Conditions: Paroxysmal Nocturnal Hemoglobinuria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
Evaluation of the Efficacy and Safety of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria .

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: APL-2
Intervention descriptions: intervention 1: Complement (C3) Inhibitor

Protocol document:
Prot_000.pdf: 
Apellis Pharmaceuticals, Inc
Page 1 of 106
Confidential
PEGCETACOPLAN (APL-2) 
PROTOCOL APL2-308 
A PHASE 3, RANDOMIZED, MULTICENTER, 
OPEN-LABEL, CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF PEGCETACOPLAN 
IN PATIENTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA (PNH)
US IND No.: 123087 
EudraCT No.: 2018-004220-11 
Phase: 3  
Version: Amendment 3 
Date: 10 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. 


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INVESTIGATOR AGREEMENT 
Long Title:  
A Phase 3, Randomized, Multicenter, Open-Label, 
Controlled Study to Evaluate the Efficacy and 
Safety of Pegcetacoplan in Patients with 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Short Title:  
PRINCE 
Protocol Number, Version, and Date: 
10 August 2020  
Study Phase: 
Phase 3  
Sponsor Name and Address:  
Apellis Pharmaceuticals, Inc 
 
100 5th Ave 
Waltham, MA 02451 
USA  
Investigational Test Article:  
Pegcetacoplan (APL- 2)
US IND Number: 
123087  
EudraCT Number: 
2018-004220-11  
Indication Studied: 
PNH  
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) 


PPD
PPD
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 3: Summary of Changes From the Previous Version
Amendment date: 10 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 editorial and technical changes that did not impact content 
of the document have been made for grammar, clarity, and document 
usability. 
Entire document 
Removed language regarding an altitude correction factor for hemoglobin
because no subjects enrolled in the study live at altitudes 1000 meters 
above sea level. 
Synopsis, Section 4, Figure 2, 
Section 8, Section 9.1, 
Section 9.3, Section 10.2.3.3, 
Section 10.7, Section 11.1.1, 
formerly Appendix 5 
Added a section regarding the collection of COVID-19 test results. 
Section 12.8 
Updated the definition of an adverse event to be consistent with the new 
Apellis standard language. 
Section 13.1 
Updated the information regarding the recording of adverse events to be 
consistent with the new Apellis standard language. 
Section 13.2 
Removed Section 13.3 (Treatment and Follow-up of Adverse Events) 
because this information is now included in other updated sections. 
formerly Section 13.3 
Updated the information regarding the reporting of adverse events to be 
consistent with the new Apellis standard language and updated the section 
number from Section 13.4 to Section 13.3 given the removal of the 
original Section 13.3. 
Section 13.3 
Updated the information regarding serious adverse events to be consistent 
with the new Apellis standard language and updated the section number 
from Section 13.5 to Section 13.4. 
Section 13.4 
Removed Section 13.6 (Unexpected Adverse Events or Unexpected 
Suspected Adverse Reactions) because this information is now included in 
other updated sections. 
formerly Section 13.6 
Updated the information regarding pregnancy to be consistent with the 
new Apellis standard language and updated the section number from 
Section 13.7 to Section 13.5 
Section 13.5 
Added a new section, Section 13.6, regarding drug abuse, misuse, 
overdose, and medication error. 
Section 13.6 
Removed the reference related to the altitude correction factor. 
Section 16 


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Updated Appendix 4 (Amendment History) with the Amendment 2 
summary of changes. 
Appendix 4 
Removed Appendix 5 because it contained the altitude correction factor 
information that has been removed from the protocol. 
formerly Appendix 5 
The previously-labeled Appendix 6 (COVID-19 Changes) is now labeled 
Appendix 5 due to the removal of the previous Appendix 5. 
Appendix 5


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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.
SCHEDULE OF EVENTS .........................................................................................23
5.
INTRODUCTION ......................................................................................................29
5.1. 
Paroxysmal Nocturnal Hemoglobinuria .....................................................................29
5.2. 
Pegcetacoplan .............................................................................................................29
5.2.1.
Rationale for Treatment with Pegcetacoplan ......................................................30
5.2.2.
Summary of Clinical Experience .........................................................................30
6.
RATIONALE .............................................................................................................32
6.1. 
Purpose of the Study ...................................................................................................32
6.2. 
Dose Selection ............................................................................................................32
6.2.1.
Target Level of Pegcetacoplan Serum Concentration .........................................32
6.2.2.
Dosing Adjustment Option ..................................................................................33
6.3. 
Risk/Benefit ................................................................................................................33
7.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................36
7.1. 
Primary Objective .......................................................................................................36
7.2. 
Secondary Objectives .................................................................................................36
7.3. 
Exploratory Objectives ...............................................................................................37
8.
STUDY DESIGN .......................................................................................................38
9.
SUBJECT SELECTION .............................................................................................41
9.1. 
Inclusion Criteria ........................................................................................................41
9.1.1.
Approved Methods of Contraception ..................................................................41
9.2. 
Exclusion Criteria .......................................................................................................42
9.3. 
Randomization Criteria ...............................................................................................43
10.
STUDY TREATMENTS ............................................................................................44


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10.1. 
Identity of Investigational Product .............................................................................44
10.1.1.
Blinding the Treatment Assignment ...............................................................44
10.2. 
Administration of Investigational Product ..................................................................44
10.2.1.
Interactive Response Technology (IRT) for Investigational Product 
Management ...................................................................................................44
10.2.2.
Allocation to Treatment ..................................................................................44
10.2.3.
Pegcetacoplan Dosing .....................................................................................44
10.2.3.1. Pegcetacoplan Administration ......................................................................45
10.2.3.2. Pegcetacoplan Dose Adjustments ................................................................45
10.2.3.3. Pegcetacoplan Escape Therapy ....................................................................46
10.3. 
Labeling, Packaging, Storage, and Handling ..............................................................46
10.3.1.
Labeling ..........................................................................................................46
10.3.2.
Packaging ........................................................................................................47
10.3.3.
Infusion Supplies ............................................................................................47
10.3.4.
Storage ............................................................................................................47
10.4. 
Investigational Product Accountability ......................................................................47
10.5. 
Subject Compliance ....................................................................................................47
10.6. 
Control:  Standard of Care (Excluding Complement Inhibitors) ................................48
10.7. 
Transfusions ................................................................................................................48
10.8. 
Prior and Concomitant Treatment ..............................................................................48
10.9. 
Vaccination .................................................................................................................49
10.10. Prophylactic Antibiotics .............................................................................................50
10.11. Rescue Antibiotics ......................................................................................................50
11.
STUDY PROCEDURES ............................................................................................51
11.1. 
Screening Period:  Visit 1 (up to Week –4 [Day –28]) ...............................................51
11.1.1.
Hemoglobin Stability:  Randomization Criteria .............................................52
11.2. 
Randomized Controlled Period:  Visit 2 (Week 0) to Visit 15 (Week 26) .................54
11.2.1.
Visit 2:  Day 1 .................................................................................................54
11.2.2.
Visit 3 to Visit 15 (Week 2 to Week 26) ........................................................55
11.2.2.1. Pegcetacoplan Administration Training .......................................................56
11.2.2.2. Vaccination and Prophylactic Antibiotic Procedures ...................................56
11.3. 
Pegcetacoplan Initiation Visit (for SOC [Excluding Complement Inhibitors] 
Treatment Arm Failures) ......................................................................................56


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11.4. 
Follow-up (if Required):  Visit 16 (Week 28), Visit 17 (Week 30), and 
Visit 18 (Week 34) ................................................................................................57
11.5. 
Unscheduled Visits .....................................................................................................57
11.5.1.
Data Monitoring Committee ...........................................................................58
11.6. 
Treatment Discontinuation and Study Withdrawal ....................................................58
11.6.1.
Discontinuation of Subjects ............................................................................58
11.6.2.
Reasons for Discontinuation ...........................................................................59
11.6.3.
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ..........................59
12.
ASSESSMENTS .........................................................................................................60
12.1. 
Assessments ................................................................................................................60
12.1.1.
Medical History ..............................................................................................60
12.1.2.
Thrombosis History ........................................................................................60
12.1.3.
Transfusion History ........................................................................................60
12.1.4.
Body Height and Weight ................................................................................60
12.1.5.
Subject Demographics ....................................................................................60
12.1.6.
Physical Examination .....................................................................................60
12.1.7.
Vital Signs ......................................................................................................61
12.1.8.
Electrocardiogram Monitoring .......................................................................61
12.1.9.
Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue 
Scale ................................................................................................................61
12.1.10.
Linear Analog Scale Assessment (LASA) for Quality of Life .......................62
12.1.11.
European Organisation for Research and Treatment of Cancer 
(EORTC) 30-Item Quality of Life Questionnaire ..........................................62
12.1.12.
Clinical Laboratory Tests ...............................................................................62
12.1.12.1.Hematology ..................................................................................................62
12.1.12.2.Coagulation ..................................................................................................62
12.1.12.3.Serum Chemistry .........................................................................................63
12.1.12.4.Urinalysis .....................................................................................................63
12.1.12.5.Other Panels .................................................................................................63
12.1.12.6.Human Chorionic Gonadotropin (Serum Pregnancy Test) and 
Follicle-Stimulating Hormone ..................................................................63
12.1.13.
Infusion Site and Pump-Safety Assessment ...................................................64
12.2. 
Pharmacokinetic Assessments ....................................................................................64
12.2.1.
Blood Sampling and Processing .....................................................................64


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12.2.2.
Analytical Method ..........................................................................................64
12.3. 
Flow Cytometry Assessments .....................................................................................64
12.4. 
Pharmacodynamic Assessments .................................................................................65
12.5. 
Antidrug Antibody Assessment ..................................................................................65
12.6. 
Blood Volume for Study Assessments .......................................................................65
12.7. 
Pregnancy Tests ..........................................................................................................66
12.8. 
COVID-19 Assessment ..............................................................................................66
13.
ADVERSE EVENTS ..................................................................................................67
13.1. 
Definition ....................................................................................................................67
13.2. 
Recording Adverse Events .........................................................................................67
13.3. 
Reporting Adverse Events ..........................................................................................68
13.3.1.
Relationship of Events to Study Treatment ....................................................68
13.3.2.
Severity of Events ...........................................................................................69
13.4. 
Serious Adverse Events ..............................................................................................69
13.5. 
Pregnancy ...................................................................................................................69
13.6. 
Drug Abuse, Misuse, Overdose, and Medication Error ..............................................70
14.
DATA MANAGEMENT AND STATISTICAL METHODS ...................................71
14.1. 
Data Collection ...........................................................................................................71
14.2. 
Clinical Data Management .........................................................................................71
14.3. 
Statistical Analysis Process ........................................................................................71
14.4. 
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee .............................................................................................................71
14.5. 
Sample Size Justification ............................................................................................71
14.6. 
Preservation of Type 1 Error ......................................................................................72
14.7. 
Statistical Analysis Methodology ...............................................................................72
14.7.1.
Analysis Sets ...................................................................................................72
14.7.1.1. Screened Set .................................................................................................72
14.7.1.2. Safety Set ......................................................................................................72
14.7.1.3. Intent-to-Treat (ITT) Set ..............................................................................72
14.7.1.4. Modified Intent-To-Treat (mITT) Set ..........................................................73
14.7.1.5. Per-Protocol Set ............................................................................................73
14.7.1.6. Pharmacokinetic (PK) Set ............................................................................73
14.7.1.7. Pharmacodynamic (PD) Set .........................................................................73


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14.7.1.8. Data Review for Analysis Sets .....................................................................73
14.7.2.
Efficacy Analyses ...........................................................................................73
14.7.2.1. Primary Endpoints ........................................................................................73
14.7.2.2. Secondary Endpoints ....................................................................................74
14.7.3.
Safety Analyses ..............................................................................................75
14.7.3.1. Adverse Events .............................................................................................75
14.7.3.2. Clinical Laboratory Tests .............................................................................75
14.7.3.3. Vital Signs and ECGs ...................................................................................76
14.7.4.
Pharmacokinetic Analyses ..............................................................................76
14.7.5.
Pharmacodynamic Analyses ...........................................................................76
14.7.6.
Other Data Analyses .......................................................................................76
14.8. 
Direct Access to Source Data/Documents ..................................................................77
14.9. 
Quality Control and Quality Assurance ......................................................................77
14.9.1.
Monitoring ......................................................................................................77
15.
ETHICS ......................................................................................................................78
15.1. 
Ethical Conduct of the Study ......................................................................................78
15.2. 
Institutional Review Board/Ethics Committee ...........................................................78
15.3. 
Subject Information and Consent ...............................................................................78
15.4. 
Confidentiality ............................................................................................................78
15.5. 
ClinicalTrials.gov .......................................................................................................78
15.6. 
Termination of Study ..................................................................................................78
15.7. 
Data Handling and Record Keeping ...........................................................................79
15.8. 
Protocol Amendments ................................................................................................79
15.9. 
Report Format .............................................................................................................79
15.10. Finance and Insurance ................................................................................................79
15.11. Publication Policy .......................................................................................................79
16.
REFERENCES ...........................................................................................................81
17.
APPENDICES ............................................................................................................82
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LIST OF TABLES 
Table 1:  Blood Volume During Study ..........................................................................................65
LIST OF FIGURES 
Figure 1: 
Predicted PK profile (green line) at the planned dose of 1080 mg biw, 
compared to the summary PK data at the NOAEL (13CATX-004 [black 
line]), ongoing PNH study APL-CP0514 270 mg/day cohort (blue line) and 
healthy volunteer study APL2-101 for both the 360 mg/day (brown line) and 
1300 mg biw cohorts (light blue line). ........................................................................33
Figure 2: 
APL2-308 Study Design .............................................................................................38
Figure 3: 
Screening Period Hemoglobin Requirements for Visit 2 Eligibility ..........................53
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2.
SYNOPSIS
Protocol Number: 
APL2-308 
Protocol Title: 
A Phase 3, Randomized, Multicenter, Open-Label, Controlled Study to Evaluate the Efficacy and 
Safety of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Version Number:
Amendment 3 
Investigational Product, Dose, and Route of Administration: 
 Investigational Product: pegcetacoplan (also known as APL-2) 
 Doses: 
1080 mg twice weekly, or 
 1080 mg every 3 days (ie, a dose on every third day) 
 Route of Administration: Subcutaneous (SC) infusion 
Dose adjustment may be considered based on clinical response. 
Study Phase and Type: 
This is a multicenter, randomized, open-label, controlled, Phase 3 study.  
Number of Planned Subjects: 
54 randomized subjects: 
 pegcetacoplan:  36 subjects  
 standard of care (SOC), excluding complement inhibitors:  18 subjects 
Subjects must not have received treatment with a complement inhibitor for at least 3 months 
prior to screening.
Duration of Study Participation:  
The study consists of 3 periods. The maximum duration of subject participation will be 
approximately 38 weeks: 
 Screening Period:  up to 4 weeks 
 Randomized Controlled Period:  26 weeks 
 Safety Follow-up:  8 weeks 
Following the completion of the Randomized Controlled Period, subjects may be offered entry 
into an open-label extension study in order to continue to receive treatment with pegcetacoplan. 
These subjects will not complete the Safety Follow-up procedures for this study but will enter 
the extension study at the conclusion of the Randomized Controlled Period. 


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Rationale for the Study:
Phase 1 clinical experience has demonstrated that pegcetacoplan provides sustained inhibition of 
hemolytic activity in PNH patients who have never received treatment with a complement 
inhibitor (eg, eculizumab; Study APL2-CP-PNH-204 [Paddock]). To date, no safety signals have 
emerged from ongoing studies in PNH patients that preclude further development. Thus, this 
proposed Phase 3 study is to further evaluate treatment efficacy and safety of pegcetacoplan as 
monotherapy in patients with PNH. 
Study Objectives and Endpoints:  
Primary Objective 
The primary objective of this study is to evaluate the efficacy of pegcetacoplan, compared to 
SOC (excluding complement inhibitors), in patients with PNH, as assessed by:  
 Hemoglobin stabilization defined as avoidance of a >1-g/dL decrease in Hb levels 
from baseline in the absence of transfusion through Week 26 (Yes/No) 
AND 
 Reduction in lactate dehydrogenase (LDH) level from baseline to Week 26 
Secondary Objectives 
Secondary objectives of this study are:  
 To evaluate the efficacy of pegcetacoplan, compared to SOC (excluding complement 
inhibitors), as assessed by: 
Hemoglobin response (Yes/No) in the absence of transfusions (Hb response is 
-g/dL increase in Hb from baseline at Week 26) 
Change from baseline to Week 26 in absolute reticulocyte count (ARC)  
Change from baseline to Week 26 in Hb level  
 Number of packed red blood cell (PRBC) units transfused from baseline to 
Week 26 
 Change from baseline to Week 26 in Functional Assessment of Chronic Illness 
Therapy (FACIT)–Fatigue Scale score
 × the upper limit of normal [ULN]) 
from baseline to Week 26 in the absence of transfusions (Yes/No) 
 Normalization of LDH levels of 
× ULN from Week 4 to Week 26 (Yes/No) 
 Change from baseline to Week 26 in European Organization for Research and 
Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire 
(QLQ-C30) scores (version 3) 
Change from baseline to Week 26 in Linear Analog Assessment (LASA) scale 
scores


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Absolute reticulocyte count normalization (<1 × ULN) at Week 26 (Yes/No) 
 Time to failure of Hb stabilization  
Time to transfusion 
To evaluate the safety of pegcetacoplan as assessed by:
Incidence and severity of treatment-emergent adverse events (TEAEs)
Incidence of thromboembolic events 
Changes from baseline in laboratory parameters 
 Changes from baseline in electrocardiogram (ECG) parameters 
Incidence of anti-pegcetacoplan antibodies 
Exploratory Objectives
Exploratory objectives of the study are to evaluate: 
 
 
 Pegcetacoplan pharmacokinetic/pharmacodynamic (PK/PD), as assessed by:
Pegcetacoplan PK concentrations from baseline to Week 26 
Change from baseline to Week 26 in PNH clone distribution (red blood cells 
[RBCs] and white blood cells [WBCs]) 
Change from baseline to Week 26 in complement component 3 (C3) deposition in 
PNH Type II and III RBCs  
Complement levels from baseline to Week 26 (eg, total hemolytic complement 
activity assay [CH50], alternate complement pathway assay [AH50], and C3) 
Study Design: 
This is a prospective, randomized, multicenter, open-label, controlled study. Following 
screening, subjects will complete biweekly (biw) visits from Week 0 to Week 26. Subjects will 
be randomized either to pegcetacoplan or SOC (excluding complement inhibitors). Subjects 
randomized to the SOC (excluding complement inhibitors) treatment arm may receive 
2 g/dL below their baseline value.  
Inclusion Criteria 
At Visit 1 screening, subjects must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
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1. Be at least 18 years old (inclusive).
2. 
× ULN at the screening visit.
3. Have PNH diagnosis, confirmed by high sensitivity flow cytometry (granulocyte or 
monocyte clone >10%). 
4. Have Hb less than the lower limit of normal (LLN) at the screening visit.  
5. Have ferritin greater than/equal to the LLN, or total iron binding capacity (TIBC) less 
than/equal to ULN at the screening visit, based on central laboratory reference ranges. If 
a subject is receiving iron supplements at screening, the investigator must ensure that the 
subject’s dose has been stable for 4 weeks prior to screening, and it must be maintained 
throughout the study. Subjects not receiving iron at screening must not start iron 
supplementation during the course of the study. 
6. Body mass index (BMI) 35 kg/m2 at the screening visit.
7. Have a platelet count of >50,000/mm3 at the screening visit. 
8. Have an absolute neutrophil count >500/mm3 at the screening visit. 
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test at 
screening and must agree to use protocol-defined methods of contraception for the 
duration of the study and for 90 days after their last dose of study drug. 
10. Males must agree to use protocol-defined methods of contraception and agree to refrain 
from donating sperm for the duration of the study and for 90 days after their last dose of 
study drug. 
11. Have vaccination against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, 
W, Y, and B), and Haemophilus influenzae (type B) either within 2 years prior to Day 1 
dosing, or agree to receive vaccination 14 days after starting treatment with 
pegcetacoplan (along with prophylactic antibiotic therapy for at least the 14 days between 
pegcetacoplan treatment initiation and vaccination and 14 days post vaccination).  
Vaccination is mandatory, unless documented evidence exists that subjects are 
nonresponders to vaccination (as evidenced by titers or display titer levels within 
acceptable local limits).  
12. Be willing and able to give informed consent. 
Exclusion Criteria
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening:
1. Treatment with any complement inhibitor (eg, eculizumab) within 3 months prior to 
screening.  
2. Hereditary complement deficiency. 
3. History of bone marrow transplantation. 
4. Concomitant use of any of the following medications is prohibited if not on a stable 
regimen for the time period indicated below prior to screening: 


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 Erythropoietin or immunosuppressants for at least 8 weeks 
 Systemic corticosteroids for at least 4 weeks 
Vitamin K antagonists (eg, warfarin) with a stable international normalized ratio 
(INR) for at least 4 weeks 
 Iron supplements, vitamin B12 or folic acid for at least 4 weeks 
Low-molecular-weight heparin for at least 4 weeks 
5. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to 
the investigational product or SC administration. 
6. Participation in any other investigational drug trial or exposure to other investigational 
agent, device, or procedure within 30 days or 5 half-lives, whichever is longer. 
7. Planning to become pregnant or currently a breastfeeding woman. 
8. History of meningococcal disease. 
9. Any comorbidity or condition (such as malignancy) that, in the opinion of the 
investigator, could put the subject at increased risk or potentially confound study data. 
Randomization Criteria 
At Visit 2 (Day 1), subjects must meet the following criteria in order to be randomized: 
10. 
9 g/dL, or Hb <9 g/
7 g/dL without signs or symptoms 
of sufficient severity to warrant a transfusion.
11. Negative urine pregnancy test for WOCBP. 
12. No active systemic bacterial, viral, or fungal infection within the 2-week period prior to 
receiving treatment with pegcetacoplan.
Sample Size Justification: 
A total of 48 randomized subjects (32 subjects to pegcetacoplan and 16 subjects to SOC) are 
required to achieve 90% power, at the 5% significance level (2-sided), using a 2-group Fisher's 
exact test with unequal allocation 2:1 to treatment groups (pegcetacoplan and SOC). Calculation 
assumes an increase of 45% in the proportion of subjects achieving Hb stabilization with 
pegcetacoplan compared to SOC (ie, a change from 5% [no treatment] to 50% [pegcetacoplan]). 
With the same number of subjects and an effect size of at least 1.2, the study will be at 96% for 
the LDH reduction endpoint. 
To account for loss of power due to discontinuations, the study will attempt to randomize 
54 subjects.
Statistical Methods:
Analysis Sets
Screened Set 
The screened set will include all subjects who signed the informed consent form (ICF). This set 
will be used only for the purpose of describing subject disposition.  


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Safety Set
The safety set will include all subjects who receive at least 1 dose of study medication 
(pegcetacoplan), or subjects who are randomized to SOC (excluding complement inhibitors). 
Subjects will be analyzed according to the treatment they received.  
Intent-to-Treat (ITT) Set 
The ITT set will include all randomized subjects. Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received. 
Modified Intent-To-Treat (mITT) Set 
The mITT will include all subjects in the ITT set who continue study treatment beyond Visit 4 
(Week 4). 
Per-Protocol (PP) Set
The per-protocol (PP) set will include all subjects in the ITT set who have not violated any 
inclusion or exclusion criteria and/or deviated from the protocol in a way that could influence 
their efficacy assessment. Decisions concerning the exclusion of subjects from the PP analysis 
set will be made and documented prior to database lock. 
Pharmacokinetic (PK) Set 
The PK population will include all subjects in the ITT Set who receive pegcetacoplan and have 
at least 1 evaluable postdose- PK measurement.
Pharmacodynamic (PD) Set
The PD population will include all subjects in the ITT set who have at least 1 evaluable 
postdose- PD measurement. 
Efficacy Analyses 
The efficacy endpoints will primarily be evaluated with the ITT set. All statistical testing will be 
at the 5% level of significance (2-sided) and all point estimates for the comparison between 
treatment groups will be accompanied by 2-sided 95% confidence intervals (CIs). 
All possible efforts will be made to ensure that subjects complete all the required assessments.  
Endpoints will be summarized and, where appropriate, plotted over time for each treatment 
group.  
Baseline assessments will be performed on Day 1 prior to the start of study treatment for subjects 
randomized to pegcetacoplan and at Day 1 for subjects randomized to SOC. 
Co-Primary Endpoints 
The co-primary efficacy endpoints will be analyzed, based on the ITT set.  


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The co-primary efficacy endpoints are:
1 g/dL in Hb levels from baseline 
to Week 26 in the absence of transfusions (Yes/No)
AND 
 Reduction in lactate dehydrogenase (LDH) level from baseline to Week 26   
For the first co-primary endpoint, the number and percentage of subjects who achieve Hb 
stabilization will be computed for treatment groups and compared between treatment groups 
using a stratified Cochran-Mantel-Haenszel (CMH) chi-square test. The treatment difference in 
percentages and 95% CI for the difference will be presented using the stratified Miettinen-
Nurminen method.  
Subjects who receive a transfusion through Week 26 or withdraw from the study before 
providing primary efficacy assessment will be categorized as failing to achieve Hb stabilization.
The second co-primary endpoint, change from baseline to Week 26 in LDH, will be analyzed 
using mixed model for repeated measures (MMRM) with:  the effects of treatment; stratification 
randomization; visit, visit-by-treatment interaction; baseline LDH level and baseline LDH level-
by-visit interaction using an unstructured covariance matrix.  The difference between treatment 
groups will be estimated, along with its 95% CI and p-value.  
All the subjects LDH levels prior to transfusion and/or switch to pegcetacoplan will be included 
in the model.
As missing data may potentially bias the outcome of the statistical analyses and the subsequent 
estimation of the magnitude of the treatment effect, the following sensitivity and supportive 
analyses will be performed to evaluate the robustness of the results from the primary analysis 
methods: 
 The first co-primary efficacy endpoint will also be analyzed using a logistic 
regression with the effects of treatment group and stratification factors included. The 
odds ratio of being an Hb stabilization achiever the pegcetacoplan versus SOC group 
and associated 95% CI will be estimated from the final model.
The second co-primary endpoint will be analyzed using an analysis of covariance 
(ANCOVA) model (ITT set) with a last observation carried forward (LOCF) 
approach for handling missing data. The ANCOVA model will include terms for 
treatment, stratification factors, and baseline LDH level.
The second co-primary endpoint will be analyzed using an ANCOVA model (ITT 
Set) with a best observation carried forward (BOCF) approach for handling missing 
data. The ANCOVA model will include terms for treatment, stratification factors, and 
baseline LDH level. 
 Analyses will be repeated using the mITT and PP sets. 
Secondary Endpoints 
The secondary endpoints will be analyzed using the ITT set and will be repeated using the PP 
set. 


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Summary statistics by randomization strata and by treatment groups will presented at each 
assessment visit during the 26-week randomized treatment period.  
Continuous endpoints will be analyzed using MMRM with the effects of:  treatment; 
stratification factors; visit, visit-by-treatment interaction; the relevant baseline level; and the 
Baseline level-by-visit interaction using an unstructured covariance matrix. The difference 
between treatment groups will be estimated, along with its 95% CI and p-value. If a subject 
receives a transfusion during his/her treatment period, the pre-transfusion Hb values, reticulocyte 
values, and FACIT-Fatigue Scale score will be used in the model.  
For categorical endpoints, the number and percentage of subjects will be tabulated by treatment 
group and compared between treatment groups using a stratified CMH chi-square test. 
Kaplan-Meier plots will be presented for time-to-event endpoints for each treatment group, and 
survival estimates will be provided. 
The number of units of PRBCs transfused will be compared between the treatment groups using 
a Wilcoxon rank-sum test. The difference between the medians will be estimated along with its 
95% CI (stratified). Subjects who withdraw before Week 26 will have the number of units 
estimated from the duration that they were in the study (ie, number per week × 12). This equates 
to an analysis of the frequency of transfusions.  
Safety Analyses
Safety analyses will be based on the safety set.
Safety measures assessed at study visits, including vital signs (temperature, systolic and diastolic 
blood pressures, pulse, and respiratory rate), clinical laboratory results, ECGs and 
anti-pegcetacoplan antibodies will be descriptively summarized by treatment group at baseline 
and for each postbaseline visit. Absolute values and changes from baseline will be summarized. 


