functional endpoints.  
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Table 1: 
Power to Detect a Difference among Three Groups with an Equal Size of 200 
Subjects 
Common 
Standard 
Deviation 
(mm2) 
 
 
Alpha 
(two-sided) 
Power for a true mean of 1.47, 1.70, and 2.13  
mm2/year for PM, PEOM and Sham, respectively 
PM vs Sham 
PEOM vs 
Sham 
Overall (Among 3 
groups) 
1.25 
0.0495 
> 99.9% 
92.9% 
99.9% 
1.25 
0.0248 
99.9% 
88.2% 
99.7% 
1.40 
0.0495 
99.7% 
86.5% 
99.3% 
1.40 
0.0248 
99.3% 
79.4% 
98.6% 
1.50 
0.0495 
99.2% 
81.5% 
98.4% 
1.50 
0.0248 
98.4% 
73.1% 
97.0% 
PM = pegcetacoplan Monthly, PEOM = pegcetacoplan Every-Other-Month; Sham = Sham Monthly + Sham Every-Other-Month 
3.5. 
Analysis Timing and Unmasking 
The analysis of data from the first 12 months of the study will be performed when all subjects 
have completed the Month 12 visit in the study or discontinued early and all corresponding data 
have been entered into the database, reviewed, cleaned, and finalized as the Month 12 dataset per 
the 12-Month Primary Analysis Data Cut Plan and the Programming Plan. At the time of the 
analysis of the Month 12 dataset, subjects who have not completed or discontinued from the 
study will still be followed by the sites as part of the second year. 
At the time of the Month 12 reporting, Sponsor personnel who are analyzing, interpreting, and 
reporting data from the Month 12 dataset will be unmasked to treatment assignment. To maintain 
data integrity for the remainder of the study, sponsor and contract research organization (CRO) 
personnel responsible for continuing study oversight will remain masked as documented in the 
Study Masking Plan and the GA Internal Unmasking Plan. 
Analyses will include formal hypothesis testing of the primary efficacy endpoint at Month 12. 
Key secondary, secondary, and exploratory endpoints will be evaluated based on the Month 12 
dataset in a descriptive manner. An analysis of the safety data in the Month 12 dataset will also 
be performed.  
The final study reporting will be based on data after all subjects have either completed the Month 
24 visit in the study or discontinued the study early, and all data from the study are entered in the 
database and the database is reviewed, cleaned, and locked as the final dataset. Minor changes 
are expected from the Month 12 dataset (e.g. adverse event end dates for events ongoing in the 
Month 12 dataset), however, all subsequent differences in data prior to the Month 12 visit will be 
listed. Analysis of the final dataset will include testing of hypotheses of the key secondary 
endpoints at Month 24 as described in Section 6.3.1. A cumulative analysis of all data through 
the end of the study will be produced based on the final dataset. 
Aggregate results of the Month 12 reporting may be reported before completion of the study. 
However, subjects, masked study site personnel, masked CRO personnel at Covance, Sponsor 
team members with study oversight responsibility, and central reading center personnel will 
remain masked to individual treatment assignments until after the study is completed 
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(after all subjects have either completed Month 24 or discontinued early from the study), the 
database is locked and the unmasking has been approved.  
3.6. 
Definition of 12-Month Data in the Month 12 Dataset 
All screening and post-baseline data with a clinical date (i.e., administration/assessment/ 
onset/start date) on or before the defined Month 12 data cutoff date will be included in the Month 
12 Dataset. The 12-month data cutoff will include all data regardless of the type of study visit at 
which it was collected. This may include data collected at unscheduled visits or early termination 
visits if the visit date was on or before the 12-month data cutoff date. The Month 12 data cutoff 
is defined as: 
All data except microperimetry 
• If the subject completed Month 12 (Visit 14) assessments, then the data cutoff will be 
the day that the Month 12 (Visit 14) assessments are completed, regardless of Study 
Day.  
• If the subject did not complete the Month 12 (Visit 14) assessments (e.g. missed or 
early terminated) then Study Day 375 (Study Day 360 (target date) + 15) will be used 
as the Month 12 cutoff.  
Microperimetry 
• Study Day 450 (Study Day 360 (target date) + 90) will be used as the Month 12 
cutoff. This is to allow any unscheduled assessments including repeated 
microperimetry assessments collected as of the Month 12 datacut date to be 
considered for the Month 12 analysis visit according to the analysis visit windowing 
algorithm as specified in Section 13.4.2 
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4. 
STATISTICAL ANALYSIS SETS 
Two sham treatment arms (SM and SEOM) will be pooled into a single control (Sham) group for 
analyses. 
4.1. 
Screened Set  
The screened set consists of all subjects who provided written informed consent and are screened 
for participation in this study. This population will only be used for the purposes of describing 
the subject disposition and for listing the data. 
4.2. 
Intent-to-Treat Set  
The Intent-to-treat (ITT) set consists of all randomized subjects. Subjects will be analyzed in the 
treatment arm assigned at randomization. 
4.3. 
Modified Intent-to-Treat Set 
The modified ITT (mITT) set consists of all randomized subjects who receive at least one 
injection of pegcetacoplan or sham and have baseline and at least one post-baseline value of GA 
lesion area in the study eye as assessed by FAF. Subjects will be analyzed in the treatment arm 
assigned at randomization. 
4.4. 
Safety Set  
The Safety set consists of all subjects randomized who receive at least one injection of 
pegcetacoplan or sham. Subjects will be analyzed according to the actual treatment received. In 
the case a subject received an incorrect injection of study medication than what they were 
randomized to, subjects will be presented under the corresponding pegcetacoplan arm if they 
received at least one injection of pegcetacoplan during the study and will only be presented 
under the corresponding sham arm if they did not receive any injections of pegcetacoplan. 
This population will be used for all safety analyses. 
4.5. 
Per-Protocol Sets  
The Per-Protocol (PP) sets will be identified separately for Month 12 and Month 24 analysis, 
respectively (i.e., Month 12 PP set and Month 24 PP set). The PP sets consist of all mITT 
subjects who have a valid GA lesion area assessment for either Month 10 or 12 (Month 12 PP 
set) or a valid GA lesion area assessment for at least one of Month 18, 20, 22, 24 (Month 24 PP 
set) and who follow the protocol without any major deviation(s) that could affect the primary 
efficacy data.  
A valid GA lesion area assessment is defined as a non-missing measured GA lesion area 
assessment at a given timepoint where at least 75% of the expected injections over the course of 
participation ahead of the given timepoint have been received by the subject. For example: 
• A valid GA lesion measurement at Month 10 in the Monthly arm would be a result 
available at Month 10 with no more than 2 missed injections prior to the Month 10 
assessment (10 scheduled before Month 10, 2 missed = 80% compliance). 
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• A valid GA lesion measurement at Month 20 in the every other month (EOM) arm 
would be a result available at Month 20 with no more than 2 missing injections prior 
to the Month 20 assessment (10 scheduled before Month 20, 2 missed = 80% 
compliance). 
Major protocol deviations (PDVs) that lead to exclusion from the Month 12 PP set and the 
Month 24 PP set are as follows: 
(i) 
Violations of inclusion and/or exclusion criteria 
A PDV with any of the following inclusion and/or exclusion criteria violations will be classified 
as a major PDV: 
Inclusion Criterion #3: Clinical diagnosis of GA of the macula secondary to AMD as determined 
by the Investigator and confirmed by the Reading Center 
Inclusion Criterion #4: The GA lesion must meet the criteria listed in the protocol as determined 
by the central Reading Center’s assessment of FAF 
• Total GA area must be ≥ 2.5 and ≤ 17.5 mm2 (1 and 7 disk areas [DA] respectively). 
• If GA is multifocal, at least one focal lesion must be ≥ 1.25 mm2 (0.5 DA), with the 
overall aggregate area of GA as specified above in 4a. 
• The entire GA lesion must be completely visualized on the macula centered image 
and must be able to be imaged in its entirety and not contiguous with any areas of 
peripapillary atrophy. 
• Presence of any pattern of hyperautofluorescence in the junctional zone of GA. 
Absence of hyperautofluorescence (i.e., pattern = none) is exclusionary. 
Exclusion Criterion #1: GA secondary to a condition other than AMD such as Stargardt disease, 
cone rod dystrophy or toxic maculopathies like plaquenil maculopathy in either eye. 
Exclusion Criterion #3: Any history or active choroidal neovascularization (CNV), associated 
with AMD or any other cause, including any evidence of retinal pigment epithelium rips or 
evidence of neovascularization anywhere based on spectral domain optical coherence 
tomography (SD-OCT) imaging and/or fluorescein angiography as assessed by the 
Reading Center. 
Exclusion Criterion #13: Prior participation in another interventional clinical study for 
geographic atrophy in either eye including investigational oral medication and placebo. 
(ii) 
Not receiving assigned treatment 
Not receiving assigned treatment at more than 25% of the treatment visits over the analysis 
timeframe, either 12-month or 24-month, will be classified as a major PDV. 
4.6. 
Genotyping Set  
The genotyping set consists of all ITT subjects who have at least one non-missing genotyping 
result for a single nucleotide polymorphism (SNP) associated with age-related macular 
degeneration from the genotype sequencing analysis.  
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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects 
The number of subjects screened, passed screening, screened failed, and the reasons for screen 
failure will be presented overall.  
The number of subjects randomized and in each defined analysis set will be summarized by 
treatment group and overall for the ITT Set. In addition, the reasons for exclusion from the mITT 
and per-protocol populations will be summarized. 
Subjects’ disposition by region and country will also be provided for the ITT set. All summaries 
on subject disposition will be produced based on the Month 12 dataset for the Month 12 
reporting and based on the final study dataset for the final reporting, as appropriate. 
Overall summary of subjects’ disposition includes: 
• Number of subjects randomized 
• Number of subjects completed treatment [through Month 12 or Month 24, as appropriate] 
• Number of subjects discontinued from treatment and reason for discontinuation [prior 
to Month 12 or Month 24 as appropriate] 
− Subjects who discontinued from treatment without concurrent study discontinuation 
will be singled out [prior to Month 12 or Month 24 as appropriate] 
• Number of subjects completed study [through Month 12 or Month 24, as appropriate] 
• Number of subjects discontinued from study and reason for discontinuation [prior to 
Month 12 or Month 24 as appropriate] 
A summary of the disposition through each study visit will also be presented by treatment group 
and overall for the ITT set. 
In addition, to assess the impact of COVID-19 pandemic on disposition of subjects, the 
following summary will be provided for each study visit and by reason (COVID-19 vs. 
non-COVID-19) for the ITT set: 
• Number of subjects discontinued from treatment 
• Number of subjects discontinued from study 
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5.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be tabulated using descriptive statistics by 
treatment group and overall. Tables will be produced for the following analysis sets: ITT, Safety, 
mITT, Month 12 PP and Month 24 PP (as appropriate), and Genotyping. The following variables 
will be included in the tables:  
The demographic data are: 
• Age at screening (years) and in categories  
o < 65 
o 65-<75 
o 75-<85  
o ≥ 85 
• Sex 
• Race 
• Ethnicity 
• Geographic Region (United States vs. Rest of World) 
• Country 
• Weight (kg) at baseline 
• Height (cm) at baseline 
• Body Mass Index (kg/m2) 
• Tobacco use status (ever, never) 
Baseline characteristics will be summarized for both study eye and fellow eye whenever 
applicable. Baseline characteristics include: 
• Study eye laterality (OD, OS) 
• Study eye status (better-seeing eye vs. worse-seeing eye, based on NL-BCVA – in the 
case of ties, study eye status will be classified as the better-seeing eye) 
• GA lesion size (mm2) (assessed by FAF)  
• GA lesion size in categories, determined by reading center (as randomized status and 
actual status): 
o < 7.5 mm2 
o ≥ 7.5 mm2 
• GA lesion size categories (approximately tertiles based on APL2-303/304 combined 
data*) – study eye only 
• Square root GA lesion size (mm)  
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• GA lesion location (subfoveal involvement vs. non-subfoveal involvement) (assessed 
by FAF) 
• GA focality (unifocal vs. multifocal) (assessed by FAF) 
• Number of areas of atrophy (none, 1, 2-5, 6-10, 11-20, >20, cannot be determined) 
(assessed from FAF) 
• Presence of double-layer sign (DLS) (assessed by SD-OCT) 
• Central subfield thickness (CST) (assessed by SD-OCT) 
• Presence of macular neovascularization (MNV) (i.e., subclinical CNV) (assessed by 
Optical Coherence Tomography Angiography (OCT-A)) 
• Presence of pseudodrusen (assessed by near-infrared reflectance imaging) 
• Number of intermediate/large drusen (0-5, 6-10, 11-20, and >20) (assessed by color 
fundus photography) 
• NL-BCVA in ETDRS letters 
• NL-BCVA categories (≥70, ≥60 - <70, ≥35 - <60, <35 ETDRS letters) 
• NL-BCVA (<60 vs. ≥60 ETDRS letters) 
• LL-BCVA in ETDRS letters 
• LL-BCVA categories (approximately tertiles based on APL2-303/304 combined 
data*) – study eye only 
• IOP 
• LLD in ETDRS letters 
• LLD categories (<20 vs. ≥ 20 ETDRS letters)  
• LLD categories (approximately tertiles based on the APL2-303/304 combined data*) 
– study eye only 
• NL-BCVA (<60 vs. ≥60 ETDRS letters) and LLD (<20 vs. ≥ 20 ETDRS letters) 
combinations  
• Advanced AMD (fellow eye with: GA only, GA with CNV, CNV only, neither GA 
nor CNV) 
• GA laterality (bilateral GA vs. study eye GA Only) 
• Presence of CNV in fellow eye (as randomized and actual status (based on medical 
history)) 
• Lens status: 
o Phakic 
o Pseudophakic 
• Reading speed assessment method 
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• Monocular and binocular maximum reading speed and critical print size (without 
adjustment for reading inaccuracy) 
• Monocular maximum reading speed categories (<60, 60-<160, ≥160 words per 
minute (wpm)) 
• Monocular maximum reading speed categories (approximately tertiles based on 
APL2-303/304 combined data*) – study eye only 
• Mean FRI Index score 
• FRI Level (1,2,3,4) 
• Mean threshold sensitivity of (assessed by microperimetry) 
o All points 
o Perilesional points 
o Paralesional points 
o Extralesional points 
• Mean threshold sensitivity of all points categories (approximately tertiles) 
• Number of scotomatous points (assessed by microperimetry) 
• Fixation stability (95% BCEA) (assessed by microperimetry) 
• Fixation stability (95% BCEA) categories (approximately tertiles) 
• NEI VFQ-25 distance activity subscale score 
• NEI VFQ-25 near activity subscale score 
• NEI VFQ-25 driving subscale score 
• Number of subjects currently driving at baseline 
• NEI VFQ-25 composite score 
• Dry AMD status (iRORA, large drusen) (at Month 24 reporting only) 
*Approximately tertiles will be specified consistently across the APL2-303/304 studies to the 
nearest clinically relevant level. 
Baseline will be defined as the last available pre-treatment value taken on or before the first dose 
date of study drug. In the case a subject did not receive study drug in the ITT population, the last 
assessment prior to study exit will be used as baseline. 
Conversions for height and BMI are as follows: 
• Height (m) = Height (cm) x 0.01 
• Body mass index (kg/m2) = Weight (kg) / [Height (m)]2 
Demographics and baseline characteristics will also be listed for the ITT set. 
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5.3. 
Medical ocular and non-ocular History  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary version 23.1. Summaries will be presented by System Organ Class (SOC) and 
Preferred Term (PT) with counts and percentages by treatment group and overall. Each subject 
will be counted only once in each SOC or SOC/PT summary. 
All ocular history will be summarized by SOC and PT with counts and percentages by treatment 
group and overall. The summaries will be produced separately for the study eye and the fellow 
eye. Any ocular condition associated with both eyes will be included in both summaries. 
Data listings of medical history and ocular history will be provided for the ITT set. 
5.4. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary version WHO Drug Global B3-format March 2021. Non-ocular medications will be 
presented for the ITT set by anatomical therapeutic class (ATC) level 2 (therapeutic main group) 
and preferred term with counts and percentages by treatment group and overall. A subject who 
took more than one medication will be counted only once if these medications belong to the 
same extended ATC classification. In addition, prior and concomitant ocular medications used in 
study eye will be summarized. Similar summaries will be provided for the ocular medications 
used in the fellow eye. Any ophthalmological medications (ATC2 = ‘Ophthalmologicals’) that 
are not assigned to an eye will be presented under both eyes in the ocular medications tables and 
will not be presented in the non-ocular medications tables. 
Prior medications will be defined as those medications taken prior to the administration of study drug 
on Day 1. Concomitant medications will be defined as those medications taken following the first 
administration of study drug on Day 1. Hence medications started before study dosing and 
continuing into the treatment period are considered as both prior and concomitant medications.  
Separate tables will be provided for prior and concomitant medications, respectively. A data 
listing of prior and concomitant medications, for both ocular and non-ocular medications will be 
provided for the ITT set. 
5.5. 
Concomitant Procedures  
Concomitant procedures will be coded using MedDRA version 23.1. Non-ocular procedures will 
be presented for the ITT set by preferred term with counts and percentages by treatment group 
and overall. A subject who had more than one procedure will be counted only once in the 
summary. In addition, concomitant ocular procedures in study eye will be summarized. Similar 
summaries will be provided for the ocular procedures used in the fellow eye. 
Concomitant procedures will be defined as those procedures taken following the first 
administration of study drug on Day 1.  
A data listing of all procedures, for both non-ocular and ocular procedures will be provided for 
the ITT set. 
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5.6. 
Exposure to Investigational Product 
Exposure to the investigational product will be summarized for the ITT, mITT, and Safety sets. 
All analyses will be repeated for the first 12 months at both the Month 12 and final reporting as 
well as the full 24 months for the final reporting.  
For the analysis of exposure data for the first 12 months, exposure data prior to the Month 12 visit 
will be summarized (i.e., the Month 12 injection will not be included in the summaries). For analyses 
of the full 24 months, all data will be summarized. 
Injections in the fellow eye will be considered in the calculation of the duration of treatment but will 
otherwise be considered as a missed injection in the study eye for all other measures of exposure. 
The total number of injections and total number of missed injections received in each treatment 
group will be summarized by treatment group to support per-injection based TEAE rates. The 
following categories for reason for missed injections will be summarized by treatment group 
using frequency counts and percentages based on the total number of missed injections: COVID-
19 (with a breakdown of COVID-19 reasons as collected in the electronic case report form 
(eCRF)) vs. non-COVID-19 reasons (any reasons other than eCRF documented COVID-19 
reasons). The total number of injections per subject will be summarized by treatment group both 
as a continuous summary and as a frequency and percent summary. In addition, the following 
categories of the total number of injections per subject will be summarized by treatment group 
using frequency counts and percentages: 
• First 12 months summaries 
o Monthly: 1-3, 4-6, 7-9, 10-12  
o EOM: 1-2, 3-5, 5-6 
• Full 24 months summaries 
o Monthly: 1-3, 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24 
o EOM: 1-2, 3-5, 5-6, 7-8, 9-10, 11-12 
The number of subjects who received at least 75% of the planned injections for the study period 
(first 12 months or full 24 months) will be presented. For the first 12 months, subjects will be 
considered to have received 75% of the planned injections if they received at least 9 (out of 12) 
injections for the Monthly group or 5 at least (out of 6) injections for the EOM group. For the 
full 24 months, subjects will be considered to have received 75% of the planned injections if they 
received at least 18 (out of 24) injections for the Monthly group or at least 9 (out of 12) 
injections for the EOM group. 
The number of subjects missing at least one injection will be summarized by treatment group. 
The number of missed injections per subject as well as well as a breakdown of the number of 
missed injections per subject due to COVID-19 reasons and due to non-COVID-19 reasons will 
be summarized by frequency and counts. Additionally, for the missed injections due to COVID-
19, the subjects will be summarized by their maximum drug holiday in the following categories:  
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• No Consecutive Injections (Subjects who are missing an injection due to COVID-19 
but not at 2 injection visits in a row) 
• 2 Consecutive Injections 
• 3 Consecutive Injections 
• 4 or More Consecutive Injections 
The number of missed injections is defined as the scheduled injections missed up to completion 
or discontinuation of study treatment. 
Additionally, the duration of treatment and compliance will be summarized by treatment group.  
Duration of treatment will be defined as 
• Monthly group: (date of last injection +30) – date of first injection +1 
• EOM group: (date of last injection +60) – date of first injection +1 
The duration of treatment will be truncated to a subject’s early termination date, month 12 cutoff 
date, or study completion date as appropriate. 
Compliance (%) is defined as the number of injections administered divided by the number of 
scheduled injections up to completion or discontinuation of study treatment × 100. Compliance 
will be summarized in the following groups: <75%, ≥75% to <100%, 100%, and >100%. 
The number of subjects with scheduled IVT injection visits as well as the number of subjects 
receiving injections at each of the Months (1-24) will also be summarized by treatment group 
using frequency counts and percentages. For the EOM group, any injections given on the odd-
numbered months will be presented as an unscheduled injection. In addition, to assess the impact 
of the COVID-19 pandemic on study drug exposure, the following summary will be provided by 
study visit: 
• Number of missed IVT injection visits for study drug 
• Number of missed IVT injection visits for study drug due to COVID-19 pandemic 
reasons 
• Number of missed IVT injection visits for study drug due to non-COVID-19 
pandemic reasons 
Study drug administration will be listed by treatment group. In addition, a listing of total number 
of injections, duration of treatment, date and day of first and last dose and number of missed 
injections will be provided for the ITT set. 
5.7. 
Protocol Deviations 
Major and minor PDVs will be assessed by sponsor personnel following Protocol Deviation 
Management Plan.  
A PDV is classified as major if there is the potential to significantly impact the completeness, 
accuracy, and/or reliability of the study data, or affect a subject’s rights, safety, or well-being. 
All PDVs will be identified and finalized prior to the analysis of the first 12 months as well as 
the analysis of the full 24 month and documented.  
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In addition, a major PDV will be derived for any subjects who did not have a valid GA lesion 
area assessment for either Month 10 or 12 and who had not discontinued treatment prior to 
Month 12. The category for this deviation will be “Study Conduct/Procedures”, the subcategory 
will be “Study Assessment”, and the study specific category will be “No valid GA lesion area 
assessment for either Month 10 or Month 12”. 
PDVs will be presented for the ITT set by deviation category, subcategory, and study specific 
category with counts and percentages by treatment group and overall. In addition, similar summaries 
will be provided for major PDVs as well as for PDVs due to the COVID-19 pandemic.  
All PDVs will be listed for the ITT set. 
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6. 
EFFICACY ANALYSES 
Efficacy analysis including primary, key secondary, secondary, and exploratory analysis will be 
performed primarily using the mITT set, with subjects grouped according to the treatment 
assigned at randomization. Available data from all randomized subjects regardless of adherence 
to the protocol will be included in the efficacy analyses; this includes data from subjects who 
discontinued study drug early but continued with study assessments. All efficacy data will be 
listed for the ITT set.  
Unless otherwise noted, hypothesis testing and estimation of treatment effects will be performed 
with a mixed effect model for repeated measure (MMRM) that includes data from all three 
treatment arms (PM, PEOM, and Sham). The Sham arm will represent the pool of the two sham 
treatment groups: SM and SEOM (i.e., the two sham arms will be pooled into a single “control” 
group). All hypothesis tests for efficacy endpoints will be two-sided. 
Unless otherwise noted, analysis of efficacy endpoints (primary, key secondary, secondary, and 
exploratory) in the overall population will be adjusted for the following randomization 
stratification factors (actual status) and baseline covariates: 
For primary efficacy endpoint 
• Presence of CNV in the fellow eye (yes; no) 
• Baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) 
For key secondary, secondary, and exploratory endpoints  
• Presence of CNV in the fellow eye (yes; no) 
• Baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) 
• Baseline value of the endpoint 
Of note, the randomization stratification factors were assessed at the screening visit. In the event 
of a change in status in the GA lesion area between the screening visit and the baseline visit 
(i.e., GA lesion area < 7.5 mm2 at screening to ≥ 7.5 mm2) then the baseline status will be used. 
If a statistical model is not directly specified and if necessary, data will be analyzed with the 
following approaches:  
• For continuous endpoints, the MMRM analysis described for the primary endpoint in 
Section 6.2.2. 
• For categorical or ordinal variables, a Cochran Mantel Haenszel (CMH) test with the 
baseline category status, presence of CNV in the fellow eye (yes or no), and baseline 
GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as stratification factors. 
6.1. 
Estimands 
The primary scientific research question of this study is to assess the effect of pegcetacoplan 
compared with that of sham at Month 12 regarding the impact on GA lesion progression 
under-real-life conditions following the ITT principal.  
The primary estimand in the study is defined through the following 5 attributes: 
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• Population: GA subjects defined through inclusion and exclusion criteria in the 
mITT population. 
• Treatment conditions: The treatment regimen of interest in this study is PM, PEOM, 
and Sham. 
• Variable (or endpoint): Change in total area of GA lesions in the study eye from 
baseline measured by FAF to Month 12. 
• Strategy for addressing intercurrent events: See description of intercurrent events 
below. 
• Population-level summary: Difference in mean change of GA lesion from baseline 
to Month 12 between pegcetacoplan and sham groups according to MMRM analysis.  
The intercurrent events that will be considered are: 
• Treatment discontinuation  
• Lost to follow up 
• Withdrawal from the study 
The intercurrent events will be handled with a treatment policy strategy whereby any measured 
value will be used as is. Missing data resulting from these intercurrent events will be handled 
implicitly within the MMRM analysis that assumes missing at random. 
The key secondary estimands will be defined and analyzed in the similar fashion as the primary 
estimand. The primary and key secondary estimands are summarized in Table 2. 
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Table 2: 
Estimands of Study 
 