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3.
ABBREVIATIONS
Term
Definition
51Cr 
chromium 51 
ADA 
antidrug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AH50 
alternate complement pathway assay 
AIV 
pegcetacoplan initiation visit 
ANCOVA 
analysis of covariance 
ARC 
absolute reticulocyte count 
biw 
twice weekly administration 
BMI 
body mass index 
BOCF 
best observation carried forward 
C3 
complement component 3 
CD71+ 
transferrin receptor 
CH50 
total hemolytic complement activity assay
CI 
confidence interval 
Cmax 
maximum drug plasma concentration 
CMH 
Cochran-Mantel-Haenszel (chi-square test) 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EORTC 
European Organisation for Research and Treatment of Cancer 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials (database) 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GLP 
good laboratory practice 
Hb 
hemoglobin 
Hib 
Haemophilus influenzae Type B (vaccine) 


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Term 
Definition 
HV
healthy volunteer
IB 
investigator’s brochure 
ICH 
International Council for Harmonisation 
ICF 
informed consent form 
IEC 
institutional ethics committee 
IND 
investigational new drug application 
INR 
international normalized ratio 
IRB 
institutional review board  
IRT 
interactive response technology 
ITT 
intent-to-treat (population) 
LASA 
Linear Analog Assessment Scale 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MAC 
membrane attack complex 
MAVE 
major adverse vascular event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat (population) 
MMRM 
mixed model repeated measures 
NOAEL 
no observed adverse effect level 
PCV13 
pneumococcal conjugate vaccine 
PD 
pharmacodynamic(s) 
PEG 
polyethylene glycol 
PI  
principal investigator  
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
per-protocol (set) 
PPSV23 
pneumococcal polysaccharide vaccine 23  
PRBC 
packed red blood cells 
PT 
prothrombin time 
QLQ-C30 
30-item Core Quality of Life Questionnaire 
QoL 
quality of life 
QTc 
corrected QT interval 


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Term 
Definition 
QTcB
Bazett’s corrected QT interval
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SOC 
standard of care 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TMDD 
target-mediated drug disposition 
ULN 
upper limit of normal 
USA 
United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman/women of childbearing potential 


Pegcetacoplan
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4. 
SCHEDULE OF EVENTS 
Study period
Screen
-ingA
Randomized controlled period 
Follow upB 
AIVC 
Study week 
Up to 
–4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study day
Up to
–28
1 
15
29
43
57
71 
85 
99 
113
127 
141 
155 
169 
183 
197 
211 
239 
--
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
15 
16 
17
18
-- 
Clinic visit window 
(±days) 
N/A
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
--
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
Height/weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombosis history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion
X 
Confirm Hb entry criteriaD
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
 
 
XE 
E 
XE 
E 
 
 
Preventive antibioticsF 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical examinationG
X 
X 
X 
X 
X 
X 
X 
CCI
C
C
I


Pegcetacoplan
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10 Aug 2020 
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Study period 
Screen
-ingA 
Randomized controlled period 
Follow upB 
AIVC 
Study week
Up to
–4 
0 
2 
4 
6 
8 
10
12
14
16
18
20
22
24
26
28
30
34
--
Study day 
Up to 
–28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
15 
16 
17
18
-- 
Clinic visit window 
(±days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
12-lead electrocardiogramH 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
APL-2 administration trainingI 
 
X 
I 
 
 
 
X 
APL-2 administrationI 
 
 
X 
 
 
 
X 
Concomitant medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurementsJ
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
BloodK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PharmacokineticsL 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
Anti-APL-2 Ab assay L 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
Direct Antibody Test (Coombs)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lactate dehydrogenase
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistryS
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Absolute reticulocyte count
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profileM
X 
X 
X 
X 
X 
X
X 
X
X 


Pegcetacoplan
APL2-308 Protocol Amendment 3 
10 Aug 2020 
Apellis Pharmaceuticals, Inc 
Page 25 of 106 
Confidential 
Study period 
Screen
-ingA 
Randomized controlled period 
Follow upB 
AIVC 
Study week
Up to
–4 
0 
2 
4 
6 
8 
10
12
14
16
18
20
22
24
26
28
30
34
--
Study day 
Up to 
–28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
15 
16 
17
18
-- 
Clinic visit window 
(±days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Complement profile T 
(CH50, and AH50) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
C3 Profile T 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry T 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Plasma (free) Hb
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy ( -HCG) or FSHN 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping for Gilbert’s 
SyndromeO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACIT-Fatigue Scale 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
LASA Scale
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsQ
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense investigational 
productr, 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 


Pegcetacoplan
APL2-308 Protocol Amendment 3 
10 Aug 2020 
Apellis Pharmaceuticals, Inc 
Page 26 of 106 
Confidential 
Study period 
Screen
-ingA 
Randomized controlled period 
Follow upB 
AIVC 
Study week
Up to
–4 
0 
2 
4 
6 
8 
10
12
14
16
18
20
22
24
26
28
30
34
--
Study day 
Up to 
–28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
15 
16 
17
18
-- 
Clinic visit window 
(±days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Return investigational product
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations:  Ab = antibodies; AE = adverse event; AH50 = alternate complement pathway assay; AIV = APL-2 Initiation Visit; APL-2 = pegcetacoplan; -
HCG = beta-human chorionic gonadotropin; C3 = complement component 3; CH50 = total hemolytic complement activity assay; COVID-19 = coronavirus 
disease 2019; CRFs = case report forms; ECG = electrocardiogram; eCRF = electronic case report form; EORTC-QLQ-C30 = 30-item European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire; FACIT = Functional Assessment of Chronic Illness Therapy; FSH = follicle-stimulating 
hormone; Hb = hemoglobin; LASA = Linear Analog Assessment Scale; N/A = not applicable; PCV13 = pneumococcal conjugate vaccine (13-valent); PI = principal 
investigator; PK = pharmacokinetic(s); PPSV23 = pneumococcal polysaccharide vaccine (23-valent); PRBC = packed red blood cell; QTc = corrected QT 
interval; QTcF = Fridericia’s corrected QT interval; SC subcutaneous; SOC = standard of care; WOCBP = women of childbearing potential. 
A Within 5 days prior to Visit 2 (Week 0), each subject’s Hb must be evaluated by a local or central laboratory. If the subject meets the protocol-specified 
transfusion criteria, the subject must receive a PRBC transfusion so that the subject’s Hb levels no longer meets the protocol-specified requirements for PRBC 
transfusion. The posttransfusion Hb value should be confirmed by a local or central laboratory. Patients must not be randomized if they meet the protocol-
specified requirements for transfusion, and the Hb assessment to confirm eligibility should be scheduled so that the subject does not fall outside the screening 
window (up to Day –28). All Hb levels must be recorded in the eCRF.
B All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label extension study will be asked to return to the investigator site for 
the Visit 16 (Week 28), Visit 17 (Week 30), and Visit 18 (Week 34) follow-up visits.  Subjects who discontinue treatment will be encouraged to continue to 
attend study visits to complete study assessments (except for treatment with pegcetacoplan) as detailed in the Schedule of Events. At minimum, subjects who 
discontinue dosing should complete follow-up procedures outlined in the Schedule of Events 2, 4, and 8 weeks after treatment discontinuation. If withdrawal of 
pegcetacoplan treatment is necessary, slow weaning should be considered and subjects should carefully be monitored for at least 8 weeks to detect serious 
hemolysis or other complications, as detailed in the investigator’s brochure. 
C Following Visit 2 (Week 0), subjects assigned to the SOC (excluding complement inhibitors) treatment arm who have a Hb level measured by the central  
laboratory (or local laboratory if necessary due to COVID-19) that is 2 g/dL below the baseline value will be switched to escape therapy with pegcetacoplan.  
These subjects will return to the site for a pegcetacoplan initiation visit. Following the pegcetacoplan initiation visit, subjects will maintain their regular visit 
schedule. 
D T
-Visit 2 Hb qualification assessment must be assessed to confirm subject eligibility at Visit 2 before the subject can be randomized into the 
study. 


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E In order to receive treatment with pegcetacoplan, subjects must have documented evidence of vaccination against the following within 2 years of screening: 
Neisseria meningitidis types A, C, W, Y, and B (administered as 2 separate vaccinations), Streptococcus pneumoniae (with a PCV13 or PPSV23 vaccine), and 
Haemophilus influenzae type B (Hib vaccine).  
Subjects randomized to pegcetacoplan: For subjects randomized to pegcetacoplan who do not have documented evidence of receiving any of the above 
vaccinations within 2 years prior to screening, the required missing vaccination(s) will be administered at Visit 3 (Week 2), prior to dosing with 
pegcetacoplan (along with boosters administered during the study at or after Visit 7 [Week 10], if required [see below]). Vaccination is mandatory, unless 
documented evidence exists that subjects are nonresponders to vaccination (as evidenced by titers or display titer levels within acceptable local limits). The PI 
will discuss with the sponsor regarding individual patient circumstances.  
If the subject requires vaccination against Neisseria meningitidis, a booster (for both vaccinations) should be administered after at least 8 weeks (Visit 7). If the 
subject requires vaccination against Streptococcus pneumoniae, PCV13 will be administered at Visit 3, and PPSV23 will be administered after at least 
8 weeks (Visit 7). 
Subjects randomized to SOC (excluding complement inhibitors): Subjects who are initially randomized to SOC (excluding complement inhibitors) who 
become eligible for pegcetacoplan escape therapy will receive any required vaccination(s) 2 weeks after initiation of treatment with pegcetacoplan. If 
required, as detailed above), the Neisseria meningitidis booster (for both vaccinations), and/or PPSV23 vaccination should be administered at least 8 weeks 
following the initial vaccination(s).      
F  In order to receive treatment with pegcetacoplan, subjects will require preventive antibiotics if they need to be vaccinated, as detailed in Footnote E above. In 
addition, subjects who do not require vaccination are recommended to receive preventive antibiotic therapy, as detailed below.  
Subjects randomized to pegcetacoplan: Subjects will be required to take ciprofloxacin 500 mg twice daily from Visit 2 (Day 1) to Visit 3 (Week 2) and 
continue to receive antibiotic prophylaxis until at least 14 days post vaccination. From that point forward, it is recommended that all subjects take penicillin V 
500 mg twice daily through the course of pegcetacoplan treatment.  
Subjects randomized to SOC (excluding complement inhibitors):  Subjects who are initially randomized to SOC (excluding complement inhibitors) do not 
need to initiate preventive antibiotic therapy at Day 1. If a subject becomes eligible for and initiates pegcetacoplan escape therapy, the subject should take 
ciprofloxacin 500 mg twice daily for 2 weeks, beginning on the first day of treatment with pegcetacoplan and continue to receive antibiotic prophylaxis until 
at least 14 days post vaccination. After 2 weeks of ciprofloxacin, it is recommended that subjects take penicillin V 500 mg twice daily through the course of 
pegcetacoplan treatment. 
G A full physical examination should be conducted, as indicated by the study schedule. A symptom-driven physical examination may be performed at other 
visits, at the PI’s discretion. 
H Triplicate 12-lead ECGs are to be performed within 1 hour predose at Visit 2 (Day 1).  Triplicate 12-lead ECGs will be performed prior to dosing at all other 
visits, if pegcetacoplan administration is occurring at the study site.  During the study, if the QTcF at any on-
 ms (mean of QTcF 
replicate values), the investigator should perform 3 additional ECGs over 20-60 minutes; if the mean QTcF of the 3 
 ms, the site should 
instruct the subject to return the following day to perform repeat triplicate ECGs.  An evaluation will be performed to look for other factors which may have 
contributed to QTc prolongation (eg, new concomitant medications, hypokalemia, etc.). 
I Subjects randomized to pegcetacoplan: For subjects randomized to the pegcetacoplan treatment arm, research nurses or other appropriately qualified 
research personnel will administer the first pegcetacoplan SC infusion at Visit 2 (Day 1) and will train subjects on how to self-administer. Following Visit 2, 
appropriately qualified research personnel will supervise self-administration of pegcetacoplan for at least the following 3 doses (which will be administered 
prior to Visit 3). Supervision of self-administration may be conducted at the subject’s home, at the study site, or at an off-site location convenient for the 
subject. Supervision of self-administration must continue until the subject is qualified to self-administer. 
Following self-administration qualification, subjects may self-administer pegcetacoplan SC infusions without supervision. Subjects may continue to self-
administer infusions at the study site on those days when a study visit occurs, but this is not required. Self-administration conducted at the study site will be 


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Page 28 of 106 
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supervised to ensure that the subject continues to remain compliant with the administration guidelines. On all other days, subjects may self-administer at 
home, at the study site, or at an off-site location convenient to the subject. 
Subjects randomized to SOC (excluding complement inhibitors):  Subjects randomized to the SOC (excluding complement inhibitor) treatment arm that are 
assigned to pegcetacoplan escape therapy during the study will have research nurses or other appropriately qualified research personnel administer the first 
pegcetacoplan SC infusion and provide self-administration training at the study visit in which pegcetacoplan escape therapy is initiated.  Following this visit, 
appropriately qualified research personnel will supervise self-administration of pegcetacoplan for at least the following 3 doses at the subject’s home, the study 
site, or an off-site location convenient for the subject. Supervision of self-administration must continue until the subject is qualified to self-administer, and 
pegcetacoplan will be self-administered and supervised at the study site on days of study visits, if the subject elects to administer pegcetacoplan during the 
study visit. 
J Vital signs will be measured before venipuncture and ECG.  Monitoring of vital signs will occur at Visit 2 (Day 1) predose and 2 hours post dose 
(±30 minutes).  In addition, monitoring of vital signs will occur predose and 2 hours post dose (±30 minutes) during the pegcetacoplan Initiation Visit, if 
applicable.  At all other visits, if the subject elects to administer pegcetacoplan during the visit, vital signs should be measured predose. 
K If pegcetacoplan will be administered at the study visit, blood samples must be taken predose. The date and time of the last dose of pegcetacoplan should be 
recorded on the eCRF, as well as the date and time of the blood sample draw (to be used for PK analysis). 
L  Samples for PK and anti-pegcetacoplan assay assessments should not be collected for subjects randomized to the SOC (excluding complement inhibitors) 
treatment arm unless they become eligible for and elect to receive pegcetacoplan escape therapy. If a subject from the SOC (excluding complement inhibitors) 
treatment arm is to begin receiving pegcetacoplan escape therapy, a predose PK sample should be collected at the pegcetacoplan initiation visit and at each 
subsequent visit, as detailed in the Schedule of Events.  
M The use of silica reagents in coagulation panels should be avoided in subjects treated with pegcetacoplan. 
N -HCG for WOCBP; FSH for postmenopausal women. 
O Sample for genotyping to be obtained via buccal swab test completed at the Screening Visit.  
P  Urine pregnancy test should be completed for WOCBP prior to dosing on Day 1. 
Q On the days of clinic visits, an assessment of the pegcetacoplan infusion site will be made as a part of the AE assessment. If pegcetacoplan is administered at 
the visit, the site staff will observe the dosing and pump-use safety will be assessed and the infusion site will be checked again within 30 minutes after study 
drug administration. The infusion site assessments will be performed by an appropriately trained staff, as delegated by the investigator. The infusion site and 
surrounding area will be inspected for redness, swelling, induration, and bruising. The subject will be asked about the presence of pain and/or tenderness, and 
any issue related to pump use. The date, time, and outcome of the infusion-site assessment will be recorded on the source documents and CRFs. Subjects will 
be instructed to notify the PI or other study personnel in the event that an infusion site reaction occurs after self-administration of APL 2. All clinically relevant 
AEs, as determined by the investigator, from infusion site or related to pump use will be recorded as AEs. 
R Subjects randomized to pegcetacoplan treatment arm or receiving pegcetacoplan escape therapy only. Dispensation will depend on the subject’s dose regimen. 
Please consult the dispensation schedule. 
S  Hb, LDH, and reticulocyte count should be collected PRIOR to any transfusion. The assessment may be performed at a central or certified local laboratory. 
T Samples for PD assessments (Complement profile, C3 Profile, and Flow Cytometry) should be collected for subjects randomized both to the SOC (excluding   
complement inhibitors) and pegcetacoplan treatment arms.  


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5.
INTRODUCTION
This study is being conducted as part of a series of studies for the clinical development of 
pegcetacoplan. The study will be conducted in compliance with the protocol, Good Clinical 
Practice (GCP), and applicable regulatory requirements. The subject population will comprise 
adult male and female subjects with paroxysmal nocturnal hemoglobinuria (PNH). 
5.1.
Paroxysmal Nocturnal Hemoglobinuria
PNH is an acquired, rare, clonal, nonmalignant hematologic disease characterized by 
complement-mediated red blood cell (RBC) hemolysis, with or without hemoglobinuria, an 
increased susceptibility to thrombotic episodes, and/or some degree of bone marrow dysfunction. 
The onset of PNH is often insidious. Although there have been reports of spontaneous remission, 
the course of the disease is generally chronically progressive. 
It has been known for many years that PNH is caused by complement-mediated lysis of 
erythrocyte clones lacking functional CD55 and CD59 on their surface to protect them against 
this process. As such, these erythrocytes are particularly susceptible to the membrane attack 
complex (MAC) and have been shown to lyse readily in the presence of complement activation. 
Any therapy that effectively inhibits MAC formation is anticipated to be a plausible 
candidate-treatment for PNH. Eculizumab is a monoclonal anti-C5 antibody that inhibits the 
formation of the MAC, and eculizumab treatment has been approved for the treatment of this 
serious condition. However, inhibition of MAC formation does not appear to be sufficient to fully 
control the disease, as many PNH patients receiving eculizumab treatment still suffer from anemia, 
with only roughly 13% of patients being classified as complete responders (ie, achieving 
transfusion independence and normal hemoglobin [Hb] levels). Most of the patients (53%) were 
classified as partial responders with decreased transfusion needs and reduced lactate 
dehydrogenase (LDH), and 33% of patients were poor responders, with unchanged transfusion 
needs and persistent symptoms (DeZern et al. 2013).
Recent studies have suggested that significant opsonization of PNH erythrocytes by complement 
component 3 (C3) fragments is observed in patients receiving eculizumab treatment. This 
opsonization is believed to cause the removal of erythrocytes by the spleen and the liver, 
resulting in extravascular hemolysis. Extravascular hemolysis can be significant in a subset of 
eculizumab-treated PNH patients and is considered to be the principal contributor to the lack of 
complete eculizumab response in most patients.  
5.2. 
Pegcetacoplan 
Pegcetacoplan (also known as APL-2) is formed by a pentadecapeptide (combining a bioactive 
cyclic tridecapeptide C3-inhibiting moiety and a 2–amino acid linker) covalently coupled to each 
end of a linear 40-kDa polyethylene glycol (PEG) chain, so that 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 


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multiple inflammatory processes. The PEGylation of the molecule imparts slower elimination 
from mammalian systems following administration.  
Pegcetacoplan infusion (drug product) is a solution of pegcetacoplan in 5% dextrose or a solution 
of pegcetacoplan in acetate-buffered mannitol or a solution of pegcetacoplan in acetate-buffered 
sorbitol for subcutaneous (SC) administration. Pegcetacoplan is being developed for the 
treatment of PNH. 
Further details can be found in the current version of the pegcetacoplan investigator’s brochure 
(IB). 
5.2.1. 
Rationale for Treatment with Pegcetacoplan 
Extravascular hemolysis, one of the parameters contributing to the ongoing need for RBC 
transfusions despite eculizumab therapy, is believed to be mediated by C3b opsonization rather 
than C5-dependent MAC-mediated intravascular hemolysis (Risitano et al. 2009).  While 
eculizumab is effective in addressing CD59 deficiency by preventing C5-dependent 
MAC-mediated hemolysis, PNH cells are also deficient in CD55, which normally accelerates the 
dissociation of C3-convertase enzymes, inhibiting the production of C3 fragments and 
subsequent opsonization. As a result, in the setting of eculizumab therapy, surviving PNH RBCs 
become opsonized with C3b, targeting them for clearance through extravascular hemolysis by 
macrophages bearing complement receptors in the liver and spleen.
Evidence for C3b-mediated extravascular hemolysis was observed in 3 patients exhibiting a 
“suboptimal hematologic response [to eculizumab] and massive C3 RBC binding” using 
chromium-51 (51Cr)–labeled RBCs. Although these subjects were still receiving eculizumab and 
had normal LDH levels, they demonstrated markedly reduced RBC half-lives (10, 11, and 
13 days, with a normal range of 25-35 days) and excess counts on images of the spleen and liver 
(Risitano et al.  2009). In contrast, C3b opsonization of RBCs is not observed in PNH patients 
who have not been treated with eculizumab, presumably because RBCs in these patients are 
rapidly lysed by MAC (Risitano et al. 2009).
In summary, while C5 inhibition has had a dramatic positive impact on the lives of many PNH 
patients, anti-C5 therapy has also led to the emergence of a subpopulation of PNH patients with 
persistent extravascular hemolysis and RBC transfusion requirements, despite continuous 
eculizumab therapy, that appear to result at least in part from C3b opsonization of RBCs.  It is 
reasonable, therefore, to expect that a treatment able to inhibit both MAC formation and C3 
opsonization will provide improved therapeutic benefit to PNH patients, compared to 
eculizumab.
5.2.2.
Summary of Clinical Experience
Clinical data from studies with pegcetacoplan in subjects with PNH indicates that pegcetacoplan
is effective in providing broad control of intravascular and extravascular hemolysis, as evidenced 
by increased and stable Hb levels, along with improvement in Functional Assessment of Chronic 
Illness Therapy- (FACIT-) Fatigue Scale score, normalization of LDH, normalization of absolute 
reticulocyte count (ARC), normalization of total bilirubin levels, along with reduction in C3 
fragment opsonization and increased numbers of PNH RBCs.  To date, pegcetacoplan at doses of 
270 mg/dL has been generally safe and well tolerated when administered via SC infusion. No 


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expected serious adverse drug reactions (ADRs) have been identified, and no deaths have 
occurred that are considered related to treatment with pegcetacoplan. 
Results from the Phase 3 APL2-302, a randomized, multicenter, open-label, active-comparator 
controlled study in adults with PNH, showed that pegcetacoplan at a dose of 1080 mg SC every 
2 weeks controlled the hematologic manifestations of PNH, with superiority for control of 
anemia, as compared with the C5 inhibitor, eculizumab. Pegcetacoplan was superior to 
eculizumab with regard to change from baseline (CFB) in Hb level. At Week 16, the 
pegcetacoplan group (n = 41) had an adjusted mean hemoglobin CFB of 2.4 g/dL from a baseline 
of 8.7 g/dL, compared to the eculizumab group (n = 39) who had a CFB of –1.5 g/dL from a 
baseline of 8.7 g/dL, resulting in a 3.8 g/dL difference between treatment groups (P<.0001).  
Additionally, pegcetacoplan met noninferiority on the key secondary endpoints of transfusion 
avoidance and absolute reticulocyte count (ARC). Transfusion avoidance was shown in 85% in 
the pegcetacoplan group, but only 15.4% in the eculizumab group. The adjusted mean CFB in 
absolute reticulocyte count was –136 x109/L, in the pegcetacoplan group vs 28 x109/L in the 
eculizumab group, resulting in a treatment difference of –164 x109/L. 
Pegcetacoplan did not demonstrate noninferiority to eculizumab in the change from baseline in 
LDH. However, the adjusted mean CFB were comparable at Week 16; –15 U/L in the 
pegcetacoplan group vs –10 U/L in the eculizumab group. Noninferiority for the FACIT-Fatigue 
score was not assessed due to the prespecified hierarchical testing; however, the adjusted mean 
CFB was 9.2 points in the pegcetacoplan group vs -2.7 points in the eculizumab group with a 
difference of 11.9 points between treatment groups. The magnitude of this treatment difference 
in FACIT-Fatigue score (a 3-point increase is generally accepted as clinically significant), as 
well as the consistency of results favoring pegcetacoplan across all primary and secondary 
endpoints, suggests that these improvements in fatigue are meaningful, even though the study 
was conducted in an open-label fashion. 
The safety of pegcetacoplan was comparable to eculizumab in this randomized controlled 
Phase 3 study, with a similar incidence of adverse events in each study group. The most common 
adverse events reported during the randomized controlled treatment period were injection site 
reactions (ISR), hemolysis, abdominal pain, and diarrhea. While some TEAEs occurred more 
frequently in the pegcetacoplan group (eg, ISRs and diarrhea), others occurred more frequently 
in the eculizumab group (eg, hemolysis and headache). TEAEs such as ISRs and diarrhea that 
occurred more frequently in the pegcetacoplan group did not limit overall tolerability, as none 
were serious, severe, or led to study drug discontinuation. The incidence of serious adverse 
events (SAEs) were comparable between the 2 treatment groups. There were 4 serious infections 
during the study, but none required study drug discontinuation, and none were cases of 
meningitis. Although there were 3 subjects who discontinued pegcetacoplan due to hemolysis 
(7.3% in the pegcetacoplan group vs. 0 in the eculizumab group), adverse events of hemolysis 
occurred less frequently in the pegcetacoplan group than in the eculizumab group (9.8% vs 
28.2%, respectively). Therefore, discontinuation of pegcetacoplan due to hemolysis does not 
reflect a safety concern, but rather a return to the currently approved PNH therapy, eculizumab. 
Overall, pegcetacoplan was generally well tolerated with an acceptable safety profile that can be 
managed effectively with monitoring.  
 


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6.
RATIONALE
Phase 1 clinical experience has demonstrated that pegcetacoplan provides sustained inhibition of 
hemolytic activity in PNH patients who have never received treatment with a complement 
inhibitor (eg, eculizumab; Study APL2-CP-PNH-204 [Paddock]). To date, no safety signals have 
emerged from ongoing studies of pegcetacoplan in PNH patients that would preclude further 
development. Thus, this proposed Phase 3 study is to further evaluate treatment efficacy and 
safety of pegcetacoplan as monotherapy in patients with PNH. 
6.1. 
Purpose of the Study 
This is a 2-arm, controlled study comparing pegcetacoplan administration against standard of 
care (SOC) for patients with PNH. 
The SOC arm will exclude any concurrent or recent (within 3 months) use of complement 
inhibitors. 
6.2. 
Dose Selection 
6.2.1. 
Target Level of Pegcetacoplan Serum Concentration 
The toxicological data accumulated from the animal studies were used to guide dose selection 
during the Phase 1 single ascending dose and multiple ascending dose studies in healthy 
volunteers (HVs) (Study
, Study 
, and Study 
). In 
particular, the highest doses were selected, based on exposure predicted by a PK model, and 
compared with the exposures observed at the no observed adverse effect level (NOAEL) in 
cynomolgus monkeys.   
The planned dose of pegcetacoplan is 1080 mg SC twice weekly, equivalent to 308 mg/day. 
Dose selection is based on past clinical experience with SC pegcetacoplan, coupled with 
nonclinical toxicological studies. Daily doses up to 360 mg/day have been tested in past and 
ongoing clinical trials and have been found to be well tolerated, with exposures that are well 
below the pegcetacoplan levels associated with the NOAEL in monkeys. While doses of 
180 mg/day and above have been shown to be pharmacologically active in both HVs and PNH 
patients, clinical and biomarker responses increased in a dose-dependent manner and with the 
maximum benefits being observed at doses of either 270 or 360 mg/day.    
Using a target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) 
model (Mager and Jusko 2001), the relationship between dosing regimen and pegcetacoplan 
serum concentration is well-understood and well-predicted by the model.  Figure 1 is the 
predicted PK profile for the planned dose of 1080 mg twice weekly (green line), compared to the 
NOAEL PK data observed in the pivotal 9-month chronic toxicological study in monkeys (Study 
 [black line]). For comparison with previous human exposure, also included is the 
summary PK data from the ongoing PNH study, 
 (270 mg/day Cohort [blue line]), 
and healthy volunteer study, 
, at 360 mg/day (brown line) and 1300 mg biweekly 
(biw) (light blue line).  Both studies demonstrated pegcetacoplan to be safe and well tolerated. 
The figure illustrates that the PK exposure at the proposed Phase 3 dosing regimen should only 
derive a small increase in PK exposure previously observed in the PNH study 270 mg/day 
Cohort (Study APL-CP0514), a lower PK exposure (maximum concentration [Cmax]) than that 
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observed in Study 
 (higher dose, 1300 mg biw) and should be safely below that 
observed at the NOAEL.  
6.2.2. 
Dosing Adjustment Option
If a subject does not respond sufficiently to the planned dose of 1080 mg twice weekly, the 
dosing regimen may be changed to 1080 mg every 3 days upon agreement with the sponsor. The 
premise being that, to derive a sufficient response in some subjects, a higher level of 
pegcetacoplan serum concentrations may need to be targeted. The adjusted dosing regimen will 
result in a higher PK exposure than that originally planned (twice weekly versus once every 
3 days). As illustrated in Figure 1, the increase in PK exposure will be small, continue to be 
lower (Cmax) than that observed in study
 (higher dose, 1300 mg twice weekly) and 
safely below that observed at the NOAEL. 
Details on the criteria to be used to determine whether a subject should receive the dosing 
adjustment is provided in Section 10.2.3.2. 
Figure 1: Predicted PK profile (green line) at the planned dose of 1080 mg biw, compared 
to the summary PK data at the NOAEL (
 [black line]), ongoing PNH 
study APL-CP0514 270 mg/day cohort (blue line) and healthy volunteer study 
 for both the 360 mg/day (brown line) and 1300 mg biw cohorts (light 
blue line). 
 
 
6.3. 
Risk/Benefit 
There is an anticipated health benefit for study participants from receipt of study drug. At the 
proposed dose levels of pegcetacoplan, a significant decrease in complement-mediated hemolytic 
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activity was observed in all pegcetacoplan-treated subjects (both treatment-naive and those 
treated previously with eculizumab) in PNH Phase 1b studies. Pegcetacoplan is, therefore, 
expected to reduce complement-mediated hemolytic activity in PNH patients. In this context, a 
careful evaluation of the risk/benefit ratio should be made.  
A number of safety monitoring procedures are being monitored and assessed within this protocol 
(including, but not limited to:  physical examination, vital signs monitoring at specified intervals, 
12-lead electrocardiogram [ECG], hematology, serum chemistry, urinalysis, coagulation, and 
prompt reporting of predefined adverse events [AEs]) in order to ensure the subjects’ safety.
Infusion site and pump-use safety will be assessed during clinical visits, where pegcetacoplan is 
administered (see Section 12.1.13). 
The volume of blood planned for collection from each subject over the course of the study (see 
Section 12.6) will be kept to a minimum to limit the impact on the overall health of these anemic 
subjects. 
Systemic complement inhibition might predispose individuals to infections caused by 
encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis 
(serogroups A, C, W, Y, and B), and Haemophilus influenza type B. Subjects will be required to
have documented evidence of vaccination against these within 2 years of screening or will be 
required to receive vaccination upon initiation of pegcetacoplan therapy.  Section 10.9 provides 
the details of the vaccination requirements and procedures for this study.  
Prophylactic antibiotic therapy is required for any subject who necessitates vaccination(s) up 
until, and for 14 days after the required vaccination(s) has/have been administered. Following 
this, or for any subject who does not require vaccination, prophylactic antibiotic therapy is 
recommended. Section 10.10 provides the details of the prophylactic antibiotic therapy 
requirements and procedures for this study. Administration of prophylactic antibiotic therapy 
should be conducted, at the discretion of the treating investigator, in accordance with local 
treatment guidelines for patients with PNH who are receiving treatment with a complement 
inhibitor.  
Body temperature and vital signs will be monitored at all clinic visits, as well as relevant blood 
parameters throughout the study, to assess for signs of infection. Subjects will be provided with 
emergency study cards that include a list of symptoms associated with the aforementioned 
infections. This study card also guides subjects with instructions to contact their study physician 
or seek emergency medical care in the event they experience any of the listed symptoms. In the 
event of a suspected infection, the principal investigator (PI) should provide guidance on 
appropriate action to be taken, thereafter. 
The use of silica reagents in coagulation panels should be avoided. Apellis previously conducted 
an investigation into prolonged activated partial thromboplastin time (aPTTs) observed in 
subjects treated with pegcetacoplan. It was confirmed that false positive aPTT prolongation 
occurred when coagulation panels were performed using a Stago Analyzer and, specifically, 
silica reagents. It was determined that there was interference between the silica reagents and 
PEGylated pegcetacoplan, resulting in artificially prolonged aPTTs. 
Details regarding the dosing regimen and administration of pegcetacoplan are provided in 
Section 10. Subjects should be instructed to take their pegcetacoplan treatment as prescribed, and 


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to contact the investigator immediately for guidance in the event of any missed doses.
Discontinuation with pegcetacoplan or noncompliance with the prescribed dose regimen may 
lead to the potential for an increased risk for serious hemolysis. The sponsor’s medical monitor 
should be contacted before interrupting or discontinuing treatment with pegcetacoplan. 
Apellis is not currently aware of any evidence associating pegcetacoplan use with specific risks 
or complications of coronavirus disease 2019 (COVID-19)  Apellis recognizes the need to 
consider the public health risks of the COVID-19 pandemic within the context of conducting a 
geographic location, Apellis will continue to evaluate the risk/benefit around study conduct on an 
ongoing and patient-by-patient basis.