Estimand 
 
Definition 
Attributes 
A: 
Population 
B: Variable (or 
endpoint) 
C: Strategy for addressing 
intercurrent event 
D: Population-level 
summary 
 
 
Main Analyses 
Primary 
The effect of 
pegcetacoplan 
compared to sham at 
Month 12 in impact 
on GA progression  
mITT 
Change in the total 
area of GA lesions 
from baseline 
measured by FAF to 
Month 12 
• Treatment policy strategy 
for subjects who 
discontinue treatment, are 
lost to follow-up, or 
withdraw from the study 
 
Difference in mean 
change of GA lesion from 
baseline at Month 12 
between pegcetacoplan 
and sham groups based on 
MMRM analysis 
Key 
Secondary 
#1 
The effects of 
pegcetacoplan 
compared to sham at 
Month 24 in impact 
on macular functional 
response 
mITT 
Change in mean 
threshold sensitivity 
of all points from 
baseline to Month 24 
 
• Treatment policy strategy 
for subjects who 
discontinue treatment, are 
lost to follow-up, or 
withdraw from the study 
Difference in mean 
change in mean threshold 
sensitivity of all points 
from baseline at Month 
24 between pegcetacoplan 
and Sham groups based 
on MMRM analysis 
Key 
Secondary 
#2 
The effects of 
pegcetacoplan 
compared to sham at 
Month 24 in impact 
on monocular 
maximum reading 
speed 
mITT 
Change in monocular 
maximum reading 
speed from baseline 
to Month 24 
 
• Treatment policy strategy 
for subjects who 
discontinue treatment, are 
lost to follow-up, or 
withdraw from the study 
Difference in mean 
change in monocular 
maximum reading speed 
from baseline at Month 
24 between pegcetacoplan 
and Sham groups based 
on MMRM analysis 
Key 
Secondary 
#3 
The effects of 
pegcetacoplan 
compared to Sham at 
Month 24 in impact 
on mean FRI Index 
score 
mITT 
Change in mean FRI 
Index score from 
baseline to Month 24 
 
• Treatment policy strategy 
for subjects who 
discontinue treatment, are 
lost to follow-up, or 
withdraw from the study 
Difference in mean 
change in mean FRI 
Index score, from 
baseline at Month 24 
between pegcetacoplan 
and sham groups based on 
MMRM analysis 
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Table 2: 
Estimands of Study 
 
Estimand 
 
Definition 
Attributes 
A: 
Population 
B: Variable (or 
endpoint) 
C: Strategy for addressing 
intercurrent event 
D: Population-level 
summary 
Key 
Secondary 
#4 
The effects of 
pegcetacoplan 
compared to Sham at 
Month 24 in impact 
on NL-BCVA score 
mITT 
Change in NL-BCVA 
score from baseline to 
Month 24 
 