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7.
STUDY OBJECTIVES AND ENDPOINTS
7.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of pegcetacoplan, compared to 
SOC (excluding complement inhibitors), in patients with PNH, as assessed by:  
 Hemoglobin stabilization defined as avoidance of a >1 g/dl decrease in Hb levels 
from baseline in the absence of transfusion through Week 26 (Yes/No) 
AND 
 Reduction in lactate dehydrogenase (LDH) level from baseline to Week 26  
7.2. 
Secondary Objectives 
Secondary objectives of this study are:  
 To evaluate the efficacy of pegcetacoplan, compared to SOC (excluding complement 
inhibitors), as assessed by: 
 Hemoglobin response (Yes/No) in the absence of transfusions (Hb response is 
 g/dL increase in Hb from baseline at Week 26)
 Change from baseline to Week 26 in absolute reticulocyte count  
 Change from baseline to Week 26 in Hb level  
 Number of packed red blood cell (PRBC) units transfused from baseline to 
Week 26 
 Change from baseline to Week 26 in Functional Assessment of Chronic 
Illness Therapy- (FACIT-) Fatigue Scale score
 Normalization of Hb levels (defined as 1 × the upper limit of normal [ULN]) 
from baseline at Week 26 in the absence of transfusions (Yes/No) 
N
× ULN from Week 4 to Week 26 in the 
absence of transfusions (Yes/No) 
 Change from baseline to Week 26 in European Organization for Research and 
Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire 
(QLQ C30) scores (Version 3) 
 Change from baseline to Week 26 in Linear Analog Assessment (LASA) scale 
scores
 Absolute reticulocyte count normalization (<1 × ULN) at Week 26 (Yes/No) 
 Time of failure of Hb stabilization  
 Time to transfusion 
To evaluate the safety of pegcetacoplan as assessed by:
Incidence and severity of treatment-emergent adverse events (TEAEs) 


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 Incidence of thromboembolic events 
 Changes from baseline in laboratory parameters 
Changes from baseline in ECG parameters
Incidence of anti-APL2 antibodies 
7.3. 
Exploratory Objectives 
Exploratory objectives of the study are to evaluate: 
 
 
 
 Pegcetacoplan PK/PD, as assessed by: 
 Pegcetacoplan PK concentrations from baseline to Week 26 
 Change from baseline to Week 26 in PNH clone distribution (RBCs and white 
blood cells [WBCs]) 
 Change from baseline to Week 26 in C3 deposition in PNH Type II and III 
RBCs  
 Complement levels from baseline to Week 26 (eg, total hemolytic 
complement activity assay [CH50], alternate complement pathway assay 
[AH50], and complement component 3 [C3]) 
 
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8.
STUDY DESIGN
Figure 2 depicts the study design. This is a randomized, multicenter, open-label, controlled 
study. The study will consist of a screening period of up to 4-weeks, followed by a randomized 
controlled period of 26 weeks. A total of approximately 54 patients with PNH who meet all of 
the inclusion criteria and none of the exclusion criteria will be randomized (2:1 ratio) to receive 
either pegcetacoplan or to remain on their current SOC (excluding complement inhibitors) only 
from Visit 2 (Day 1) to Visit 15 (Week 26).  All patients who complete Visit 15 (Week 26) may 
roll over into a separate open-label, long-term extension study, or will complete the safety 
follow-up (Visit 16 [Week 28], Visit 17 [Week 30], and Visit 18 [Week 34]).  
Figure 2: 
APL2-308 Study Design 
 
 
Abbreviations:  APL-2 = pegcetacoplan; Tx = treatment; V = visit; W = week. 
a Screening may occur up to 4 weeks prior to Visit 2. Subjects may proceed from Visit 1 to Visit 2 once eligibility is 
confirmed (there is no required duration between screening at Visit 1 and Visit 2). Within 5 days prior to Visit 2, 
each subject’s Hb must be evaluated by a local or central laboratory. If the subject meets the protocol-specified 
transfusion guidelines (see Section 10.7), the subject must receive a PRBC transfusion so that the subject’s Hb level 
no longer meets the protocol-specified requirements for PRBC transfusion. The posttransfusion Hb value should be 
confirmed by a local or central laboratory. Patients must not be randomized if they meet the protocol-specified 
requirements for transfusion.
b Subjects randomized to pegcetacoplan will be assigned pegcetacoplan at a dose of 1080 mg twice weekly. The 
dose may be adjusted to pegcetacoplan at a dose of 1080 mg every 3 days (see Section 10.2.3.2).  
c Subjects assigned to the SOC (excluding complement inhibitors) treatment arm will commence escape 
pegcetacoplan therapy if they are classified as a failure for the first co-primary endpoint (see Section 10.2.3.3).   
d All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label extension study will 
be asked to return to the investigator site for the Visit 16 (Week 28), Visit 17 (Week 30), and Visit 18 (Week 34) 
follow-up visits.  Subjects who discontinue treatment will be encouraged to continue to attend study visits to 
complete study assessments (except for treatment with pegcetacoplan), as detailed in the Schedule of Events. At a 
minimum, subjects who discontinue dosing should complete follow-up procedures outlined in the Schedule of 
Events 2, 4, and 8 weeks after treatment discontinuation. If withdrawal of pegcetacoplan treatment is necessary, 
slow weaning should be considered and subjects should carefully be monitored for at least 8 weeks to detect serious 
hemolysis or other complications, as detailed in the investigator’s brochure. 
APL-2 Treatment B
EscapeC
SCREENING A
Standard of Care 
(excluding complement inhibitors)
For all subjects not 
enrolling in 
extension trial
RANDOMIZED CONTROLLED PERIOD
FOLLOW-UP PERIOD D
All 
Subjects
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
Up to 4 
Weeks
W0            W2         W4         W6         W8        W10      W12      W14      W16     W18      W20      W22       W24       W26              W28         W30             W34    
V16
V17
V18


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Randomization will be stratified by the number of PRBC transfusions within the 12 months prior 
to screening (<4; 
) (ie, number of transfusion events regardless of PRBC units transfused). 
The protocol-specified transfusion threshold is that a PRBC transfusion will be administered if 
Hb is <7 
and <9 g/dL with signs or symptoms of sufficient severity to warrant a 
transfusion. The corrected pretransfusion and posttransfusion Hb and number of units transfused 
must be documented in the case report form (CRF) (see Section 10.7).  
Within 5 days prior to Visit 2 (Week 0), each subject’s Hb must be evaluated by a local or 
central laboratory. If the subject meets the protocol-specified transfusion guidelines described 
above, the subject must receive a PRBC transfusion so that the subject’s Hb level no longer 
meets the protocol-specified requirements for PRBC transfusion. The post-transfusion Hb value 
should be confirmed by a local or central laboratory. Subjects must not be randomized if they 
meet the protocol-specified requirements for transfusion, and the Hb assessment to confirm 
eligibility should be scheduled so that the subject does not fall outside the screening window (up 
to Day –28). Screening-period Hb requirements to determine Hb eligibility are depicted in
Figure 3. 
On Day 1, subjects will be randomized to either pegcetacoplan or SOC (excluding complement 
inhibitors) using a 2:1 ratio. During the randomized controlled period, subjects will return to the 
clinical site every 2 weeks until Week 26 for efficacy and safety assessments. 
Subjects randomized to the SOC (excluding complement inhibitors) arm will continue to receive 
SOC treatment (with transfusions allowed per the instructions of the protocol), but will not be 
allowed to receive treatment with a complement inhibitor (eg, eculizumab) unless they qualify 
for pegcetacoplan escape therapy (see Section 10.2.3.3).  Similarly, subjects randomized to 
pegcetacoplan will not be allowed to receive treatment with other complement inhibitors. 
If, at any point during the study, any subject assigned to the SOC (excluding complement 
inhibitors) treatment arm that qualifies as a failure for the first co-primary endpoint will be 
offered early escape therapy with pegcetacoplan (see Section 10.2.3.3). 
Subjects who reach Visit 15 (Week 26) will be offered entry into an open-label extension study 
to continue treatment with pegcetacoplan. Visit 15 of Study APL2-308 will serve as the first visit 
for the open-label extension. These subjects will not complete the follow-up procedures detailed 
in this protocol.  
All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label 
extension study will be asked to return to the investigator site for the Visit 16 (Week 28), 
Visit 17 (Week 30), and Visit 18 (Week 34) follow-up visits.  Subjects who discontinue 
treatment will be encouraged to continue to attend study visits to complete study assessments 
(except for treatment with pegcetacoplan), as detailed in the Schedule of Events (Section 4).  At 
minimum, subjects who discontinue dosing should complete follow-up procedures outlined in 
the Schedule of Events (Section 4) 2, 4, and 8 weeks after treatment discontinuation.  If 
withdrawal of pegcetacoplan treatment is necessary, slow weaning should be considered, and 
subjects should carefully be monitored for at least 8 weeks to detect serious hemolysis or other 
complications, as detailed in the IB. 
An external, independent data monitoring committee (DMC) will assess the safety/tolerability 
data of the study periodically. 


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Subjects who fail the screening procedures should not be rescreened for the study unless this is 
agreed upon in advance and documented in writing by the sponsor. 


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9.
SUBJECT SELECTION
The study is planned to randomize approximately 54 subjects with PNH. 
9.1.
Inclusion Criteria
At Visit 1 screening, subjects must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Be at least 18 years old (inclusive). 
2. Have LDH 1.5 × ULN at the screening visit. 
3. Have PNH diagnosis, confirmed by high sensitivity flow cytometry (granulocyte or 
monocyte clone >10%). 
4. Have Hb less than the lower limit of normal (LLN) at the screening visit.  
5. Have ferritin greater than/equal to the LLN, or total iron binding capacity (TIBC) less 
than/equal to ULN at the screening visit, based on central laboratory reference ranges. If 
a subject is receiving iron supplements at screening, the investigator must ensure that the 
subject’s dose has been stable for 4 weeks prior to screening, and it must be maintained 
throughout the study. Subjects not receiving iron at screening must not start iron 
supplementation during the course of the study. 
6. Body mass index (BMI) 35 kg/m2 at the screening visit.
7. Have a platelet count of >50,000/mm3 at the screening visit. 
8. Have an absolute neutrophil count >500/mm3 at the screening visit. 
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test at 
screening and must agree to use protocol-defined methods of contraception for the 
duration of the study and for 90 days after their last dose of study drug. 
10. Males must agree to use protocol-defined methods of contraception and agree to refrain 
from donating sperm for the duration of the study and for 90 days after their last dose of 
study drug. 
11. Have vaccination against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, 
W, Y, and B), and Haemophilus influenzae (type B) either within 2 years prior to Day 1 
dosing, or agree to receive vaccination 14 days after starting treatment with 
pegcetacoplan (along with prophylactic antibiotic therapy for at least the 14 days between 
pegcetacoplan treatment initiation and vaccination and for 14 days post vaccination).  
Vaccination is mandatory, unless documented evidence exists that subjects are 
nonresponders to vaccination (as evidenced by titers or display titer levels within 
acceptable local limits).  
12. Be willing and able to give informed consent. 
9.1.1. 
Approved Methods of Contraception 
Approved methods of contraception include:  oral contraceptives, intrauterine device, medically 
acceptable barrier methods (diaphragm or condom), implantable or injectable contraceptives (eg, 


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Depo-Provera) or removable birth control device (eg, NuvaRing or Ortho Evra patches); sexual 
abstinence (defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments); and/or surgical sterilization (at least 6 months before 
dosing).  Sexual abstinence is only accepted when it is the preferred and usual lifestyle of the 
subject. Subjects not practicing abstinence as defined above and/or subjects practicing 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. 
9.2. 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening: 
13. Treatment with any complement inhibitor (eg, eculizumab) within 3 months prior to 
screening.  
14. Hereditary complement deficiency. 
15. History of bone marrow transplantation. 
16. Concomitant use of any of the following medications is prohibited if not on a stable 
regimen for the time period indicated below prior to screening: 
 Erythropoietin or immunosuppressants for at least 8 weeks 
 Systemic corticosteroids for at least 4 weeks 
Vitamin K antagonists (eg, warfarin) with a stable international normalized 
ratio (INR) for at least 4 weeks 
 Iron supplements, vitamin B12, or folic acid for at least 4 weeks 
 Low-molecular-weight heparin for at least 4 weeks 
17. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to 
the investigational product or SC administration. 
18. Participation in any other investigational drug trial or exposure to other investigational 
agent, device, or procedure within 30 days or 5 half-lives, whichever is longer. 
19. Planning to become pregnant or currently a breastfeeding woman. 
20. History of meningococcal disease. 
21. Any comorbidity or condition (such as malignancy) that, in the opinion of the 
investigator, could put the subject at increased risk or potentially confound study data. 


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9.3.
Randomization Criteria
At Visit 2 (Day 1), subjects must meet the following criteria in order to be randomized: 
1. Subjects must have Hb 
 g/dL, or Hb 7 g/dL and <9 g/dL without signs or symptoms 
of sufficient severity to warrant a transfusion.
2. Negative urine pregnancy test for WOCBP. 
3. No active systemic bacterial, viral, or fungal infection within the 2-week period prior to 
receiving treatment with pegcetacoplan. 


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10.
STUDY TREATMENTS
10.1. 
Identity of Investigational Product 
The test product is pegcetacoplan, which will be provided as a sterile solution of pegcetacoplan
(54 mg/mL) in acetate-buffered sorbitol, supplied in stoppered glass vials. Additional 
information regarding the investigational product is provided in the pegcetacoplan IB. 
10.1.1. 
Blinding the Treatment Assignment  
This is an open-label study. Treatment assignment will not be blinded.  
10.2.
Administration of Investigational Product
10.2.1. 
Interactive Response Technology (IRT) for Investigational Product Management 
A centralized IRT will be utilized for (but not limited to) the following investigational product 
management tasks:  randomization; investigational product supply management; inventory 
management and supply ordering; expiration tracking; and return of investigational product (if 
applicable). Please refer to the IRT Manual for further information. 
10.2.2. 
Allocation to Treatment 
Subjects who meet all the inclusion criteria and none of the exclusion criteria at screening 
(Visit 1), along with the randomization criteria at Visit 2 (Day 1), will be eligible to enter the 
study. Subjects will be randomly assigned at a 2:1 ratio to either the pegcetacoplan treatment arm 
or the SOC (excluding complement inhibitors) controlled treatment arm. 
Subject numbers are assigned to all subjects as they consent to take part in the study.  
The randomization number represents a unique number corresponding to the treatment arm 
allocated to the subject, once eligibility has been determined. 
The randomization will be stratified by the number of PRBC transfusions within the 12 months 
prior to Day –28 (<4
4) (ie, number of transfusion events regardless of PRBC units transfused). 
Individual subject treatment will be automatically assigned by the IRT. 
10.2.3. 
Pegcetacoplan Dosing 
Starting at Visit 2 (Day 1), subjects assigned to the pegcetacoplan treatment arm will receive SC 
infusions pegcetacoplan at a dosage of 1080 mg twice weekly. During the course of the study, 
subjects may be switched to an alternate dosing regimen of pegcetacoplan at 1080 mg every 
3 days, if warranted, based on clinical response and agreement from the sponsor (see 
Section 10.2.3.2). 
Dosing diaries will be utilized for pegcetacoplan and are to be completed for each dose 
administered at the study site or outside regular clinic visits. Subjects should not deviate from 
their pegcetacoplan dosing schedule:  Day 1 and Day 4 of each treatment week (eg, 
Monday/Thursday/Monday) or every 3 days (eg, Monday/Thursday/Sunday).  
Note:  Discontinuation with pegcetacoplan or noncompliance with the prescribed dose regimen 
may lead to the potential for an increased risk for serious hemolysis. Subjects should be 


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instructed to take their pegcetacoplan treatment as prescribed, and to contact the investigator 
immediately for guidance in the event of any missed doses. If withdrawal of pegcetacoplan 
treatment is necessary or a subject completes the trial and does not elect to participate in the 
extension study, slow weaning should be considered, and subjects should carefully be monitored 
for at least 8 weeks to detect serious hemolysis or other complications, as detailed in the IB. 
10.2.3.1. Pegcetacoplan Administration
Pegcetacoplan will be administered as a 20-mL SC infusion. The preferred site of infusion will 
be the abdomen; however, if a subject does not tolerate administration to the abdomen, 
alternative sites may be considered. 
For subjects randomized to the pegcetacoplan treatment arm, research nurses or other 
appropriately qualified research personnel will administer the first pegcetacoplan SC infusion at 
Visit 2 (Day 1) and will train subjects on how to self-administer.  Following Visit 2, 
appropriately qualified research personnel will supervise self-administration of pegcetacoplan for 
the following 3 doses (which will occur prior to Visit 3 [Week 4]). Supervision of self-
administration may be conducted at the subject’s home, at the study site, or at an off-site location 
convenient for the subject. Supervision of self-administration must continue until the subject is 
qualified to self-administer. 
Subjects randomized to the SOC (excluding complement inhibitors) treatment arm may qualify 
to receive pegcetacoplan escape therapy, as described in Section 10.2.3.3.  Subjects assigned to 
pegcetacoplan escape therapy will have research nurses or other appropriately qualified research 
personnel administer the first pegcetacoplan SC infusion and provide self-administration training 
at the study visit in which pegcetacoplan escape therapy is initiated, with the 3 doses following 
that visit supervised by appropriately qualified research personnel as detailed above. 
Following self-administration qualification, subjects may self-administer pegcetacoplan SC 
infusions without supervision at home, or at an off-site location convenient to the subject. 
Subjects may choose to continue to self-administer pegcetacoplan infusions at the study site on 
scheduled dosing days when a study visit coincides, although this is not required. 
Self-administration conducted at the study site will be supervised to ensure that the subject 
continues to remain compliant with the administration guidelines.
NOTE:  Self-administration may also be conducted by a member of the subject’s household or 
family member, etc. It is not intended to be restricted to the individual subject. Please refer to the 
Study Operations Manual for further details regarding the self-administration qualification. 
10.2.3.2. Pegcetacoplan Dose Adjustments 
Following commencement of monotherapy with pegcetacoplan, ie, at Day 1 (randomization; for 
subjects assigned to the pegcetacoplan treatment arm) or at any point following assignment to 
escape therapy with pegcetacoplan (see Section 10.2.3.3), LDH will be monitored as part of the 
scheduled assessments at the planned clinic visits. After Visit 4 (Week 4; after steady state has 
been achieved), for any subject receiving pegcetacoplan monotherapy, if LDH is >2 × ULN on 1 
occasion, a pegcetacoplan dose increase to 1080 mg every third day should be considered (see 
Section 6.2).  Any adjustment in dose will be discussed and confirmed, in writing, by Apellis. In 
the event of a dose increase, LDH will be monitored biweekly (unscheduled assessments, if 
applicable) for at least 4 weeks to assess the impact of the dose adjustment on LDH levels. 


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Decisions to escalate or de-escalate between the 2 pegcetacoplan dose regimens may be made by 
the sponsor.  
Doses above pegcetacoplan at 1080 mg every third day may be considered, if clinically 
indicated. Prior to implementation review by the DMC and institutional review board 
(IRB)/independent ethics committee (IEC) will occur and consist of examination of all 
cumulative safety, tolerability and efficacy data (eg, physical examinations, ECGs, vital signs, 
clinical laboratory tests, and AEs) and a thorough assessment of all safety data.  PK/PD data and 
predicted exposure for subsequent doses, based on emerging PK data, will also be reviewed prior 
to determining any proposed dose adjustment.  
10.2.3.3. Pegcetacoplan Escape Therapy  
Following Visit 2 (Week 0), subjects assigned to the SOC (excluding complement inhibitors) 
treatment arm who have an Hb level measured by the central laboratory that is 2 g/dL below the 
baseline value will be offered the opportunity to receive escape therapy with pegcetacoplan.  
In addition, if a subject presents with a thromboembolic event during this period, and the 
investigator excludes other possible causes of thrombosis and believes that the event was 
secondary to PNH, he/she may request a discussion with Apellis’ clinical team to evaluate 
whether the subject might be a candidate for escape therapy. Approval, if granted, will be 
documented in writing. 
Once it is confirmed that a subject randomized to the SOC (excluding complement inhibitors) 
treatment arm qualifies for and agrees to receive pegcetacoplan escape therapy, the subject 
should be encouraged to return to the site for an unscheduled visit to begin treatment with 
pegcetacoplan. Procedures for this visit are provided in Section 11.3. 
10.3. 
Labeling, Packaging, Storage, and Handling 
10.3.1. 
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following:  protocol number; 
dosage form (including product name and quantity in pack); route of administration; directions 
for use; storage conditions; batch number and/or packaging reference; the statements, “For 
clinical trial use only,” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use,” and name/address of sponsor. 
Space is allocated on the label so that the site representative can record a unique subject 
identifier and date dispensed by the site to the subject. 
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy national, local, or institutional requirements, but it must not: 
 Contradict the clinical study label 
 Obscure the clinical study label 
 Identify the study subject by name 


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Additional labels may not be added without the sponsor’s prior full agreement.
10.3.2.
Packaging
Investigational product is supplied in 20-cc glass vials. 
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement, in 
advance, by the sponsor. 
10.3.3. 
Infusion Supplies 
The sponsor will supply syringes, vial adapters, infusion sets, and ambulatory syringe infusion 
pumps, as required. Refer to the Study Operations Manual for further details. 
10.3.4. 
Storage 
The investigational product should be stored refrigerated at 2 to 8°C. 
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
A pharmacist or appropriately qualified designated person will be responsible for storing the 
investigational product at the site appropriately and dispensing the vials of investigational 
product to the subject. The pharmacist/nominated team member will enter the unique subject 
identifier on the investigational product bottle/carton labels, as they are distributed. 
Temperature monitoring is required at the investigator site (or documented storage location) to 
ensure that the investigational product is maintained within an established temperature range. 
The investigator is responsible for ensuring that the temperature is monitored at the site 
throughout the duration of the study and that records are maintained. 
Subjects who are dispensed investigational product must be instructed on appropriate 
transportation requirements and storage conditions in their home environment. Subjects will not 
be required to log or record the temperature at which their investigational product is stored. 
10.4.
Investigational Product Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records must be maintained of all investigational product dispensed, used, returned, and/or 
destroyed. The investigator is responsible for ensuring the retrieval of all required study supplies 
from subjects. 
At the conclusion of the study, any unused investigational product will either be destroyed at the 
investigator site or be returned to the sponsor or designee for destruction, and destruction will be 
documented appropriately. If no supplies remain, this fact will be documented appropriately. 
10.5. 
Subject Compliance 
Subjects must be instructed to bring their empty/used investigational product packaging to every 
visit. The pharmacist/nominated person will record details on the drug accountability form. 


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Subjects will be instructed on the specific investigational product packaging that will be required 
to return to the site.
10.6. 
Control:  Standard of Care (Excluding Complement Inhibitors) 
Subjects randomized to SOC (excluding complement inhibitors) are eligible to receive any 
treatment considered to be local SOC except for complement inhibitors. Any transfusions 
received must be reported.   
Iron supplementation requirements are detailed in Section 10.8. 
10.7. 
Transfusions 
Transfusion history collected at the Screening Visit (Visit 1; up to Week –4) is described in 
Section 12.1.3. 
During the study treatment period (Visit 2 [Week 0] to Visit 15 [Week 26]), transfusions will be 
administered if subjects have either of the following:  
 Hb is <7 g/dL  
 
 g/dL - <9 g/dL with symptoms.  
In addition, Hb, LDH, and reticulocyte count should be collected PRIOR to any transfusion. The 
assessment may be performed at a central or certified local laboratory. 
If these criteria are not met and the PI believes that a transfusion is necessary, the PI should 
discuss with the sponsor before administering the transfusion. Transfusions that do not meet this 
criterion will be considered protocol deviations and may lead to data being excluded from the 
primary analysis. 
10.8. 
Prior and Concomitant Treatment 
Prior medications (including vitamins and herbal preparations), including those discussed in the 
exclusion criteria (Section 9.2), and procedures (any therapeutic intervention, such as 
surgery/biopsy or physical therapy) the subject takes or undergoes within 28 days (or 2 years for 
documentation of vaccination [see Section 11.2.2.2]) prior to the start of screening (Visit 1) until 
the first dose of study drug will be recorded on the subject’s CRF. 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate CRF page. Except for complement inhibitors 
(other than pegcetacoplan [eg, eculizumab]) and/or phlebotomy/venesection for iron overload, 
any concomitant medication deemed necessary for the subject’s SOC during the study, or for the 
treatment of any AE (along with the allowed medications described below) may be given at the 
discretion of the investigator.  It is the responsibility of the investigator to ensure that the details 
regarding all medications are recorded in full in the subject’s CRF. 
The following concomitant medications are allowed if the following conditions apply, and dose 
adjustments are not expected during the randomized controlled period (Visit 2 to Visit 15): 


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 Erythropoietin, if the subject has been receiving a stable dose for at least 8 weeks 
before screening. 
 Immunosuppressants, if the subject has been receiving a stable dose for at least 
8 weeks before screening. 
 Corticosteroids, if the subject has been receiving a stable dose for at least 4 weeks 
before screening. 
 Vitamin K antagonists (eg, warfarin) with a stable INR for at least 4 weeks before 
screening. 
 Iron supplements, vitamin B12, or folic acid, if the subject has been receiving a stable 
dose for at least 4 weeks before screening. If patients have previously received and 
tolerated iron chelation, this may be continued or reinitiated throughout the study if 
clinically indicated and upon discussion with the sponsor’s medical monitor. 
 Low-molecular-weight heparin, if the subject has been receiving a stable dose for at 
least 4 weeks before screening. 
If clinically indicated and deemed in the best interest of the subject, the frequency or dose level 
of any of the above may be adjusted by the investigator in consultation with the Apellis medical 
monitor. 
10.9. 
 Vaccination 
In order to receive treatment with pegcetacoplan, subjects must have documented evidence of 
vaccination against the following within 2 years of screening:  
 Neisseria meningitidis types A, C, W, Y, and B (administered as 2 separate 
vaccinations)  
 Streptococcus pneumoniae (with a PCV13 or PPSV23 vaccine)  
 Haemophilus influenzae type B (Hib vaccine).  
Subjects randomized to pegcetacoplan: For subjects randomized to pegcetacoplan who do not 
have documented evidence of receiving any of the above vaccinations within 2 years prior to 
screening, the required missing vaccination(s) will be administered at Visit 3 (Week 2), prior to 
dosing with pegcetacoplan (along with boosters administered during the study at or after Visit 7 
[Week 10], if required [see below]).  Vaccination is mandatory, unless documented evidence 
exists that subjects are nonresponders to vaccination (as evidenced by titers or display titer levels 
within acceptable local limits). The PI will discuss with the sponsor regarding individual patient 
circumstances.  
If the subject requires vaccination against Neisseria meningitidis, a booster (for both 
vaccinations) should be administered after at least 8 weeks (Visit 7).  
If the subject requires vaccination against Streptococcus pneumoniae, PCV13 will be 
administered at Visit 3, and PPSV23 will be administered after at least 8 weeks (Visit 7). 
Subjects randomized to SOC (excluding complement inhibitors):  Subjects who are initially 
randomized to SOC (excluding complement inhibitors) who become eligible for pegcetacoplan 


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escape therapy will receive any required vaccination(s) 2 weeks after initiation of treatment with 
pegcetacoplan. If required as detailed above, the Neisseria meningitidis booster (for both 
vaccinations), and/or PPSV23 vaccination should be administered at least 8 weeks following the 
initial vaccination(s). 
10.10. 
 Prophylactic Antibiotics 
In order to receive treatment with pegcetacoplan, subjects will require preventive antibiotics, as 
detailed below.  
Subjects randomized to pegcetacoplan:  Subjects will be required to take ciprofloxacin 500 mg 
twice daily from Visit 2 (Week 0) to Visit 3 (Week 2) and continue to receive antibiotic 
prophylaxis until 14 days post vaccination. From that point forward, it is recommended that 
subjects take penicillin V 500 mg twice daily through the course of pegcetacoplan treatment. 
Subjects randomized to SOC (excluding complement inhibitors):  Subjects who are initially 
randomized to SOC (excluding complement inhibitors) do not need to initiate preventive 
antibiotic therapy at Day 1. If a subject becomes eligible for and initiates pegcetacoplan escape 
therapy, the subject is required to take ciprofloxacin 500 mg twice daily for 2 weeks, beginning 
on the first day of treatment with pegcetacoplan and continue to receive antibiotic prophylaxis 
until 14 days post vaccination. After 2 weeks of ciprofloxacin, it is recommended that subjects 
take penicillin V 500 mg twice daily through the course of pegcetacoplan treatment.  
10.11. 
Rescue Antibiotics 
Body temperature, vital signs, and relevant blood parameters will be monitored regularly 
throughout the study to assess for signs of infection. Subjects will be provided with emergency 
study cards that include a list of symptoms associated with infections. This study card also 
guides subjects with instructions to contact their study physician or seek emergency medical care 
in the event they experience any of the listed symptoms. In the event of a suspected infection, the 
PI should provide guidance on appropriate action to be taken, thereafter. Action to be taken may 
include administration of a broad-spectrum antibiotic. 