• Treatment policy strategy 
for subjects who 
discontinue treatment, are 
lost to follow-up, or 
withdraw from the study 
Difference in mean 
change of NL-BCVA 
score from baseline at 
Month 24 between 
pegcetacoplan and sham 
groups based on MMRM 
analysis 
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6.2. 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline to Month 12 in total area of GA lesion(s) 
in the study eye (in mm2) based on FAF.  
The hypotheses of interest and Type I error management for analyses of the primary endpoint are 
specified below and take precedence over that specified in the study protocol.  
For the primary efficacy endpoint, sensitivity analyses (Section 6.2.3), supplementary analyses 
(Section 6.2.4), and subgroup analyses (Section 6.2.5) will be performed.  
All analyses of the first 12 months will be performed at the Month 12 reporting as well as 
repeated at the final reporting. Unless otherwise specified, at the time of the final reporting, all 
analyses will be repeated using the data for the full 24 months.  
6.2.1. 
Type I Error Management 
The null hypotheses for the primary efficacy endpoint are the following: 
• H1a: There is no difference between PM and Sham in mean change from baseline to 
Month 12 in total area of GA lesion(s) in the study eye (in mm2) based on FAF for the 
mITT set. 
• H1b: There is no difference between PEOM and Sham in mean change from baseline 
to Month 12 in total area of GA lesion(s) in the study eye (in mm2) based on FAF for 
the mITT set. 
For hypothesis testing of the primary efficacy endpoint, type I error will be controlled using a 
fixed sequencing approach by testing the two hypotheses (H1a and H1b) sequentially, beginning 
with H1b. All hypothesis tests for the primary endpoint will be based on a two-sided alpha level 
of 0.05. The alpha will be adjusted in accordance with the protocol for the number of Data 
Monitoring Committee (DMC) unmasked reviews prior to the Month 12 analysis timepoint 
(i.e., 4 DMC unmasked reviews prior to Month 12: 2-sided alpha level = 0.0496). Testing for 
statistical significance proceeds to H1b only if H1a is statistically significant. The study will be 
considered positive if the first hypothesis (H1a) is rejected. 
6.2.2. 
Main Analysis of Primary Efficacy Endpoint 
The primary endpoint will be analyzed in the mITT population with subjects grouped according 
to the treatment assigned at randomization.  
A MMRM model will be used to analyze the primary endpoint. The analysis model will include 
treatment (PM, PEOM, sham), presence of choroidal neovascularization in the fellow eye at 
baseline (Yes, No) and baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects, time 
(study month, categorical) as a factor, the time × treatment interaction term, and the baseline GA 
lesion area (< 7.5 mm2 or ≥ 7.5 mm2) × time interaction term. The least square [LS] mean change 
from baseline to Month 12 will be estimated from the model for each of three arms as well as the 
comparisons of each of the three arms to each other. For other time points of interest, LS mean 
change from baseline will be estimated and compared between treatments. For each estimated 
LS mean, the corresponding 95% CI will be presented based on the model. For the comparison 
of the LSmeans, the corresponding 95% CI and the 2-sided P-value along with the percentage 
difference (difference in LS means between the arms/the comparison group LS mean) will be 
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presented. A common unstructured covariance matrix will be used to model the within-subject 
errors, the sandwich estimator (Diggle, Liang, and Zeger 1994) will be used to estimate the 
standard errors of the fixed effects parameters, and the degrees of freedom will be partitioned 
into between-subject and within-subject portions. If there are convergence problems with the 
model, then a heterogeneous autoregressive (1) covariance matrix will be used. If convergence 
problems still exist, an autoregressive (1) covariance matrix will be used. The LS mean of the 
change from baseline in the total area of GA lesion(s) ± the standard error will be plotted over 
time by treatment group. 
The observed values for the total area of GA lesion(s) will be summarized by treatment group 
and visit for both the study and the fellow eye. Summaries will present the descriptive statistics 
for baseline, absolute values and change from baseline data by visit. 
The mean change from baseline in the total area of GA lesion (s) in the study eye ± the standard 
error will be plotted over time by treatment group.  
All GA lesion (s) size data will be listed for the ITT set. 
6.2.3. 
Sensitivity Analyses of Primary Efficacy Endpoint 
Sensitivity analyses will be performed to evaluate the robustness of the primary analysis results. 
Analyses will be performed for the overall population based on the outcome of the primary 
analyses including all subjects in the mITT set.  
6.2.3.1. 
Missing Data Analyses Based on Multiple Imputation 
The following sensitivity analysis based on multiple imputation will be performed, as 
appropriate, using the same statistical approach as the one used in the primary analysis: 
• Subjects with treatment discontinuation or study withdrawal assessed as potentially 
related to study drug or lack of efficacy will have missing data after the 
discontinuation or withdrawal imputed via a control-based imputation based on the 
sham control subjects. This will be based on the mITT set. 
o Subjects who discontinue the treatment or study due to reasons that are 
potentially related to study drug or lack of efficacy include 
 Subjects who discontinue due to ocular adverse event, adverse event 
related to treatment, or adverse event related to injection procedure 
 Subjects who withdraw consent due to lack of efficacy (specify field 
includes ‘Lack of efficacy’) or not otherwise specified as not related to 
efficacy (specify field includes “Not specified”) 
• Subjects with a monotone missing data pattern due to treatment discontinuation or 
study withdrawal will have missing data after the last assessment explicitly imputed 
by multiple imputation using a tipping point analysis method assuming missing not at 
random (MNAR). This will be based on the mITT set. 
Imputation for the non-monotone missing pattern (i.e., arbitrary missing pattern) will be 
performed prior to the multiple imputation for the monotone missing pattern 
(i.e., where a missing GA area measurement at a visit for a subject implies that GA area 
measurements at all subsequent visits for that subject are missing).  
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For the nonmonotone missing pattern, missing value(s) between two visits with measured GA 
area will be imputed using the monotone data MCMC method, which was first proposed by 
Li (1988) and Liu (1993) described the algorithm. Multiple imputation will then be carried out 
for monotone missing pattern. 
The two imputation methods will be implemented in SAS using the three standard steps to generate 
inference from imputed data: imputation step, analysis step, and pooling step. Details are illustrated 
with SAS codes in Section 1.2.2. 
• The missing data are filled in 1000 times to generate 1000 complete datasets.  
• The 1000 complete datasets are analyzed by using the same approach as for the 
analysis for the primary objective.  
• The results from the 1000 complete datasets are combined for the inference. 
Methods used in the imputation step are described below. 
• Pattern Mixture Model Method (a copy-reference approach): The pattern mixture 
model method will be implemented.  
o Subjects with monotone missing data in the pooled sham arm will have 
missing data imputed based on the observed values in the pooled sham arm.  
o For the active treatment arms, subjects with monotone missing data who 
discontinued treatment or withdrew from the study due to reasons that are 
potentially related to study drug or lack of efficacy will have missing data 
imputed based on the pooled sham arm.  
o For the active treatment arms, subjects with monotone missing data who did 
not discontinue treatment or withdraw from the study due to reasons that are 
potentially related to study drug or lack of efficacy will have missing data 
imputed based on the observed values in the corresponding treatment arm. 
• Tipping Point Analysis Method (a delta-adjusted approach): The tipping point 
analysis method will be implemented for each active treatment arm under the MNAR 
assumption by searching for a tipping point that reverses the conclusion regarding 
positive treatment effect. For the pooled sham arm, subjects will have missing data 
imputed based on the observed values in the pooled sham arm. For the active 
treatments, subjects with monotone missing data without treatment discontinuation or 
early withdrawal will have missing data imputed based on the observed values in the 
corresponding treatment arm. For the active treatment arms, subjects with monotone 
missing data due to treatment discontinuation or early withdrawal will have the 
missing data imputed based on the available values (observed values plus values 
imputed for non-monotone missing data) in the same treatment arm with a shift 
parameter added to the imputed values. Multiple imputation will be implemented on 
the differences between two consecutive visits, with the shift parameter allocated to 
the missing data point(s) proportionally across timepoints. (e.g. For a shift parameter 
of 0.48 mm2 at Month 12, incremental shifts of 0.08 mm2, would apply to Month 2, 
Month 4, … and Month 12, respectively. 0.08 mm2 x 6 visits = 0.48 mm2) The range 
of the shift parameters will be from 0.06 mm2 to 0.72 mm2 by increments of 0.06 
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mm2 for Month 12 and 0.12 mm2 to 1.44 mm2 for Month 24 for the difference in the 
change of GA area from baseline between each pegcetacoplan arm (PM or PEOM) 
and Sham arm. The precision of the tipping point will be at two decimal points. 
A tipping point may not exist within reasonable clinical assumptions. 
For each analysis, the number and percent of subjects without monotone missing data, the 
number of subjects with monotone missing data and a breakdown of reasons will be reported. 
The reasons will include monotone missing without treatment discontinuation or early 
withdrawal, monotone missing due to treatment discontinuation or early withdrawal due to 
reasons that are potentially related to study drug or lack of efficacy, and monotone missing due 
to treatment discontinuation or early withdrawal not due to reasons that are potentially related to 
study drug or lack of efficacy. 
6.2.3.2. 
Other Sensitivity Analyses 
The primary endpoint will also be analyzed without pooling the two sham arms (SM and 
SEOM). The comparison for pegcetacoplan and sham injection within each dose schedule 
(i.e., PM vs SM and PEOM vs SEOM, respectively) will be conducted using the MMRM 
analyses described in Section 6.2.2. 
The primary endpoint will also be summarized excluding GA total area assessments with an 
indeterminate boundary. The summary and presentation of the observed values for the total area 
of GA lesion(s) by treatment group and visit described in Section 6.2.2 will be repeated. 
The summary and presentation of the analysis results for all timepoints described in Section 6.2.2 
will be repeated.  
6.2.4. 
Supplemental Analyses of the Primary Efficacy Endpoint 
6.2.4.1. 
COVID-19 Adjusted Estimand  
Despite the occurrence of the COVID-19 pandemic, the scientific question of interest in this study 
remains unchanged. The primary scientific research question of this study is to assess the effect of 
pegcetacoplan compared with that of sham at Month 12 on GA lesion progression under-real life 
conditions without COVID-19 pandemic impact.  
To manage the increase in missed/not received injections due to COVID-19 pandemic (as collected 
on the eCRF), i.e., undertreatment with an expected relevant impact on efficacy, the hypothetical 
strategy will be used whereby assessments after the intercurrent event (relevant undertreatment) 
occurs will be set to missing/censored in the analysis. The threshold for missed/not received 
injections due to the COVID-19 pandemic is missing a pre-specified number of scheduled injections 
prior to the analysis timepoint of interest. For the Monthly schedule group, this is missing 2 or more 
injections and for the EOM schedule group, this is missing 1 or more injections prior to the Month 12 
visit attributable due to the COVID-19 pandemic. 
In terms of the underlying cause of the excessive missing/not received injections and subsequent 
missing data, it is assumed that the missingness resulting from censoring occurs at random 
because of the ongoing pandemic and not because of the subjects’ unobserved outcome, 
so missing data resulting from this intercurrent event in the primary analysis model will be 
handled implicitly in the MMRM analysis.  
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The number of subjects with any censoring included in the model, the number of subjects with 
any censoring not included in the model, and the number of assessments censored by visit will be 
presented for each treatment group. 
All summaries and presentations of the observed values for the total area of GA lesion(s) in the 
study eye by treatment group and visit described in Section 6.2.2 will be repeated for the 
COVID-19 adjusted estimand. All summaries and presentations of the analysis results for all 
timepoints described in Section 6.2.2 will be repeated for the COVID-19 adjusted estimand. 
The same plots as for the primary endpoint analysis will be presented.  
In addition, a supplemental analysis will also be performed where the threshold for missed/not 
received injections will be restricted to external events attributable to COVID-19. These events 
are defined based on the COVID-19 collection form and include COVID-19 diagnosis, 
COVID-19 Suspected, Site Closure, Travel Ban, Shelter in Place, City Lockdown, and Other. 
Except for the plots, the analyses described above will be repeated for the threshold based only 
on these external events attributable to COVID-19.  
6.2.4.2. 
Per Protocol Set  
The main analysis described in Section 6.2.2 will be repeated using the Month 12 PP set to 
investigate the impact of changing the population in the estimand. Any GA lesion area assessments 
that are deemed not valid according to what is described in Section 4.5 will be set to missing in this 
analysis. The summary and presentation of the observed values for the total area of GA lesion(s) by 
treatment group and visit described in Section 6.2.2 will be repeated. The summary and presentation 
of the analysis results for all timepoints described in Section 6.2.2 will be repeated.  
6.2.4.3. 
Rate of Change Analyses 
The mean rate of change in GA area (i.e., slope) will be compared between each pegcetacoplan 
arm and the pooled sham arm by use of linear mixed effects model assuming time as continuous 
and linear (“slope model”). The analysis model will include treatment (PM, PEOM, sham), 
presence of choroidal neovascularization in the fellow eye at baseline (Yes, No), baseline GA 
lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects, time (study month, continuous assuming 
linearity), the time × treatment interaction term as well as the baseline GA lesion area × time 
interaction term. The response variable will be the GA lesion area. A common unstructured 
covariance matrix will be used to model the within-subject errors, the sandwich estimator will be 
used to estimate the standard errors of the fixed effects parameters, and the degrees of freedom 
will be partitioned into between-subject and within-subject portions. If there are convergence 
problems with the model, then a heterogeneous autoregressive (1) covariance matrix will be 
used. If convergence problems still exist, an autoregressive (1) covariance matrix will be used. 
The mean rate of change (slope), standard error, and confidence interval will be estimated for the 
baseline to Month 12 as well as the baseline to Month 6 and Month 6 to Month 12 periods for 
each treatment group. In addition, the estimated difference in slopes among the treatment groups 
along with the 95% CIs and p-value will be reported. The slopes and 95% CIs will be converted 
to an annualized rate of growth for each period and each treatment group. 
The observed values for the total area of GA lesion(s) will be summarized by treatment group 
and visit for the baseline to Month 6 and Month 6 to Month 12 time periods. Summaries will 
present the descriptive statistics for baseline, absolute values and change from baseline to 
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Month 6 and change from Month 6 to Month 12 data. In addition, the annualized rate of growth 
for each time period will also be presented. 
The mean rate of change in GA area will be compared between each pegcetacoplan arm and the 
pooled sham arm by use of a piecewise linear mixed effect model assuming time as continuous 
and piecewise linear (“piecewise slope model”). The analysis to be performed will be similar to 
what is described above in the “slope model” except that a knot at the Month 6 visit will be 
added which allows for the slope of lesion growth to differ between the two periods for each of 
the treatment groups. The same presentation as for the “slope model” will be prepared except for 
the Baseline to Month 12 slope. Additionally, an investigation of the impact of changing the knot 
to Month 2, 4, 8, 10 will be explored if necessary. 
6.2.5. 
Subgroup Analyses of Primary Efficacy Endpoint 
Subgroup analyses will be performed to evaluate the consistency of the primary analysis results 
across subgroups defined by demographic and baseline characteristics. Analyses will be performed 
for the primary efficacy endpoint (change from baseline in total area of GA lesion(s) in the study eye 
at Month 12) for each of the following subgroups (as appropriate per actual subgroup sample size, 
levels with low sample size may be pooled to allow for an analysis to be conducted): 
• Age Group (<75 years, 75 to <85 years, ≥85 years) 
• Sex (male, female) 
• Race (White, Black or African American, Asian, American Indian or Alaskan Native, 
Native Hawaiian or other Pacific Islander, multiple, unknown) 
− Note: If most subjects (e.g., >90%) are of a single race, this analysis will not be 
conducted. 
• Geographic Region (United States vs Rest of World) 
• Subgroups indicative of disease severity at baseline 
− Study eye baseline GA lesion size (<7.5 mm2; ≥7.5 mm2) 
− Study eye baseline GA lesion size categories (approximately tertiles based on 
APL2-303/304 combined data*) 
− Study eye baseline NL-BCVA categories (≥70, ≥60 - <70, ≥35 - <60, <35 ETDRS 
letters) 
− Study eye baseline NL-BCVA categories (<60 vs. ≥60 ETDRS letters) 
− Study eye baseline LL-BCVA categories (approximately tertiles based on 
APL2-303/304 combined data*) 
− Study eye baseline monocular maximum reading speed categories (approximately 
tertiles based on APL2-303/304 combined data*) 
− Baseline FRI Level (1,2,3,4) 
− Study eye mean threshold sensitivity of all points categories (approximately tertiles) 
• Subgroups associated with GA progression 
− Study eye baseline GA focality (multifocal, unifocal) 
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− Study eye baseline GA lesion location (subfoveal involvement, without subfoveal 
involvement) 
− Baseline GA laterality (bilateral GA (with or without CNV in fellow eye) vs. 
Study eye GA Only) 
− Baseline CNV in fellow eye (Fellow eye CNV vs. No fellow eye CNV)  
− Study eye baseline LLD categories (<20 vs. ≥ 20 ETDRS letters) 
− Study eye baseline LLD categories (approximately tertiles based on the APL2-
303/304 combined data*)  
− Study eye baseline NL-BCVA (<60 vs. ≥60 ETDRS letters) and LLD (<20 vs. ≥ 
20 ETDRS letters) combinations 
*Approximately tertiles will be specified consistently across the APL2-303/304 studies to the 
nearest clinically relevant level. 
For the primary efficacy endpoint, the approach described in the Section 6.2.2 will be used for 
each subgroup analysis based on the data subset for the subject subgroup of interest. Baseline 
covariates included in the main analysis but no longer relevant given the subgroup of interest 
will be excluded from the model. The estimated treatment effects (PM vs. Sham; PEOM vs. 
Sham) and corresponding 95% CIs and p-values from the models will be displayed graphically 
for each pegcetacoplan treatment arm and each level of the subgroups specified (e.g., via forest 
plots). 
6.2.6. 
Full 24 Month Analyses 
In general, the same analysis approach for the changes from baseline GA lesion size for the final 
reporting of the full 24 months will be repeated as described in Sections 6.2.2, 6.2.3, 6.2.4, 6.2.5. 
Key differences include: 
• The definition of excessive missed/not received injection in the supplementary 
estimand will be defined based on the Month 24 period. The threshold for missed/not 
received injections due to the COVID-19 pandemic is missing 4 or more injections 
for the Monthly schedule group and 2 or more injections for the EOM schedule group 
prior to the Month 24 visit attributable due to the COVID-19 pandemic. 
• The Month 12 PP set will be replaced with the Month 24 PP set for the supplementary 
analysis. 
6.2.7. 
Exploratory Endpoints Closely Related to the Primary Efficacy Endpoint 
Analyses of the following endpoints closely related to the primary efficacy endpoint, will be 
performed for the mITT set to provide supplemental information. 
6.2.7.1. 
Change in Square Root of GA Area  
For each subject and timepoint, the square root of GA area will be calculated. The change from 
baseline in square root of GA area will be analyzed using the same methodology as described for 
the primary endpoint analysis in Section 6.2.2, except that change from baseline in the square 
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root of GA area will be the response variable. This analysis will be conducted both for the first 
12 months summaries as well as the full 24 months summaries.  
6.2.7.2. 
Percent Change in GA Area and Square Root of GA Area  
For each subject and timepoint, the percent change in GA area will be defined as the change 
from baseline in GA area (mm2) divided by the GA area (mm2) at baseline and the percent 
change in square root of GA area will be defined as the change from baseline in GA area (mm) 
divided by the GA area (mm) at baseline. The percent change in GA area from baseline and 
percent change in square root of GA area will be analyzed using the same methodology as 
described for the primary endpoint analysis in Section 6.2.2, except that percent change from 
baseline will be the response variable. This analysis will be conducted both for the first 
12 months summaries as well as the full 24 months summaries. 
6.3. 
Analyses of Key Secondary Efficacy Endpoints  
The key secondary efficacy endpoints are listed in Section 2.2.2. At the Month 12 reporting, all 
key secondary efficacy endpoints will be evaluated based on data from baseline to Month 12 
(see Section 3.5). For the Month 12 analyses, post-baseline visits, up to and including Month 12, 
will be included and nominal p-values will be presented. At the time of the final study analysis, 
all key secondary efficacy endpoints will be evaluated based on data from baseline to Month 24, 
and formal statistical testing for key secondary endpoints will be performed as described in 
Section 6.3.1. Unless otherwise specified, all secondary efficacy endpoints will be analyzed for 
the mITT set. 
6.3.1. 
Type I Error Management 
The planned submission of pegcetacoplan in GA consists of 2 studies of very similar design 
(APL2-303 and APL2-304), each with multiple endpoints. It is planned to control the type I error 
rate for the primary endpoint hypotheses testing at the level of the individual studies (as 
described in Section 6.2.1), and at a level of the submission as a whole for the key secondary 
endpoints hypotheses testing based on pooling APL2-303 and APL2-304. Figure 2 presents the 
overall hypotheses testing strategy for the APL2-303 and APL2-304 studies. 
The primary endpoint hypotheses in the PM vs. Sham and PEOM vs. Sham will be tested in a 
hierarchical order within a study. If both hypothesis tests for the primary endpoint in both studies 
are statistically significant, then hypotheses testing will be performed for the key secondary 
endpoints within the pooled APL2-303/APL2-304 data for hypotheses H2a – H4b and within the 
APL2-304 study for H5a and H5b at the presented α level. The key secondary efficacy 
endpoints hypotheses that will be tested in the pooled APL2-303/APL2-304 studies are below:  
• H2a There is no difference between PM and Sham regarding mean change from 
baseline in monocular maximum reading speed (study eye), as assessed 
by MNRead or Radner Reading Charts at Month 24.  
• H2b: There is no difference between PEOM and Sham regarding mean change from 
baseline in monocular maximum reading speed (study eye), as assessed 
by MNRead or Radner Reading Charts at Month 24.  
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• H3a: There is no difference between PM and Sham regarding mean change from 
baseline in mean FRI Index score at Month 24.  
• H3b: There is no difference between PEOM and Sham regarding mean change from 
baseline in mean FRI Index score at Month 24.  
• H4a: There is no difference between PM and Sham regarding mean change from 
baseline in NL-BCVA score at Month 24 (study eye) as assessed by ETDRS chart.  
• H4b: There is no difference between PEOM and Sham regarding mean change from 
baseline in NL-BCVA score at Month 24 (study eye) as assessed by ETDRS chart.  
The key secondary efficacy endpoints hypotheses that will be tested within the APL2-304 study 
are below: 
• H5a: There is no difference between PM and Sham regarding mean change from 
baseline in mean threshold sensitivity of all points (study eye) for the evaluation of 
the macular functional response, as assessed by mesopic microperimetry at Month 24. 
• H5b: There is no difference between PEOM and Sham regarding mean change from 
baseline in mean threshold sensitivity of all points (study eye) for the evaluation of 
the macular functional response, as assessed by mesopic microperimetry at Month 24. 
Hypothesis tests will be conducted in the order indicated by the arrows in Figure 2 and will 
continue as long as all preceding hypotheses are rejected at a given α level. If both the PM vs. 
Sham and the PEOM vs. Sham comparisons are statistically significant for a given key 
secondary endpoint, then the α will be allocated equally to the other key secondary hypotheses. 
At the study-level, the type I error rate (one-sided) is controlled at 0.025 for the primary endpoint 
hypotheses. In the submission, the type I error rate (one-sided) is controlled at 0.000625 
(0.0252) for the primary endpoint hypotheses and at 0.025 for the key secondary endpoint 
hypotheses. All hypothesis tests will be adjusted for the number of DMC unmasked reviews 
prior to the Month 12 analysis.  
Type I error will be controlled by the testing procedure via the graphical methods approach 
(Bretz 2009). All confidence intervals and p-values will be presented without adjustments.  
If at least one of the hypothesis tests for the primary endpoint in the APL2-303 study is not 
statistically significant but both hypothesis tests for the primary endpoint in the APL2-304 study 
are statistically significant, then any hypothesis testing for the key secondary endpoints will not 
be rejected at the submission level.  Within the APL2-304 study hypotheses testing for the key 
secondary endpoints will be tested as shown in Figure 3 and type I error will be controlled using 
a fixed sequencing approach. All hypotheses tests will be adjusted for the number of DMC 
unmasked reviews prior to the Month 12 analysis. All confidence intervals and p-values will be 
presented without adjustments.  
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Figure 3: 
APL2-304 Hypothesis Testing and Type I Error Control If There is No α 
Remaining in APL2-303 to Allow Pooling Secondary Functional Endpoints
MONTHLY DOSING
EVERY OTHER MONTH
H1a 
H1b
H5a 
H3a
H4a
H5b 
H3b
H4b
Monocular Maximum 
Reading Speed
Mean FRI Index
NL-BCVA
Endpoint data are compared to sham injections in hypotheses testing. Hypotheses can only be 
tested in sequential order as indicated by arrows. Sequential testing will continue as long as all 
preceding hypotheses can successfully be rejected at the given alpha level. This testing tree will 
only be used when APL2-303 cannot pass α from the primary endpoint testing to the pooled 
secondary functional endpoint testing.
Month 12
Key Secondary: Month 24
Primary Endpoint: 
GA Lesion(s) Size
H5a
H5b
Mean Threshold 
Sensitivity of All 
Points 
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6.3.2. 
Main Analyses of Key Secondary Efficacy Endpoints 
6.3.2.1. 
Mean Threshold Sensitivity of All Points  
Mean threshold sensitivity of all points will be determined from the mesopic microperimetry as 
an assessment of the macular functional response. 
Mean threshold sensitivity of all points in the study eye will be summarized and analyzed in a similar 
fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. The model will 
include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and baseline 
GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline mean threshold sensitivity of all 
points as a covariate, time (in months) as a factor; the time × treatment interaction term as well as the 
mean threshold sensitivity of all points × time interaction term. 
The observed values for mean threshold sensitivity of all points will be summarized by treatment 
group and visit for both the study and the fellow eye. Summaries will present the descriptive 
statistics for baseline, absolute values and change from baseline data. 
The mean change from baseline in the mean threshold sensitivity of all points of the study eye ± 
the standard error as well as the LS mean of the change from baseline in the mean threshold 
sensitivity of all points of the study eye ± the standard error will be plotted over time by 
treatment group.  
Data that is not acceptable quality for the main analysis, as identified by the reading center per 
the Imaging Charter, will not be included in this analysis. 
All microperimetry data will be listed for the ITT Set.  
6.3.2.2. 
Monocular Maximum Reading Speed 
Maximum reading speed will be calculated per MNRead or Radner user manuals, with no 
adjustment for reading inaccuracy. An additional step to cap resulting reading speed values at a 
maximum of 300 words per minute will be implemented. Values above 300 words per minute exceed 
values reported in the literature for adults with no vision impairment for MNRead 
(Calabrese et al. 2016) or Radner (Radner et al. 2002; Radner and Diendorfer 2014) assessments. 
Maximum reading speed will be calculated as the mean of the three highest nonzero reading speeds 
(or two, or one value, as available) (Baskaran et al. 2019; Patel et al. 2011), except when all words 
per minute are calculated as 0: then the maximum reading speed will be calculated as 0.  
Monocular maximum reading speed in the study eye will be summarized and analyzed in a 
similar fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. 
The model will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye 
(yes or no), and baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline 
monocular maximum reading speed as well as the chart type (MNRead or Radner) as covariates, 
time (in months) as a factor; the time × treatment interaction term as well as the baseline 
monocular maximum reading speed × time interaction term. 
The observed values for the monocular maximum reading speed will be summarized by 
treatment group and visit for both the study and the fellow eye. Summaries will present the 
descriptive statistics for baseline, absolute values and change from baseline data. 
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The mean change from baseline in the monocular maximum reading speed of the study eye ± the 
standard error as well as the LS mean of the change from baseline in the monocular maximum 
reading speed of the study eye ± the standard error will be plotted over time by treatment group. 
In addition, the categorical changes (improvements of ≥ 20 to <40, ≥ 40 to <60, ≥ 60 and 
minimal/no change (-20 to 20), worsening of ≥ 20 to <40, ≥ 40 to <60, ≥ 60) for the study eye 
will be summarized by treatment group and visit. 
The shift from baseline in the monocular maximum reading speed for the study eye categories 
over time will be presented by treatment group for the following categories: 
• < 40 wpm 
• 40 to < 80 wpm 
• 80 to <160 wpm 
• ≥ 160 wpm 
All monocular maximum reading speed data will be listed for the ITT set. 
6.3.2.3. 
Mean FRI Index Score 
The mean FRI Index score will be calculated per the scoring algorithm in the FRI Index 
user’s manual. 
The mean FRI Index score will be summarized and analyzed in a similar fashion as the primary 
efficacy endpoint using MMRM described in Section 6.2.2. The model will include treatment (PM, 
PEOM, Sham), presence of CNV in the fellow eye (yes or no), and baseline GA lesion area (< 7.5 
mm2 or ≥ 7.5 mm2) as fixed effects; baseline mean FRI Index score and baseline study eye status 
(Better-seeing Eye vs. Worse-seeing Eye) as covariates, time (in months) as a factor; the time × 
treatment interaction term as well as the baseline mean FRI Index score × time interaction term. 
The observed values for the mean FRI Index score will be summarized by treatment group and 
visit. Summaries will present the descriptive statistics for baseline, absolute values and change 
from baseline data. 
The mean change from baseline in the mean FRI Index score ± the standard error as well as the 
LS mean of the change from baseline in the mean FRI Index score ± the standard error will be 
plotted over time by treatment group. 
In addition, the mean FRI Index score will be converted to the FRI Level variable, as per the user 
manual, ranging from 1 (Unable to do) to 4 (Totally independent). The categorical changes from 
baseline (improvements (an increase in FRI level), minimal/no change (no change in FRI level), 
and worsening (decrease in FRI level)) will be summarized by treatment group and visit. 
The shift from baseline in the FRI level over time will be presented by treatment group.  
All FRI data will be listed for the ITT set. 
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6.3.2.4. 
NL-BCVA Score 
The mean NL-BCVA score for the study eye will be summarized and analyzed in a similar 
fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. The model 
will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and 
baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline NL-BCVA score as 
a covariate, time (in months) as a factor; the time × treatment interaction term as well as the 
baseline NL-BCVA score × time interaction term. Note, for the second year, only timepoints that 
were measured for all three treatment groups will be included in the model. 
The observed values for the NL-BCVA will be summarized by treatment group and visit for both 
the study and the fellow eye. Summaries will present the descriptive statistics for baseline, 
absolute values and change from baseline data. 
The mean change from baseline in the NL-BCVA score for the study eye +/- the standard error 
as well as the LS mean of the change from baseline in the NL-BCVA score for the study eye ± 
the standard error will be plotted over time by treatment group. 
In addition, the categorical changes (improvements of ≥15, ≥10 to <15, ≥5 to <10, and 
minimal/no change (-4 to 4 ), worsening of ≥5 to <10, and ≥10 to <15 and ≥15) for the study eye 
will be summarized by treatment group and visit. 
The shift from baseline in the NL-BCVA of the study eye categories (≥70, ≥60 - <70, ≥35 - <60, 
≥20 - <35, <20 ETDRS letters over time will be presented by treatment group and visit. 
The above-mentioned ETDRS letter thresholds are based on WHO definitions for vision impairment 
and blindness. WHO criteria were implemented in an attempt to capture the progressive nature of 
Geographic Atrophy and the ultimate treatment goal of avoiding successive vision impairment and 
blindness through application of active treatment (Pegcetacoplan vs. Sham).[1] 
The average NL-BCVA score over the last 3 months for each reporting period (Month 10 - Month 12 
for the Month 12 reporting; Month 22 - Month 24 for the Month 24 reporting) will be calculated for 
each subject who has at least one NL-BCVA assessment in these windows. The observed values for 
the NL-BCVA and changes from baseline will be summarized by treatment group for the study eye. 
Summaries will present the descriptive statistics for baseline, absolute values and change from 
baseline data. 
All NL-BCVA data will be listed for the ITT set.   
6.3.3. 
Sensitivity Analyses of Key Secondary Efficacy Endpoints 
The missing data analyses based on imputation described in Section 6.2.3.1 will be repeated for 
the key secondary efficacy endpoints at the time of the final study analysis for the full 24 months 
only. The key secondary endpoints will also be analyzed without pooling the two sham arms 
(SM and SEOM) for the full 24 months only. 
In addition, to assess the potential effect of different assessment tools, the main analysis of 
monocular maximum reading speed will be repeated by reading chart type. 
 