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11.
STUDY PROCEDURES
Please see the Schedule of Events (Section 4) for a summary of the schedule of study 
participation and procedures.  The schedule of visit dates should be established, either prior to or 
at the time of screening, allowing subjects an opportunity to assess whether there are likely to be 
significant conflicts with other activities or planned absences. To the extent possible, subjects 
will be expected to adhere to the visit schedule and any re-scheduling of visits outside of the 
window specified in the Schedule of Events (Section 4) must be agreed upon, in advance, with 
the PI and sponsor.  
11.1.
Screening Period: Visit 1 (up to Week –4 [Day –28]) 
Screening procedures are listed in the Schedule of Events (Section 4). 
The subject will be screened to confirm that the subject-selection criteria for the study has been 
met. Informed consent will be obtained at screening prior to any study-related procedures being 
conducted (see Section 15.3).  
A screen failure is a subject who has given informed consent and failed to meet at least 1 of the 
inclusion criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered investigational product(s).  
Subjects should not be rescreened once they have been designated as a screen failure unless this 
is discussed in advance with the sponsor and documented in writing.  
Sufficient supplementation of iron, folic acid, and vitamin B12 must be confirmed prior the 
initiation of the Randomized Controlled Period.  Subjects taking supplements need to be on a 
stable dose 4 weeks prior to screening.   
The following assessments will be performed:
Informed consent 
 Demographics 
 Height/Weight 
 Medical history (including thrombosis history) 
Transfusion history
 Review of inclusion/exclusion criteria 
 Physical examination  
 Triplicate 12-lead ECG  
 Prior and concomitant medications 
 Vital sign measurements 
Urinalysis 
Blood tests (see Schedule of Events [Section 4] for details)
Buccal swab test (genotyping for Gilbert’s Syndrome) 


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 Adverse event assessment 
11.1.1. 
Hemoglobin Stability:  Randomization Criteria 
Within 5 days prior to Visit 2 (Week 0), each subject’s Hb must be evaluated by a local or 
central laboratory.  It is not required that the subject’s lab draw occur at the study site.  If the 
subject meets the protocol-specified transfusion guidelines described above, the subject must 
receive a PRBC transfusion so that the subject’s Hb level no longer meets the protocol-specified 
requirements for PRBC transfusion.  The posttransfusion Hb value should be confirmed by a 
local or central laboratory.  Subjects must not be randomized if they meet the protocol-specified 
requirements for transfusion as outlined in Section 10.7.  The blood draw to confirm Hb 
eligibility for study entry should be scheduled so that the subject is able to receive transfusion if 
necessary for study entry without falling out of the 28-day screening window. Figure 3 provides 
a graphic depiction of the Hb confirmation process for study entry between Visit 1 and Visit 2. 




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11.2.
Randomized Controlled Period: Visit 2 (Week 0) to Visit 15
(Week 26) 
11.2.1. 
Visit 2:  Day 1 
Following completion of the Screening Period, subjects will enter the Randomized Controlled 
Period and will be randomized to either the pegcetacoplan treatment arm or SOC (excluding 
complement inhibitors) treatment arm. Assessments will be performed as listed below and in the 
Schedule of Events (Section 4). 
Baseline values for subjects randomized to the pegcetacoplan treatment arm will be those
measurements taken prior to the start of study treatment. 
Prior to randomization and dosing: 
 
 
 Triplicate 12-lead ECG:  within 1 hour predose  
 Physical examination 
 Concomitant medications review
 Confirm inclusion/exclusion criteria
 Vital sign measurements 
 Urinalysis 
 Blood tests (see schedule of events [Section 4] for details) 
 Urine pregnancy test 
 FACIT-Fatigue scale
 LASA for Quality of Life 
 EORTC QLQ-C30 
 Randomization  
For subjects randomized to pegcetacoplan treatment arm only:
 Dispense investigational product and infusion materials 
 Train subject to perform home infusion  
 Pegcetacoplan infusion 
Assess infusion site
Vital sign measurements (2 hours post dose [±30 minutes])
Subjects will be required to have documented evidence of vaccination against Streptococcus 
pneumoniae, and Neisseria meningitidis (serogroups A, C, W, Y, and B), and Haemophilus 
influenza type B within 2 years of screening or will be required to receive vaccination upon 
initiation of pegcetacoplan therapy.  Section 10.9 provides the details of the vaccination 
requirements and procedures for this study.  
CCI


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Prophylactic antibiotic therapy is required for any subject taking pegcetacoplan. Section 10.10
provides the details of the prophylactic antibiotic therapy requirements and procedures for this 
study.  
11.2.2. 
Visit 3 to Visit 15 (Week 2 to Week 26) 
Through the Randomized Controlled Period, subjects randomized to the pegcetacoplan treatment 
arm will receive self-administered SC doses 1080 mg of pegcetacoplan twice weekly or every 
3 days, and subjects randomized to the SOC (excluding complement inhibitors) treatment arm 
will continue their SOC therapy. Subjects assigned to the SOC (excluding complement 
inhibitors) treatment arm may be assigned to pegcetacoplan escape therapy during the course of 
the Randomized Controlled Period if they meet the criteria to switch to escape therapy as 
detailed in Section 10.2.3.3. 
Study visits at the investigator site will be conducted biweekly from Visit 3 (Week 2) to Visit 15 
(Week 26). All visits will have a ±3-day visit window. 
Subjects may self-administer pegcetacoplan infusions at the study site but are not required to do 
so if the visit is not occurring on a scheduled dosing occasion.  Outside of study visit days, 
subjects will self-administer pegcetacoplan infusions at the subject’s home or at an off-site 
location convenient for the subject.  
Assessments will be performed as listed below and in the Schedule of Events (Section 4). 
 Vital sign measurements (performed prior to ECG and venipuncture)  
 Triplicate 12-lead ECG (prior to blood draw:  Weeks 4, 8, 12, 16, 20, and 26 only) 
 Concomitant medications review 
 Adverse event review 
 Urinalysis (Weeks 4, 8, 10, 12, 16, 18, 22, 24, and 26 only) 
 Blood tests (see Schedule of Events [Section 4] for details) 
 Urine pregnancy test  
 FACIT-Fatigue scale (Weeks 4, 8, 12, 16, 20, and 26 only) 
 LASA for Quality of Life (Weeks 4, 8, 12, 16, 20, and 26 only) 
 EORTC QLQ-C30 (Weeks 4, 8, 12, 16, 20, and 26 only) 
 Physical examination (Week 16 only) 
 Vaccination (Week 2 and Week 10 [if necessary], or following initiation of 
pegcetacoplan escape therapy; see Section 10.9) 
For subjects randomized to pegcetacoplan treatment arm or receiving pegcetacoplan 
escape therapy: 
 Dispense investigational product and infusion materials 
 Reconcile used investigation product returned by the patient 


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For subjects administering pegcetacoplan at the study visit:
Infuse pegcetacoplan
 Assess infusion site 
Subjects who reach Visit 15 (Week 26) of the Randomized Controlled Period will be offered 
entry into an open-label extension study, if eligible, per the extension study’s inclusion and 
exclusion criteria. For subjects who elect to enter the open-label extension study, Visit 15 will 
also serve as the first visit of the open-label extension study and follow-up procedures as detailed 
in this protocol will not be conducted. 
Subjects who do not enter the open-label extension study will complete the follow-up visits and 
will exit the study (see Section 11.4). 
11.2.2.1. Pegcetacoplan Administration Training 
Please see Section 10.2.3.1 for self-administration training requirements for subjects randomized 
to the pegcetacoplan treatment arm, or subjects who begin pegcetacoplan escape therapy during 
the course of the Randomized Controlled Period. 
11.2.2.2. Vaccination and Prophylactic Antibiotic Procedures 
Subjects will be required to have documented evidence of vaccination against Streptococcus 
pneumoniae, Neisseria meningitidis (serogroups A, C, W, Y, and B), and Haemophilus influenza 
type B within 2 years of screening or will be required to receive vaccination upon initiation of 
pegcetacoplan therapy.  Section 10.9 provides the details of the vaccination requirements and 
procedures for this study.  
Prophylactic antibiotic therapy is required for any subject that necessitates vaccination(s) until 
the required vaccination(s) has/have been administered and for 14 days post vaccination. 
Section 10.10 provides the details of the prophylactic antibiotic therapy requirements and 
procedures for this study.  
11.3. 
Pegcetacoplan Initiation Visit (for SOC [Excluding Complement 
Inhibitors] Treatment Arm Failures) 
Following Visit 2 (Week 0), subjects assigned to the SOC (excluding complement inhibitors) 
treatment arm who have a Hb level measured by the central laboratory that is 2 g/dL below the 
baseline value will be switched to escape therapy with pegcetacoplan. 
These subjects will return to the site for a pegcetacoplan initiation visit.  Assessments will be 
performed as listed below and in the Schedule of Events (Section 4). 
Prior to dosing: 
 Concomitant medications review
 Adverse event review
 Vital sign measurements 
 PK sample (see Schedule of Events [Section 4] for details) 


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 Dispense investigational product and infusion materials 
 Train subject to perform home infusion  
Pegcetacoplan infusion 
Assess infusion site
Vital sign measurements (2 hours post-dose [±30 minutes])
Following the pegcetacoplan initiation visit, subjects will maintain their regular visit schedule. 
11.4. 
Follow-up (if Required):  Visit 16 (Week 28), Visit 17 (Week 30), and 
Visit 18 (Week 34) 
All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label 
extension study will be asked to return to the investigator site for the Visit 16 (Week 28), 
Visit 17 (Week 30), and Visit 18 (Week 34) follow-up visits.  
In addition, subjects who discontinue treatment and elect to withdraw prior to completing 
Visit 15 (Week 26) should complete the procedures outlined in this section 2, 4, and 8 weeks 
after treatment discontinuation. 
The Visit 16 (Week 28) follow-up visit has a visit window of ±3 days. The Visit 17 (Week 30) 
and Visit 18 (Week 34) follow-up visits have a visit window of ±7 days.  
Assessments listed below and outlined in the Schedule of Events (Section 4), will be performed: 
 Vital sign measurements (performed prior to ECG and venipuncture)  
 Triplicate 12-lead ECG 
 Concomitant medications 
Adverse event review
 Urinalysis  
Blood tests (see Schedule of Events [Section 4] for details)
 Urine pregnancy test  
 FACIT-Fatigue scale 
 LASA for Quality of Life 
 EORTC QLQ-C30  
 Physical examination  
 Reconcile used investigational product returned by the patient 
11.5. 
Unscheduled Visits 
Subjects may be asked to return to the clinical facility for additional visits if considered 
necessary by the PI or as relevant to subjects’ dosing regimens. 


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Unscheduled visits may include (but are not limited to) any of the procedures listed in the 
Schedule of Events (Section 4).  Examples of unscheduled visits include:
Initiation of pegcetacoplan escape therapy (see Section 11.3) 
Subjects return to the clinic to complete additional assessments and/or procedures, at 
the discretion of the investigator 
Subjects return to the clinic for pegcetacoplan dosing (based on patient’s dose, dosing 
schedule, ability to self-administer pegcetacoplan, and potential dose adjustments)
 LDH assessment in case of dose adjustment 
Safety monitoring
11.5.1.
Data Monitoring Committee
A DMC will review cumulative safety/tolerability data (eg, physical examinations, ECGs, vital 
signs, clinical laboratory tests, and AEs), efficacy (Hb and LDH levels, haptoglobin level, ARC, 
and RBC transfusions), and PK data. The DMC will have the responsibility to conduct a 
thorough safety assessment at regular predefined intervals during the Randomized Controlled 
Period of the study, as described in the DMC charter.  
In addition, an ad hoc data review may be recommended by the DMC or requested by the 
sponsor at any time during the study. 
The remit, roles, and responsibilities of the DMC will be specified in a separate DMC charter.
11.6. 
Treatment Discontinuation and Study Withdrawal 
11.6.1. 
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 investigational product with the medical 
monitor, when possible.  
Subjects who discontinue treatment will be encouraged to continue to attend study visits to 
complete study assessments (except for treatment with pegcetacoplan) as detailed in the 
Schedule of Events (Section 4).  At minimum, subjects who discontinue dosing should complete 
follow-up procedures outlined in the Schedule of Events (Section 4) 2, 4, and 8 weeks after 
treatment discontinuation (Follow-up Visits; see Section 11.3).  If withdrawal of pegcetacoplan
treatment is necessary, slow weaning should be considered, and subjects should carefully be 
monitored for at least 8 weeks to detect serious hemolysis or other complications, as detailed in 
the IB.  
Any subject withdrawn due to an AE (whether serious or nonserious) or clinically significant 
abnormal laboratory test values will be evaluated by the investigator and will be treated and/or 
followed up until the symptoms or values return to normal or acceptable levels, as judged by the 
PI.
Subjects who discontinue will not be replaced.  


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11.6.2. 
Reasons for Discontinuation 
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.  
Reasons for discontinuation include, but are not limited to: 
 Adverse event which, in the opinion of the investigator, could jeopardize the safety of 
the subject. Any serious adverse event (SAE), clinically significant AE, severe 
laboratory abnormality, intercurrent illness, pregnancy, or other medical condition 
that indicates to the PI that continued participation is not in the best interest of the 
subject. 
 Withdrawal by subject. 
 Lost to follow-up. 
 Pregnancy.  
 Other (If “Other” is selected, the investigator must specify on the CRF). 
 Death. 
 Failure to meet randomization criteria. 
 Noncompliance with investigational product. 
 Noncompliance with protocol requirements or study-related procedures. 
 Physician decision. 
 Site terminated by sponsor. 
 Study terminated by sponsor, the Food and Drug Administration (FDA), or other 
regulatory authorities. 
 Withdrawal by parent/guardian. 
 Phlebotomy/venesection for iron overload. 
11.6.3. 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that 
he/she return to the site for final safety evaluations and to return any unused investigational 
product. 


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12.
ASSESSMENTS
12.1. 
Assessments 
Assessments to be performed during the study are described below. Every effort should be made 
to ensure that the protocol-required assessments are completed as described.
If deemed necessary, additional safety measurements may be performed, at the discretion of the 
PI. 
12.1.1. 
Medical History 
Medical history will be collected at the Screening Visit (Visit 1; up to Week –4). Medical history 
relating to Hb levels and pretransfusion Hb levels in the past year prior to study enrollment will 
be collected.  
12.1.2.
Thrombosis History
Thrombosis history will be collected at the Screening Visit (Visit 1; up to Week –4). 
12.1.3. 
Transfusion History 
At the Screening Visit, (Visit 1; up to Week –4), transfusion history from the previous 12 months 
must be obtained and recorded in the patient CRF. Historical information to be obtained will be: 
 Date of transfusion 
 Type of infusion (whole blood, PRBCs, or other) 
 Number of units transfused 
 Pretransfusion Hb value and associated date of sample (must be within 14 days prior 
to transfusion) 
12.1.4. 
Body Height and Weight 
Body height and body weight will be measured at the Screening Visit (Visit 1; up to Week –4). 
12.1.5. 
Subject Demographics
Subject demographics will be collected at the Screening Visit (Visit 1; up to Week –4). 
12.1.6. 
Physical Examination 
All physical examinations will include, at a minimum, assessment of the following:  general, 
head, ears, eyes, nose and throat, dentition, thyroid (endocrine), heart, chest, lungs, abdomen, 
skin, extremities, back/neck, musculoskeletal, and lymph nodes. 
The investigator (or designee) at the study site will examine each subject, as outlined in the 
Schedule of Events (Section 4). 
A symptom-driven physical examination may be performed at various unscheduled time points, 
if deemed necessary by the investigator. 


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12.1.7. 
Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate will be 
measured prior to dosing, as outlined in the Schedule of Events (Section 4).  
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and heart rate 
measurements will be performed with subjects in a seated position after resting for 5 minutes, 
except when they are supine or semireclined because of study procedures and/or AEs (eg, nausea, 
dizziness) or if deemed necessary by the PI. 
Vital signs will be measured before venipuncture and ECG assessment, vital signs collected post 
dose will be timed from the completion of the study drug administration. 
Additional monitoring of vital signs will occur 2 hours post dose (±15 minutes) at Visit 2 
(Day 1) for subjects randomized to pegcetacoplan and at the pegcetacoplan Initiation Visit for 
subjects randomized to SOC who subsequently meet treatment failure criteria. 
12.1.8. 
Electrocardiogram Monitoring
Triplicate 12-lead ECGs will be measured at the time points outlined in the Schedule of Events 
(Section 4) with 3 readings taken 
 minute and 5 minutes apart.  Predose ECGs will be taken 
following resting in the supine position for 10 minutes in a quiet environment and prior to any 
blood sampling procedures. 
All ECGs will be recorded at the sites using the equipment provided by the vendor performing 
the centralized ECG analysis. 
The ECGs will be classified as normal, having a not clinically significant abnormality, or having 
a clinically significant abnormality. In addition, ECG parameters of ventricular rate, PR interval, 
QRS duration, and QT interval (uncorrected and corrected using both Bazett’s [QTcB] and 
Fridericia’s [QTcF] methods) will be reviewed for eligibility and ongoing safety. 
During the study, i
 ms (mean of QTcF replicate values), the investigator 
should perform 3 additional ECGs over 20-60 minutes; if the mean QTcF of the 3 repeat ECGs is 
 ms, the site should instruct the subject to return the following day to perform repeat 
triplicate ECGs.  An evaluation will be performed to look for other factors which may have 
contributed to QTc prolongation (eg, new concomitant medications, hypokalemia, etc.).
The full set of ECGs should be sent as soon as possible to the ECG central laboratory for 
verification; if the QTcF (mean of QTcF replicate values) has declined to below 500 ms and is 
returning towards baseline, dosing may continue. 
 ms, the 
investigator, medical monitor, and cardiology consultant will assess the timing of additional 
ECGs and possible discontinuation of pegcetacoplan dosing. Recommendation for 
discontinuation of pegcetacoplan will be made on an individualized management plan, based on 
the totality of the data. Because abrupt discontinuation of pegcetacoplan could result in rebound 
hemolysis and an associated risk of thrombosis, attention will be directed towards avoiding 
unnecessary dosing interruptions and all decisions regarding dosing will be clearly documented. 
12.1.9. 
Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale
The FACIT-Fatigue Scale is a 13-item Likert scaled instrument which is self-administered by the 
subjects during clinic visits, as outlined in the Schedule of Events (Section 4).  Subjects are


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presented with 13 statements and asked to indicate their responses as it applies to the past 7 days. 
The 5 possible responses are:  “Not at all” (0); “A little bit” (1); “Somewhat” (2); “Quite a 
bit” (3); and “Very much” (4). With 13 statements, the total score has a range of 0 to 52. Before 
calculating the total score, some responses are reversed to ensure that the higher score 
corresponds to a higher quality of life. The FACIT-Fatigue Scale and scoring guidelines are 
provided in Appendix 1.  
12.1.10. 
Linear Analog Scale Assessment (LASA) for Quality of Life 
The LASA consists of 3 items asking respondents to rate their perceived level of functioning. 
Specific domains include:  activity level, ability to carry out daily activities, and an item for 
overall QoL. A representation of the scale is presented in Appendix 2. Scores for the 3 individual 
components of the scale and the combined score will be included in the analysis; this will be 
described in the Statistical Analysis Plan (SAP). 
12.1.11. 
European Organisation for Research and Treatment of Cancer (EORTC) 
30-Item Quality of Life Questionnaire 
The EORTC QLQ-C30 (version 3.0) consists of 30 questions comprised of both multi-item 
scales and single-item measures to assess overall quality of life in subjects. Questions are 
designated by functional scales, symptom scales, and global patient QoL/overall perceived health 
status. Scoring guidelines from EORTC will be used to calculate patients’ scores. The QLQ-C30 
and scoring guidelines are provided in Appendix 3. 
12.1.12. 
Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Schedule of Events (Section 4).  In 
addition, laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the PI or recommended by the DMC. The clinical laboratory tests include (but are 
not limited to) the following (see Section 12.1.12.1, Section 12.1.12.2, Section 12.1.12.3, 
Section 12.1.12.4, Section 12.1.12.5, and Section 12.1.12.6):  
12.1.12.1. Hematology 
 Hb 
 Hematocrit 
 RBC count 
 Platelet count  
 WBC count with differential 
 Reticulocytes 
12.1.12.2. Coagulation 
 Prothrombin time (PT) 
 Fibrinogen 
 aPTT 
 D-Dimer 
NOTE:  The use of silica reagents in coagulation panels should be avoided in subjects treated 
with pegcetacoplan. 


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12.1.12.3. Serum Chemistry 
 Blood urea nitrogen (BUN) 
 Creatinine 
Estimated creatinine clearance 
(using Cockcroft-Gault formula) 
–screening only
 Bilirubin (total and direct)
 Albumin 
 Alkaline phosphatase (ALP) 
LDH 
Haptoglobin 
Gamma-glutamyl transferase 
(GGT) 
LDH isoenzymes
 Creatine kinase (CK) 
 Aspartate aminotransferase 
(AST) 
 Alanine aminotransferase 
(ALT)
 Uric acid 
 Glucose  
 Sodium 
 Potassium 
 Chloride 
 Ferritin 
 Erythropoietin (EPO) 
12.1.12.4. Urinalysis 
 pH 
 Specific gravity
 Protein 
 Glucose 
 Ketones 
 Bilirubin 
 Blood 
 Nitrite 
 Urobilinogen 
 Leukocyte esterase 
If an abnormality is noted for protein, blood, nitrite, and/or leukocyte esterase, a microscopic 
examination will be performed. 
12.1.12.5. Other Panels 
Plasma (free) Hb  
Direct Coombs 
Samples for genotyping (for Gilbert’s Syndrome) will be obtained via buccal swab tests done at 
the screening visit.
12.1.12.6. Human Chorionic Gonadotropin (Serum Pregnancy Test) and 
Follicle-Stimulating Hormone 
A serum pregnancy test will be performed for females only. Follicle-stimulating hormone (FSH) 
measurement will be performed for postmenopausal females at Visit 1 (up to Week –4) screening 
period only. 


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12.1.13. 
Infusion Site and Pump-Safety Assessment 
On the days of clinic visits, if pegcetacoplan is administered at the visit site, an assessment of the 
pegcetacoplan infusion site will be made as a part of the AE assessment. If pegcetacoplan is 
administered at the visit the site staff will observe the dosing and pump use safety will be 
assessed and the infusion site will be checked again within 30 minutes after study drug 
administration. The infusion site assessments will be performed by an appropriately trained staff, 
as delegated by the investigator. The infusion site and surrounding area will be inspected for 
redness, swelling, induration, and bruising. The subject will be asked about the presence of pain 
and/or tenderness, and any issue related to pump use. The date, time, and outcome of the infusion 
site assessment will be recorded on the source documents and CRFs. 
Subjects will be instructed to notify the PI or other study personnel in the event that an infusion 
site reaction occurs after self-administration of pegcetacoplan. All clinically relevant AEs, as 
determined by the investigator, from infusion site or related to pump use will be recorded as 
AEs. 
12.2. 
Pharmacokinetic Assessments 
12.2.1. 
Blood Sampling and Processing 
Blood samples for PK assessment of pegcetacoplan will be collected via direct venipuncture at 
all visits as detailed in the Schedule of Events (Section 4).  If pegcetacoplan is to be administered 
at the study site the blood sample must be taken predose.  
The date and time of the last dose of pegcetacoplan should be recorded in the eCRF, along with 
the date and time of the PK sample.  
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation. 
Note:  Samples for PK assessment should not be collected for subjects randomized to the SOC 
(excluding complement inhibitors) treatment arm unless they become eligible for and elect to 
receive pegcetacoplan escape therapy. If a subject from the SOC (excluding complement 
inhibitors) treatment arm is to begin receiving pegcetacoplan escape therapy, a predose PK 
sample should be collected at the pegcetacoplan initiation visit and at each subsequent visit as 
detailed in the Schedule of Events (Section 4). 
12.2.2. 
Analytical Method 
Serum sample analysis will be performed using good laboratory practice- (GLP-) compliant 
validated procedures and methods. The methods used and the results obtained will be included in 
the final report as an appendix. 
12.3. 
Flow Cytometry Assessments 
Blood samples for flow cytometry assessment will be collected via direct venipuncture at the 
time points delineated in the Schedule of Events (Section 4).  Flow cytometry assessment will 
include, but not be limited to:  PNH clonal distribution of RBCs; PNH clonal distribution of 
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Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation. 
12.4. 
Pharmacodynamic Assessments 
Blood samples will be collected via direct venipuncture at the time points delineated in the 
Schedule of Events (Section 4) for PD assessment of complement activation through the classical 
(ie, CH50) and alternative (ie, AP50) pathways.  Blood samples will also be collected to measure 
C3 levels. Other relevant PD markers may also be assessed.
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate Laboratory Reference Manual, prior to study initiation. 
12.5. 
Antidrug Antibody Assessment  
Subjects who test positive for anti–pegcetacoplan peptide antibodies or anti-PEG antibodies will 
be followed until the antibody levels revert to baseline and characterize their antibodies for titer, 
binding to the cyclic pentadecapeptide and PEG domains, and the neutralizing capacity. 
Subjects who discontinue dosing will need to have antidrug antibody (ADA) samples collected at 
the follow-up visits.  
Subjects who test positive for anti- pegcetacoplan peptide antibodies or anti-PEG antibodies at 
any time will be followed with ADA samples being collected every 6 months until the antibody 
levels revert to baseline. Samples that test positive will be characterized by an assay that will 
determine antibody titer, binding to the cyclic peptide or PEG domains, and measure neutralizing 
capacity. 
The proposed ADA sampling schedule was established to capture the ADA signal at baseline, 
along with any potential early onset and the dynamic profile (transient or persistent) of antibody 
formation while minimizing pegcetacoplan level in the sample. 
12.6. 
Blood Volume for Study Assessments 
Table 1:  Blood Volume During Study 
Assay
Number of 
time points 
Approximate 
volume per 
time point * 
(mL) 
Approximate 
sample 
volume over 
course of study 
(mL) 
Pharmacokinetics 
7 
5 
35 
Anti-pegcetacoplan peptide antibody and anti-
PEG antibody 
6 
5 
30 
Hematology 
17 
4 
68 
Chemistry (including pregnancy screening) 
17 
7.5 
127.5 
Coagulation profile 
8 
2.7 
21.6 
Complement profile (CH50, and AH50) 
7 
8 
56 


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Table 1:  Blood Volume During Study (Continued)
C3 Profile 
16 
8 
128 
Flow cytometry, PNH clones and C3 deposition 
8 
2 
16 
Plasma (free) Hb 
17 
6 
102 
Direct Coombs
12
3 
36
Total Approximate Blood Volume For Study: 
620.1* 
Abbreviations:  Ab = antibody; AH50 = alternate complement pathway assay; C3 = complement component 3; 
CH50 = total hemolytic complement activity assay; Hb = hemoglobin; PNH = paroxysmal nocturnal 
hemoglobinuria. 
*Represents the standard collection volume planned over the duration of the study; actual volume may vary. 
 
12.7.
Pregnancy Tests
For WOCBP, a serum pregnancy test will be performed at screening Visit 1 (up to Week –4), 
and subjects with a positive test will be excluded from the study. A follow-up urine pregnancy 
test will be performed at Visit 2 (Day 1) (a negative urine pregnancy test must be received before 
dosing with study drug). A urine pregnancy test will also be performed at each site visit, if 
applicable. A final urine pregnancy test will be performed at the follow-up Visit 16 (Week 32) or 
the Early Termination Visit. Male subjects will be counseled to avoid donating sperm during the 
time between the first dose at Visit 2 (Day 1) through 90 days after their last dose of study drug. 
12.8. 
COVID-19 Assessment 
If a subject has been tested for COVID-19, the results, if available, will be documented in the 
eCRF. 