 
[1] approximated from 6/18; see https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1103667651  
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Maximum reading speed with adjustment for reading inaccuracy will also be analyzed, only in 
the study eye, for the first 12 months as well as the full 24 months. 
6.3.4. 
Supplementary Analyses of Key Secondary Efficacy Endpoints 
The supplementary analyses described for the primary endpoint in Section 6.2.4.1 and 
Section 6.2.4.2 will also be performed for the key secondary endpoints for the first 12 months as 
well as the full 24 months.  
In addition, the analysis of mean threshold sensitivity of all points will be repeated for the study 
eye excluding data not of acceptable quality for either the main or supplementary analysis, as 
identified by the reading center, per the Imaging Charter or where the fixation loss was > 20%. 
This analysis will be performed for the first 12 months as well as the full 24 months. 
6.3.5. 
Subgroup Analyses of Key Secondary Efficacy Endpoints 
The subgroup analyses of the key secondary endpoints will be performed for the full 24 months. 
Select subgroup analyses of the key secondary endpoints may be performed at Month 12, if 
necessary, to support regulatory filings. The subgroups evaluated for key secondary endpoints 
will be the same as evaluated for the primary efficacy endpoint (see Section 6.2.5). 
In addition, the following subgroup analyses will be performed: 
Monocular Maximum Reading Speed 
• Study eye baseline monocular maximum reading speed (<60, 60-<160, ≥160) 
• Study eye fixation stability (95% BCEA) categories (approximately tertiles) 
Mean FRI Index score 
• Baseline Study Eye Status (Better-seeing Eye vs. Worse-seeing Eye) 
• Study eye fixation stability (95% BCEA) categories (approximately tertiles) 
NL-BCVA 
• Study eye fixation stability (95% BCEA) categories (approximately tertiles) 
For each endpoint, a MMRM similar to that specified for the main analysis of the key secondary 
endpoints (Section 6.3.2) will be used for each subgroup analysis based on the data subset for the 
subject subgroup of interest. Baseline covariates included in the main analysis but no longer 
relevant given the subgroup of interest will be excluded from the model. The estimated treatment 
effects (PM vs. Sham or PEOM vs. Sham) and corresponding 95% CIs and p-values from the 
models will be displayed graphically for each pegcetacoplan arm and each level of the subgroups 
specified (e.g. via forest plots). 
6.4. 
Analyses of Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed in Section 2.2.3. At the time of the Month 12 
reporting, all secondary efficacy endpoints will be evaluated based on data from baseline to 
Month 12 (see Section 3.5). For the Month 12 analyses, post-baseline visits, up to and including 
Month 12, will be included. At the time of the final study analysis, all secondary efficacy 
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endpoints will be evaluated based on data from baseline to Month 24. For the Month 24 analyses, 
post-baseline visits, up to and including Month 24, will be included.  
Unless otherwise specified, all secondary efficacy endpoints will be analyzed for the mITT set.  
6.4.1. 
Low Luminance Best-Corrected Visual Acuity (LL-BCVA) 
LL-BCVA of the study eye will be summarized and analyzed in the similar fashion as the 
primary efficacy endpoint using MMRM described in Section 6.2.2. The model will include 
treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and baseline GA 
lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline LL-BCVA score as a covariate, 
time (in months) as a factor; the time × treatment interaction term as well as the baseline 
LL-BCVA score × time interaction term. Note, for the second year, only timepoints that were 
measured for all three treatment groups will be included in the model. 
The observed values for the LL-BCVA will be summarized by treatment group and visit for both 
the study and the fellow eye. Summaries will present the descriptive statistics for baseline, 
absolute values and change from baseline data. 
The mean change from baseline in the LL-BCVA score in the study eye ± the standard error as 
well as the LS mean of the change from baseline in the LL-BCVA score in the study eye ± the 
standard error will be plotted over time by treatment group. 
The categorical changes (improvements of ≥15, ≥10 to <15, ≥5 to <10, and minimal/no change 
(-4 to 4 ), worsening of ≥5 to <10, and ≥10 to <15 and ≥15) for the study eye will be summarized 
by treatment group and visit. 
Additionally, the average LL-BCVA score over the last 3 months for each reporting period 
(Month 10 - Month 12 for the Month 12 reporting; Month 22 - Month 24 for the Month 24 
reporting) will be calculated for each subject who has at least one LL-BCVA assessment in these 
windows. The observed values for the LL-BCVA and changes from baseline will be summarized 
by treatment group for the study eye. Summaries will present the descriptive statistics for 
baseline, absolute values and change from baseline data.  
The same subgroup analyses as described for NL-BCVA in Section 6.3.5 will also be repeated 
for LL-BCVA for the full 24 months. 
All LL-BCVA data will be listed for the ITT set. In addition, the low luminance deficit will be 
calculated as the difference between NL-BCVA and LL-BCVA and listed for the ITT set. 
6.4.2. 
Total Area of GA lesion(s) at each planned assessment 
The change from baseline at each planned assessment (other than Month 12 and Month 24) in the 
total area of GA lesion(s) in the study eye, as assessed by FAF, will be estimated from the 
MMRM analyses described in Section 6.2.2. 
6.4.3. 
Monocular critical print size 
Critical print size will be calculated as the smallest print size which support reading speed at 
80% of the maximum reading speed, without adjustment for reading inaccuracy 
(Baskaran et al. 2019). 
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Monocular critical print size of the study eye will be summarized and analyzed in a similar 
fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. The model 
will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and 
baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline monocular critical 
print size as well as the chart type (MNRead or Radner) as covariates, time (in months) as a 
factor; the time × treatment interaction term as well as the baseline monocular critical print size 
× time interaction term. 
The observed values for the monocular critical print size will be summarized by treatment group 
and visit for both the study and the fellow eye. Summaries will present the descriptive statistics 
for baseline, absolute values and change from baseline data. 
To assess the potential effect of different assessment tools, the analysis of monocular critical 
print size will be repeated by chart type. 
All monocular critical print size data will be listed for the ITT set. 
6.4.4. 
NEI VFQ-25 Distance Activity Subscale Score  
NEI VFQ-25 distance activity subscale score will be calculated per the scoring algorithms in 
user’s manual. 
NEI VFQ-25 distance activity subscale score will be summarized and analyzed in a similar 
fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. The model 
will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and 
baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline NEI VFQ-25 
distance activity subscale score and baseline study eye status (Better-seeing Eye vs. 
Worse-seeing Eye) as covariates, time (in months) as a factor; as well as the time × treatment 
interaction term as well as the baseline NEI VFQ-25 distance activity subscale score × time 
interaction term. 
The observed values for the NEI VFQ-25 distance activity subscale score will be summarized by 
treatment group and visit. Summaries will present the descriptive statistics for baseline, absolute 
values and change from baseline data. 
The categorical changes (improvements of >5 units and minimal/no change (-5 to 5), worsening 
of a decrease of >5 units) will be summarized by treatment group and visit. 
In addition, the shift from baseline in NEI VFQ-25 distance activity subscale score categories 
(>80, >65 - ≤80, >50 - ≤65, ≥35 - ≤50, <35) will be summarized by treatment group and visit. 
All NEI VFQ-25 data will be listed for the ITT set. 
6.4.5. 
Macular Functional Response based on Microperimetry 
The number of scotomatous points will be determined from the mesopic microperimetry as an 
assessment of the macular functional response. 
Number of scotomatous points in the study eye will be summarized and analyzed in a similar 
fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. The model 
will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye (yes or no), and 
baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; baseline number of 
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scotomatous points as a covariate, time (in months) as a factor; the time × treatment interaction 
term as well as the number of scotomatous points × time interaction term. 
The observed values for number of scotomatous points will be summarized by treatment group 
and visit for both the study and the fellow eye. Summaries will present the descriptive statistics 
for baseline, absolute values and change from baseline data. 
The mean change from baseline for number of scotomatous points in the study eye ± the standard 
error as well as the LS mean of the change from baseline for number of scotomatous points in the 
study eye ± the standard error will be plotted over time by treatment group. 
The analysis described above will also be repeated for the change from baseline in the mean 
threshold sensitivity of perilesional points over time.  
Data not of acceptable quality for the main analysis, as identified by the reading center as per the 
Imaging Charter, will not be included in these analyses. 
6.5. 
Multiplicity Adjustment 
No hypothesis testing of the (non-key) secondary endpoints will be performed. Control of Type I 
error for (non-key) secondary endpoints is not applicable. 
6.6. 
Analyses of Exploratory Endpoints  
The exploratory efficacy endpoints are listed in Section 2.2.4. At the time of Month 12 reporting, 
all exploratory efficacy endpoints will be evaluated based on data from baseline to Month 12 
(see Section 3.5). For the Month 12 analyses, post-baseline visits, up to and including Month 12, 
will be included. At the time of the final study analysis, all exploratory efficacy endpoints will be 
evaluated based on data from baseline to Month 24. For the Month 24 analyses, post-baseline 
visits, up to and including Month 24, will be included.  
Unless otherwise specified, all exploratory efficacy endpoints will be analyzed for the mITT set. 
6.6.1. 
Other Microperimetry Endpoints 
In addition to the analyses performed in Sections 6.3.2.1, 6.3.2.4, and 6.4.5, the following 
analyses will be performed for microperimetry. 
• Change from baseline in the fixation stability (95% BCEA) over time. 
• Change from baseline in the mean threshold sensitivity of paralesional points over 
time. 
• Change from baseline in the mean threshold sensitivity of extralesional points over 
time. 
• Number of points with a clinically significant progression (number of points with a 
≥ 4 dB decrease from baseline for points ≥3 dB at baseline) over time. 
These endpoints except for the last endpoint in the study eye will be summarized and analyzed in 
a similar fashion as the primary efficacy endpoint using MMRM described in Section 6.2.2. 
The model will include treatment (PM, PEOM, Sham), presence of CNV in the fellow eye 
(yes or no), and baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as fixed effects; the baseline 
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value of the endpoint as a covariate, time (in months) as a factor; as well as the time × treatment 
interaction term as well as the baseline value of the endpoint × time interaction term. 
The observed values for the endpoints will be summarized by treatment group and visit for both 
the study and the fellow eye. Summaries will present the descriptive statistics for baseline, 
absolute values and change from baseline data. 
The mean change from baseline for each endpoint in the study eye ± the standard error as well as 
the LS mean of the change from baseline for each endpoint in the study eye ± the standard error 
will be plotted over time by treatment group. 
Data not acceptable quality for the main analysis as identified by the reading center per the 
Imaging Charter, will not be included in these analyses. 
6.6.2. 
NEI VFQ-25 and NEI VFQ-39 Additional Analyses 
Descriptive summary statistics for baseline, absolute values and change from baseline data will be 
provided by treatment group and visit for the following NEI VFQ-25 and NEI VFQ-39 scores: 
• NEI VFQ-39 distance activity subscale 
• NEI VFQ-25 composite score 
• NEI VFQ-39 composite score 
• NEI VFQ-25 near activity subscale score  
• NEI VFQ-39 near activity subscale score  
• NEI VFQ-25 driving subscale score (for subjects who are currently driving at 
baseline) 
The shift from baseline in NEI VFQ score categories (>80, >65 - ≤80, >50 - ≤65, ≥35 - ≤50, 
<35) will be summarized by treatment group and visit for the scores described above. 
In addition, the categorical changes (improvements of >5 units and minimal/no change (-5 to 5), 
worsening of a decrease of >5 units) will be summarized by treatment group and visit for the 
following NEI VFQ-25 Scores: Composite and Near Activity. 
For the NEI VFQ-25 Driving subscale score, the number and percentage of subjects with a 
worsening driving outcome compared to baseline will be summarized by treatment group and 
visit. Each visit will display the number of patients who were driving at baseline with at least one 
of the worsening driving outcomes. The categories to determine worsening driving outcomes are: 
conversion to no longer currently driving, increase in difficulty driving in familiar places in 
daytime, increase in difficult driving at night or stopped doing this due to vision, increase in 
difficulty driving in difficult conditions or stopped doing this due to vision.  
All NEI VFQ-25 data will be listed for the ITT set. 
6.6.3. 
Binocular Maximum Reading Speed and Critical Print Size 
Descriptive summary statistics for baseline, absolute values and change from baseline data will 
be provided by treatment group and visit for the binocular maximum reading speed and critical 
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print size with no adjustment for reading inaccuracy. All binocular maximum reading speed and 
critical print size data will be listed for the ITT set. 
Categorical changes over time and categorical shifts from baseline will be presented, as will be 
done for the monocular reading speed. 
6.6.4. 
GA Lesion (s) Study Eye to Fellow Eye Comparisons 
Descriptive summary statistics will be provided by treatment and visit for the change from 
baseline in total area of GA Lesion(s) for the study eye as well as for the fellow eye in subjects 
with bilateral GA with fellow eyes that satisfy the following characteristics at baseline: 
• Absence of CNV in the medical history 
• Baseline GA lesion size between 2.5 and 17.5 mm2 
• Presence of any pattern of hyperautofluorescence in the junctional zone of GA  
• GA not confluent with any peripapillary atrophy 
The change from baseline in total area of GA Lesion(s) ± the standard error in the study eye as 
well as the fellow eye will be plotted over time by treatment group for the subjects with bilateral 
GA with fellow eyes that satisfy the above characteristics. 
6.6.5. 
Digital Reading Index and Visual Function Application 
The digital reading index will only be analyzed at the Month 24 reporting while the digital visual 
functional application will be analyzed at both the Month 12 and Month 24 reporting. 
Descriptive summary statistics for baseline, absolute values and change from baseline data to 
Month 12 and Month 24 will be provided by treatment group for digital reading index.  
Additionally, the average digital reading index score over the last 3 months for each reporting 
period (Month 10 - Month 12 for the Month 12 reporting; Month 22 - Month 24 for the Month 
24 reporting) will be calculated for each subject who has at least one digital reading index 
assessment in these windows. The observed values for the digital reading index and changes 
from baseline will be summarized by treatment group. Summaries will present the descriptive 
statistics for baseline, absolute values and change from baseline data.  
Descriptive summary statistics for baseline, absolute values and change from baseline data to 
Month 12 and Month 24 will be provided by treatment group for digital visual function.  
Additionally, the average digital visual function score over the last 3 months for each reporting 
period (Month 10 - Month 12 for the Month 12 reporting; Month 22 - Month 24 for the Month 
24 reporting) will be calculated for each subject who has at least one digital visual function 
assessment in these windows. The observed values for the digital visual function and changes 
from baseline will be summarized by treatment group. Summaries will present the descriptive 
statistics for baseline, absolute values and change from baseline data. 
6.6.6. 
Genetic Polymorphisms 
The genetic polymorphisms data will be analyzed and reported in a separate report and briefly 
summarized in the clinical study report (CSR). The genetic polymorphisms data will be listed for 
the genotyping set. 
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6.6.7. 
Dry AMD Analysis 
Biomarkers of early and intermediate stage of AMD outside the GA area will also be evaluated 
in this study. The number and percentage of subjects with at least one lesion (up to 5) area in the 
study eye classified as iRORA will be summarized at baseline by treatment group in the mITT 
set. The number and percentage of subjects with a progression from iRORA to cRORA based on 
SD-OCT in the study eye will be summarized over time by treatment group. A CMH test with 
the number of baseline iRORA lesions (0, 1, 2, 3, 4, ≥ 5), presence of CNV in the fellow eye 
(yes or no), and baseline GA lesion area (< 7.5 mm2 or ≥ 7.5 mm2) as the stratification factors 
will be presented for each post-baseline visit. If necessary due to sparse cells, an unadjusted 
analysis may be performed. In addition, the percentage of baseline lesions with a progression 
will also be presented over time by treatment group. 
The above summary and analysis will also be repeated in those subjects with at least one lesion 
in the study eye classified as large drusen at baseline and whether these progressed to iRORA or 
cRORA in the study eye. Large drusen is defined as a drusen that is greater than or equal to 40 
microns in height on SD-OCT. 
This analysis will not be conducted at the Month 12 reporting and will only be conducted for the 
final study reporting.  
All dry AMD data will be listed for the ITT set. 
6.6.8. 
Analyses of Other Ophthalmology Efficacy Imaging Data  
In addition to the GA lesion(s) size data from the FAF, analysis of additional efficacy parameters will 
be performed from this imaging instrument for the mITT set. The following summaries will be 
performed separately by study eye and by fellow eye and will be presented by treatment group. 
• Descriptive summary statistics for baseline, absolute values and change from baseline 
data for the distance of GA lesion from atrophy junction to the fovea in study eyes 
with non-subfoveal involvement of the GA lesion at baseline (assessed from FAF). 
For the fellow eye, this will be presented for fellow-eyes with non-subfoveal 
involvement of the GA lesion at baseline. Non-subfoveal involvement is defined as 
distance of the atrophy junction to the fovea > 0. 
• Conversion from non-subfoveal involvement to subfoveal involvement of the GA 
lesion at each visit (assessed from FAF). This will include only study eyes with 
non-subfoveal involvement for GA lesions at baseline. For the fellow eye, this should 
be presented for fellow eyes with non-subfoveal involvement at baseline. This will be 
presented as a cumulative incidence at each scheduled visit. 
All FAF data will be listed for the ITT set. 
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7. 
SAFETY ANALYSES  
Safety analyses will be performed using the Safety set. Safety variables include adverse events 
(AEs), deaths, clinical laboratory results, vital signs, incidence of ADA against pegcetacoplan, 
ocular assessments (e.g., NL-BCVA, IOP and ophthalmic examinations), and ocular imaging.  
At the time of the Month 12 reporting, safety summaries will be produced based on the complete 
Month 12 data. At the time of the final study reporting, safety summaries will be produced based 
on cumulative data. 
For each safety variable, the last value collected before the first dose of investigational product 
will be used as baseline for all analyses of that safety variable. Last Observed Value (LOV) will 
be defined as the last valid assessment obtained after baseline. The LOV will be presented for the 
Month 12 reporting as well as the final study reporting. 
All safety analyses will be conducted according to the actual treatment the subject received. 
Unless otherwise specified, all safety summaries will be performed on the Safety set. 
7.1. 
Adverse Events  
AEs will be coded using the MedDRA version 23.1 and summarized separately for those 
occurred in the study eye, those in the fellow eye, and the non-ocular events.  
An AE will be considered a TEAE if it has a start date on or after the first dose of investigational 
product or if it has a start date before the date of the first dose of investigational product but 
increases in severity on or after the date of the first dose of investigational product.  
An overall summary of the number of subjects with TEAEs will be presented, including the 
number and percentage of subjects with: 
• Any TEAEs 
• TEAEs related to study drug (evaluated by the investigator as definitely related, 
possibly related) 
• TEAEs related to study drug injection procedure 
• All TEAEs by maximum severity 
• Serious TEAEs 
• Serious TEAEs related to study drug (evaluated by the investigator as definitely 
related, possibly related) 
• Serious TEAEs related to study drug injection procedure 
• Serious TEAEs by maximum severity 
• TEAEs leading to interruption of study treatment 
• TEAEs leading to discontinuation of study treatment 
• TEAEs leading to study discontinuation 
• TEAEs leading to death 
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This overall summary will also include the total number of TEAEs reported. This overall 
summary will also be summarized separately for those occurred in the study eye, those in the 
fellow eye, and the non-ocular events.  
The number and percentage of subjects reporting TEAEs in each treatment group and overall 
will be tabulated by SOC and PT for all of the categories in the list above. If more than 1 AE 
occurs with the same preferred term for the same subject, then the subject will be counted only 
once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to investigational product. 
Endophthalmitis and intraocular inflammation ocular TEAEs will be presented by PT for study 
eye and fellow eye. 
Endophthalmitis and intraocular inflammation ocular TEAEs in the study eye will also be 
presented on a per-injection basis (i.e., number of events/total number of injections given).  
All SOC and PT summaries will be ordered alphabetically by SOC and within SOC, by 
descending order of the total number of subjects in the PM, PEOM, and Sham groups combined. 
Non-ocular AEs, ocular AEs in the study eye and ocular AEs in the fellow eye will be listed 
separately. This presentation will be repeated for serious AEs. Additionally, separate listings for 
deaths, AEs leading to discontinuation of study, AEs leading to discontinuation of study drug, 
and AEs due to COVID-19 will also be generated.  
7.1.1. 
TEAEs of New Onset Exudative AMD 
For subjects who experience a TEAE of “Choroidal neovascularization” or “Neovascular AMD” 
(“Exudative AMD TEAE”), the following summaries will be performed: 
• The overall summary table described in Section 7.1 will be repeated replacing 
“TEAEs” with “Exudative AMD TEAEs”. This will be reported for the study eye.  
• The incidence of Exudative AMD TEAEs in the study eye will be presented by 
treatment group and overall. In addition, the analysis will be repeated by fellow eye 
CNV status at baseline and study eye DLS on SD-OCT at baseline. A similar analysis 
will be repeated for the Exudative AMD TEAEs in the fellow eye with an additional 
analysis by fellow eye DLS on SD-OCT at baseline. Subjects with a medical history 
of CNV in the corresponding eye will be excluded from the analysis. 
• The incidence and rate per 100 subject-years of Exudative AMD TEAEs in the study 
and fellow eye as well as a summary (for study and fellow eye) and Kaplan Meier 
plot for the time to development of Exudative AMD TEAEs in the study eye will be 
presented by treatment group and overall. Subjects with a medical history of CNV in 
the corresponding eye will be excluded from the analysis. 
• In addition, the characteristics of the Exudative AMD TEAEs in the study eye will be 
presented at baseline, study visit preceding exudation, study visit at exudation and at 
Month 12 (or Month 24 if the final analysis) for characteristics based on SD-OCT and 
baseline, study visit at exudation and at Month 12 (or Month 24 if the final analysis) 
for characteristics based on Fluorescein Angiography (FA). The following 
characteristics will be presented by treatment group and overall: 
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o Presence of cystoid spaces on SD-OCT 
o Central (center point) retinal thickness on SD-OCT 
o Central subfield thickness on SD-OCT 
o Presence of CNV on FA. 
o CNV type on FA 
o Presence of subretinal fluid on SD-OCT 
• A summary of concomitant anti-VEGF therapy for new exudative AMD in the study 
eye will be provided by treatment group and overall. This summary will include the 
total number of subjects that received any anti-VEGF for new exudative AMD as 
well as the average number of injections per month post exudative AMD. There will 
also be a breakdown by preferred term of ranibizumab or aflibercept and the average 
number of injections per month for each term. Subjects will be presented by the 
number of injections received for that medication.  
• BCVA scores at the baseline visit, study visit preceding exudation, the study visit at 
the exudation, and at Month 12 (or Month 24 if the final analysis) will be presented 
for all subjects with an Exudative AMD TEAE in the study eye by treatment group 
and overall. In addition, the change in BCVA scores from baseline, the visit prior to 
the exudation, and the exudation visit will be presented where appropriate. 
A listing of Exudative AMD TEAEs and baseline characteristics including fellow eye CNV 
status, study eye double layer sign and study eye MNV presence, a listing of the characteristics 
of the new Exudative AMD TEAEs, anti-VEGF exposure, and the BCVA values for subjects 
with the new Exudative AMD TEAEs will be provided. 
7.2. 
Clinical Laboratory Data 
All laboratory parameters collected at each center’s local laboratory will be normalized by 
converting values in original units to values in SI units and classified as normal, low, or high 
based on normal ranges supplied by the local laboratories and upon employing standardization.  
Observed and change from baseline clinical laboratory data (hematology, chemistry and 
urinalysis) will be summarized by treatment group and protocol specified time points for the 
following clinical laboratory variables.  
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white blood cell 
count (WBC) – total and differential. 
Biochemistry 
Aspartate transaminase, alanine transaminase, alkaline phosphatase, sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen (BUN), bilirubin (total, 
direct and indirect), creatinine, creatine kinase, glucose, and albumin. 
Urinalysis 
Glucose, specific gravity, blood, ketones, protein, bilirubin, pH, urobilinogen, 
leukocyte esterase, and nitrite. 
Clinical laboratory test values are potentially clinically significant (PCS) if they meet either the 
low or high PCS criteria listed in Table 3. The number and percentage of subjects with baseline 
and/or post-baseline PCS values will be tabulated by treatment group and overall. 
The percentages will be calculated relative to the number of subjects with available values for 
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each lab parameter in each treatment group at the analysis visit. The numerator is the total 
number of subjects with at least 1 PCS value at the analysis visit. A supportive listing of subjects 
with post-baseline PCS values will be provided including the subject number, site, baseline, and 
post-baseline values.  
Table 3: 
Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Biochemistry 
Albumin 
g/L 
<25 g/L 
 