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13.
ADVERSE EVENTS
13.1. 
Definition 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not 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 investigational product, whether or not 
considered related to the investigational product. 
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 
reporting. If these changes in laboratory values are assessed as clinically significant and/or lead 
to discontinuation of administration of investigational product, these should be reported as an 
AE. If these laboratory values are linked to a diagnosis, only the diagnosis should be reported as 
an AE.  
13.2. 
Recording Adverse Events 
Adverse events and SAEs will be collected from the signing of the informed consent form (ICF) 
until the completion of Visit 15 (for subjects who roll over into the open-label extension), or 
until the completion of follow-up (for subjects who do not roll over).   
Any events that occur prior to dosing will be categorized as pretreatment events; events 
occurring after dosing will be recorded as 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 investigational product. Subjects experiencing AEs that cause interruption or 
discontinuation of investigational product, or those experiencing AEs that are present at the 
follow-up 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, 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. 
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. 
CCI


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13.3.
Reporting Adverse Events
The sponsor has the responsibility to inform concerned health authorities, ethics committees, and 
investigators about Serious Unexpected Serious Adverse Reactions (SUSARs) in line with GCP 
guidance and applicable regulatory requirements. 
If required, specific SAEs should be reported to the concerned ethics committees in compliance 
with local requirements. 
13.3.1. 
Relationship of Events to Study Treatment 
All AEs that occur during this study will be recorded. The PI will review each event and assess 
its relationship to study drug treatment (definitely related, possibly related, unlikely related, not 
related). 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 [lost to follow-up]) 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) 
Rechallenge 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 


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13.3.2. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Mild 
Event results in mild or transient discomfort, not requiring intervention or treatment; 
does not limit or interfere with daily activities (eg, insomnia, mild headache). 
Moderate 
Event is sufficiently discomforting so as to limit or interfere with daily activities; may 
require interventional treatment (eg, febrile illness requiring oral medication). 
Severe 
Event results in significant symptoms that prevent normal daily activities; may require 
hospitalization or invasive intervention (eg, anemia resulting in blood transfusion). 
13.4. 
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/surgical intervention to prevent one of the 
outcomes listed in the above definition.   
Examples of important 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 investigator brochure (IB) in effect at the time of event onset. 
13.5. 
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 
 
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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. 
13.6.
Drug Abuse, Misuse, Overdose, and Medication Error
Occurrences of events of drug abuse, drug misuse, drug overdose, and medication error must be 
reported to Apellis Safety. 
Abuse of a medicinal product: persistent or sporadic, intentional excessive use of medicinal 
products, which is accompanied by harmful physical or psychological effects. 
Misuse: intentional and inappropriate use of a medicinal product not in accordance with the 
prescribed or authorized dose, route of administration and/or the indication(s) or not within the 
legal status of its supply. 
Overdose: administration of a quantity of study drug given per administration or per day, which 
is above the assigned dose. 
Medication Error: an error made in prescribing, dispensing, administration and/or use of the 
study drug. Medication errors are reportable to the sponsor as defined below: 
 The dispensing, administration, and/or use of the unassigned study drug. 
 The administration and/or use of an expired study drug. 
All AEs or SAEs associated with drug abuse, drug misuse, drug overdose, or medication error 
must be reported as appropriate. 
 


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14.
DATA MANAGEMENT AND STATISTICAL METHODS
14.1. 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the eCRF 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. Once a subject is randomized, it is expected 
that site personnel will complete the eCRF entry within approximately 3 business days of the 
subject’s visit. 
14.2. 
Clinical Data Management 
Data are to be entered into a clinical database, as specified in the study-specific 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. 
14.3. 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS (SAS Institute, Cary, NC, USA), version 9.3 or higher. 
The 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, 
investigational product exposure, and prior and concomitant medications. The SAP will also 
include a description of how missing, unused, and spurious data will be addressed. 
The SAP for the final analysis will be finalized prior to final database lock and performing 
analyses to preserve the integrity of the statistical analysis and study conclusions. 
14.4. 
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee 
No interim analysis is planned. An external, independent data monitoring committee (DMC) will 
assess the safety/tolerability data of the study periodically. 
14.5. 
Sample Size Justification 
A total of 48 randomized subjects (32 subjects to pegcetacoplan and 16 subjects to SOC) are 
required to achieve 90% power, at the 5% significance level (2-sided), using a 2-group Fisher's 
exact test with unequal allocation 2:1 to treatment groups (pegcetacoplan and SOC). Calculation 


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assumes an increase of 45% in the proportion of subjects achieving Hb stabilization with 
pegcetacoplan, compared to SOC (ie, a change from 5% [no treatment] to 50% [pegcetacoplan]). 
With the same number of subjects and assuming an effect size of at least 1.2, the study will be at 
96% for the LDH reduction endpoint. 
To account for loss of power due to discontinuations, the study will attempt to randomize 
54 subjects.  
14.6.
Preservation of Type 1 Error
To preserve the Type 1 error, a fixed sequence testing strategy will be used; hence, statistical 
significance with the first secondary endpoint (Week 26 Hb response in the absence of 
transfusion [Yes/No]) will only be concluded if statistical significance is achieved with the 
primary analysis of the co-primary endpoints.  
The ordering of the secondary endpoints in this testing strategy will match the order in which 
they are presented in Secondary Efficacy Endpoints (see Section 7.2). 
14.7. 
Statistical Analysis Methodology  
A formal SAP will be developed and finalized prior to locking the database. The full details of 
data presentations and analyses will be provided in the SAP. Additional statistical analyses (other 
than those described in this section) may be performed, if deemed appropriate and included in 
the SAP. Any deviations from the final SAP or from what is outlined in the protocol will be 
discussed in the final study report.  
All endpoints will be summarized by treatment group and, where appropriate, by visit. 
Continuous data will be summarized using descriptive statistics (eg, mean and standard 
deviation), and categorical data will be summarized using frequency tables (counts and 
percentages). 
14.7.1. 
Analysis Sets  
14.7.1.1.
Screened Set
The screened set will include all subjects who signed the ICF. This set will be used only for the 
purpose of describing subject disposition.  
14.7.1.2.
Safety Set
The safety set will include all subjects who receive at least 1 dose of study medication 
(pegcetacoplan), and subjects who are randomized to SOC (excluding complement inhibitors). 
Subjects will be analyzed according to the treatment they received.  
14.7.1.3.
Intent-to-Treat (ITT) Set
The ITT set will include all randomized subjects. Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received. 


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14.7.1.4. Modified Intent-To-Treat (mITT) Set 
The mITT set will include all subjects in the ITT set who continue study treatment beyond 
Visit 4 (Week 4). 
14.7.1.5.
Per-Protocol Set 
The PP set will include all subjects in the ITT set who have not violated any inclusion or 
exclusion criteria and/or deviated from the protocol in a way that could influence their efficacy 
assessment. Decisions concerning the exclusion of subjects from the PP analysis set will be made 
and documented prior to database lock. 
14.7.1.6. Pharmacokinetic (PK) Set 
The PK population will include all subjects in the ITT set who receive pegcetacoplan and have at 
least 1 evaluable post-dose PK measurement. 
14.7.1.7. Pharmacodynamic (PD) Set 
The PD population will include all subjects in the ITT set who have at least 1 evaluable 
post-dose PD measurement. 
14.7.1.8. Data Review for Analysis Sets 
After all of the data have been verified/coded/entered into the database, a review will be 
performed. The purpose of this review will be to define the analysis sets. The review will also 
check the quality of the data, identifying outliers, and make decisions on how to deal with any 
data issues (eg, missing values, withdrawals, protocol deviations). After the preanalysis review, 
resolution of all issues, and documentation of all decisions, the database will be locked. 
14.7.2. 
Efficacy Analyses 
The efficacy endpoints will primarily be evaluated with the ITT set. All statistical testing will be 
at the 5% level of significance (2-sided) and all point estimates for the comparison between 
treatment groups will be accompanied by 2-sided 95% confidence intervals (CIs).  
All possible efforts will be made to ensure that subjects complete all the required assessments. 
As missing data may potentially bias the outcome of the statistical analyses and the subsequent 
estimation of the magnitude of the treatment effect, different strategies will be applied to provide 
a balanced assessment of treatment efficacy. 
Endpoints will be summarized and, where appropriate, plotted over time for each treatment 
group.  
Baseline will be taken at Day 1 prior to the start of study treatment for subjects randomized to 
pegcetacoplan and at Day 1 for subjects randomized to SOC. 
14.7.2.1. Primary Endpoints 
The co-primary efficacy endpoints will be analyzed, based on the ITT set.  
The co-primary efficacy endpoints are: 


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 Hemoglobin stabilization defined as avoidance of a > 1 g/dl decrease  in Hb levels 
from baseline in the absence of transfusion through Week 26 (Yes/No) 
AND 
 Reduction in lactate dehydrogenase (LDH) level from baseline to Week 26  
For the first co-primary endpoint, the number and percentage of subjects who achieve Hb 
stabilization will be computed for treatment groups and compared between treatment groups 
using a stratified Cochran-Mantel-Haenszel (CMH) chi-square test. The treatment difference in 
percentages and 95% CI for the difference will be presented using the stratified Miettinen-
Nurminen method.  
Subjects who receive a transfusion through Week 26 or withdraw from the study before 
providing primary efficacy assessment will be categorized as failing to achieve Hb stabilization.
The second co-primary endpoint, change from baseline to Week 26 in LDH, will be analyzed 
using mixed model for repeated measures (MMRM) with:  the effects of treatment; stratification 
randomization; visit, visit-by-treatment interaction; baseline LDH level; and baseline LDH level-
by-visit interaction using an unstructured covariance matrix.  The difference between treatment 
groups will be estimated, along with its 95% CI and p-value.  
All the subjects LDH levels prior to transfusion and/or switch to pegcetacoplan will included in 
the model. 
As missing data may potentially bias the outcome of the statistical analyses and the subsequent 
estimation of the magnitude of the treatment effect, the following sensitivity and supportive 
analyses will be performed to evaluate the robustness of the results from the primary analysis 
methods: 
 The first co-primary efficacy endpoint will also be analyzed using a logistic 
regression with the effects of treatment group and stratification factors included. The 
odds ratio of being an Hb stabilization achiever the pegcetacoplan versus SOC group 
and associated 95% CI will be estimated from the final model. 
 The second co-primary endpoint will be analyzed using an analysis of covariance 
(ANCOVA) model (ITT set) with a last observation carried forward (LOCF) 
approach for handling missing data. The ANCOVA model will include terms for 
treatment, stratification factors, and baseline LDH level. 
 The second co-primary endpoint will be analyzed using an ANCOVA model (ITT 
set) with a best observation carried forward (BOCF) approach for handling missing 
data. The ANCOVA model will include terms for treatment, stratification factors, and 
baseline LDH level. 
 Analyses will be repeated using the mITT and PP sets. 
14.7.2.2. Secondary Endpoints
The secondary endpoints will be analyzed using the ITT set and will be repeated using the PP 
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Summary statistics by randomization strata and by treatment groups will presented at each 
assessment visit during the 26-week randomized treatment period.  
Continuous endpoints will be analyzed using MMRM with the effects of:  treatment; 
stratification factors; visit; visit-by-treatment interaction; the relevant baseline level; and the 
baseline level-by-visit interaction using an unstructured covariance matrix. The difference 
between treatment groups will be estimated, along with its 95% CI and p-value. If a subject 
receives a transfusion during his/her treatment period, the pretransfusion Hb values, reticulocyte 
values, and FACIT-Fatigue Scale score will be used in the model.  
For categorical endpoints, the number and percentage of subjects will be tabulated by treatment 
group and compared between treatment groups using a stratified CMH chi-square test. 
Kaplan-Meier plots will be presented for time-to-event endpoints for each treatment group, and 
survival estimates will be provided. 
The number of units of PRBCs transfused will be compared between the treatment groups using 
a Wilcoxon rank-sum test. The difference between the medians will be estimated along with its 
95% CI (stratified). Subjects who withdraw before Week 26 will have the number of units 
estimated from the duration that they were in the study (ie, number per week × 12).  This equates 
to an analysis of the frequency of transfusions.  
14.7.3. 
Safety Analyses 
Safety analyses will be based on the safety set. 
Safety measures assessed at study visits, including vital signs (temperature, systolic and diastolic 
blood pressures, pulse, and respiratory rate), clinical laboratory results, ECGs and 
anti-pegcetacoplan antibodies will be descriptively summarized by treatment group at baseline 
and for each postbaseline visit. Absolute values and changes from baseline will be summarized. 
14.7.3.1. Adverse Events 
Treatment-emergent adverse events are defined as those AEs that develop or worsen after the 
first dose of study medication and for 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 MedDRA. The number of subjects reporting each AE preferred term 
will be tabulated for all TEAEs and separately for those considered as possibly related to study 
treatment by the investigator. The number of subjects reporting SAEs will also be tabulated. 
Adverse-event summaries will be presented for each period of the study (randomized treatment 
and after early escape) separately, within each treatment group. 
The number of subjects reporting thromboembolic events will be tabulated for each period of the 
study, separately, within each treatment group.  
14.7.3.2. Clinical Laboratory Tests 
Changes from baseline in laboratory will be summarized using descriptive statistics by treatment, 
visit, and nominal time post dose. Baseline will be taken as the last measurement prior to the first 
dose of pegcetacoplan.  


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Out-of-range values will be flagged in the data listings.
14.7.3.3.
Vital Signs and ECGs
Changes from baseline in vital signs and ECG parameters will be summarized using descriptive 
statistics by treatment, visit, and nominal time post dose. Baseline will be taken as the last 
measurement prior to the first dose of pegcetacoplan.  
Values of potential clinical significance (eg, 
 ms from baseline) will be 
flagged in listings and summarized by treatment. 
Electrocardiogram parameters will be analyzed using concentration effect models. 
14.7.4. 
Pharmacokinetic Analyses  
The PK concentrations will be evaluated using the PK set. 
Concentrations will be summarized using descriptive statistics over time for the run-in period (all 
subjects) and the randomized treatment period (pegcetacoplan group).  
Individual subject concentration-time data will be plotted against actual sampling time. Median 
profiles of the concentration-time data, using nominal sampling times, will also be presented. 
Both linear-linear and linear-log plots will be presented.  
Population PK and exposure-response modeling of the safety and efficacy data will be described 
in a pegcetacoplan Population PK/PD Analysis Plan.  The methods will be based on the FDA 
Guidances for both Exposure-Response and Population Pharmacokinetics (FDA 1999; FDA 
2003). 
14.7.5. 
Pharmacodynamic Analyses 
The PD endpoints will be evaluated using the PD set. 
Absolute values, changes from baseline, and percent changes from baseline will be summarized 
using descriptive statistics over time for the run-in period (all subjects) and the randomized 
treatment period by treatment group.  
Individual subject-time profiles will be plotted against actual sampling time. Median profiles 
over time, using nominal sampling time, will also be presented.  
The PD endpoints will be compared between treatment groups using mixed effect repeated 
measures analyses.  
14.7.6. 
Other Data Analyses 
Demographic data, baseline characteristics, physical examination, concomitant medication, 
medical history data, and study medication exposure will be summarized by treatment group. 
World Health Organization (WHO) and MedDRA coding dictionaries will be used for the 
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14.8.
Direct Access to Source Data/Documents
The PI 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 eCRFs that are used as the source. 
The PI will permit study-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 PI 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.  
14.9.
Quality Control and Quality Assurance
This study is to be performed in full compliance with the protocol, GCP, and applicable 
regulatory requirements. The PI, sponsor, and/or designee(s) 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, applicable regulatory requirement(s), and national and local 
laws, rules, and 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.  
14.9.1. 
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 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 PI will provide direct access to source data/documents for study-
related monitoring. It is important that the PI and the 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 PI. 


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15.
ETHICS
15.1. 
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 International Council for 
Harmonisation (ICH) Harmonised Tripartite Guideline (Guideline for Good Clinical Practice), 
E6, R2 (ICH GCP). 
15.2.
Institutional Review Board/Ethics Committee
The study protocol, any amendments to the protocol, the 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 the sponsor’s 
trial master file. 
The IRB/IEC must be constituted and operate in accordance with the all applicable regulatory 
requirements. 
15.3. 
Subject Information and Consent 
The PI or appropriate designee is responsible for obtaining an informed consent. A written 
informed consent, in compliance with ICH Guideline E6, must be obtained from each subject 
prior to screening and enrollment or 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 that 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. 
15.4. 
Confidentiality 
Confidentiality of subject’s information must be maintained in accordance with national and 
local privacy laws. 
15.5. 
ClinicalTrials.gov 
This study has been listed with ClinicalTrials.gov, as required. 
15.6. 
Termination of Study 
The sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons, at any time. The PI reserves the right to discontinue dosing subjects, at any time, 


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for safety reasons, but should contact the sponsor prior to discontinuing a subject from 
pegcetacoplan. 
15.7. 
Data Handling and Record Keeping 
The PI must maintain all documentation related to this study. All essential documents (as defined 
in the ICH Guideline E6) and the data generated in connection with this study, together with the 
original copy of the final report, will be retained for at least 5 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  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 PI/Institution as to when these documents no 
longer need to be retained. 
15.8. 
Protocol Amendments 
Any amendments to the study protocol deemed necessary as the study progresses will be 
discussed between sponsor and the PI. The PI will not implement any changes to the protocol 
without an agreement by the sponsor and prior review and documented approval 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). 
Amendment(s) will be approved and signed off in the same way as the protocol.  
15.9. 
Report Format 
According to the ICH Harmonised 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). 
15.10. 
 
Finance and Insurance 
Finance and insurance will be addressed in a Clinical Trial Agreement between the PI/Institution
and the sponsor. 
15.11. 
 
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 


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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 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the PI will own (or share with other authors) the copyright on 
his/her publications. To the extent that the PI has such sole, joint, or shared rights, the PI 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 PI 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 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications. 
 


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16.
 
REFERENCES
DeZern AE, Dorr D, Brodsky RA. Predictors of hemoglobin response to eculizumab therapy in 
paroxysmal nocturnal hemoglobinuria. Eur J Haematol. 2013;90(1):16–24. 
[FDA] Food and Drug Administration. Guidance for industry: population pharmacokinetics. 
Available at: https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf. 1999. Accessed 
20 September 2018. 
[FDA] Food and Drug Administration. Guidance for industry: exposure-response relationships – 
study design, data analysis, and regulatory applications. Available at: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
072109.pdf. 2003. Accessed: 20 September 2018. 
[FDA] Food and Drug Administration. Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies. Available at: 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm227351.pdf. 2012. Accessed: 09 November 2018. 
Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug 
disposition. J Pharmacokinet Pharmacodyn. 2001;28(6):507-532. 
Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as 
additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by 
eculizumab. Blood. 2009;113(17):4094-4100.  
 
 
 
 


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17.
 
APPENDICES


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SAP_001.pdf: 
Statistical Analysis Plan 3.0 
Protocol Number: APL2-308
27 April 2021
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STATISTICAL ANALYSIS PLAN
Pegcetacoplan 
PHASE 3
A Phase 3, Randomized, Multicenter, Open-Label, Controlled Study to Evaluate the 
Efficacy and Safety of Pegcetacoplan in Patients with Paroxysmal Nocturnal 
Hemoglobinuria (PNH)
PROTOCOL IDENTIFIER: APL2-308
Study Sponsor(s):
Apellis Pharmaceuticals, Inc.
100 5th Ave
Waltham, MA 0245 
USA
Author:
Protocol:
Version 1.0 (09 November 2018)
Amendment 1, Version 1.0 (5th March 2019)
Amendment 2, Version 1.0 (23 January 2020)
Amendment 2, Version 2.0 (20 May 2020)
Amendment 3, (10 August 2020)
SAP Version #:
3.0
SAP Date:
04/27/2021
Status
Final
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TABLE OF CONTENTS 
APPROVAL SIGNATURES .............................................................................................. 2 
ABBREVIATIONS ............................................................................................................ 7 
1. 
INTRODUCTION .................................................................................................. 9 
2. 
OBJECTIVES, AND ENDPOINTS ....................................................................... 9 
2.1 
Objectives ............................................................................................................ 9 
2.2 
Endpoints ............................................................................................................. 9 
2.2.1 Primary Endpoint ......................................................................................... 9 
2.2.2 Secondary Endpoints .................................................................................... 9 
2.2.3 Exploratory Endpoints................................................................................ 10 
2.2.4 Safety Endpoints ........................................................................................ 10 
2.2.5 Pharmacokinetic Endpoint ......................................................................... 10 
2.2.6 Pharmacodynamics Endpoint(s) .................................................................. 11 
3. 
STUDY DESIGN .................................................................................................. 11 
3.1 
General Description ........................................................................................... 11 
3.2 
Randomization ................................................................................................... 13 
3.3 
Sample Size and Power Considerations ............................................................. 14 
3.4 
Preservation of Type I Error .............................................................................. 14 
3.5 
Pre- and During COVID-19 Pandemic .............................................................. 14 
4. 
STATISTICAL ANALYSIS SETS ..................................................................... 14 
4.1 
Screened Set ...................................................................................................... 14 
4.2 
Intent-to-Treat Set ............................................................................................. 14 
4.3 
Safety Set ........................................................................................................... 15 
4.4 
Per-protocol Set ................................................................................................. 15 
4.5 
Pharmacokinetic Set .......................................................................................... 15 
4.6 
Pharmacodynamic Set ....................................................................................... 15 
5. 
STUDY SUBJECTS .............................................................................................. 15 
5.1 
Disposition of Subjects ...................................................................................... 15 
5.2 
Demographic and Other Baseline Characteristics ............................................. 17 
5.3 
Medical, Thrombosis and Transfusion History ................................................. 18 
5.4 
Prior and Concomitant Medications .................................................................. 18 
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5.5 
Exposure to Investigational Product .................................................................. 19 
5.6 
Measurements of Treatment Compliance .......................................................... 20 
5.7 
Protocol Deviations ............................................................................................ 20 
6. 
EFFICACY ANALYSES ..................................................................................... 21 
6.1 
Estimands .......................................................................................................... 22 
6.2 
Analyses of Primary Efficacy Endpoints ........................................................... 27 
6.2.1 First Co-Primary Efficacy Endpoint ........................................................... 27 
6.2.2 Second Co-Primary Efficacy Endpoint ...................................................... 27 
6.3 
Sensitivity Analyses of Co-Primary Efficacy Endpoints ................................... 28 
6.3.1 Second Co-Primary Efficacy Endpoints..................................................... 28 
6.4 
Supportive Analyses of Co-Primary Efficacy Endpoints .................................. 29 
6.4.1 First Co-Primary Efficacy Endpoints ......................................................... 29 
6.4.2 Second Co-Primary Efficacy Endpoints..................................................... 29 
6.5 
Analyses of Secondary Efficacy Endpoints ....................................................... 30 
6.5.1 Categorical Secondary Efficacy Endpoints ................................................ 30 
6.5.2 Continuous Secondary Efficacy Endpoints ................................................ 31 
6.6 
Subgroup Analyses ............................................................................................ 33 
6.7 
Exploratory Endpoints ....................................................................................... 33 
6.8 
Additional Secondary Efficacy Endpoints ........................................................ 34 
7. 
SAFETY ANALYSIS ........................................................................................... 35 
7.1 
Adverse Events .................................................................................................. 35 
7.1.1 Exploratory Adverse Events Endpoint ....................................................... 37 
7.2 
Clinical Laboratory Data ................................................................................... 37 
7.3 
Vital Signs ......................................................................................................... 39 
7.4 
Electrocardiogram (ECG) .................................................................................. 39 
7.5 
Other Safety Data .............................................................................................. 40 
8. 
PHARMACOKINETIC ANALYSIS .................................................................. 41 
9. 
PHARMACODYNAMIC ANALYSIS ............................................................... 42 
10. 
OTHER ANALYSES ........................................................................................... 43 
11. 
INTERIM ANALYSIS ......................................................................................... 43 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE ................. 43 
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13. 
DATA HANDLING CONVENTIONS ............................................................... 43 
13.1 
General Data Reporting Conventions ................................................................ 43 
13.2 
Definition of Baseline........................................................................................ 44 
13.3 
Summary Table and Listing Presentations ........................................................ 44 
13.4 
Definition of Visit Windows ............................................................................. 44 
13.5 
Derived Efficacy Endpoints............................................................................... 46 
13.6 
Repeated or Unscheduled Assessments of Safety Parameters ........................... 48 
13.7 
Handling of Missing, Unused, and Spurious Data ............................................. 48 
13.7.1 Missing Data Imputation for Efficacy Endpoints ....................................... 48 
13.7.2 Missing Date of Investigational Product .................................................... 48 
13.7.2.1 Incomplete Start Date ................................................................... 49 
13.7.2.2 Incomplete Stop Date ................................................................... 49 
13.7.3 Missing Date Information for Adverse Events ........................................... 50 
13.7.3.1 Incomplete Start Date ................................................................... 51 
13.7.3.2 Incomplete Stop Date ................................................................... 51 
13.7.4 Missing Severity Assessment for Adverse Events ..................................... 51 
13.7.5 Missing Relationship to Investigational Product for Adverse Events ........ 51 
13.7.6 Character Values of Clinical Laboratory Variables ................................... 51 
14. 
ANALYSIS SOFTWARE .................................................................................... 51 
15. 
CHANGES TO ANALYSES ................................................................................ 52 
15.1 
Changes to Analyses Specified in the protocol ................................................. 52 
15.2 
Changes from Analyses Specified in the Previous Version of the SAP ............ 52 
15.3 
Changes from Analyses Specified in Version 2.0 of the SAP ........................... 53 
16. 
REFERENCES .....................................................................................................54 
17. 
APPENDICES ......................................................................................................55 
17.1 
Schedule of Assessments ...................................................................................55 
17.2 
Sample SAS codes .............................................................................................64 
17.2.1 Sample SAS Code for First Co-primary and Categorical Secondary 
Endpoints Analyses ....................................................................................64 
17.2.2 Sample Pseudo SAS Code for Second Co-Primary and Continuous 
Secondary Endpoints Analyses ..................................................................65 
17.2.3 Sample SAS Code for Sensitivity Analyses of Second Co-Primary 
Endpoint .....................................................................................................66 
17.2.4 Sample SAS Code for Time to Event Endpoints........................................70 
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17.2.5 SAS Macros for Nonparametric Randomization-Based Analysis using 
Log-Incidence Density Ratios ....................................................................71 
17.3 
Sensitivity Analyses for the Primary Efficacy Endpoint ...................................72 
17.3.1 Imputation for the Second Co-primary Efficacy Endpoint ........................72 
17.4 
COVID-19 Changes ..........................................................................................75 
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ABBREVIATIONS 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Class 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
CBER 
Center for Biologics Evaluation and Research 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Clinical Research Organization 
DMC 
Data Monitoring Committee 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EORTC 
FACIT 
European Organisation for Research and Treatment of Cancer 
Functional Assessment of Chronic Illness Therapy 
FDA 
Food and Drug Administration 
Hb 
Hemoglobin 
ICE 
Intercurrent Event 
ITT 
Intention-To-Treat 
IRT 
Interactive Response Technology 
LLN 
Lower Limit of Normal 
LASA 
Linear Analog Scale Assessment 
LDH 
lactate dehydrogenase 
LOV 
Last Observed Value 
LVOT 
Last Value on Treatment 
MAR 
Missing at Random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing not at Random 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRBC 
Packed red blood cell 
PT 
Preferred Term (MedDRA) 
QOL 
Quality of Life 
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QLQ-C30 
EORTC Quality of Life Questionnaire – Core 30 Scale 
QTcB 
QT Interval Corrected for Heart Rate Using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate Using Fridericia’s Formula 
RBC 
Red Blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SE 
Standard Error 
STD 
Standard Deviation 
SI 
Système International 
SOC 
System Organ Class 
SOC 
TA 
Standard of Care 
Transfusion Avoidance 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy, safety and pharmacokinetic (PK)/pharmacodynamic (PD) 
data as described in the final study protocol version 1.0, dated 09 November 2018, 
incorporating the most recent amendment # 3 (10 Aug 2020). Specifications for tables, 
figures, and listings are contained in a separate document. Details in this SAP take 
precedence over those provided in the statistical section of the protocol. 
 
2. 
OBJECTIVES, AND ENDPOINTS 
 
2.1 
Objectives 
The primary objective of this study is to evaluate the efficacy of pegcetacoplan, 
compared to SOC (excluding complement inhibitors), in patients with paroxysmal 
nocturnal hemoglobinuria (PNH). 
 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
• Hemoglobin stabilization defined as avoidance of a > 1 g/dL decrease in Hb 
levels from Baseline in the absence of transfusion through Week 26 (Yes/No) 
AND 
• Reduction in lactate dehydrogenase (LDH) level from Baseline to Week 26 
2.2.2 Secondary Endpoints 
• Hemoglobin response (Yes/No) in the absence of transfusions (Hb 
response is defined as a ≥1g/dL increase in Hb from Baseline at Week 26) 
• Change from Baseline to Week 26 in absolute reticulocyte count (ARC) 
• Change from Baseline to Week 26 in Hb level 
• Proportion of subjects who received transfusion or had decrease of Hb > 2 
g/dL from Baseline (Yes/No). 
• Transfusion avoidance (TA) (Yes/No), defined as the proportion of 
subjects who do not require a transfusion during the Randomized 
Controlled Period (RCP). 
• Number of packed red blood cell (PRBC) units transfused from Baseline 
through Week 26 
• Change from Baseline to Week 26 in Functional Assessment of Chronic 
Illness Therapy- (FACIT-Fatigue) Scale score 
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• Normalization of Hb levels (defined as ≥1xLLN) from Baseline to Week 
26 in the absence of transfusions (Yes/No) 
• Normalization of LDH levels (defined as ≤1 x ULN) from Week 4 to 
Week 26 in the absence of transfusions (Yes/No) 
• Change from Baseline to Week 26 in European Organization for Research 
and Treatment of Cancer (EORTC) 30-item Core Quality of Life 
Questionnaire (QLQ-C30) scores (version 3) 
• Change from Baseline to Week 26 in Linear Analog Assessment (LASA) 
scale scores (Version 3) 
• Absolute reticulocyte count (ARC) normalization (defined as <1 x ULN) 
at Week 26 in the absence of transfusion (Yes/No) 
• Time to failure of Hb stabilization 
• Time to first transfusion 
 
2.2.3 Exploratory Endpoints 
• 
• 
 
2.2.4 Safety Endpoints 
• Incidence and severity of treatment-emergent adverse events (TEAEs) 
• Incidence of thromboembolic events 
• Changes from Baseline in laboratory parameters 
• Changes from Baseline in electrocardiogram (ECG) parameters 
• Incidence of anti-pegcetacoplan antibodies 
 
2.2.5 Pharmacokinetic Endpoint 
Pegcetacoplan pharmacokinetics (PK), as assessed by: 
Pegcetacoplan PK concentrations from baseline to Week 26 
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2.2.6 Pharmacodynamics Endpoint(s) 
Pegcetacoplan pharmacodynamic (PD), as assessed by: 
• Change from Baseline to Week 26 in PNH clone distribution (red blood 
cells [RBCs] and white blood cells [WBCs]) 
• Change from Baseline to Week 26 in complement component 3 (C3) 
deposition in PNH Type II and III RBCs 
• Complement levels from Baseline to Week 26 (e.g., total hemolytic 
complement activity assay [CH50], alternate complement pathway assay 
[AH50], and C3) 
 
 
3. 
STUDY DESIGN 
 
3.1 
General Description 
This is a prospective, randomized, multicenter, open-label, controlled study. The study 
will consist of a screening period of up to 4 weeks, followed by a randomized-controlled 
period of 26 weeks. A total of approximately 54 subjects with PNH who meet all the 
inclusion criteria and none of the exclusion criteria will be randomized (2:1 ratio) to 
receive either pegcetacoplan or to remain on their current SOC (excluding complement 
inhibitors) only from Visit 2 (Day 1) to Visit 15 (Week 26). All subjects who complete 
Visit 15 (Week 26) may roll over into a separate open-label, long-term extension study 
(APL2-307), or will complete the safety follow-up (Visit 16 [Week 28], Visit 17 [Week 
30], and Visit 18 [Week 34]). 
 
Due to COVID-19 pandemic, subjects unable to have central laboratory assessments are 
allowed to have hematologic parameters analyzed by a certified local lab. 
 
Following Visit 2 (Week 0), subjects assigned to the SOC (excluding complement 
inhibitors) treatment group who have a Hb level measured by the central laboratory or 
certified local laboratory that is ≥2 g/dL below the Baseline value will be offered the 
opportunity to receive escape therapy with pegcetacoplan. 
 
Transfusion history collected at the Screening Visit (Visit 1; up to Week -4) is described 
in Section 12.1.3 of the protocol. During the study treatment period (Visit 2 [Week 0] to 
Visit 15 [Week 26]), transfusions (received a transfusion of packed red cells (PRBC)) 
will be administered if subjects have either of the following: 
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V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
•
Hb is <7 g/dL
•
Hb ≥7 g/dL - <9 g/dL with symptoms
In addition, Hb, LDH, and Absolute reticulocyte count (ARC) should be collected 
PRIOR to any transfusion. The assessment may be performed at a central or certified 
local laboratory.
If these criteria are not met and the PI believes that a transfusion is necessary, the PI 
should discuss with the sponsor before administering the transfusion. Transfusions that 
do not meet this criterion will be considered protocol deviations and may lead to data 
being excluded from the primary analysis.
Figure 1 depicts the study design:
Figure 1APL2-308 study design.
Up to 4
Weeks
W0
W2
W4
W6
W8
W10  W12  W14  W16  W18  W20  W22  W24  W26
W28
W30
W34
Abbreviations: Tx = treatment; V = visit; W = week.
a
Screening may occur up to 4 weeks prior to Visit 2. Subjects may proceed from Visit 1 to Visit 2 once 
eligibility is confirmed (there is no required duration between screening at Visit 1 and Visit 2). Within 
5 days prior to Visit 2, each subject’s Hb must be evaluated by a certified local or central laboratory. If 
the subject meets the protocol-specified transfusion guidelines (see Section 10.7 of the protocol), the 
subject must receive a PRBC transfusion so that the subject’s Hb level no longer meets the protocol-
specified requirements for PRBC transfusion. The post-transfusion Hb value should be confirmed by a 
certified local or central laboratory. Subjects must not be randomized if they meet the protocol-
specified requirements for transfusion.
SCREENING A
RANDOMIZED CONTROLLED PERIOD
FOLLOW-UP PERIOD D
APL-2 Treatment B
All
Subjects
Standard of Care
(excluding complement inhibitors)
EscapeC
For all subjects not
enrolling in
extension trial
Randomization
End of Tx or Extension Entry
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b 
Subjects randomized to pegcetacoplan will be assigned pegcetacoplan at a dose of 1,080 mg twice 
weekly. The dose may be adjusted to pegcetacoplan at a dose of 1,080 mg every 3 days (see Section 
10.2.3.2 of the protocol). 
c 
Subjects assigned to the SOC (excluding complement inhibitors) treatment group will commence 
escape pegcetacoplan therapy if they are classified as a failure for the first co-primary endpoint. 
d 
All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label 
extension study (APL2-307) will be asked to return to the Investigator site for the Visit 16 (Week 28), 
Visit 17 (Week 30), and Visit 18 (Week 34) follow-up visits. Subjects who discontinue treatment will 
be encouraged to continue to attend study visits to complete study assessments (except for treatment 
with pegcetacoplan), as detailed in the Schedule of Events. At a minimum, subjects who discontinue 
dosing should complete follow-up procedures outlined in the Schedule of Events 2, 4, and 8 weeks 
after treatment discontinuation. If withdrawal of pegcetacoplan treatment is necessary, slow weaning 
should be considered and subjects should carefully be monitored for at least 8 weeks to detect serious 
hemolysis or other complications, as detailed in the IB. 
 
 
3.2 
Randomization 
Subject numbers will be assigned to subjects as they consent to take part in the study. 
 
A total of approximately 54 subjects who meet all the eligibility criteria and none of the 
exclusion criteria will be randomized (2:1 ratio) to receive either pegcetacoplan or current 
SOC (excluding complement inhibitors) using interactive response technology (IRT). 
 
Randomization will be stratified by the number of PRBCs transfused within the 12 
months prior to screening (<4; ≥4) (i.e., number of transfusion events regardless of PRBC 
units transfused). 
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3.3 
Sample Size and Power Considerations 
A total of 48 randomized subjects (32 subjects to pegcetacoplan and 16 subjects to SOC) 
are required to achieve 90% power, at the 5% significance level (2-sided), using a 2- 
group Fisher's exact test with unequal allocation 2:1 to treatment groups (pegcetacoplan 
and SOC). Calculation assumes an increase of 45% in the proportion of subjects 
achieving Hb stabilization with pegcetacoplan, compared to SOC (i.e., a change from 5% 
[no treatment] to 50% [pegcetacoplan]). With the same number of subjects and assuming 
an effect size of at least 1.2, the study will be at 96% power for the LDH reduction 
endpoint. 
To account for loss of power due to discontinuations, the study will attempt to randomize 
54 subjects. 
 
3.4 
Preservation of Type I Error 
To preserve the Type 1 error, a fixed sequence testing strategy will be used; hence, 
statistical significance with the first secondary endpoint (Week 26 Hb response in the 
absence of transfusion [Yes/No]) will only be concluded if statistical significance is 
achieved with the primary analysis of the co-primary endpoints. 
The ordering of the secondary endpoints in this testing strategy will match the order in 
which they are presented in Secondary Efficacy Endpoints (see section 2.2.2). 
 
 
3.5 
Pre- and During COVID-19 Pandemic 
The Pre- and During COVID-19 Pandemic is defined as follows: 
• Pre-COVID-19 is any subject who completed the week 26 visit (RCP) before the 
beginning of the pandemic (March 11, 2020). 
• During COVID-19 is any subject who completed the week 26 visit (RCP) during 
or after the beginning of pandemic (March 11, 2020). 
 
4. 
STATISTICAL ANALYSIS SETS 
 
4.1 
Screened Set 
The screened set will include all subjects who provided written informed consent. This 
set will be used only for the purpose of describing subject disposition. 
 
4.2 
Intent-to-Treat Set 
The ITT set will include all randomized subjects. Subjects will be analyzed according to 
their assigned treatment, regardless of the treatment actually received. 
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4.3 
Safety Set 
The safety set will include all subjects who receive at least 1 dose of study medication 
(pegcetacoplan), and subjects who are randomized to SOC (excluding complement 
inhibitors). Subjects will be analyzed according to the treatment they received. 
 
4.4 
Per-protocol Set 
The per-protocol (PP) set will include all subjects in the ITT set who did not have any 
major protocol deviation (PD) that could potentially impact final data analyses (see 
section 5.7 for detail). 
 
Subjects who have had major protocol deviation, including but not limited to: 
 
a- eligibility violation, 
 
b- taking prohibited medications, and 
 
c- missing 3 or more consecutive study visits, which may impact the interpretation 
of safety and efficacy will be excluded from Per Protocol analysis. 
 
Decisions concerning the inclusion or exclusion of subjects from the PP analysis set will 
be made and documented prior to database lock. 
 
4.5 
Pharmacokinetic Set 
The Pharmacokinetic (PK) set will include all subjects in the ITT analysis set who have 
at least 1 evaluable (i.e. not impacted by any major protocol deviations or other events) 
post- dose PK measurement (even if below the limit of quantification). The analyses 
using this set will be based upon the actual treatment received. 
 
4.6 
Pharmacodynamic Set 
The Pharmacodynamic (PD) set will include all subjects in the ITT analysis set who have 
at least 1 evaluable (i.e. not impacted by any major protocol deviations or other events) 
post-dose PD measurement. The analyses using this set will be based upon the actual 
treatment received. 
 
5. 
STUDY SUBJECTS 
 
5.1 
Disposition of Subjects 
For the Screened set, the number and percentage of subjects screened, who failed screening 
and the reason for screen failure will be summarized. 
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For the Safety set, the following will be presented by treatment group and overall: 
 
• Number and percentage of subjects who received at least one dose of randomized 
treatment (pegcetacoplan or SOC, and total) 
• Number and percentage of subjects who completed study treatment. 
• Number and percentage of subjects who completed the study pre- and during 
COVID-19 pandemic. 
• Number and percentage of subjects who discontinued study treatmen.t 
For those subjects who discontinue study treatment, the reason for discontinuation will be 
summarized for the Randomized Controlled Period (Visit 2 (Week 0) to Visit 15 (Week 
26) (Adverse Events, Withdrawal by Subject, Lost to Follow-Up, Pregnancy, death, Failure 
to Meet Randomization Criteria, Non-Compliance with Investigation Product, Protocol, 
Requirements, or Study Related Procedures, Physician Decision, Site Terminated by 
Sponsor, and Other). 
• Number and percentage of subjects who completed the study. 
• Number and percentage of subjects who enter the extension study. 
• Number and percentage of subjects who withdrew from the study. 
• Number and percentage of subjects who discontinue from the study due to COVID- 
19 pandemic. 
• Number and percentage of subjects who Receive a transfusion during the 
randomized Controlled Period. 
• Number of subjects withdraw from study due to receiving transfusion 
• Number and percentage of subjects who Withdrew from the study before Week 
26. 
• Number and percentage of subjects who escape from SOC to pegcetacoplan 
during the Randomized Controlled Period 
 
 
The number of subjects in each analysis set will be tabulated by treatment group and 
overall and by region (Latin America, Europe, and Asia pacific) and will be presented in 
a listing. 
 
Subject data listings with disposition will be provided as well as a listing of subjects who 
did not satisfy the inclusion/exclusion criteria. 
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5.2 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and 
overall using the ITT and Safety sets (if sets are different). 
 
Demographic variables to be presented include age (years), age category (<65 years, ≥65 
-<75, ≥75 -80, ≥80 years, and ≥80 years), sex, race, ethnicity, region, weight (kg), 
height (m), BMI (kg/m2), and BMI category (<18.5, ≥18.5 - <25, ≥25 - <30, ≥30 - < 35, ≥ 
35 kg/m2). 
 
As date of birth may not be recorded for all subjects, the age recorded on the eCRF will 
be used for analyses. 
 
Baseline characteristics to be presented include the following: 
• Time since diagnosis of PNH (years) to Visit 2 (Week 0) 
• Number of transfusions in the last 12 months prior to Visit 2 (Week 0) (<4; ≥4) 
• Number of subjects with zero Vs nonzero transfusions. 
• Time since last transfusion to Visit 2 (Week 0) 
• Hemoglobin level (value recorded at Visit 2 prior to randomization and dosing 
with pegcetacoplan or SOC) 
• Absolute reticulocyte count (value recorded at Visit 2 prior to randomization and 
dosing with pegcetacoplan or SOC) 
• LDH level (value recorded at Visit 2 prior to randomization and dosing with 
pegcetacoplan or SOC) 
• Haptoglobin level (value recorded at Visit 2 prior to randomization and dosing 
with pegcetacoplan or SOC) 
• Total bilirubin level (value recorded at Visit 2 prior to randomization and dosing 
with pegcetacoplan or SOC) 
• 
 Indirect bilirubin level (value recorded at Visit 2 prior to randomization and 
dosing with pegcetacoplan or SOC) 
• Platelet count (value recorded at Visit 2 prior to randomization and dosing with 
pegcetacoplan or SOC) 
• RBC and granulocyte PNH clone size at baseline 
• Total FACIT-fatigue score (nominally recorded on Visit 2 prior to randomization 
and dosing with pegcetacoplan) 
• LASA total score 
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• EORTC QLQ-C30 Global Health score 
• genotyping for Gilbert’s Syndrome 
 
Baseline values for subjects randomized to the pegcetacoplan or SOC treatment group 
will be those measurements taken prior to the start of study treatment which will be the 
average of measurements prior to randomization to the pegcetacoplan or SOC treatment 
group for efficacy endpoints, but as the last measurement before the first dose of 
pegcetacoplan or SOC for other endpoints (see sections 6 and 13.2 for details). 
 
5.3 
Medical, Thrombosis and Transfusion History 
Medical history will be collected at the Screening Visit (Visit 1; up to Week -4 [Day - 
28]). Medical history relating to Hb levels and pre-transfusion Hb levels in the past year 
prior to study enrollment will also be collected. 
Thrombosis history will be collected at the Screening Visit (Visit 1; up to Week -4 [Day - 
28]). 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) Version available. Summaries will be presented for the Safety set by System 
Organ Class (SOC) and Preferred Term (PT) with numbers and percentages by treatment 
group and overall. Each subject will be counted only once in each SOC or SOC/PT 
summary. 
 
In the summary table, medical history will be presented by decreasing frequency of 
subjects overall within each SOC and then similarly by decreasing frequency of subjects 
overall within each PT. In cases of SOCs or PTs with equal frequencies, medical history 
will be sorted alphabetically. 
 
A summary of thrombosis history will also be presented for the safety set with numbers 
and percentages for each type of thrombosis by treatment group and overall. 
 
A summary of transfusion history will also be presented for the safety set with numbers 
and percentages for each type of transfusion and the number of units transfused by 
treatment group and overall. 
 
5.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary version 
available. Medication will be presented by ATC level 2 (therapeutic main group) and ATC 
level 5 (standardized medication name) with numbers and percentages by treatment group 
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and overall. A subject who takes more than one medication will be counted only once if 
these medications belong to the same extended ATC classification. 
 
In the summary tables, prior medication and concomitant medications will be presented by 
decreasing frequency of subjects overall within each ATC level 2 class and then similarly 
by decreasing frequency of subjects overall within each ATC level 5 class. In cases of ATC 
level 2 classes or ATC level 5 classes with equal frequencies, medications will be sorted 
alphabetically. 
 
Prior medications (including vitamins and herbal preparations), including those discussed 
in the exclusion criteria (Section 9.2 of the protocol), and procedures (any therapeutic 
intervention, such as surgery/biopsy or physical therapy) the subject takes or undergoes 
within 28 days (or 2 years for documentation of vaccination [see Section 11.2.2.2 of the 
protocol]) prior to the start of screening (Visit 1) until the first dose of study drug will be 
recorded on the subject’s CRF. 
 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. 
Hence, medications started before receiving the first dose of the investigation drug but 
continuing after will be considered as both prior and concomitant medications. The listing 
of medications will identify prior and concomitant medications. 
 
 
 
5.5 
Exposure to Investigational Product 
The following parameters will be calculated and presented by treatment group for the 
Randomized Controlled Period (Visit 2 (Week 0) to Visit 15 (Week 26)) using the safety 
set: 
 
• Total Dose administered (mg) 
• Duration of Treatment (days) 
• Number and percentage of subjects received infusions. 
o Number and percentage of subjects with all infusions completed. 
o Number and percentage of subjects with any infusions interrupted. 
o Number and percentage of subjects who did not complete the full dose 
due to infusion interruption. 
o Number and percentage of subjects received only 1, only 2, etc infusion. 
• Total number of infusions 
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• Number and percentage of infusions completed. 
• Number and percentage of infusions interrupted. 
 
Total time on study treatment (Days) calculated as the time in days from first study drug 
infusion date until the last study drug infusion date for the Randomized Controlled Period 
(i.e., treatment duration = last study drug infusion in the Randomized Controlled Period – 
first study drug infusion + 1). The data will be summarized by treatment group. 
Number of infusions for each subject will summarized using descriptive statistics. 
 
5.6 
Measurements of Treatment Compliance 
Percent compliance will be calculated for the Randomized Controlled Period using the 
safety set for the pegcetacoplan treatment group only. 
 
Percent compliance is calculated as total number of study infusions taken from Visit 2 
(Week 2) to end of Randomization Controlled Period (Week 26) divided by the total 
number of expected infusions to end of Randomization Controlled Period. 
 
The percent compliance formula for pegcetacoplan twice weekly dosing is: 
 
 
Percent compliance = 
total number of infusions received. 
 
* 100.0 
[ (last dose date-first dose date +3.5) / 7] * 2.0 
 
 
The number and percentage of subjects who had a percentage of drug compliance range by 
increment of 10% (≥ 80% - 90%, ≥ 90 - ≤100%, >100% - ≤120%) will then be presented 
in a table by treatment group. Summary statistics will also be presented for for the 
pegcetacoplan treatment group only. 
 
The number of expected doses for the pegcetacoplan treatment group in the Randomized 
Controlled Period is between 52 to 61 for pegcetacoplan twice weekly or every 3 days, 
respectively. 
 
By-subjects listing will be produced for treatment compliance and exposure. 
 
5.7 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. The 
CRO/Apellis will classify major and minor protocol deviations per the agreed protocol 
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deviation management plan. The Apellis study team will review the protocol deviations 
and their classification throughout the study and before database lock. 
 
For any criteria for protocol deviations that can be completely implemented by a 
computer program, the detailed algorithm will be agreed upon. Details of such algorithms 
will be included in the derived dataset specifications and finalized before database lock. 
 
Confirmed major and minor protocol deviations will be documented in the Protocol 
Deviation tracker for the study. Major/minor protocol deviations will be summarized by 
category and site for each treatment group (pegcetacoplan and SOC) and overall, for the 
Safety set and will be listed. 
 
6. 
EFFICACY ANALYSES 
The efficacy endpoints will primarily be evaluated using the ITT set. All statistical 
testing will be at the 5% level of significance (2-sided) and all point estimates for the 
comparison between treatment groups will be accompanied by 2-sided 95% confidence 
intervals (CIs). 
Summary Tables 
 
For continuous data, absolute values and changes from baseline will be summarized by 
treatment group and visit during the Randomized Control Period. 
 
For categorical data, the number and percentage will be summarized by treatment group 
and visit within the Randomized Control Period. 
 
For second co-primary efficacy endpoint (LDH) and all continuous secondary endpoints, 
if a subject escape from SOC to pegcetacoplan during the Randomized Controlled Period, 
their data collected after the escape will be excluded from the calculation of descriptive 
statistics. Additional summary statistics tables will include all data collected after 
transfusion or escape. 
 
If a subject escape from SOC to pegcetacoplan, their values will be summarized under 
the pegcetacoplan / SOC Escape group. 
 
Summary statistics by randomization strata and by treatment group will be presented at 
each assessment visit during the 26 Week Randomized Controlled Period for all primary 
and secondary endpoints. 
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Hemoglobin (Hb) level will also be categorized as increase from baseline (< 1.0 g/dL, 
≥1.0 - < 2.0 g/dL and ≥ 2 g/dL) and the number and percentage of each category will be 
presented by treatment group. 
 
In case a subject completed the study and agreed to enroll in the long-term safety and 
efficacy study (APL2-307) but are unable due to COVID-19, this subject with delayed 
enrollment will continue on the current study treatment until enrolling in the APL2-307 
and any data collected (e.g. AE, Lab, VS) will be summarized and presented in tables and 
Listings. 
 
Plots of Continuous Variables 
 
Mean (± SE) plots and mean (± SE) change from baseline for all continuous primary and 
secondary efficacy variables will be displayed for the Randomized Controlled Period. 
The plots will be presented by treatment group. 
 
Listings 
 
Absolute values and changes from baseline will be included in the listings. Flags will 
also be included to identify values that meet the responder/normalization/stabilization 
criteria. 
 
6.1 
Estimands 
The co-primary efficacy endpoints are: 
• Hemoglobin stabilization defined as avoidance of a > 1 g/dL decrease in Hb 
levels from Baseline in the absence of transfusion through Week 26 (Yes/No) 
AND 
• Reduction in lactate dehydrogenase (LDH) level from Baseline to Week 26 
The intercurrent events (ICE) that will be considered are: 
1. Transfusions 
2. Treatment escape 
3. Discontinuation of Study Treatment 
4. Withdraw from Study 
5. Lost to follow up 
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Transfusions 
 
For any subject who receives a transfusion (per the transfusion criteria listed in Section 
10.7 of the protocol), the first co-primary endpoint will be considered failure to achieve 
Hb stabilization (Composite Strategy). 
 
Treatment Escape 
 
For any subject who escapes from SOC to pegcetacoplan, the response will be considered 
failure to achieve Hb stabilization for the first co-primary endpoint (Composite Strategy). 
 
Discontinuation of Study Treatment 
 
If a subject discontinues study treatment, any values collected after discontinuation will 
continue to be used in analyses (Treatment Policy strategy) 
 
Pandemic-Related ICE due to COVID-19 
Pandemic related ICE due to COVID-19 (e.g., discontinuation of study treatment, 
missing outcomes because of missing evaluation visits) is typically unrelated to study 
medication or outcome, therefore, the Hypothetical Strategy for dealing with this ICE 
will be used, as it is aligned with the clinical goal of evaluating outcomes that would have 
been observed had no COVID-19 pandemic interfered with the treatment regimen. 
 
The following table shows the primary Estimands, the sensitivity and the supportive 
analyses for the co-primary efficacy endpoints. 
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Definition 
Attributes 
A: Population 
B: Variable (or 
C: Strategy for addressing 
D: Population-level summary 
1- First Co-Primary 
Endpoint: 
The effect of 
pegcetacoplan 
compared to 
SOC on 
Hemoglobin 
stabilization 
after 26 weeks 
of 
monotherapy 
treatment to 
PNH subjects. 
endpoint) 
intercurrent event (ICE) 
ITT 
Week 26 Hemoglobin 
stabilization 
The composite strategy will be 
followed (i.e., Subject who experienced 
one of the following events will be 
considered failure): 
• 
Transfusions 
• 
Treatment escape 
• 
Discontinuation of Study 
Treatment 
• 
Withdrawal from the study 
• 
Lost to follow up 
The adjusted odd ratio (OR) of 
achieving Hb stabilization for the 
pegcetacoplan group versus SOC and 
associated 95% CI will be presented 
along with the difference between 
treatment proportion with associated 
95% confidence interval and 
appropriate p-value using CMH. 
Supportive Analyses 
ITT, PP 
Week 26 Hemoglobin 
The strategy will be the same as for the 
The adjusted odd ratio (OR) of 
stabilization 
first co-primary endpoint shown above. 
achieving Hb stabilization for the 
pegcetacoplan group versus SOC and 
associated 95% CI and appropriate p- 
value. Logistic regression with the 
effects of treatment and stratification 
factor will be used. In case of 
nonconvergence exact logistic 
regression with the effects of 
2-Second Co-Primary 
Endpoint: 
treatment and stratification factor will 
be used to compare the two-treatment 
group and to estimate the p-value. 
Reduction in 
lactate 
dehydrogenase 
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(LDH) level 
from Baseline 
to Week 26 
ITT 
Week 26 LDH level change 
from baseline 
Any LDH values before escape from 
SOC to pegcetacoplan will be used in 
the analysis and all values after the 
SOC escape will be set to missing. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on 
ANCOVA adjusting for LDH 
baseline, treatment, and stratification 
factor. 
Sensitivity Analyses 
ITT 
Week 26 LDH level change 
from baseline 
The strategy will be the same as for the 
second co-primary endpoint shown 
above. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on Mixed 
Model for Repeated Measures 
(MMRM) 
ITT 
Week 26 LDH level change 
from baseline 
Imputation based on the delta-adjusted 
stress testing method (Tipping Point) 
using the strategy will be the same as 
for the second co-primary endpoint 
shown above. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on MMRM 
Supportive Analyses 
ITT 
Week 26 LDH level change 
from baseline 
The strategy will be the same as for the 
second co-primary endpoint with 
Last observation carried forward 
(LOCF) approach for handling missing 
data using the strategy will be the same 
as for the second co-primary endpoint 
shown above. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on 
ANCOVA adjusting for LDH 
baseline, treatment, and stratification 
factor. 
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ITT 
Week 26 LDH level change 
from baseline 
The strategy will be the same as for the 
second co-primary endpoint with 
Best observation carried forward 
(BOCF) approach for handling missing 
data. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on 
ANCOVA adjusting for LDH 
baseline, treatment, and stratification 
factor. 
PP 
Week 26 Hb change from 
baseline 
The strategy will be the same as for the 
second co-primary endpoint. 
Difference between treatment means 
with 95% confidence interval and 
appropriate p-value based on 
ANCOVA adjusting for LDH 
baseline, treatment, and stratification 
factor. 
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6.2 
Analyses of Primary Efficacy Endpoints 
6.2.1 
First Co-Primary Efficacy Endpoint 
For the first co-primary endpoint (Hb stabilization), the number and percentage of 
subjects who achieve Hb stabilization using ITT set will be computed and compared 
between treatment groups using a stratified Cochran-Mantel-Haenszel (CMH) chi-square 
test. The adjusted odd ratio (OR) of achieving Hb stabilization for the pegcetacoplan 
group versus SOC with associated 95% CI will be presented along with the difference 
between treatment proportion with associated 95% confidence interval and appropriate p 
values. 
Subjects who receive a transfusion through Week 26 or escape from SOC to 
pegcetacoplan treatment group or withdraw from the study or treatment or lost to follow 
up before providing primary efficacy assessment will be categorized as failing to achieve 
Hb stabilization. 
6.2.2 
Second Co-Primary Efficacy Endpoint 
The second co-primary efficacy endpoint is the change from baseline in LDH level at 
Week 26. 
If a subject escape from SOC to pegcetacoplan treatment group, the LDH level up to 
escape will be included in the model. If subject receives transfusion, the pre transfusion 
LDH level from the certified local laboratory will be used, however, if it is not collected 
or missing, then the pre transfusion central laboratory LDH value will be used. 
The following steps will be taken for the analyses: 
1. The post baseline missing LDH values will be imputed using Multiple imputation 
(MI) method with Markov Chain Mont Carlo (MCMC) methodology using PROC 
MI of SAS with a total of 1000 imputations and the random seed will be 123876. 
An appropriate transformation such as a natural Log will be utilized to normalize 
the data before imputation and using the EXP to unnormalize after the imputation 
utilizing TRANSFORM LOG function in PROC MI or other transformation as 
appropriate. 
2. The MCMC method in PROC MI will be invoked with multiple chains 
(CHAIN=MULTIPLE), 200 burn-in iterations (NBITER=200) and a non- 
informative prior (PRIOR=RIDGE=1) to produce complete data set. 
3. The change from baseline (CFB) in LDH level to Week 26 visit will be calculated 
for each of the 1000 completed data sets generated in step 2. 
4. Transformation of CFB might be applied to achieve data normality if deemed 
appropriate. 
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5. Each of the 1000 complete data sets from Step 3 will be analyzed using analysis 
of covariance (ANCOVA) with CFB for LDH level at Week 26 as the response 
variable and with treatment as fixed effect, adjusted for baseline LDH level and 
stratification factor using PROC GLM or PROC MIXED of SAS. 
6. The results obtained in each 1000 imputed data sets, including the treatment 
differences and their standard errors, will be combined using Rubin’s imputation 
rules (Rubin, 1987) to produce a pooled estimate of the treatment differences, 
corresponding 95% confidence interval and a pooled treatment effect P-value 
using PROC MIANALYZE of SAS. 
 
 
6.3 
Sensitivity Analyses of Co-Primary Efficacy Endpoints 
Sensitivity analyses will be performed to evaluate the robustness of the results from the 
primary analysis methods. 
 
No sensitivity analysis is planned for first co-primary analyses and this section presents 
only the sensitivity analyses for the second co-primary endpoint. 
 
6.3.1 
Second Co-Primary Efficacy Endpoints 
Mixed model for repeated measures (MMRM) will be used as the first sensitivity analysis 
for the second co-primary endpoint (change in LDH from baseline at Week 26) after setting 
values to missing when subjects escape from SOC to pegcetacoplan. 
 
The between-treatment group comparison for the second co-primary efficacy endpoint 
will be performed using a mixed effect model for repeated measures (MMRM); 
(Mallinckrodt CH, 2008); The model will include fixed categorical effects for treatment 
group, study visit, stratification variables (based on transfusion history) and the study 
visit-by-treatment group interaction, as well as the continuous, fixed covariate of baseline 
LDH level. Initially an unstructured covariance matrix will be investigated. If this 
analysis fails to converge, other structure will be tested such as compound symmetry 
(CS). The Kenward Roger’s approximation will be used to estimate denominator degrees 
of freedom. 
 
The difference between pegcetacoplan and SOC mean LDH level changes from baseline 
at Week 26 will be calculated along with its 2-sided 95% CI and associated P-value from 
the MMRM model. 
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The Imputation based on the delta-adjusted stress testing (Tipping Point) analysis will be 
performed for the second co-primary endpoint (mean LDH level change from baseline at 
Week 26) using MMRM model. 
 
This method can be considered as sensitivity analysis for the second co-primary Missing 
at Random (MAR) based analyses where deterioration of the future unobserved outcomes 
constitutes specific types of departure from the MAR assumption towards the 
Missingness Not At Random (MNAR) assumption. 
 
The Tipping point imputation approach will be based on the delta-adjusted stress testing 
method, also known as the tipping point analysis (O’Kelly and Ratitch, 2014, Chapter 7). 
This method assumes that subjects who discontinue from the pegcetacoplan group 
experience worsening defined by a pre-specified adjustment in the second co-primary 
endpoint (LDH level). After the initial imputation, a range of shifts will be added to the 
imputed missing data in both pegcetacoplan and SOC groups. 
 