Alanine Aminotransferase (ALT) 
U/L 
 
≥3*ULN 
Alkaline Phosphatase (ALP) 
U/L 
 
≥3*ULN 
Aspartate Aminotransferase (AST) 
U/L 
 
≥3*ULN 
Bilirubin, Direct 
umol/L 
 
>1.5*ULN 
Bilirubin, Total 
umol/L 
 
>1.5*ULN 
Bicarbonate 
mmol/L 
<LLN 
 
Blood Urea nitrogen 
mmol/L 
 
>2.5*ULN 
Chloride 
mmol/L 
<90 mmol/L 
>115mmol/L 
Creatinine 
umol/L 
 
≥178.8 umol/L 
Creatine kinases 
U/L 
 
≥3*ULN 
Glucose 
mmol/L 
<3.05 mmol/L 
≥8.88 mmol/L 
Potassium 
mmol/L 
<3.5 mmol/L 
>5.5 mmol/L 
Sodium 
mmol/L 
<130 mmol/L 
>150 mmol/L 
Hematology 
Hemoglobin 
g/L 
<0.9*LLN 
 
Hematocrit 
% 
<0.9*LLN 
 
Platelet Count 
10^9/L 
<LLN 
 
Urinalysis 
Specific Gravity 
 
<0.9*LLN 
>1.1*ULN 
pH 
 
<LLN 
 
Protein 
 
 
>2+ 
Glucose 
 
 
>1+ 
Blood 
 
 
>2+ 
LLN: Lower limit of normal value provided by the laboratory 
ULN: Upper limit of normal value provided by the laboratory 
Descriptive statistics will be used for continuous data and frequency counts and percentages for 
categorical data. A shift table from baseline, by treatment group and protocol specified time 
points, of normal, abnormal low, and abnormal high records will also be summarized for 
hematology and chemistry data with marginal totals using frequency counts and percentages. 
All laboratory data will be listed for the safety set. 
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7.3. 
Vital Signs 
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, respiratory rate, 
temperature, and pulse rate) and their changes from baseline at each post-baseline visit will be 
presented by treatment group and overall.  
Vital sign values will be considered PCS if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 4. The number and percentage of subjects with PCS 
baseline and/or post-baseline values will be tabulated by treatment group and overall. 
The percentages will be calculated relative to the number of subjects with values for each vital 
sign parameter in each treatment group at the analysis visit. The numerator is the total number of 
subjects with at least 1 PCS vital sign value at the analysis visit. A supportive listing of subjects 
with post-baseline PCS values will be provided including the subject number, site, baseline, and 
post-baseline PCS values.  
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Systolic blood pressure 
(mmHg) 
High 
≥180 
Increase of ≥20 
Low 
≤90 
Decrease of ≥20 
Diastolic blood pressure 
(mmHg) 
High 
≥105 
Increase of ≥15 
Low 
≤50 
Decrease of ≥15 
Pulse rate 
(beats per minute) 
High 
≥120 
Increase of ≥15 
Low 
≤50 
Decrease of ≥15 
a A post-baseline value is considered as a PCS value if its meets both criteria for observed value and change from baseline. 
All vital signs data will be listed for the safety set. 
7.4. 
Physical Examination Findings 
Any relevant findings from the baseline physical examination are to be reported on the medical 
history. Any relevant findings from the post-baseline physical examination are to be reported as 
AE’s. No separate physical examination findings were collected to summarize. 
7.5. 
Complete Ophthalmic Exam 
Results of the ocular assessments will be summarized by shift tables showing the shift from 
baseline in the individual slit-lamp examination and indirect ophthalmoscopy endpoint. 
These will be provided by treatment group, overall and visit for study eye and fellow eye. 
The visits to be presented are Month 12, Month 24, and LOV. 
Any relevant findings from the post-baseline ophthalmic examination are to be reported as AEs. 
The change from baseline in chronic (first measurement of the day) IOP will be summarized 
over time by treatment group. In addition, the incidence of IOP above specified thresholds 
(i.e., >21 mmHg at pre-injection/chronic (first measurement of the day); >30 mmHg post 
injection) will be summarized by treatment group and overall, protocol specified timepoint 
(at Month 12 and Month 24 readout, respectively) and over the whole study. 
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The mean change from baseline in the chronic IOP ± the standard error will be plotted over time 
by treatment group.  
Details of the ocular assessments will be provided in listings for the safety set and for IOP, the 
ITT set. 
7.6. 
NL-BCVA 
The number and percentage of subjects who lost letters compared with baseline at each visit 
based on NL-BCVA in the study and fellow eye will be presented. The three categories are 
>=15, ≥15- < 30 and ≥30 ETDRS letters.  
7.7. 
Other Ophthalmology Imaging Assessments 
Unless otherwise stated, ocular imaging data collected will be listed by treatment group and 
overall for the Safety set. The summary will be performed separately by study eye and by fellow 
eye. The ophthalmology imaging assessments performed in this study include the following: 
• Digital Color Fundus Photographs (DCFP) 
o Shift from baseline in the presence/absence of hemorrhage at each visit 
• FA 
o The following analyses will be performed in all study eyes and in non-study 
eyes without a history of CNV at baseline (in medical history) in the 
corresponding eye. 
 Incidence of new CNV. This will be summarized as the cumulative 
number of CNV events by each visit and the cumulative incidence by that 
visit based on Kaplan Meier methods.  
 Incidence of new CNV by type (classic, occult, classic & occult, disciform 
scar) at first emergence will be summarized at each visit for the 
cumulative number of events. 
 Total CNV size (diameter) at first emergence will be summarized at each 
visit for the cumulative number of events. 
• SD-OCT 
o Descriptive statistics on central subfield thickness at each visit 
o Plot of the mean change from baseline in central subfield thickness in the 
study eye ± the standard error over time by treatment group. 
o Descriptive statistics on central (center point) retinal thickness at each visit 
o Shift from baseline in the presence/absence of subretinal fluid at each visit 
o Shift from baseline in the presence/absence of cystoid spaces at each visit 
• Specular Microscopy 
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o Endothelial Cell Count is assessed using specular microscopy, and the change 
from baseline in cell density (cells/mm2) as well as the change from baseline 
in average cell-size will be summarized with descriptive statistics. 
• OCT-A 
o Incidence of subclinical CNV (referred to as MNV in the datasets) determined 
by OCT-A in eyes without previous CNV reported in the medical history or as 
an adverse event in the corresponding eye at each visit.  
In addition, the following summary of suspected and reading-center confirmed CNV cases will 
be presented by treatment group. This will be presented separately for the study eye only. 
• The number and percentage of subjects with an Exudative AMD TEAE on or before 
Month 12 (or Month 24 if the final analysis) 
• The number and percentage of subjects with at least one suspected new onset CNV 
case submitted to the reading center by the Investigator post-baseline through 
Month 12 (or Month 24 if the final analysis) 
• The number and percentage of subjects with a reading-center confirmed new onset 
CNV case (out of the suspected CNV cases submitted by the Investigator) 
post-baseline through Month 12 (or Month 24 if the final analysis). Reading-center 
confirmed CNV case is identified as either: 
o Presence of CNV on FA (Type = classic, occult, classic & occult, disciform 
scar) OR 
o Presence of CNV thickness on SD-OCT 
• The number and percentage of subjects with a reading-center confirmed new onset 
CNV case (out of the suspected CNV cases submitted by the Investigator) 
post-baseline through Month 12 (or Month 24 if the final analysis) and also reported 
as an Exudative AMD TEAE. 
• The number and percentage of subjects with a reading-center confirmed new onset 
CNV case (out of the suspected CNV cases submitted by the Investigator) 
post-baseline through Month 12 (or Month 24 if the final analysis) without an 
Exudative AMD TEAE ever reported. 
• The number and percentage of subjects with at least one suspected CNV case, 
confirmed by the reading-center but previously reported as an Exudative AMD 
TEAE. 
• The number and percentage of subjects with at least one suspected CNV case, not 
confirmed by the reading-center but still reported as an Exudative AMD TEAE. 
• The number and percentage of subjects with a reading-center finding of presence of 
new-onset CNV (defined in the same way as a confirmed new onset CNV case) 
without any other submission to the reading center of a suspected case post-baseline 
through Month 12 (or Month 24 if the final analysis) and also reported as an 
Exudative AMD TEAE on or before Month 12 (or Month 24 if the final analysis)  
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• The number and percentage of subjects with a reading-center finding of presence of 
new-onset CNV (defined in the same way as a confirmed new onset CNV case) 
without any other submission to the reading center of a suspected case post-baseline 
through Month 12 (or Month 24 if the final analysis) and no report of an Exudative 
AMD TEAE. 
• The number and percentage of subjects with Exudative AMD TEAE and without a 
suspected case submitted to the reading center as well as without a reading center finding 
of new-onset CNV (defined in the same way as a confirmed new onset CNV case).  
7.8. 
Immunogenicity 
Immunogenicity data will be listed separately for anti-pegcetacoplan peptide antibody and anti-
PEG antibody results. The number and percentage of samples confirmed positive for ADA 
response will be summarized by treatment groups (i.e., PM, PEOM, and Sham). The number and 
percentage of subjects with treatment-emergent and treatment-boosted responses will be 
presented by treatment group. Treatment emergent response is defined as a confirmed positive 
antibody result postdose after a negative antibody result reported at baseline. Treatment-boosted 
response is defined as a ≥4-fold increase in titer from the baseline level. 
7.9. 
Death 
Subject deaths and primary cause of death will be summarized. 
7.10. 
Other Safety Data 
Urine pregnancy test will be provided in a listing. 
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8. 
PHARMACOKINETICS ANALYSIS 
No pharmacokinetic analyses are planned for this study. 
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9. 
PHARMACODYNAMIC ANALYSES 
No pharmacodynamic analyses are planned for this study. 
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10. 
OTHER ANALYSES 
No other analyses are planned for this study. 
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11. 
INTERIM ANALYSIS  
No formal interim analyses are planned for this study.  
To support regulatory submissions, data cuts of the Month 12 – Month 24 data of the study may 
be taken prior to the final database lock and summarized prior to the final study reporting. 
The analysis of this data will not be used to modify the pre-planned analyses of this study. 
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12. 
DATA MONITORING COMMITTEE  
An external, independent DMC reviews unmasked data across the conduct of the study 
approximately every 6 months. A charter for the DMC as well as a DMC statistical analysis plan 
was prepared separately. 
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13. 
 DATA HANDLING CONVENTIONS  
13.1. 
General Data Reporting Conventions  
Continuous variables will be summarized using the number of non-missing observations (n), 
mean, SD, median, quartile 1, quartile 3, minimum, and maximum. Categorical variables will be 
summarized using frequencies and percentages. Unless stated otherwise, for all percentages, the 
number of subjects in the analysis population for the treatment group will be the denominator. 
Unless otherwise specified, the estimated mean and median for a set of values should be printed 
out to 1 more decimal place than the original values, and standard deviations should be printed 
out to 2 more decimal places than the original values. The minimum and maximum should report 
the same number of decimal places as the original values. Percentages will be displayed with 
1 decimal place; except percentages will not be presented when the count is zero and 100% will 
be presented as an integer. 
13.2. 
Definition of Baseline  
Unless stated otherwise, baseline will be defined as the last available pre-treatment value taken 
on or before the first dose date of study drug, and will be used for summary of baseline 
characteristics, as well as for all change-from-baseline analyses of efficacy and safety endpoints. 
13.3. 
Definition of Relative Study Days 
Unless otherwise noted, relative study days (Rel Days) of an evaluation are defined as number of 
days relative to the first dose date of study drug which is designated as Day 1, and the preceding 
day is Day -1, the day before that is Day -2, etc.  
If evaluation date is on or after first dose date, then relative study days are calculated as  
Evaluation date - first dose date of study drug + 1.  
If evaluation date is before first dose date, then relative study days are calculated as  
Evaluation date - first dose date of study drug  
Relative study days take negative values if evaluation date occurs prior to first dose date and take 
positive values if evaluation date occurs on or after first dose date of study drug. 
13.4. 
Definition of Visit Windows  
13.4.1. 
All Assessments Except Microperimetry 
All assessments occurring on or before the first date of dosing (Analysis Study Day (ADY) ≤ 1) 
will be assigned to the Baseline analysis visit window. 
Unless otherwise specified, the actual scheduled nominal post-baseline visit will be used for over 
time summaries. Post-baseline unscheduled visits and early termination visits will be mapped to 
a scheduled visit and will only be used in the analysis if the nominal scheduled visit result is 
missing, Table 5 and Table 6 presents the analysis visit window mapping for unscheduled and 
early term visits. In the case that multiple unscheduled or early termination visits are in the same 
analysis window, the one closest to the target date will be used. In the event that windowed visit 
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is mapped to an illogical sequence of visits when considering nearby scheduled visits 
(i.e., windowed visit is higher than the subsequent visit or lower than the preceding visit), 
the windowed visit will be set to the logical scheduled visit. 
Table 5: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: All Assessments Except Microperimetry: Monthly 
Regimen 
Analysis  
Visit 
Target 
Study Day 
Analysis Window 
(days) 
Month 1 
30 
2 to 45 
Month 2 
60 
46 to 75 
Month 3 
90 
76 to 105 
Month 4 
120 
106 to 135 
Month 5 
150 
136 to 165 
Month 6 
180 
166 to 195 
Month 7 
210 
196 to 225 
Month 8 
240 
226 to 255 
Month 9 
270 
256 to 285 
Month 10 
300 
286 to 315 
Month 11 
330 
316 to 345 
Month 12 
360 
346 to 375 
Month 13 
390 
376 to 405 
Month 14 
420 
406 to 435 
Month 15 
450 
436 to 465 
Month 16 
480 
466 to 495 
Month 17 
510 
496 to 525 
Month 18 
540 
526 to 555 
Month 19 
570 
556 to 585 
Month 20 
600 
586 to 615 
Month 21 
630 
616 to 645 
Month 22 
660 
646 to 675 
Month 23 
690 
676 to 705 
Month 24 
720 
706 to EOS 
 
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Table 6: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: All Assessments Except Microperimetry: Every Other 
Month Regimen 
Analysis  
Visit 
Target 
Study Day 
Analysis Window 
(days) 
Month 1 
30 
2 to 45 
Month 2 
60 
46 to 75 
Month 3 
90 
76 to 105 
Month 4 
120 
106 to 135 
Month 5 
150 
136 to 165 
Month 6 
180 
166 to 195 
Month 7 
210 
196 to 225 
Month 8 
240 
226 to 255 
Month 9 
270 
256 to 285 
Month 10 
300 
286 to 315 
Month 11 
330 
316 to 345 
Month 12 
360 
346 to 375 
Month 14 
420 
376 to 450 
Month 16 
480 
451 to 510 
Month 18 
540 
511 to 570 
Month 20 
600 
571 to 630 
Month 22 
660 
631 to 690 
Month 24 
720 
690 to EOS 
13.4.2. 
Microperimetry Assessments 
All assessments occurring on or before the first date of dosing (Analysis Study Day (ADY) ≤ 1) 
will be assigned to the Baseline analysis visit window. 
Unless otherwise specified, the actual scheduled nominal post-baseline visit will be used for over 
time summaries unless a better assessment, as determined by the reading center, is within the 
analysis window. Post-baseline unscheduled visits and early termination visits will be mapped to 
a scheduled visit and will only be used in the analysis if the nominal scheduled visit result is 
missing, not suitable for analysis by the reading center, or the assessment was assessed as better 
than the nominal scheduled visit by the reading center, Table 7 presents the analysis visit 
window mapping for unscheduled and early term visits. In the case that multiple unscheduled or 
early termination visits are in the same analysis window, the one closest to the target date will be 
used. In the event that windowed visit is mapped to an illogical sequence of visits when 
considering nearby scheduled visits (i.e., windowed visit is higher than the subsequent visit or 
lower than the preceding visit), the windowed visit will be set to the logical scheduled visit. 
Table 7: 
Post-Baseline Analysis Visit Window for Unscheduled and Early 
Termination Visits: Microperimetry Assessments 
Analysis  
Visit 
Target 
Study Day 
Analysis Window 
(days) 
Month 6 
180 
2 to 270 
Month 12 
360 
271 to 450 
Month 18 
540 
451 to 630 
Month 24 
720 
631 to EOS 
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13.5. 
Derived Efficacy Endpoints  
13.5.1. 
GA Lesion Size 
For all independent ophthalmic assessments (performed by DARC laboratory), which includes 
GA lesion size, if assessments by only two independent readers are available, then the median of 
the 2 readings will be used in the calculation of summary statistics. If assessments by three 
independent readers are available, then the median of the three readings will be used for the 
summary calculations. 
In the case that the GA lesion size has an indeterminate boundary noted, then the lesion size for 
this indeterminate boundary will be used in all analyses of GA lesion size unless otherwise noted 
in the case that primary lesions size assessment for an individual reader is missing.  
13.5.2. 
MNRead Reading Chart 
13.5.2.1. Reading Speed 
13.5.2.1.1. Without adjustment for reading inaccuracy 
Any print size with “Not Done” will have the associated wpm marked as 0. 
Reading speed (wpm) = 600 / (reading time in seconds) 
If reading speed >300 wpm, reading speed = 300. 
13.5.2.1.2. With adjustment for reading inaccuracy 
Any print size with “Not Done” will have the associated wpm marked as 0. 
Reading speed (wpm) = 60 (10 – errors) / (reading time in seconds) 
If reading speed >300 wpm, reading speed = 300. 
If 10 or more errors were made in a sentence (implying wpm<0), then the reading speed for that 
sentence can be assumed to be zero (wpm).  