6.4 
Supportive Analyses of Co-Primary Efficacy Endpoints 
 
 
6.4.1 
First Co-Primary Efficacy Endpoints 
The first co-primary efficacy endpoint (Hb stabilization) will also be analyzed using 
logistic regression with the effects of treatment group and stratification factor included in 
the model using ITT set. The adjusted odd ratio (OR) of achieving Hb stabilization for 
the pegcetacoplan group versus SOC with associated 95% CI and associate p-value will 
be estimated from the final model. In case of nonconvergence exact logistic regression 
with the effects of treatment and stratification factor will be used to compare the two- 
treatment group and to estimate the p-value 
The analyses will be repeated using the PP set (if sets are different from ITT set). 
 
6.4.2 
Second Co-Primary Efficacy Endpoints 
Per FDA comments (Letter dated Feb 12, 2020), the second co-primary endpoint (LDH) 
will be analyzed using an analysis of covariance (ANCOVA) model (ITT set) with a last 
observation carried forward (LOCF) approach for handling missing data. The ANCOVA 
model will include terms for treatment as fixed effect, adjusted for baseline LDH level 
and stratification factor using PROC GLM or PROC MIXED. 
The second co-primary endpoint (LDH) will be analyzed using an ANCOVA model (ITT 
set) with a Baseline observation carried forward (BOCF) approach for handling missing 
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data. The ANCOVA model will include terms for treatment as fixed effect, adjusted for 
baseline LDH level and stratification factor using PROC GLM or PROC MIXED. 
The LOCF and BOCF imputations analyses will be performed after setting all data after 
escape from SOC to pegcetacoplan to missing. 
The PP set supportive analysis will also be provided for the second co-primary endpoint. 
 
The difference between pegcetacoplan and SOC in mean LDH changes from baseline at 
Week 26 will be calculated along with its 2-sided 95% CI and p-values. 
 
6.5 
Analyses of Secondary Efficacy Endpoints 
The secondary endpoints will be analyzed using the ITT set. Summary statistics by 
randomization strata and by treatment group will be presented at each assessment visit 
during the 26-week Randomized Controlled Period. 
 
The continuous secondary endpoints will be performed whereby all data after escape to 
pegcetacoplan will be set to missing for: 
• Hemoglobin level 
• LDH level 
• Absolute Reticulocyte count (ARC) 
• Hemoglobin level 
• Bilirubin level (Indirect & Total) 
• Haptoglobin level 
• FACIT-Fatigue scale score 
• LASA scores 
• QLQ-C30 scores 
6.5.1 
Categorical Secondary Efficacy Endpoints 
The number and percentage of subjects meeting the following criteria will be tabulated 
by treatment group at Week 26 and the superiority test will be used to compare the 2 
treatment groups: 
 
• Hemoglobin response (Yes/No) in the absence of transfusions (Hb response is 
defined as a ≥1g/dL increase in Hb from Baseline at Week 26) 
• Proportion of subjects who received transfusion or had decrease of Hb > 2 g/dL 
from Baseline (Yes/No). 
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• Transfusion avoidance (TA) (Yes/No), defined as the proportion of subjects who 
do not require a transfusion during the Randomized Controlled Period. 
• Normalization of Hb levels (Yes/No) (defined as ≥1x LLN) from Baseline to 
Week 26 in the absence of transfusions (Yes/No) 
• Normalization of LDH levels (Yes/No) of ≤1 x the upper limit of normal (ULN) 
from Week 4 to Week 26 in the absence of transfusions (Yes/No) 
• Normalization of ARC levels (Yes/No) of <1 x the upper limit of normal (ULN) 
at Week 26 in the absence of transfusions (Yes/No) 
 
The hemoglobin response, transfusion avoidance (TA), and hemoglobin, LDH and ARC 
normalization endpoints are binary responses (i.e., Yes / No); each endpoint will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for stratification 
factor at randomization. The odds ratio of being a responder (Yes) on each of the 
endpoints for the pegcetacoplan vs. SOC and associated 95% confidence interval (CI) 
will be provided. Subjects who received a transfusion or withdraw or escaped from SOC 
to pegcetacoplan treatment group or withdraw from the study or treatment or lost to 
follow up without providing efficacy data at Week 26 will be classified as non- 
responders in these analyses. 
 
For the transfusion avoidance (TA) endpoint, subjects who received a transfusion will be 
classified as non-responders in this analysis, otherwise the subject will be classified as 
responder. 
 
For the proportion of subjects who received transfusion or had decrease of Hb > 2 g/dL 
from Baseline, the subject will be classified as non-responder in this analysis, otherwise 
the subject will be classified as responder. 
 
The above binary endpoints will be tabulated by treatment group. 
 
6.5.2 
Continuous Secondary Efficacy Endpoints 
Change from Baseline Endpoints 
 
Superiority will be assessed for the change from baseline to Week 26 for the continuous 
secondary endpoints: 
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The absolute values and changes from baseline in ARC, Hb level, indirect and total 
bilirubin level, haptoglobin level, FACIT-Fatigue scale score. LASA scores and QLQ- 
C30 scores will be summarized by treatment group at Baseline and each study visit. 
 
The indirect bilirubin is not reported in the database and it will be derived from the total 
and direct bilirubin as follow: 
 
indirect bilirubin = total bilirubin – direct bilirubin 
 
The Change from baseline at Week 26 will be analyzed using the same methods 
described for the primary analysis of the second co-primary endpoint, except using their 
own baseline as a covariate. The ITT set will be used. These analyses will be done by 
setting values to missing after subject escape to pegcetacoplan from SOC. 
 
 
Number of PRBC units and Number of Transfusions 
 
The number of PRBC from Baseline to Week 26 is reported in units and mL in the 
database, therefore, the mL will be converted to units using the following formula: 
 
Number of PRBC units = Round (PRBC (mL) / 300),1). 
 
The total number of units of PRBCs transfused and number of transfusions during the 
Randomized Controlled Period will be compared between the treatment groups using 
Wilcoxon rank-sum test. The difference between the medians will be estimated along 
with its 95% confidence interval (stratified). 
 
The following supporting analyses for the number of PRBC units and number of 
transfusions to account for subjects who withdraw during the Randomized Controlled 
Period before Week 26 will be provided: 
 
• The number of units of PRBCs transfused and the number of transfusions will be 
analyzed using log-incidence density ratios (non-parametric) adjusting for 
treatment (Dmitrienko & Koch). For each treatment, the incidence density will be 
the number units of PRBCs transfused or number of transfusions that a subject 
experienced, normalized by the number of days during the Randomized 
Controlled Period. 
 
• The number of units of PRBC and the number of transfusions will be estimated 
based on the duration they were in the Randomized Controlled Period (i.e. 
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number per week x duration of endpoint). Hence the analysis of this endpoint will 
equate to an analysis of the frequency of transfusions. 
 
Time to failure of Hb Stabilization and Time to Transfusions 
 
For the secondary endpoints of Time to first-on-study failure of Hb Stabilization and 
Time to Transfusions, Kaplan-Meier method will be used to describe the survival data. 
The comparison of the median survival time between treatment group will be assessed 
using log-rank test and generalized Wilcoxon test. The subject who lost to follow-up, 
discontinue the study or escape will be censored at the last visit. For subject who 
randomized but did not receive any treatment will be censored at the date of 
randomization. For subject who missed ≥ 3 consecutive visits will be censored at the visit 
before the first missing visit. For censored subjects, the time to the last observation date 
will be used for the Kaplan-Meier plot. The hazard ratio (HR) of the pegcetacoplan group 
to SOC and associated 95% CI will be provided. 
The Time to first-on-study escape from SOC to APL-2 group will also be analyzed and 
presented in table and figure. 
 
6.6 
Subgroup Analyses 
The co-primary endpoints will be summarized and analyzed by the following subgroups 
using the ITT set: 
 
1- Number of PRBC transfusions within the 12 months prior to Day -28 (<4; ≥4) 
(i.e., number of transfusion events regardless of PRBC units transfused. 
 
2- Summary statistics of the co- primary endpoints will also be provided for 
subgroups based on sex, race, and age (≤65 years and > 65 years). 
 
 
6.7 
Exploratory Endpoints 
• 
• 
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6.8 
Additional Secondary Efficacy Endpoints 
 
The following additional secondary endpoints will also be summarized by treatment 
group using ITT set: 
1. Number and percentage of subjects achieved Hb level ≥ 11 g/dL and ≥ 12 g/dL at 
week 26. 
2. Number and percentage of subjects without PRBC transfusion during the RCP. 
3. Total and Indirect Bilirubin normalization levels (defined as <=1xULN) at Week 
26 in the absence of transfusion (Yes/No). 
4. Number and percentage of subjects achieving ≥ 3 points improvement in FACIT- 
Fatigue score from baseline to Week 26. 
 
5. Normalization of Hb levels (defined as ≥1xLLN) from Baseline at Week 26 in the 
absence of transfusions (Yes/No) 
 
6. Normalization of LDH levels ≤1 x the upper limit of normal (ULN) at Week 26 in 
the absence of transfusions (Yes/No) 
 
7. Absolute reticulocyte count (ARC) normalization (<1 x ULN) from Baseline to 
Week 26 in the absence of transfusion (Yes/No) 
8. Normalization of LDH levels (Yes/No) of ≤1 x the upper limit of normal (ULN) 
from Baseline to Week 26 in the absence of transfusions (Yes/No) 
9. Normalization of Hb levels (defined as ≥1xLLN) from Week 4 to Week 26 in the 
absence of transfusions (Yes/No) 
10. Absolute reticulocyte count (ARC) normalization (<1 x ULN) from Week 4 to 
Week 26 in the absence of transfusion (Yes/No) 
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7. 
SAFETY ANALYSIS 
The safety analysis will be performed using the Safety set. 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 on Treatment 
(LVOT) will be defined as the last valid assessment obtained after Baseline and whilst on 
investigational product. Last Observed Value (LOV) will be defined as the last valid 
assessment obtained after Baseline. 
 
All safety data available at the time of database lock for Week 26 will be provided. 
Safety analyses will be conducted according to the treatment the subject received. 
 
7.1 
Adverse Events 
Adverse events will be coded using the Version 23.0 of MedDRA®. 
 
An AE (classified by preferred term) that occurs during the study will be considered a 
TEAE if it has a start date on or after the first dose of investigational product for APL2 
group, on or after randomization date for SOC group or if it has a start date before the 
date of the first dose but increases in severity on or after the date of the first dose. If 
more than 1 AE with the same preferred term is reported before the date of the first dose, 
then the AE with the greatest severity will be in summaries. An AE that occurs more 
than 8 weeks (week 34 or visit 18) after the date of the last dose will not be counted as a 
TEAE. 
 
Only TEAEs will be included in the summary tables. 
 
An overall summary will be provided for the Randomized Controlled Period of the study 
as follow: 
 
• any TEAE 
• any TEAE considered as related to pegcetacoplan (evaluated by the investigator 
as definitely related, possibly related) 
• any TEAE considered as related to SOC (evaluated by the investigator as 
definitely related, possibly related) 
• any TEAE considered as related to infusion procedure (evaluated by the 
investigator as definitely related, possibly related) 
• maximum severity TEAE of mild, moderate, or severe, i.e. a subject with TEAEs 
at different intensities will be summarized at the most severe intensity 
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• any injection site reaction 
• any serious TEAE 
• any serious TEAE considered related (definitely, probably, possibly) to either 
study drug. 
• any TEAE leading to death. 
• Any treatment emergent infections, serious infections, and related infections 
• Exposure-Adjusted Incidence TEAE, SAE and ISR. 
• TEAE Reported by 5% or More Subjects in Any treatment group. 
• Time to Onset of TEAE of Special Search Category 
o Hemolytic Disorders 
o Hypersensitivity 
o Sepsis 
o Infections 
o Thrombosis 
• TEAE without Injection Site Reaction 
• Injection Site Reaction TEAE 
 
The number and percentage of subjects reporting TEAEs in each treatment group and 
overall will be tabulated by system organ class (SOC) and preferred term; by system organ 
class (SOC), preferred term, and maximum severity. TEAEs considered related to 
investigational product will also be summarized by SOC and preferred term. 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. Any 
TEAEs with missing severity information will be taken as severe for these summaries and 
be footnoted and any TEAEs with missing causality information will be taken as related 
for these summaries and be footnoted. 
 
AE tabulations will also be summarized over the whole study for pegcetacoplan and SOC 
up to 8 weeks (week 34 or visit 18) beyond the last dose of study medication. 
 
All summaries will be ordered by descending frequency of subjects within each SOC and 
then similarly by decreasing frequency of subjects within each PT, in the overall column. 
In cases of SOCs or PTs with equal frequencies, TEAEs will be sorted alphabetically. 
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All TEAEs will be listed by treatment group, subject and AE onset date. Onset time since 
dose (start date/time – dose date/time) and AE duration (stop date/time – start date/time) 
will be included in the listing; where applicable imputed data will be used for the 
calculation of onset time and AE duration, but the original dates/time information will be 
presented in the listing. 
 
The serious AEs and TEAE due to COVID-19 will be identified in the listing. 
 
If there are any deaths a listing will include the date of death and primary cause of death. 
 
7.1.1 Exploratory Adverse Events Endpoint 
 
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
at each assessment time point, as well as shift tables from baseline to each visit for 
quantitative variables will be presented by treatment group. The laboratory values will be 
compared to its normal ranges (N-Rs) at every visit and the following categories will be 
derived for the shift tables (below normal range (N-R), Normal, Above normal range (N- 
R), and undetermined). 
 
In case of using certified local laboratory instead of central laboratory due to COVID-19 
pandemic, the units and normal ranges might be different and therefore, there might be a 
need to convert all units to SI units and the method developed by (Stein, 1992, 2001) may 
be utilized to normalize laboratory data for the purpose of analyses. If, however, the 
normal ranges for all laboratories are close to each other, global normal ranges may be 
created for each laboratory parameter to be used for the analyses. 
 
The formula for normalizing the laboratory parameters values is as follow: 
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Z = (X-XL) / (XU-XL), 
 
Where Z is the normalized laboratory value, 
X is the original laboratory value, 
XU-XL are the lower and upper normal range values. 
 
Under this rule, values within the normal range transform into those between 0 and 1. 
The lower bound XL becomes 0 and the upper bound XU becomes 1. On the other hand, 
values outside the normal range transform to either negative values or values above 1. 
This method is applicable to all lab values without making any distributional 
assumptions. 
Since the normalized values are unit free, we can pool the normalized values from 
different centers and use them directly in the computation. The original units can be 
restored, and summary statistics will be present either without units or with the original 
units. 
 
The flowing formula will be used to convert local lab value at observation level to central 
lab value: 
 
 
𝐶𝑒𝑛𝑡𝑟𝑎𝑙 𝑣𝑎𝑙𝑢𝑒 = 𝑁𝑅𝐿𝑂(𝐶𝐿) + 𝑙𝑜𝑐𝑎𝑙 𝑣𝑎𝑙𝑢𝑒 − 𝑁𝑅𝐿𝑂 
 
 
𝑁𝑅𝐻𝐼 − 𝑁𝑅𝐿𝑂 
 
× (𝑁𝑅𝐻𝐼(𝐶𝐿) − 𝑁𝑅𝐿𝑂(𝐶𝐿)) 
 
Were, 
NRLO: 
Low normal range for local lab 
NRHIL: 
High normal range for local lab 
NRLO(CL):  Low normal range for central lab 
NRHI(CL): 
High normal range for central lab 
 
 
Clinical laboratory test values are potentially clinically significant (PCS) if they meet 
either the low or high PCS criteria listed in Table 2. The number and percentage of 
subjects with 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 
baseline values and at least 1 post-baseline assessment. The numerator is the total number 
of subjects by-visit with at least 1 post-baseline PCS value. A supportive listing of 
subjects with post-baseline PCS values will be provided including the subject number, 
site, baseline, and post-baseline values. 
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Table 2:Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Hematology 
Hemoglobin 
g/dL 
Mild 
10 
12 
Moderate 
7 
10 
Severe 
< 7 
Neutrophils Levels 
109 cell/L 
Mild 
1 
1.5 
Moderate 
0.5 
1.0 
Severe 
< 0.5 
Platelets levels 
109/L 
Mild 
100 
150 
Moderate 
50 
100 
Severe 
< 50 
 
All laboratory data will be listed for Safety set. The listing will include change from 
baseline values and values outside the laboratory reference range will be flagged. 
Any urine microscopy data collected will be listed. 
 
7.3 
Vital Signs 
Descriptive statistics for vital signs (e.g., body temperature, respiratory rate, blood 
pressure, and heart rate) and their changes from baseline will be presented by study 
Period, treatment group, visit (day) and scheduled time. 
 
All vital signs data form clinic visit only will be listed for the Safety set. The listing will 
include change from baseline values. 
 
7.4 
Electrocardiogram (ECG) 
QT Analyses will be performed by an external vendor (ERT) and the results will be 
delivered to Apellis in a separate dataset. Descriptive statistics for ECG variables (e.g., 
heart rate, PR interval, QRS interval, QT interval, and QTc interval) and their changes 
from baseline will be presented by study Period, treatment group, visit (day) and 
scheduled time. The mean of the triplicate measurements will be derived prior to 
summarizing the data. QTc interval will be calculated using both Bazett 
(QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not 
available, it will be replaced with 60/hr in the correction formula. 
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ECG interpretation will be summarized by visit. The “worst” clinical assessment of the 
triplicate ECGs (order of abnormal clinically significant, abnormal not clinically 
significant and normal) will be used. 
 
A shift table from baseline to each visit for qualitative ECG results will be presented. 
 
The number of subjects with at least one value post baseline satisfying the PCS criteria, 
will be tabulated. All replicates (i.e., individual values for triplicates) and all scheduled and 
unscheduled values will be assessed. The following categories will be used: 
 
Parameter 
Criteria 
Heart Rate 
All values within 50 -100 bpm 
At least one value ≤ 50 bpm* and no values ≥ 100 bpm 
At least one value ≥ 100 bpm* and no values ≤ 50 bpm 
At least one value ≥ 100 bpm* and one value ≤ 50 bpm* 
PR Interval 
< 200 msec 
≥ 200 msec* 
QT Interval 
< 480 msec 
≥ 480 msec* 
QRS Interval 
< 120 msec 
≥ 120 msec* 
QTcB, QTcF 
<450 msec 
≥ 450 msec and <480 msec 
≥ 480 msec and <500 msec* 
≥ 500 msec* 
QT, QTcF increase from 
baseline 
< 30 msec 
≥ 30 msec and < 60 msec* 
≥ 60 msec* 
* Values of PCS. 
 
All ECG data will be listed for the Safety set for Randomized Controlled Period. Separate 
listings will be provided for the replicate data and the means of triplicate measurements. 
Changes from baseline values will be included in the listings and in both listings PCS 
values will be flagged. 
 
7.5 
Other Safety Data 
Immunogenicity, physical examination, and pregnancy test data will be listed for the 
Safety set. For Immunogenicity data, the number and percentage of subjects developing 
antidrug antibodies (ADA) (anti-pegcetacoplan peptide antibodies and anti-PEG 
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antibodies), treatment-boosted and treatment-emergent responses where applicable, will 
be summarized and listed by treatment group. 
 
8. 
PHARMACOKINETIC ANALYSIS 
All summaries and analyses of the pharmacokinetic data will be based on the 
Pharmacokinetic set. 
 
Pegcetacoplan concentrations reported as below the limit of quantification (BLQ) will be 
taken as zero for linear plots, and equal to the lower limit of quantification (LLOQ) for 
semi-logarithmic plots. For the computation of descriptive statistics, BLQ will be taken 
as zero, except for the calculation of the geometric mean where the LLOQ will be used. 
 
The pegcetacoplan concentrations will be evaluated using the PK analysis set. 
Pegcetacoplan concentrations will be summarized by treatment group at each scheduled 
time point using descriptive statistics. If a subject discontinues pegcetacoplan dosing, 
then concentrations from samples collected more than 1 day after the last dose will be 
excluded from calculations. Follow-up samples will only be included if within 10% of 
the scheduled time after the last pegcetacoplan dose. 
 
Samples for PK assessment should not be collected for subjects randomized to the SOC 
(excluding complement inhibitors) treatment group unless they become eligible for and 
elect to receive pegcetacoplan escape therapy. If a subject from the SOC (excluding 
complement inhibitors) treatment group is to begin receiving pegcetacoplan escape 
therapy, a pre-dose PK sample should be collected at the pegcetacoplan initiation visit 
before dosing begins and at each subsequent visit as detailed in the Schedule of Events. 
Pegcetacoplan concentrations for the SOC group will be summarized additionally 
whereby all data after escape is set to missing. 
 
The number of subjects with a value > BLQ will also be tabulated. 
 
Individual subject concentration-time data will be plotted against actual sampling time. 
Median profiles of the concentration-time data, using nominal sampling times, will also 
be presented by treatment group. Both linear-linear and linear-log plots will be presented. 
 
A listing of all concentration data will be presented by dose. The actual time, deviation 
and percent deviation from nominal time will also be listed. 
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Population pharmacokinetic and exposure-response modelling of the safety and efficacy 
data will be described in the pegcetacoplan Population 
pharmacokinetic/Pharmacodynamic Analysis Plan which will be performed by consultant 
or CRO. The methods will be based on the FDA Guidance for both Exposure-Response 
and Population Pharmacokinetics (FDA Guidance for Industry Population 
Pharmacokinetics, FDA Guidance for Exposure-Response Relationships). 
 
9. 
PHARMACODYNAMIC ANALYSIS 
All summaries and analyses of the pharmacodynamic (PD) data will be based on the 
Pharmacodynamic set. 
 
Observed values, changes from baseline and percentage changes from baseline will be 
summarized by treatment group at each visit using descriptive statistics for the following 
parameters: 
 
• Change from Baseline to Week 26 in percentage of PNH Type II+III RBC cells 
opsonized with C3 
• Change from Baseline to Week 26 in percentage of PNH Type II+III RBC cells 
• Change from Baseline to Week 26 in complement (e.g., CH50, AH50, and C3) 
levels 
• Changes from baseline and percentage changes from baseline for C3 deposition 
on RBC cells (percent C3d CD59 Type I, II and III), clonal distribution of PNH 
RBCs (percent CD59 Type I, II and III), PNH granulocytes (percent FLAER) and 
PNH monocytes (percent FLAER). 
 
In addition, the following endpoints will be derived and Changes from baseline and 
percentage changes from baseline will be summarized by treatment group: 
 
• Clonal distribution of PNH RBCs (percent Type II + III); this is simply the sum 
of the clonal distribution of PNH RBCs Type II and Type III. 
 
• C3d deposition on RBC cells (percent Type II + III); this is the number of events 
for C3d deposition on RBC cells (Type II) plus number of events for C3d 
deposition on RBC cells (Type III) divided by number of events for PNH CD59 
Type II and III expressed as a percent. 
 
Median profile plots will also be presented graphically by treatment group for the 
observed values and percentage changes from baseline. The nominal sampling time will 
be used on the x-axis. 
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Changes from baseline and percentage changes from baseline will be included in listings. 
 
10. 
OTHER ANALYSES 
No other analyses are planned for this study. 
 
11. 
INTERIM ANALYSIS 
No interim analysis is planned. 
 
12. 
DATA MONITORING COMMITTEE/REVIEW COMMITTEE 
A DMC will review cumulative safety/tolerability data (e.g., physical examinations, ECGs, 
vital signs, clinical laboratory tests, and AEs), efficacy (Hb and LDH levels, haptoglobin 
level, ARC, and RBC transfusions), and PK data. The DMC will have the responsibility 
to conduct a thorough safety assessment at regular pre-defined intervals during the study, 
as described in the DMC charter. 
In addition, an ad hoc data review may be recommended by the DMC or requested by the 
sponsor at any time during the study. 
The DMC charter will be prepared in a separate document. 
 
13. 
DATA HANDLING CONVENTIONS 
 
13.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, 
mean, median, standard deviation, minimum, maximum. Categorical and count variables 
will be summarized by the number of subjects (n) and the percentage of subjects in each 
category. 
 
All subjects in the analysis set being used will be accounted for in summaries tables. 
 
Unless otherwise specified, the mean, median 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. Unless stated otherwise, for all percentages, the 
number of subjects in the analysis population for the treatment group will be the 
denominator. 
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13.2 
Definition of Baseline 
Unless stated otherwise, baseline will be taken as the average of measurements prior to 
the first dose of pegcetacoplan or prior to randomization of SOC treatment group for 
efficacy endpoints, but as the last measurement before the first dose of pegcetacoplan or 
SOC for other endpoints. 
 
Note: For SOC treatment group, any Lab taken on the randomization date will be 
included in the baseline calculation. 
 
The average baseline value for Hb, LDH and ARC will include certified local laboratory 
and central values for those subjects who have transfusions during the screening Period. 
All other Laboratory parameters, the average baseline values will be from central 
laboratory values only. 
 
13.3 
Summary Table and Listing Presentations 
In by-visit summary tables, the baseline will be summarized using all available data, but 
also for each visit using only the baseline data from subjects with available data at the 
visit; hence the mean change from baseline will equal the mean visit value – mean 
baseline value. 
 
Throughout this document ‘change from baseline’ refers to the actual change from 
baseline (i.e., visit value – baseline value). 
 
All data will be listed, and data listings will be presented by study Period and treatment 
group. Data listings will present study days in addition to dates, where study day is 
derived as (assessment date – randomization date) +1. Therefore, the date of 
randomization will be identified as Study Day 1. 
 
13.4 
Definition of Visit Windows 
Data will be summarized and analyzed based on the list of visits specified in table below. 
The relative day of each assessment [(date of assessment) – (date for randomization +1] 
will be calculated for post randomization. The relative day will be used to assign analysis 
visit following the table below. All the records post-baseline will be assigned to an 
appropriate analysis visit using the following: 
 
For the post-baseline visits, the lower and the upper bound for the analysis visit windows 
are defined as the midpoints of the target date of the scheduled visits. If the date of 
assessment falls in between the lower bound and the upper bound for a visit as specified in 
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the schedule of assessments of the protocol, then it will be assigned to that visit. If more 
that 1 record is within the same analysis visit window, the record closest to the midpoint 
of the interval will be used in the analysis. If 2 records are tied before and after the middle 
of the interval, the earlier record will be used in the analysis. If more than one assessment 
(including the early termination or unscheduled assessments) falls within the same defined 
window, the assessment closest to the target day with non-missing data will be considered 
for analysis. 
 
All assessments that occur on > Day 1 will be assigned to the Randomization Controlled 
Period, whilst any assessment that occurs prior or equal to Day 1 (≤ Day 0) will be assigned 
to the screening Period. See the table below for details on visit windows: 
 
 
 
Part 
Study Visit 
Target 
Day 
Analysis 
Window (days) 
Interval 
Screening 
1 
0 
-28 - ≤ 0 
28 
RCP 
2 
1 
1 - 8 
7 
3 
15 
9 - 22 
13 
4 
29 
23 - 36 
13 
5 
43 
37 – 50 
13 
6 
57 
51 – 64 
13 
7 
71 
65 – 78 
13 
8 
85 
79 – 92 
13 
9 
99 
93 – 106 
13 
10 
113 
107 – 120 
13 
11 
127 
121 – 134 
13 
12 
141 
135 – 148 
13 
13 
155 
149 – 162 
13 
14 
169 
163 – 176 
13 
15 
183 
177 -190 
13 
F/U 
16 
197 
191 – 203 
13 
17 
211 
204 -217 
13 
18 
232 
218 - 246 
28 
19 
261 
247 - 275 
28 
20 
290 
276 - 304 
28 
21 
319 
305 - 333 
28 
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22 
348 
334 – 362 
28 
23 
377 
363 – 391 
28 
24 
406 
392 – 420 
28 
25 
435 
421 - 449 
28 
26 
463 
450 - 477 
28 
27 
492 
478 - 506 
28 
 
 
13.5 
Derived Efficacy Endpoints 
FACIT-fatigue scale score 
The FACIT Fatigue Scale is a 13 item Likert scaled instrument which is self- 
administered by the subjects during clinic visits. Subject are presented with 13 statements 
and asked to indicate their responses as it applies to the past 7 days. The 5 possible 
responses are ‘Not at all’ (0), ‘A little bit’ (1), ‘Somewhat’ (2), ‘Quite a bit’ (3) and ‘Very 
much’ (4). With 13 statements the total score has a range of 0 to 52. Before calculating 
the total score, most responses (all except Answers 5 and 7) are reversed to ensure that 
the higher score corresponds to a higher quality of life. 
 
Linear Analog Scale Assessment (LASA) 
The Linear Analog Scale assessment (LASA) consists of three items asking respondents 
to rate their perceived level of functioning. Specific domains include activity level, ability 
to carry out daily activities, and an item for overall QOL. Their level of functioning is 
reported on a 0-100 scale with 0 representing “As low as could be” and 100 representing 
“As high as could be”. In addition to looking at each domain the combined score (range 
of 0-300) will be determined. 
 
European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30 
Questionnaire) 
The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of 
both multi-item scales and single-item measures to assess overall quality of life in 
subjects. Questions are designated by functional scales, symptom scales, and global 
subject QOL/overall perceived health status. 
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For the first 28 questions the 4 possible responses are “Not at all’ (1), ‘A little’ (2), ‘Quite 
a bit’ (3) and ‘Very much’ (4). For the remaining 2 questions the response is requested 
on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’). 
 
Number 
of Items 
Item 
Range* 
Item 
Numbers 
Global Health Status / QoL 
2 
6 
29, 30 
Functional Scales 
Physical Functioning 
5 
3 
1 to 5 
Role Functioning 
2 
3 
6, 7 
Emotional Functioning 
4 
3 
21 to 24 
Cognitive Functioning 
2 
3 
20, 25 
Social Functioning 
2 
3 
26, 27 
Symptom Scales 
Fatigue 
3 
3 
10, 12, 18 
Nausea and Vomiting 
2 
3 
14, 15 
Pain 
2 
3 
9, 19 
Dyspnoea 
1 
3 
8 
Insomnia 
1 
3 
11 
Appetite Loss 
1 
3 
13 
Constipation 
1 
3 
16 
Diarrhoea 
1 
3 
17 
Financial Difficulties 
1 
3 
28 
* the item range is the difference between the possible maximum and the minimum 
response to the individual items, hence for Questions 1-28 this is 3 and for Questions 29 
and 30 this is 6. 
 