13.5.2.2. Maximum reading speed 
Maximum reading speed will be calculated as the mean of the three highest nonzero reading 
speeds (or 2 or 1 if that is all that exists). For subjects having all wpm values = 0, the maximum 
reading speed will be set to 0, and for those same visits the critical print size will be set to 
missing. Reading speed will equal 0 wpm at each print size for which (time=0) or Not Done 
(indicating no words in the sentence could not be read or sentence was not attempted due to 
vision) is checked for that print size. 
13.5.2.3. Critical Print Size 
Critical print size will be calculated as the smallest print size which support reading speed at 
80% of the maximum reading speed. If all wpm at all print sizes = 0 at a visit then that visit’s 
critical print size will be missing. Print size will be adjusted for viewing distance as follows: 
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• MNRead Charts:  
o For all viewing distances: 
 Print size = Print size + correction, where correction=log10 [40 / (viewing 
distance in cm)], rounded to two decimal places 
Note: the CRFs for the MNRead charts have print sizes pre-filled for a 40 cm viewing distance, 
while the Radner charts have print sizes pre-filled for a 32 cm viewing distance. 
13.5.2.4. Reading acuity 
Reading acuity will be calculated at each visit as: 1.4 – (# sentences read x 0.1) + (# of words 
read incorrectly x 0.01). This variable will not be included in the CSR. 
13.5.3. 
Radner Reading Chart 
13.5.3.1. Reading Speed 
13.5.3.1.1. Without adjustment for reading inaccuracy 
Reading Speed (wpm) = 14 / (time in seconds) x 60 = 840 / (time in seconds) 
If reading speed >300 wpm, reading speed = 300. 
13.5.3.1.2. With adjustment for reading inaccuracy 
Reading Speed (wpm) = (14 – errors)/ (time in seconds) x 60 
If 14 or more errors were made in a sentence (implying wpm<0), then the reading speed for that 
sentence can be assumed to be zero (wpm).  
If reading speed >300 wpm, reading speed = 300. 
13.5.3.2. Maximum Reading Speed 
Maximum reading speed will be calculated as the mean of the three highest nonzero reading 
speeds (or 2 or 1 if that is all that exists). For subjects having all wpm values = 0, the maximum 
reading speed will be set to 0, and for those same visits the critical print size will be set to 
missing. Reading speed will equal 0 wpm at each print size for which (time=0) or Not Done 
(indicating no words in the sentence could not be read or sentence was not attempted due to 
vision) is checked for that print size. 
13.5.3.3. Critical Print Size  
Critical print size will be calculated as the smallest print size which support reading speed at 
80% of the maximum reading speed. If all wmp at all print sizes = 0 at a visit then that visit’s 
critical print size will be missing. Print size needs to be adjusted for viewing distance as follows: 
• Radner Charts:  
o For viewing distance of 32 cm  
 No correction is needed.  
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o For viewing distance of other than 32 cm: 
 Print size= Print size – 0.1 + correction, where correction=log10 [40 / 
(viewing distance in cm)], rounded to two decimal places 
Note: the CRFs for the MNRead charts have print sizes pre-filled for a 40 cm viewing distance, 
while the Radner charts have print sizes pre-filled for a 32 cm viewing distance. 
13.5.3.4. Reading Acuity 
Reading acuity will be calculated at each visit as: 1.4 – (# sentences read x 0.1) + (# of words 
read incorrectly x 0.01). This variable will not be included in the CSR. 
13.5.4. 
Mean FRI Index Score and FRI Level  
Follow Section 4.3.2 of FRI Index User Manual (Version 1.4). 
SAS code for scoring FRI Index and FRI Level is available in Appendix C of FRI Index Under 
Manual (Version 1.4). 
13.5.5. 
NL-BCVA and LL-BCVA 
13.5.5.1. BCVA Letter Score 
• If the 4-meter score is >19 letters read correctly, the visual acuity score is the sum of 
total letters correctly read at 4 meters plus the addition of 30. 
• If the 4-meter score is ≤19 letters read correctly, the visual acuity score is the sum of 
total letters read correctly at 4 meters and total letters read correctly at the 1-meter 
distance. 
• If no letters are read correctly at either the 4-meter distance or the 1-meter distance, 
the visual acuity score is 0. 
13.5.5.2. Conversion of BCVA Letter Score to Snellen Equivalent 
Conversions between letter, logMAR, and Snellen visual acuity scores are available in 
Beck et al. (2003) and Holladay et al. (2004). Letter scores are converted to logMAR equivalents 
using the formula logMAR = 1.7 – (.02)(letter score). With this conversion, a 5-letter difference 
in visual acuity is equivalent to a difference of 0.1 logMAR and to one Snellen line. Conversion 
from logMAR to Snellen can be done after rounding logMAR values to one decimal place 
following Table 1 in Holladay et al. (2004). 
13.5.6. 
Low Luminance Deficit 
LLD = NL-BCVA - LL-BCVA 
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13.5.7. 
NEI VFQ-25 scores 
Scoring VFQ-25 with or without optional item is a two-step process: 
• First, original numeric values from the survey are re-coded following the scoring 
rules outlined in Table 2 of user’s manual. All items are scored so that a high score 
represents better functioning. Each item is then converted to a 0 to 100 scale so that 
the lowest and highest possible scores are set at 0 and 100 points, respectively. In this 
format, scores represent the achieved percentage of the total possible score, e.g., a 
score of 50 represents 50% of the highest possible score. 
• In step 2, items within each sub-scale are averaged together to create the 12 sub-scale 
scores, Table 3 of user’s manual indicates which items contribute to each specific 
sub-scale. Items that are left blank (missing data) are not taken into account when 
calculating the scale scores. Sub-scales with at least one item answered can be used to 
generate a sub-scale score. Hence, scores represent the average for all items in the 
sub-scale that the respondent answered. 
13.5.7.1. NEI VFQ-25 Distance Activity Subscale Score 
Average of items 8, 9, and 14 
13.5.7.2. NEI VFQ-25 Near Activity Subscale Score 
Average of items 5, 6, and 7 
13.5.7.3. NEI VFQ-25 Driving Subscale Score 
For subjects who are currently driving at baseline only. Average of items 15c, 16, 16a 
13.5.7.4. NEI VFQ-25 Composite Scores 
To calculate an overall composite score for the VFQ-25, simply average the vision-targeted sub-
scale scores, excluding the general health rating question. 
13.5.8. 
NEI VFQ-39 Scores 
For subjects responded to additional questions A1-A13, VFQ-39 subscale scores can be 
calculated using Table 4 of user’s manual.  
13.5.8.1. NEI VFQ-39 Distance Activity Subscale Score 
Average of items 8, 9, 14, A6, A7, and A8 
13.5.8.2. NEI VFQ-39 Near Activity Subscale Score 
Average of items 5, 6, 7, A3, A4, and A5 
13.5.8.3. NEI VFQ-39 Composite score  
Calculated by simply averaging the vision related subscales, excluding the general health 
rating question. 
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13.5.9. 
Microperimetry 
The number of points with a clinically significant progression by mesopic microperimetry will be 
calculated as the number of points with a ≥ 4 dB decrease from baseline for points >= 3 dB at 
baseline. Only data from images of acceptable quality for the main analysis, as determined by the 
reading center per the Imaging Charter, will be included in the analysis of microperimetry variables. 
13.6. 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end-of-study assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics. 
However, all post-baseline assessments will be used for PCS value determination and all 
assessments will be presented in the data listings. 
13.7. 
Handling of Missing, Unused, and Spurious Data  
13.7.1. 
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the Safety set, 
all efforts should be made to obtain the date from the investigator. 
13.7.2. 
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
If either the start or stop date of medication is missing, the worst or most conservative case will 
be considered when assigning medications to categories. So for a missing start date (where stop 
date is after date of first dose or missing) the date will be imputed as the date of first dose; for a 
missing stop date the date will be imputed as the last study date.  
13.7.2.1. Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
13.7.2.1.1. Missing Day and Month 
If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of investigational 
product will be assigned to the missing fields. 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields. 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
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13.7.2.1.2. Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
13.7.2.1.3. Missing Day Only 
If the month and year of the incomplete start date are the same as the month and year of the date 
of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day. 
If either the year is before the year of the date of the first dose of investigational product or if 
both years are the same but the month is before the month of the date of the first dose of 
investigational product, then the last day of the month will be assigned to the missing day. 
If either the year is after the year of the date of the first dose of investigational product or if both 
years are the same but the month is after the month of the date of the first dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
13.7.2.2. Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date. 
13.7.2.3. Missing Day and Month 
If the year of the incomplete stop date is the same as the year as of the last study date, then the 
day and month of the date of the last study date will be assigned to the missing fields. 
If the year of the incomplete stop date is before the year of the last study date, then 31 December 
will be assigned to the missing fields. 
If the year of the incomplete stop date is after the year of the last study date, then 01 January will 
be assigned to the missing fields. 
13.7.2.3.1. Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
13.7.2.3.2. Missing Day Only 
If the month and year of the incomplete stop date are the same as the month and year of the last 
study date, then the day of the last study date will be assigned to the missing day 
If either the year is before the year of the last study date or if both years are the same but the 
month is before the month of the last study date, then the last day of the month will be assigned 
to the missing day 
If either the year is after the year of the last study date or if both years are the same but the month 
is after the month of the last study date, then the first day of the month will be assigned to the 
missing day. 
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10 August 2021 
13.7.3. 
Missing Date Information for Adverse Events  
Events with missing or partial dates will be handled such that in the absence of contradictory 
information an AE is treatment emergent. So, for a missing start date (where stop date is after 
first dosing date or missing) the date will be imputed as the first dose date; for a missing stop 
date the date will be imputed as the last study date. If a partial date is recorded, the following 
convention will be used to assign the AE: 
13.7.3.1. Incomplete Start Date  
If a start date is missing the day information and month/year is the same as first dose date then use 
first dose date, else ‘01’ will be used for the day; if a start date is missing the month and the year is 
the same as first dose date then use first dose date, else January will be used for the start month. 
If AE end date is earlier than treatment start date (i.e., could be inferred by any combination of 
year/month/day), then any missing part of AE start date will be imputed based on the AE end date. 
13.7.3.2. Incomplete Stop Date  
If a stop date is missing the day information and month/year is same as last study date then use 
last study date, else last day of the given month will be used for the stop day; if a stop date is 
missing the month and year is the same as last study date then use last study date, else December 
will be used for the stop month. 
13.7.4. 
Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
13.7.5. 
Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” to the investigational product 
will be assigned. The imputed values for relationship to double-blind investigational product will 
be used for incidence summaries, while both the actual and the imputed values will be presented 
in data listings. 
13.7.6. 
Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
(e.g., a character string is reported for a numerical variable), the appropriately determined coded 
value will be used in the statistical analysis, several examples are shown in Table 8 for an 
illustration purpose. The actual values as reported in the database will be presented in 
data listings.  
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Table 8: 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables 
Clinical Laboratory Test 
Possible Results (in SI units) 
Coded Value for Analysis 
Chemistry: Bilirubin, Total/Direct 
<1.7 
0.85 
<2 
1 
Urinalysis: Specific Gravity 
≤1.005 
0.5025 
>1.030 
1.030 
Urinalysis: Glucose 
≥55 
Positive 
≤0 
Negative 
Urinalysis: pH 
≥8.0 
8.0 
Urinalysis: Protein 
≥500 
500 
Other: FSH 
<0.2 
0.1 
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14. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.  
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10 August 2021 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
The following changes were made to the analyses specified in the protocol 
• The mITT set, which includes subjects with a baseline and at least one post-baseline 
GA lesion assessment, replaced the ITT set as the main efficacy population to be 
aligned with the primary analysis methodology. 
• The change in GA lesion(s) size at Month 24 between PM and Sham was to be the 
third hypothesis tested in the hypotheses testing strategy as specified in the protocol. 
This was removed from the hypotheses testing strategy in the SAP. 
• The change from baseline in mean threshold sensitivity in all points evaluating the 
macular functional response at Month 24 was promoted from secondary in the 
protocol to a key secondary efficacy endpoint here and included in the hypotheses 
testing algorithm. 
• The hypotheses testing strategy and α allocation for the key secondary endpoints was 
not precisely specified within the protocol and has been clarified to follow the 
hypotheses testing procedure and α allocation as described in Section 6.3.1. 
• Several new microperimetry endpoints were specified in the SAP that were not noted 
in the protocol. 
o Change from baseline in the mean threshold sensitivity within 500 microns 
outside the GA lesion, (perilesional points) assessed by mesopic 
microperimetry over time. 
o Change from baseline in 95% bivariate contour ellipse area (BCEA) over 
time. 
o Change from baseline in the mean threshold sensitivity of points beyond 500 
microns outside the atrophy border (paralesional points) over time. 
o Change from baseline in the mean threshold sensitivity of points beyond the 
GA lesion (extralesional points) over time.  
o Number of points with clinically significant progression over time. 
• Several new exploratory endpoints not specified in the protocol were added. 
o NEI-VFQ-39 distance activity, composite, near activity subscale score 
o NEI-VFQ-25 driving subscale score 
o Progression from iRORA to cRORA 
o Progression from large drusen to iRORA or cRORA 
o Change in the distance of the atrophy junction to the fovea and without 
subfoveal atrophy to subfoveal atrophy conversion 
• No pre-specified analysis will be performed on the secondary endpoint of change 
from baseline in LLD over time. This data will only be listed. 
• No formal interim analyses are planned for this study however, analyses of interim 
data from Months 12 to 24 that may support regulatory submissions may be 
conducted. 
• Other minor editorial changes were made to provide clarity. 
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10 August 2021 
16. 
REFERENCES 
Baskaran K, Macedo AF, and He Y, et al. Scoring reading parameters: An inter-rater reliability 
study using the MNREAD, PloSONE (2019) 14(6): e0216775 
Beck RW, Moke PS, and Turpin AH et al. A Computerized Method of Visual Acuity Testing: 
Adaptation of the Early Treatment of Diabetic Retinopathy Study Testing Protocol, American 
Journal of Ophthalmology (2003) 135 (2):194-205  
Bretz, F, Maurer W, Brannath W, Posch M. A Graphical Approach to Sequentially Rejective 
Multiple Test Procedures, Statistics in Medicine (2009) 28.4:586-604. 
Calabrese A, Cheong AMY, Cheung S-H, et al. Baseline MNREAD measures for normally 
sighted subjects from childhood to old age. Invest Ophthalmol Vis Sci (2016) 57(8):3836-3843. 
Diggle, P.J., Liang, K.-Y., and Zeger, S. L. (1994). Analysis of Longitudinal Data. Oxford: 
Clarendon Press. 
Holekamp N, Wykoff CC, and Schmitz-Valckenberg S et al., Natural History of Geographic 
Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective 
Proxima A and B Clinical Trials, Ophthalmology (2020), doi: 
https://doi.org/10.1016/j.ophtha.2019.12.009. 
Holladay J. Visual Acuity Measurements. Journal of Cataract & Refractive Surgery (2004) 
30(2):287-290. 
Li, K. H. Imputation Using Markov Chains. Journal of Statistical Computation and Simulation 
(1988) 30:57-79. 
Liu, C. Bartlett’s Decomposition of the Posterior Distribution of the Covariance for Normal 
Monotone Ignorable Missing Data. Journal of Multivariate Analysis (1993) 46:198-206 
Patel P, Chen F, Da Cruz L, et al. Test-retest variability of reading performance metrics using 
MNREAD in patients with age-related macular degeneration. Invest Opthalmol Vis Sci (2011). 
52(6): 3854-9. doi: 10.1167/iovs. 10-6601. 
Radner W and Diendorfer G. English sentence optotypes for measuring reading acuity and 
speed - the English version of the Radner Reading Charts. Graefes Arch Clin Exp Ophthalmol 
(2014) 252:1297-1303. 
Radner W, Obermayer W, Richter-Meuksch S, et al. The validity and reliability of short German 
sentences for measuring reading speed. Graefes Arch Clin Exp Ophthalmol (2002) 240:461-367. 
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17. 
APPENDIX 
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10 August 2021 
APPENDIX 1. SCHEDULE OF ACTIVITIES 
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L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA and OCT-A (select sites) images 
must be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand-motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study. 
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye. 
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
 
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Pegcetacoplan 
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10 August 2021 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 
10 August 2021 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center. 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital application will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye. 
 T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 
10 August 2021 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes. 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the application 
in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at 
home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis. 
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes the gross vision test and IOP is ≤30 mm Hg. 
Note: if the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab 
or aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF. 
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the investigator determines that there are any safety 
concerns, a follow-up visit should be scheduled as soon as possible. 
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. 
 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
10 August 2021 
1.1. 
Protocol Changes to be followed during COVID-19 Restrictions  
OVERVIEW  
In response to the COVID-19 crisis, to ensure the safety of study subjects and Investigative Sites 
as well as proper conduct of the study, TEMPORARY changes to the protocol have been 
implemented. These changes should be followed only during COVID-19 restrictions and include 
extended IP administration windows, changes to masking rules, rescreening instructions, and a 
revised schedule of assessments. 
Where feasible, sites could continue to follow the full schedule of assessments (based on their 
treatment group assignment). 
EXTENDED IP ADMINISTRATION WINDOWS 
In order to allow more flexibility to sites and subjects, and to potentially mitigate missed IP 
administration, an extended IP administration window can be followed. The extended window 
can ONLY be used in situations related to COVID-19 restrictions and after medical monitor 
approval. Footnote “T” of each COVID-19 assessment table below reflects these extended IP 
options. 
Per protocol, the IP administration window is as follows: 
• Monthly treatment group: +/– 8 days for the entire study duration 
• EOM treatment group: +/– 8 days for the first study year and +/- 16 days for the 
second study year 
During COVID-19 restrictions, the IP administration window can be extended to the following: 
• Monthly treatment group: –8 days to +15 days. Note, interval for consecutive 
injections must be at least 14 days. 
• EOM treatment group: –8 days to +30 days for the first study year and –16 days to 
+30 days for the second study year. 
MASKING RULES 
Due to current COVID-19 restrictions, clinical sites might encounter difficulties maintaining 
appropriate clinic staffing to satisfy the approved masking rules for the APL2-304 (Oaks) study. 
Based on this, and in an attempt to minimize the amount of missed data and IP administrations, 
Apellis is implementing a temporary adjustment to the study masking rules.  
This temporary change must be approved by the Apellis Medical Director prior to 
implementation and must be documented via a temporary and modified delegation of authority 
Log. Each masked assessment performed by an unmasked staff and vice versa (even with Apellis 
approval and following the below guidelines) should be documented.  
The principal investigator (PI) is responsible for the overall oversight of the study site data and 
s/he will not be allowed to switch into an unmasked role. Every masked individual that performs 
IP administration and/or postinjection assessment (all unmasked assessment) as a temporary 
measure, will permanently be considered an unmasked individual and will not be able to 
perform masked assessments once these exemptions are lifted. 
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APL2-304 Statistical Analysis Plan  
10 August 2021 
RESCREENING PROCEDURE 
Prior to the implementation of these temporary changes, sites continuing to screen patients have 
been encouraged to complete the screening and baseline assessments in their entirety. However, 
if a subject was deemed a screen failure for not being able to meet the original screening window 
(Day –28 to Day –1 [+/- 2 days]) due to COVID-19 related restrictions, a rescreening visit is 
allowed and should be followed according to the 2 scenarios below.  
Subjects Who Completed Screening and Were Considered Eligible by Reading Center and 
Investigator  
Subjects who were screened prior to 30 March 2020 and completed all screening assessments (as 
described in the Schedule of Assessments Table 9 [every month treatment group] and Table 11 
[every other month [EOM] treatment group]) and considered eligible by the reading center and 
investigator and are able to return to the clinic within 90 days of initial screening, will receive a 
new subject ID number and undergo an abbreviated screening, prior to randomization, that 
includes the following assessments:  
• Informed consent/assign new screening number  
• Normal luminance best corrected visual acuity assessment  
• Slitlamp examination  
• Dilated indirect ophthalmoscopy  
• IOP measurement  
• SD-OCT*  
• Concomitant medication/concomitant ocular procedures collection  
• AE collection  
*SD-OCT images collected at this visit will not be used by the reading center to determine 
eligibility but should be used by the investigator to detect any potential new exclusion criterion.  
If the investigator deems it necessary, additional assessments can be performed if there is a 
concern that the subject might now meet an exclusion criterion that was not the case during the 
original screening (eg, FFA to exclude the presence of CNV).  
Subjects With Incomplete Screening Assessment  
Subjects that signed the informed consent but were not able to complete all screening 
assessments due to COVID-19-related restrictions are not eligible for the abbreviated screening. 
These subjects can be rescreened but must follow the standard screening schedule of 
assessment (as described in the Schedule of Assessments Table 9 [every month treatment group] and 
Table 11 [EOM treatment group]). These subjects will also receive a new screening ID number.  
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APL2-304 Statistical Analysis Plan  
10 August 2021 
MINIMUM SCHEDULE OF ASSESSMENT 
Schedule of Assessments  
Where feasible, sites could continue to follow the full schedule of assessments (based on their 
treatment group assignment). The minimum assessment tables, only to be followed during this 
COVID-19 effort and if determined necessary to use based on the investigator’s clinical 
judgment, are provided below to reduce the time required for each study visit. Subjects in the 
EOM treatment group do not need to be seen for the non-IP administration visits. Assessments 
not performed (even those that have been removed in the minimum assessment table) should 
be documented.  
Subjects that are not able to come into the clinic for a study visit due to COVID-19-related 
restrictions, including visits for the EOM group that do not include IP administration, should 
be contacted via the phone for the collection of AEs (including SAEs) and concomitant 
medications. All SAEs are still required to be reported to Apellis within 24 hours of site 
awareness, even if reported via phone call. All communications via phone call should also be 
documented in the source documents and in the respective CRF page. In addition, these 
subjects should be instructed to self-monitor their vision at home and report any changes in 
vision or their overall health via phone call. The site must inform the Sponsor of any subjects lost 
to follow-up.  
It is critical that local, country, and regional governance regarding COVID-19 is followed along 
with your best clinical judgment when managing this situation. All visits or assessments missed 
as a result of COVID-19 will be captured in the case report forms. 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 
10 August 2021 
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA and OCT-A (select sites) images 
must be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 15 days after medical monitor approval. Note, interval for consecutive injections must be at least 14 days. 
 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 
10 August 2021 
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 3) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 15 days after medical monitor approval. Note, interval for consecutive injections must be at least 14 days. 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 
10 August 2021 
K. In select countries, the MNREAD or Radner Reading Charts should be done during the study visit, prior to dilating the eyes. It should be performed monocularly first, then 
binocularly.  
L. Microperimetry assessments will be performed post dilation. Data will be forwarded to the reading center.  
M. To be administered by the masked site staff prior to any other assessments performed on that day. In-clinic assessments on the digital application should be completed after 
completion of all functional tests and quality of life measures prior to dilating the eyes.  
N. At select sites, and for those subjects who decide to participate, the digital application will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the in the clinic 
at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments weekly at home. Subjects 
should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected sites) 
images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, the tonometry 
should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the IOP. If IOP is 
>30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes gross vision test and IOP is ≤30 mm Hg. Note: if 
the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with ranibizumab or 
aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the physician determines that there are any safety concerns, 
a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –8 days to + 30 days after medical monitor approval. 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
  
10 August 2021 
N. At select sites, and for those subjects who decide to participate, the digital applications will be completed on an electronic device and will consist of assessments for visual 
function and reading speed. Subjects will receive training at Day 1 on the use of the digital applications and the electronic device and will perform the tests using the 
application in the clinic at Month 1, Month 2, Month 3, Month 6, Month 12, Month 18, and Month 24. Beginning at Day 1, subjects will complete the functional assessments 
weekly at home. Subjects should be instructed to complete the assessments on the same day each week and at approximately the same time of day each week, if possible.  
O. FAF and SD-OCT images, near infrared reflectance, fluorescein angiograms, and fundus photographs will be performed for the study eye only on days where 'SE' is specified 
and for both eyes at all other visits as specified in the above schedule and will be sent to the reading center for evaluation (consult the reading center manual for specifics on 
image capture, processing, and transmission). Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit. If new active CNV is suspected, SD-OCT, FFA, and OCT-A (selected 
sites) images should be collected and sent to the reading center for analysis.  
P. Postinjection assessments should be performed within 5 minutes after dosing by the unmasked physician or study staff and should include a gross assessment of vision (finger-
counting, hand motion, then light perception when applicable). If subject passes gross vision test, the subject may leave the site. If subject fails gross vision test, 
the tonometry should be performed. IOP should be ≤30 mm Hg in order for the subject to leave the site. If necessary, antiglaucomatous medication can be given to lower the 
IOP. If IOP is >30 mm Hg, assessments will continue every approximately 30 minutes from the previous measurement until the subject passes the gross vision test and IOP is 
≤30 mm Hg. Note: if the study eye is treated with a ranibizumab or aflibercept injection during the same visit as the study treatment (pegcetacoplan or sham), the treatment with 
ranibizumab or aflibercept must be performed first. The pre- and post- anti-VEGF IOP values must be measured and recorded on the eCRF.  
Q. Starting at Day 1, study subjects will be contacted by study site staff within 4 ± 2 days after each study treatment visit (through Month 4) to collect any information on any 
safety concerns, decrease in vision, eye pain, unusual ocular events, or any new ocular symptoms in the study eye. If the investigator determines that there are any safety 
concerns, a follow-up visit should be scheduled as soon as possible.  
R. Record concomitant medications (ie, prescription and over-the-counter medications) used by the patient within 30 days of screening and throughout the subject's participation in 
the study.  
S. In addition to the time points indicated on the study schedule, OCT-A should be performed at the time of any suspected new active CNV. If new active CNV is confirmed in the 
study eye, OCT-A should be repeated every 2 months for the study eye.  
T. Administration of pegcetacoplan or sham can be done on separate days from the assessment visit if both days fall within the visit window. Administration of study treatment 
(pegcetacoplan or sham) can be done on a separate day from the assessment visit if both days fall within the visit window. If this occurs on the randomization visit, then the 
administration of pegcetacoplan or sham should be done within 3 days of randomization and after approval from the medical monitor. When study treatment administration is on 
a day other than a study visit, then the only assessment that must be done on the day of study treatment administration is preinjection IOP. During the COVID-19 pandemic, the 
following flexibility is allowed for IP administration: –16 days to + 30 days after medical monitor approval. 
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APL2-304 Statistical Analysis Plan  
 10 August 2021 
1.2. 
Sample of SAS Code 
* The SAS codes in this section are shown as examples 
* Some modifications (such as variables used in the model statement) 
* may require further changes to reflect the methods specified in the 
* SAP and analysis data structure 
* e.g., change trtan to trtpn to reflect analysis w/ the ITT set; 
1.2.1. 
Mixed Effect Model for Repeated Measure 
*---------------------------------------------------- 
* Read Analysis data 
*---------------------------------------------------- 
* In this example, repeated measures are available at 
* avisitn = 0.5 (baseline), 2 (Month 2), 
*   6 (Month 6), and 12 (Month 12) 
*----------------------------------------------------; 
 
data ga; 
 set adam.adga; 
 if paramcd = 'SEGAORG' and  
  avisitn in (0.5, 2, 6, 12) and  
  ANL01FL = 'Y'; 
 
* trtan (actual treatment[number]) 
* 1 = APL-2 Monthly 
* 2 = APL-2 Every Other Month 
* 3 = pooled Sham group; 
 if trtan in (4,5) then trtan = 3;  
 
 * trt01 are trt02 are used in multiple imputation 
 * trt01 = 1 if Sham group 
 * trt02 = 1 if APL2 Monthly group 
 * trt01 = trt02 = 0 for APL2 EOM group; 
 if trtan = 3 then trt01= 1; else trt01 = 0;  
if trtan = 1 then trt02= 1; else trt02 = 0;  
 
 * avisitc will be used in PROC TRANSPOSE;            
 if avisitn = 0.5 then avisitc = '00'; * Baseline; 
 if avisitn = 2 then avisitc = '02'; * Month 2; 
 if avisitn = 6 then avisitc = '06'; * Month 6; 
 if avisitn = 12 then avisitc = '12'; * Month 12; 
run; 
 
********************************; 
*** MAIN ANALYSIS using MMRM ***; 
********************************; 
 
proc mixed data=ga method=reml covtest empirical; 
where avisitn NE 0.5; * exclude rows for baseline; 
* cnv (CNV in the fellow eye) 
* 0 = No 
* 1 = Yes; 
*base cat (baseline lesion size (<7.5 vs. ≥ 7.5); 
class trtan cnv avisitn usubjid base_cat; 
model chg = trtan cnv base_cat avisitn trtan*avisitn base_cat*avisitn   
/cl; 
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Pegcetacoplan 
APL2-304 Statistical Analysis Plan  
 10 August 2021 
 repeated avisitn / subject=usubjid type=un r; 
 lsmeans trtan*avisitn/pdiff cl e alpha=.05; 
 ods output diffs= diff1 LSMeans= LSMean1; 
run; 
1.2.2. 
Multiple Imputation 
********************************; 
*** RESHAPE DATA FOR PROC MI ***; 
********************************; 
 
proc sort data= ga; 
 by usubjid cnv trta trtan trt01 trt02 param paramcd base base_cat avisitc;  
run; 
 
proc transpose data= ga out= ga_t(drop= _NAME_ _LABEL_) prefix=V; 
 by usubjid cnv trta trtan trt01 trt02 param paramcd base base_cat;  
 id avisitc; 
 var aval; 
run; 
 
* Examine the missing patterns of the data; 
proc mi data=ga_t nimpute=0;  
 var cnv trtan v00 -- v12;  
 ods output missPattern=pattern;  
run; 
 
*****************************************; 
*** MCMC (impute nonmonotone missing) ***; 
*****************************************; 
 
* Below statements invoke MCMC procedure and specify IMPUTE=MONOTONE  
 to turn the arbitrary missing patterns to monotone missing patterns 
 under missing at random (MAR) assumption;  
 
proc mi data=ga t out=ga t mono seed= 12135541 nimpute=1000;  
 mcmc chain=multiple impute= monotone displayinit 
      initial=em(itprint);  
 var cnv trt01 trt02 v00 -- v12;  
run; 
 
* Examine the missing patterns of the data; 
proc mi data=ga_t_mono nimpute=0;  
 var cnv trt01 trt02 v00 -- v12;  
 ods output missPattern=pattern;  
run; 
 
********************************************************************; 
*** Control-based pattern imputation(impute monotone missing) ***; 
********************************************************************; 
data ga t mono2; 
 
set ga t mono; 
 
**Identify the subjects in the active groups we want to keep  
  imputed as MAR; 
 
**DSCREASN is just an example; 
 
if trtan in (1,2) and DCSREASN = 1 then mar = 1; 
 
else mar = 0; 
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APL2-304 Statistical Analysis Plan  
 10 August 2021 
 
run; 
 
**First impute general MAR based on regression method for all subjects to get 
the true MAR; 
proc mi data=ga t_mono2 out=ga_step1 nimpute=1 seed=1284054; 
 by Imputation_; 
 class trtan; 
 monotone reg(v00 -- v12/details); 
 var cnv trtan v00 -- v12;  
run; 
 
**Identify and keep the data from the subjects in the active group that 
should remain as a MAR; 
data ga step2; 
 
set ga step1; 
 
if Mar = 1; 
 
run; 
 
**Update the dataset and keep the MAR imputed data for the subjects in the 
active group that should remain as a MAR, all others remain to be imputed 
with control based imputation; 
data ga_t_mono3; 
 
update ga t mono2 ga step2; 
 
by Imputation_ subjid; 
 
run; 
 
**Fill out the remaining missing where missing data should be imputed based 
on the controls; 
proc mi data=ga t_mono3 out=ga_t_cbp nimpute=1 seed=1284054;  
 by imputation_;  
 class trtan;  
 var cnv v00 -- v12;  
 monotone reg(/details);  
 mnar model(v02 -- v12 / modelobs= (trtan='3'));  
run; 
 
**General control based (all monotone missing); 
proc mi data=ga_t_mono out=ga_t_cbp2 nimpute=1 seed=1284054;  
 by imputation_;  
 class trtan;  
 var cnv v00 -- v12;  
 monotone reg(/details);  
 mnar model(v02 -- v12 / modelobs= (trtan='3')); 
run; 
 
********************************************************************; 
*** Delta-Adjusted Pattern Imputation (impute monotone missing) ***; 
********************************************************************; 
**First identify the subjects in the active treatment groups that we want to 
apply the shift parameter if they have monotone missing data; 
data ga t mono2; 
 
set ga_t_mono; 
 
 
**This is just an example of a reason that we do not want to  
  apply the shift parameter. The actual reasons are in the text; 
 
if DCSREAS1 = "Death" then flag = 1; 
 
else flag = 0; 
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 10 August 2021 
 
 
 
if trtan in (1,2) and flag = 0 then adjustthis = 1; 
 
else adjustthis = 0; 
 
run; 
 
proc mi data=ga t_mono2 out=ga_t_tip6 nimpute=1 seed=9484353;  
 by _imputation_;  
 class trtan adjustthis;  
 var cnv trtan v00 -- v12;  
 monotone reg(/details); 
 mnar adjust(v02 / shift=0.12 adjustobs=(adjustthis = '1' )) 
  adjust(v06 / shift=0.12 adjustobs=(adjustthis = '1' )) 
  adjust(v12 / shift=0.12 adjustobs=(adjustthis = '1' ));  
run; 
*****************************************************; 
*** SAS macro to run MIANALYZE on outputs from MMRM *; 
*****************************************************; 
 
%macro mi_results(in, lsm, dif); 
 
* After imputation, the data sets are in the wide format in which 
 different variables (V00--V12) represent the outcome measured at 
 different occasions. Before analyzing using PROC MIXED,  
 the data sets need to be converted into long format in which one 
 variable represents all outcome with different values of AVISITN 
 differentiating different occasions; 
 
proc transpose data= &in  
    out= ga mi (rename= ( NAME  = AVISITN COL1 = AVAL)); 
 by imputation  usubjid trta trtan trt01 trt02 param paramcd base base_cat; 
 var V00 -- V12; 
run; 
 
data ga_mi; 
 set ga mi; 
 label AVISITN = 'AVISITN'; 
chg = aval - base; 
* baseline record is not used in MMRM; 
 if AVISITN = 'V00' then delete;  
run; 
 
proc sort; by _imputation_; run; 
 
proc mixed data=ga_mi method=reml empirical; 
 by imputation ; 
 class trtan cnv avisitn usubjid base_cat; 
 model chg=trtan cnv base_cat avisitn trtan*avisitn base_cat*avisitn /cl; 
 repeated avisitn / subject=usubjid type=UN; 
 lsmeans trtan*avisitn / pdiff cl alpha=.05; 
 ods output diffs= diffs lsmeans= lsmeans; 
run; 
 
* In the final step, the analysis results obtained from PROC MIXED 
procedure are combined into a single estimation with standard error 
using PROC MIANALYZE; 
 
proc sort data=lsmeans; 
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 by avisitn trtan _imputation_; 
run; 
proc mianalyze parms=lsmeans;  
 by avisitn trtan; 
 modeleffects trtan*avisitn;  
 ods output ParameterEstimates=&lsm;  
run; 
 
proc sort data=diffs (where= (_trtan= 3 and (avisitn = _avisitn))); 
 by avisitn trtan _trtan _imputation_; 
run; 
 
proc mianalyze parms=diffs;  
 by avisitn trtan trtan;  
 modeleffects trtan*avisitn;  
 ods output ParameterEstimates=&dif;  
run; 
 
proc sql; *** LSMEANS using Multiple Imputation; 
select Parm as Effect, AVISITN, TRTAN, Estimate, StdErr, DF,  
  tValue, Probt, LCLMean as L95, UCLMean as U95 
 from &lsm; 
 
select Parm as Effect, AVISITN, TRTAN, TRTAN, Estimate, StdErr, DF, 
  tValue, Probt, LCLMean as L95, UCLMean as U95 
 from &dif; 
quit; 
%mend; 
 
%mi results(in= ga t mcmc, lsm= lsm mcmc, dif=dif mcmc); 
%mi_results(in= ga_t_reg, lsm= lsm_reg, dif=dif_reg ); 
%mi results(in= ga t cbp, lsm= lsm cbp, dif=dif cbp ); 
%mi_results(in= ga_t_tip6, lsm= lsm_tip6, dif=dif_tip6); 
 
 
1.2.3. 
Rate of Change Models 
********************************; 
*** Rate of Change analyses ***;  
 
* In this example, repeated measures are available at 
* avisitn = 0 (baseline), 2 (Month 2), 4 (Month 4) 
*   6 (Month 6), 8 (Month 8), 10 (Month 10) and 12 (Month 12) 
* 
* AVAL is the actual GA lesion measurement at the corresponding visit * for 
the study eye from ADGA. 
* SGALESAT is the GA lesion size (categorical) at baseline 
* FCNVAT is the fellow eye CNV status at baseline 
* TR01PG2N is the pooled treatment group (1 = PM, 2 = PEOM, 3 = Sham) 
* T is equivalent to AVISITN 
* 
* The data is read in from ADGA 
********************************; 
 
 
proc mixed data=ga method=reml covtest empirical; 
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class subjid TR01PG2N FCNVAT SGALESAT t; 
 
model aval = SGALESAT TR01PG2N avisitn TR01PG2N * avisitn  
SGALESAT*avisitn FCNVAT/cl solution; 
  
repeated t /type=un sub=subjid r ; 
 
 
**Month 6; 
 
estimate 'PM Month 0 to 6 slope' TR01PG2N*avisitn 6 0 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'PEOM Month 0 to 6 slope' TR01PG2N*avisitn 0 6 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'Sham Month 0 to 6 slope' TR01PG2N*avisitn 0 0 6  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
 
estimate 'Month 0 to Month 6 Difference in slope PM - Sham'  
TR01PG2N*avisitn 6 0 -6 /cl; 
 
estimate 'Month 0 to Month 6 Difference in slope PEOM - Sham'  
TR01PG2N*avisitn 0 6 -6 /cl; 
 
estimate 'Month 0 to Month 6 Difference in slope PM - PEOM'  
TR01PG2N*avisitn 6 -6 0 /cl; 
 
 
**Month 12; 
 
estimate 'PM Month 6 to 12 slope' TR01PG2N*avisitn 6 0 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'PEOM Month 6 to 12 slope' TR01PG2N*avisitn 0 6 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'Sham Month 6 to 12 slope' TR01PG2N*avisitn 0 0 6  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
 
estimate 'Month 6 to 12 Difference in slope PM - Sham'  
TR01PG2N*avisitn 6 0 -6 /cl; 
 
estimate 'Month 6 to 12 Difference in slope PEOM - Sham'  
TR01PG2N*avisitn 0 6 -6 /cl; 
 
estimate 'Month 6 to 12 Difference in slope PM - PEOM'  
TR01PG2N*avisitn 6 -6 0 /cl; 
 
  
ods output diffs= diff2 LSMeans= LSMean2 CovParms = COV2  
estimates = estimates2; 
 
 
**Month 0 to 12; 
 
estimate 'PM Month 0 to 12 slope' TR01PG2N*avisitn 12 0 0  
avisitn 12 SGALESAT*avisitn 6 6 /cl; 
 
estimate 'PEOM Month 0 to 12 slope' TR01PG2N*avisitn 0 12 0  
avisitn 12 SGALESAT*avisitn 6 6 /cl; 
 
estimate 'Sham Month 0 to 12 slope' TR01PG2N*avisitn 0 0 12  
avisitn 12 SGALESAT*avisitn 6 6 /cl; 
 
 
estimate 'Month 0 to Month 12 Difference in slope PM - Sham'  
TR01PG2N*avisitn 12 0 -12 /cl; 
 
estimate 'Month 0 to Month 12 Difference in slope PEOM - Sham'  
TR01PG2N*avisitn 0 12 -12 /cl; 
 
estimate 'Month 0 to Month 12 Difference in slope PM - PEOM'  
TR01PG2N*avisitn 12 -12 0 /cl; 
 
run; 
 
 
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* For the piecewise model, a knot at Month 6 is added to the dataset and 
included in the model to allow for different slopes for the two 6 month 
periods; 
 
data ga2; 
 
set ga; 
 
 
k = 6; 
 
if avisitn <= k then avisitnspl1 = 0; 
 
if avisitn > k then avisitnspl1 = avisitn - k; 
run; 
 
proc mixed data=ga2 method=reml covtest empirical; 
 
class subjid TR01PG2N FCNVAT SGALESAT t; 
 
model aval = SGALESAT TR01PG2N avisitn avisitnspl1 TR01PG2N *  
avisitn TR01PG2N*avisitnspl1 SGALESAT*avisitn 
SGALESAT*avisitnspl1 FCNVAT/cl ; 
  
repeated t /type=un sub=subjid r ; 
 
 
**Month 6; 
 
estimate 'PM Month 0 to 6 slope' TR01PG2N*avisitn 6 0 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'PEOM Month 0 to 6 slope' TR01PG2N*avisitn 0 6 0  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
estimate 'Sham Month 0 to 6 slope' TR01PG2N*avisitn 0 0 6  
avisitn 6 SGALESAT*avisitn 3 3 /cl; 
 
 
estimate 'Month 0 to Month 6 Difference in slope PM - Sham'  
TR01PG2N*avisitn 6 0 -6 /cl; 
 
estimate 'Month 0 to Month 6 Difference in slope PEOM - Sham'  
TR01PG2N*avisitn 0 6 -6 /cl; 
 
estimate 'Month 0 to Month 6 Difference in slope PM - PEOM'  
TR01PG2N*avisitn 6 -6 0 /cl; 
 
 
**Month 12; 
 
estimate 'PM Month 6 to 12 slope' TR01PG2N*avisitn 6 0 0  
avisitn 6 SGALESAT*avisitn 3 3 TR01PG2N*avisitnspl1 6 0 0  
avisitnspl1 6 SGALESAT*avisitnspl1 3 3 /cl; 
 
estimate 'PEOM Month 6 to 12 slope' TR01PG2N*avisitn 0 6 0  
avisitn 6 SGALESAT*avisitn 3 3 TR01PG2N*avisitnspl1 0 6 0 
avisitnspl1 6 SGALESAT*avisitnspl1 3 3 /cl; 
 
estimate 'Sham Month 6 to 12 slope' TR01PG2N*avisitn 0 0 6  
avisitn 6 SGALESAT*avisitn 3 3 TR01PG2N*avisitnspl1 0 0 6 
avisitnspl1 6 SGALESAT*avisitnspl1 3 3 /cl; 
 
 
estimate 'Month 6 to 12 Difference in slope PM - Sham'  
TR01PG2N*avisitn 6 0 -6 TR01PG2N*avisitnspl1 6 0 -6/cl; 
estimate 'Month 6 to 12 Difference in slope PEOM - Sham'  
TR01PG2N*avisitn 0 6 -6 TR01PG2N*avisitnspl1 0 6 -6/cl; 
 
estimate 'Month 6 to 12 Difference in slope PM - PEOM'  
TR01PG2N*avisitn 6 -6 0 TR01PG2N*avisitnspl1 6 -6 0/cl; 
 
  
ods output diffs= diff2 LSMeans= LSMean2 CovParms = COV2  
estimates = estimates2; 
run; 
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1.2.4. 
Sample Code for Maximum Reading Speed and Critical Print Size 
Please see below regarding the uncorrected and corrected reading speed calculation, and Critical 
Print Size: Flag = 1 MNREAD , 2 = Radner . 
if flag = 1 then do; 
   if (time  = 0 or notdone = 1) then urs = 0; 
   /** "Not Done" indicates the print size was not attempted due to vision or 
that the sentence was attempted but could not be read **/  
   else if time > 0 then urs = 600/time; 
   if urs > 300 then urs = 300; 
    /** Calculate Corrected Reading Speed **/ 
   if (time = 0 or numerr >= 10) or (notdone = 1) then crs = 0; 
   else if numerr >=0 and time > 0 then crs = 60*(10-numerr)/time; 
   else if (numerr = 0 or time = 0) then crs = urs; 
   if crs > 300 then crs = 300; 
  end; 
  if flag = 2 then do; 
   if (time  = 0 or notdone = 1) then urs = 0; 
   else if time > 0 then urs =  840/time; 
   if urs > 300 then urs = 300; 
   if (time = 0 or numerr >= 14) or (notdone = 1) then crs = 0; 
   else if numerr >=0 and time  > 0 then crs = 60*(14-numerr)/time; 
   else if (numerr = 0 or time = 0) then crs = urs; 
   if crs > 300 then crs = 300; 
end; 
Critical Print Size: 
if flag = 1 and n(aval,dist) =2 and dist ne 40 then aval = aval + 
round(log10(40/dist),.01); /** Apply correction for viewing distance ne 40 
**/ 
if flag = 2 and n(aval,dist) =2 and dist not in (32 40) then aval = aval - 
0.1 + round(log10(40/dist),.01); 
 
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