Once the raw scores are calculated, a linear transformation will be applied to obtain the 
particular score as follows: 
 
Functional Scale Scores = {1 – (Raw Score-1)/range} x 100 
Symptom Scale Scores = {(Raw score -1)/range} x 100 
Global Health Status / QoL Scale score = {(Raw score -1)/range} x 100 
 
Hence for the functional scales and the global health status a higher score indicates a 
better QoL, whilst for the symptom scale scores this is implied by a lower score. 
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Consequently, each scale has a range of 0% - 100%. A high scale score represents a 
higher response level. Thus, a high score for a functional scale represents a high level of 
functioning but a high score for a symptom scale represents a high level of 
symptomatology. 
 
Missing data: in the case of multi-item scales missing one of the items, raw scores can 
still be calculated using the completed items as long as more than 50% of the items were 
answered. For single-item measures, the score will be set to missing. 
 
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 average final assessments made prior to the start of investigational 
product will be used as baseline. If end of study assessments is 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 Data Imputation for Efficacy Endpoints 
Imputation methods are described in the sensitivity analyses in Section 6.2.2 and 
appendix 17.3. 
 
13.7.2 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. 
 
For prior or concomitant medications, including the rescue medication of SOC, 
incomplete (i.e., partially missing) start date and/or stop date will be imputed. 
 
For a missing start date (where stop date is after start date of pegcetacoplan dosing or 
missing) the date will be imputed as the first dose date of pegcetacoplan; for a missing stop 
date the date will be imputed as the last study date. 
 
The original dates (as recorded in the eCRF) will be presented in listings. 
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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. 
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 in section 13.7.2.1.1. 
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 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 date of 
the last dose of investigational product is missing, then replace it with the last visit date. 
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. If both start date and stop date are 
missing, then there will be no imputation. 
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13.7.2.2.1 
Missing Day and Month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose 
of investigational product will be assigned to the missing fields. 
• 
If the year of the incomplete stop date is before the year of the date of the last dose 
of investigational product, then the last day and month of the year (31 December) 
will be assigned to the missing fields. 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then the first day and month of the year (01 January) will be 
assigned to the missing fields. 
13.7.2.2.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the procedure for Missing Day and Month. 
13.7.2.2.3 
Missing Day Only 
• 
If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of investigational product, then the date of the last dose 
of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the last 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 last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
13.7.3 Missing Date Information for Adverse Events 
For AEs with partial start dates, non-missing date parts will be used to determine if the 
AE is treatment-emergent or not, and the calculation of study onset day, study stop day 
and duration. If a determination cannot be made using the non-missing date parts as to 
when the AE occurred relative to study drug administration, e.g. AE start year and month 
are the same as the year and month of the first dose of investigational product, then the 
AE will be classified as treatment-emergent. 
 
For a missing start date (where stop date is after start date of pegcetacoplan dosing or 
missing) the date will be imputed as the first dose date of pegcetacoplan; for a missing 
stop date the date will be imputed as the last study date. 
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The original dates (as recorded in the eCRF) will be presented in listings. 
 
13.7.3.1 Incomplete Start Date 
Follow the same rules as in Section 13.7.2.1.2. 
 
13.7.3.2 Incomplete Stop Date 
Follow the same rules as in Section 13.7.2.2. 
 
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” 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 due to, for example, that a character string is reported for a numerical variable. 
The appropriately determined coded value will be used in the statistical analysis. If the 
laboratory results are collected as < or > a numeric value, 0.0000000001 will be 
subtracted or added, respectively to the value. However, the actual values as reported in 
the database will be presented in data listings. 
 
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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15. 
CHANGES TO ANALYSES 
 
15.1 
Changes to Analyses Specified in the protocol 
The following changes have been introduced in this version of the SAP from the most 
recent protocol: 
 
• The second co-primary analysis specified in the protocol has been replaced by an 
ANCOVA analysis. The analysis specified in the protocol (MMRM) is 
performed as a sensitivity analysis. 
 
• Three Sensitivity analyses for the second co-primary endpoints (change from 
baseline to Week 26 for LDH) were added; 1) MMRM, 2) control-based 
imputation method and 3) tipping point analysis based on the delta-adjusted stress 
testing method. These analyses were not specified in the protocol. 
 
 
15.2 
Changes from Analyses Specified in the Previous Version of the SAP 
• 
The criteria of setting to missing continuous efficacy parameters were changed to: 
“values after SOC escape to pegcetacoplan will be set to missing” from 
“Any continuous values before escape from SOC to pegcetacoplan will be used in 
the analysis and all values after the SOC escape or have transfusion or discontinue 
the study or lost to follow up will be set to missing)” due to medical reasons. 
• 
On page 50, under section 13.7.2.1.2, 13.8.2.1.1. was changed to 13.7.2.1.1. 
• 
Added additional analysis visit windows to cover subjects’ visits waiting to enroll in 
the LTSE (APl2-307) study. 
• 
Removed All available data analyses as it is no longer applicable for continuous 
variable analyses. 
• 
Removed by COVID-19 analyses as we have only 2 subjects completed the study 
before March 11, 2020. 
• 
Removed “controlled-based imputation” analyses for the second co-primary 
endpoint. 
• 
Removed Completer set. 
• 
 
• 
The Logarithmic transformation was added to the multiple imputations to normalize 
the data as the MCMC assumes multivariate normal and LDH data is skewed to the 
right which gives unreasonable output after imputations if not normalized. 
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15.3 
Changes from Analyses Specified in Version 2.0 of the SAP 
 
 
The following changes were made to address numerical issues with statistical modeling 
and maintain consistency in the analysis of laboratory-based secondary endpoints prior to 
data cut date (April 29, 2021). 
 
• Logistics regression is a supportive analysis for the first co-primary endpoint (Hb 
stabilization). Because the responder rate may be rare for the SOC group, the 
logistic regression model may not converge. In case of non-convergence, an exact 
logistics regression will be used instead to compare the treatment groups. 
 
• Due to small sample size and a high rate of missing data subsequent to 
intercurrent events for the SOC group, the multiple imputation procedure with 
MCMC may have unstable parameter estimation, leading to issues such as non- 
convergence and extreme samples (i.e., imputed values). Therefore, a ridge prior 
with one degree freedom (i.e., Ridge=1) will be used in PROC MI procedure to 
stabilize the parameter estimation, where the small value of 1 is not expected to 
introduce any bias to the analysis results. 
 
• Added additional secondary endpoint: Normalization of LDH levels (Yes/No) of 
≤1 x the upper limit of normal (ULN) from Baseline to Week 26 in the absence of 
transfusions (Yes/No). 
• Normalization of Hb levels (defined as ≥1xLLN) from Week 4 to Week 26 in the 
absence of transfusions (Yes/No) 
• Absolute reticulocyte count (ARC) normalization (<1 x ULN) from Week 4 to 
Week 26 in the absence of transfusion (Yes/No) 
• Treatment compliance was corrected by replacing the 2.5 in the denominator with 
2.0. 
• Added additional age categories. 
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16. 
REFERENCES 
FDA. (n.d.). FDA Guidance for Industry Population Pharmacokinetics. 
https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf. 
 
Mallinckrodt CH, L. P. (2008). recommendations for the primary analysis of continuous 
endpoints in longitudinal clinical trials. DID, 42: 30. 
 
Miettinen O, Nurminen M (1985). Comparative Analysis of Two Rates. Statistics in 
Medicine, 4, 213-226. 
 
Ratitch B, O’Kelly M, Tosiello R (2013). Missing Data in Clinical Trials: From Clinical 
Assumptions to Statistical Analysis using Pattern Mixture Models. Pharmaceutical 
Statistics. 12:337-347. 
 
O’Kelly, M., Ratitch, B. (editors). Clinical Trials with Missing Data: A Guide for 
Practitioners. Wiley, 2014. 
 
Rubin, D.B multiple Imputation for Nonresponse in Surveys, New York, Wiley, 1987. 
 
Christy Chaung Stein. Summarizing Laboratory data with different refrence ranges in 
multi-center clinical trial. DIA, Vol 26, pp 77-84. 
 
Christy Chaung Stein, Some issues concerning the normalization of laboratory data based 
on reference ranges. DIA, Vol 35, pp 153-156. 
 
ICH E9 (R1) Addendum on Estimands and Sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials. 
 
Alex Dmitrienko and Gary G. Koch. Analysis of Clinical Trials Using SAS- A practical 
Guide- Second Edition, July 2017. Page 80-82. 
 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency https://www.fda.gov/media/136238/download 
 
Committee for Medical Products for Human Use. Points to consider on implications of 
Coronavirus disease 4 (COVID-19) on methodological aspects of ongoing clinical 5 trials 
European Medicines Agency, 25 March 2020 
EMA/158330/2020 https://www.ema.europa.eu/en/implications-coronavirus-disease- 
COVID-19-methodological-aspects-ongoing-clinical-trials 
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17. 
APPENDICES 
 
17.1 
Schedule of Assessments 
 
Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Informed Consent 
X 
Demographics 
X 
Height/Weight 
X 
Medical 
X 
Thrombosis history 
X 
Transfusion history 
X 
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Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Inclusion/Exclusion 
X 
Confirm Hb entry criteriaD 
X 
Randomization 
X 
 
 
 
 
Vaccination 
XE 
E 
XE 
E 
Preventive antibioticsF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationG 
X 
X 
X 
X 
X 
X 
X 
12-lead 
electrocardiogramH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
PEGCETACOPLAN 
administration trainingI 
X 
I 
X 
PEGCETACOPLAN 
administrationI 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurementsJ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BloodK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PharmacokineticsL 
X 
X 
X 
X 
X 
X 
X 
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Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Anti-PEGCETACOPLAN 
Ab assay 
X 
X 
X 
X 
X 
X 
Direct Antibody Test 
(Coombs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lactate dehydrogenase 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Absolute reticulocyte 
count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profileM 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Complement profile 
(CH50, and AH50) 
X 
X 
X 
X 
X 
X 
X 
C3 Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma (free) Hb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy (B-HCG) or 
FSHN 
X 
Genotyping for Gilbert’s 
SyndromeO 
X 
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Protocol Number: APL2-308 
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Study Period 
Screen- 
ingA 
Randomized Controlled Period 
Follow UpB 
AIVC 
Study Week 
Up to - 
4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
34 
-- 
Study Day 
Up to - 
28 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
239 
-- 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
-- 
Clinic Visit Window 
(±Days) 
N/A 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
7 
7 
-- 
Urine pregnancy testP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACIT-Fatigue Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LASA Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FOOTNOTES: 
A. Abbreviations: Ab = antibodies; AE = adverse event; AH50 = alternate complement pathway assay; AIV = pegcetacoplan Initiation Visit; B-HCG = 
beta-human chorionic gonadotropin; C3 = complement component 3; CH50 = total hemolytic complement activity assay; CRFs = case report forms; 
ECG = electrocardiogram; eCRF = electronic case report form; EORTC-QLQ-C30 = 30-item European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire; FACIT = Functional Assessment of Chronic Illness Therapy; FSH = follicle stimulating hormone; Hb = 
hemoglobin; LASA = Linear Analog Assessment Scale; N/A = not applicable; PCV13 = pneumococcal conjugate vaccine (13-valent); PI = Principal 
Investigator; PK = pharmacokinetic(s); PPSV23 = pneumococcal polysaccharide vaccine (23-valent); PRBC = packed red blood cell; QTc = corrected QT 
interval; QTcF = Fridericia’s corrected QT interval; SC subcutaneous; SOC = standard of care; WOCBP = women of child-bearing potential. 
A 
Within 5 days prior to Visit 2 (Week 0), each subject’s Hb must be evaluated by a local or central laboratory. If the subject meets the protocol-specified 
transfusion criteria, the subject must receive a PRBC transfusion so that the subject’s Hb levels no longer meets the protocol-specified requirements for 
PRBC transfusion. The post-transfusion Hb value should be confirmed by a local or central laboratory. Patients must not be randomized if they meet 
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the protocol-specified requirements for transfusion, and the Hb assessment to confirm eligibility should be scheduled so that the subject does not fall 
outside the screening window (up to Day -28). All Hb levels must be recorded in the eCRF. 
B 
All subjects who complete Visit 15 (Week 26) and do not elect to participate in the open-label extension study will be asked to return to the Investigator 
site for the Visit 16 (Week 28), Visit 17 (Week 30), and Visit 18 (Week 34) follow-up visits. Subjects who discontinue treatment will be encouraged to 
continue to attend study visits to complete study assessments (except for treatment with pegcetacoplan) as detailed in the Schedule of Events. At 
minimum, subjects who discontinue dosing should complete follow-up procedures outlined in the Schedule of Events 2, 4, and 8 weeks after treatment 
discontinuation. If withdrawal of PEGCETACOPLAN treatment is necessary, slow weaning should be considered and subjects should carefully be 
monitored for at least 8 weeks to detect serious hemolysis or other complications, as detailed in the Investigator’s Brochure. 
C 
Following Visit 2 (Week 0), subjects assigned to the SOC (excluding complement inhibitors) treatment arm who have a Hb level measured by the 
central laboratory that is ≥2 g/dL below the Baseline value will be switched to escape therapy with pegcetacoplan. These subjects will return to the site 
for an PEGCETACOPLAN initiation visit. Following the PEGCETACOPLAN initiation visit, subjects will maintain their regular visit schedule. 
D 
The ≤5 day pre-Visit 2 Hb qualification assessment must be assessed to confirm subject eligibility at Visit 2 before the subject can be randomized into 
the study. 
E 
In order to receive treatment with PEGCETACOPLAN, subjects must have documented evidence of vaccination against the following within 2 years of 
screening: Neisseria meningitides types A, C, W, Y, and B (administered as 2 separate vaccinations), Streptococcus pneumoniae (with a PCV13 or 
PPSV23 vaccine), and Haemophilus influenzae type B (Hib vaccine). 
Subjects randomized to PEGCETACOPLAN: For subjects randomized to pegcetacoplan who do not have documented evidence of receiving any of 
the above vaccinations within 2 years prior to screening, the required missing vaccination(s) will be administered at Visit 3 (Week 2), prior to dosing 
with PEGCETACOPLAN (along with boosters administered during the study at or after Visit 7 [Week 10], if required [see below]). Vaccination is 
mandatory, unless documented evidence exists that subjects are non-responders to vaccination (as evidenced by titers or display titer levels within 
acceptable local limits). The PI will discuss with the Sponsor regarding individual patient circumstances. 
If the subject requires vaccination against Neisseria meningitidis, a booster (for both vaccinations) should be administered after at least 8 weeks (Visit 
7). If the subject requires vaccination against Streptococcus pneumoniae, PCV13 will be administered at Visit 3, and PPSV23 will be administered after 
at least 8 weeks (Visit 7). 
Subjects randomized to SOC (excluding complement inhibitors): Subjects who are initially randomized to SOC (excluding complement inhibitors) 
who become eligible for pegcetacoplan escape therapy will receive any required vaccination(s) 2 weeks after initiation of treatment with 
PEGCETACOPLAN. If required, as detailed above), the Neisseria meningitidis booster (for both vaccinations), and/or PPSV23 vaccination should be 
administered at least 8 weeks following the initial vaccination(s). 
F 
In order to receive treatment with PEGCETACOPLAN, subjects will require preventive antibiotics if they need to be vaccinated, as detailed in Footnote 
E above. In addition, subjects who do not require vaccination are recommended to receive preventive antibiotic therapy, as detailed below. 
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Subjects randomized to PEGCETACOPLAN: Subjects will be required to take ciprofloxacin 500 mg twice daily from Visit 2 (Day 1) to Visit 3 
(Week 2) and continue to receive antibiotic prophylaxis until at least 14 days post vaccination. From that point forward, it is recommended that all 
subjects take penicillin V 500 mg twice daily through the course of pegcetacoplan treatment. 
Subjects randomized to SOC (excluding complement inhibitors): Subjects who are initially randomized to SOC (excluding complement inhibitors) 
do not need to initiate preventive antibiotic therapy at Day 1. If a subject becomes eligible for and initiates pegcetacoplan escape therapy, the subject 
should take ciprofloxacin 500 mg twice daily for 2 weeks, beginning on the first day of treatment with pegcetacoplan and continue to receive 
antibiotic prophylaxis until at least 14 days post vaccination. After 2 weeks of ciprofloxacin, it is recommended that subjects take penicillin V 500 mg 
twice daily through the course of PEGCETACOPLAN treatment. 
G A full physical examination should be conducted, as indicated by the study schedule. A symptom-driven physical examination may be performed at 
other visits, at the PI’s discretion. 
H Triplicate 12-lead ECGs are to be performed within 1 hour pre-dose at Visit 2 (Day 1). Triplicate 12-lead ECGs will be performed prior to dosing at all 
other visits, if PEGCETACOPLAN administration is occurring at the study site. During the study, if the QTcF at any on-treatment ECG is ≥500 ms 
(mean of QTcF replicate values), the Investigator should perform 3 additional ECGs over 20-60 minutes; if the mean QTcF of the 3 repeat ECGs is 
≥500 ms, the site should instruct the subject to return the following day to perform repeat triplicate ECGs. An evaluation will be performed to look for 
other factors which may have contributed to QTc prolongation (eg, new concomitant medications, hypokalemia, etc.). 
I 
Subjects randomized to PEGCETACOPLAN: For subjects randomized to the pegcetacoplan treatment arm, research nurses or other appropriately 
qualified research personnel will administer the first PEGCETACOPLAN SC infusion at Visit 2 (Day 1) and will train subjects on how to self- 
administer. Following Visit 2, appropriately qualified research personnel will supervise self-administration of PEGCETACOPLAN for at least the 
following 3 doses (which will be administered prior to Visit 3). Supervision of self-administration may be conducted at the subject’s home, at the study 
site, or at an off-site location convenient for the subject. Supervision of self-administration must continue until the subject is qualified to self- 
administer. 
Following self-administration qualification, subjects may self-administer pegcetacoplan SC infusions without supervision. Subjects may continue to 
self-administer infusions at the study site on those days when a study visit occurs, but this is not required. Self-administration conducted at the study 
site will be supervised to ensure that the subject continues to remain compliant with the administration guidelines. On all other days, subjects may self- 
administer at home, at the study site, or at an off-site location convenient to the subject. 
Subjects randomized to SOC (excluding complement inhibitors): Subjects randomized to the SOC (excluding complement inhibitor) treatment arm 
that are assigned to PEGCETACOPLAN escape therapy during the study will have research nurses or other appropriately qualified research personnel 
administer the first PEGCETACOPLAN SC infusion and provide self-administration training at the study visit in which pegcetacoplan escape therapy is 
initiated. Following this visit, appropriately qualified research personnel will supervise self-administration of pegcetacoplan for at least the following 3 
doses at the subject’s home, the study site, or an off-site location convenient for the subject. Supervision of self-administration must continue until the 
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subject is qualified to self-administer, and PEGCETACOPLAN will be self-administered and supervised at the study site on days of study visits, if the 
subject elects to administer PEGCETACOPLAN during the study visit. 
J 
Vital signs will be measured before venipuncture and ECG. Monitoring of vital signs will occur at Visit 2 (Day 1) pre-dose and 2 hours post-dose 
(±30 minutes). In addition, monitoring of vital signs will occur pre-dose and 2 hours post-dose (±30 minutes) during the pegcetacoplan Initiation Visit, 
if applicable. At all other visits, if the subject elects to administer PEGCETACOPLAN during the visit, vital signs should be measured pre-dose. 
K If PEGCETACOPLAN will be administered at the study visit, blood samples must be taken pre-dose. The date and time of the last dose of 
PEGCETACOPLAN should be recorded on the eCRF, as well as the date and time of the blood sample draw (to be used for PK analysis). 
L 
Samples for PK assessment should not be collected for subjects randomized to the SOC (excluding complement inhibitors) treatment arm unless they 
become eligible for and elect to receive PEGCETACOPLAN escape therapy. If a subject from the SOC (excluding complement inhibitors) treatment 
arm is to begin receiving PEGCETACOPLAN escape therapy, a pre-dose PK sample should be collected at the pegcetacoplan initiation visit and at each 
subsequent visit, as detailed in the Schedule of Events. 
M The use of silica reagents in coagulation panels should be avoided in subjects treated with pegcetacoplan. 
N 
B-HCG for WOCBP; FSH for post-menopausal women. 
O Sample for genotyping to be obtained via buccal swab test completed at the Screening Visit. 
P 
Urine pregnancy test should be completed for WOCBP prior to dosing on Day 1. 
Q On the days of clinic visits, an assessment of the PEGCETACOPLAN infusion site will be made as a part of the AE assessment. If 
PEGCETACOPLAN is administered at the visit, the site staff will observe the dosing and pump-use safety will be assessed and the infusion site will be 
checked again within 30 minutes after study drug administration. The infusion site assessments will be performed by an appropriately trained staff, as 
delegated by the Investigator. The infusion site and surrounding area will be inspected for redness, swelling, induration, and bruising. The subject will 
be asked about the presence of pain and/or tenderness, and any issue related to pump use. The date, time, and outcome of the infusion-site assessment 
will be recorded on the source documents and CRFs. Subjects will be instructed to notify the PI or other study personnel in the event that an infusion 
site reaction occurs after self-administration of APL 2. All clinically relevant AEs, as determined by the Investigator, from infusion site or related to 
pump use will be recorded as AEs. 
R 
Subjects randomized to pegcetacoplan treatment arm or receiving pegcetacoplan escape therapy only. 
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17.2 
Sample SAS codes 
17.2.1 
Sample SAS Code for First Co-primary and Categorical Secondary 
Endpoints Analyses 
For the first co-primary endpoint (Hb stabilization), the number and percentage of 
subjects who achieve Hb stabilization (Y/N), the basic SAS code for stratified CMH and 
CI is shown below: 
Proc freq data=ADTF; 
tables stragrp1n* arm * avalc / cmh riskdiff (common cl= (mn)) ; 
output out=cmh_ cmh; 
run; 
 
Where; 
ADTF is the ADaM efficacy data set 
arm is the Randomized treatment group 
avalc is the response variable (Y/N) for Hb stabilization 
stragrp1n is the stratification variable for randomization 
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17.2.2 
Sample Pseudo SAS Code for Second Co-Primary and Continuous 
Secondary Endpoints Analyses 
For the second co-primary endpoint (change of LDH from baseline to Week 26), the SAS 
code for imputation is shown below: 
 
/* Step 1: Transpose the original data so that there is response at each visit */ 
/* step 2: Impute all post- baseline missing values for LDH*/ 
 
proc mi data = Transpose_Adeff out = LDH_complete nimpute = 1000 seed = 123876 
noprint; 
var BL STRAGR1N Wk1 AVAL; 
MCMC IMPUTE = FULL CHAIN= MULTIPLE NBITER=200 PRIOR=JEFFREYS; 
where (arm in ('SOC', 'PEGCETACOPLAN') and paramcd in ('LDH')); 
Run; 
 
proc sort data= LDH_complete; 
by _Imputation; 
Run; 
 
/* step 3: Compute the change from baseline (CFB) at week 26*/ 
Data LDH_complete; set LDH_complete; 
Where (avisit in (“base, Week 26”)); 
Chg = AVAL-Base; 
by _Imputation_; 
Run; 
 
/* Step 4: Run ANCOVA at Week 26 only model using proc GLM or MIXED*/ 
Proc GLM data = LDH_together_2; 
Class arm stragrp1n; 
Model Chg = base arm StraGrp1N / solution; 
Lsmeans arm / stderr pdiffer cov out=adjmeans; 
ods output lsmeans = lsmeans_ds; 
ds output diffs = diff; 
ods output Tests3 = fixeff; 
by _Imputation_; 
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Run; 
/* Step 5: Run proc mianalyze at Week 26 with the model effects and standard error */ 
proc mianalyze data=diff; 
modeleffects Estimate; 
stderr StdErr; 
ods output parameterestimates=miparm; 
Run; 
 
 
 
 
17.2.3 
Sample SAS Code for Sensitivity Analyses of Second Co-Primary Endpoint 
1- The SAS code for the first sensitivity analyses for the second co-primary endpoint 
(change from baseline to Week 26 for LDH) using PROC MIXED with MMRM 
model. 
 
Proc mixed data=ADEFF method=reml; 
 
Class arm avisit(ref="Week 2") usubjid STRAGR1N; 
Model chg = arm | avisit base STRAGR1N / ddfm = kr solution 
OUTPM=out_hbModel covb; 
Repeated avisit / type=un subject=usubjid ; 
Lsmeans arm*avisit / cl pdiff; 
ods output SolutionF=mxparms CovB=mxcovb; 
ods output lsmeans = lsmeans_ds; 
Ods output diffs = diff; 
ods output Tests3 = fixeff; 
Run; 
 
 
Where; 
ADEFF is the ADaM efficacy data set 
arm is the Randomized treatment group 
Resp is the response variable (Y/N) for Hb stabilization 
StraGrp1N is the stratification variable for randomization 
Chg is the change from baseline for all visit 
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2- The SAS pseudo code for the second and the third sensitivity analyses for the 
second co-primary controlled based and Tipping Imputations using PROC MI, 
MIXED, and MIANALYZE with MMRM model. 
 
The SAS code for imputation of LDH level is shown below: 
/* Non-Monotone Missing */ 
/* Step 1: Transpose the original data so that there is response at each visit */ 
/*Step 2: monotonize both arms separately */ 
/*PEGCETACOPLAN */ 
 
proc mi data = ADEFF out = LDH_NMont nimpute = 500 seed = 123876 noprint; 
var base STRAGR1N AVAL; 
MCMC IMPUTE = monotone NBITER=200 PRIOR=JEFFREYS;; 
where (arm in ('PEGCETACOPLAN') and paramcd in ('LDH')); 
run; 
/*SOC */ 
proc mi data = ADEFF out = LDH_complete_SOC nimpute = 500 seed = 123876 
noprint; 
var base STRAGR1N AVAL; 
MCMC IMPUTE = monotone NBITER=200 PRIOR=JEFFREYS; 
where (arm in ('SOC') and paramcd in ('LDH')); 
run; 
 
/* Step 3 Part A */ 
/* monotone regression pattern for missing data, only need 1 impuation to impose the 
monotone reg model */ 
proc mi data = LDH_complete_SOC out = LDH_Reg_SOC nimpute = 1 seed = 123876 
noprint; 
by _Imputation_; 
var base STRAGR1N AVAL ; 
monotone REG(AVAL = base STRAGR1N); 
run; 
 
/* merge the non-monotone and monotone imputations together */ 
data LDH_together; 
set LDH_NMont LDH_Reg_SOC; 
run; 
 
proc sort data = LDH_together; 
by _Imputation_; 
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run; 
 
/* Step 3B: This PROC MI step is only required for Tipping point imputation */ 
proc MI data = LDH_together out = HB_together_2 nimpute = 1 seed = 123876 noprint; 
by _Imputation_; 
var base STRAGR1N AVAL ; 
monotone REG(chg = base STRAGR1N); 
mnar adjust(AVAL / shift = &sj); 
*- set sj=0 for controlled based, else Tip value; 
run; 
/* end for Tipping point imputation */ 
 
/* sort by imputation to fit the proc mixed */ 
proc sort data = LDH_together_2; 
by _Imputation_ arm STRAGR1N avisit; 
run; 
 
/* Step 4: compute change from baseline for all visits */ 
Data LDH_together_2; set LDH_together_2 
Chg= Base – Aval; 
Run; 
 
/* Step 5: the proc mixed step with unstructured covariance structure */ 
 
 
Proc mixed data=HB_together_2 method=reml; 
Class avisit(ref="Week 2") arm subjid STRAGR1N; 
Model chg=arm base STRAGR1N avisit arm*avisit / ddfm = kr solution 
OUTPM=out_hbModel covb; 
by _Imputation_; 
Repeated avisit / type=un subject=subjid ; 
Lsmeans arm*avisit / cl pdiff; 
ods output SolutionF=mxparms CovB=mxcovb; 
ods output lsmeans = lsmeans_ds; 
ods output diffs = diff; 
ods output Tests3 = fixeff; 
Run; 
/*Lsmeans diff synthesize the MI from lsmeans diff at each visit*/ 
proc sort data = diff; 
by _Imputation_ effect; 
Run; 
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/*subsets only where you are comparing PEGCETACOPLAN versus SOC at the 
same visit */ 
/* when the two visits you are comparing are the same you are automatically 
/* comparing PEGCETACOPLAN to SOC */ 
/* so you have subset PEGCETACOPLAN versus SOC at Week 2, 4, 8, 12, …, 
26, etc */ 
 
data diff2; 
set diff; 
where (avisit=_avisit); 
run; 
 
proc sort data= diff2; 
by avisit _imputation_; 
run; 
 
/* Step 6: proc MIANALYZE at each visit with the model effects and standard error */ 
proc mianalyze data=diff2; 
by avisit ; 
modeleffects Estimate; 
stderr StdErr; 
ods output parameterestimates=miparm; 
run; 
 
proc print data = miparm; 
run; 
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17.2.4 
Sample SAS Code for Time to Event Endpoints 
For the secondary endpoints of Ttime to failure of Hb Stabilization and Time to 
Transfusions, Kaplan-Meier method will be used to describe the survival data as shown 
below: 
 
proc lifetest data=ADTTE plots=(survival (atrisk)); 
time TTE*Censored(0); 
strata arm / test=logrank; 
run; 
 
Where; 
ADTTE is the ADaM time to event efficacy data set 
arm is the Randomized treatment group 
Censored is binary flag to identify the censored observations 
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17.2.5 
SAS Macros for Nonparametric Randomization-Based Analysis using Log- 
Incidence Density Ratios 
 
 
%NParCov4(OUTCOMES=count, EXPOSURE= days, HYPOTH=NULL, 
TRTGRPS=trt, TRANSFORM=INCIDENS, EXACT=YES, NREPS=5000, SEED= 77, 
DSNIN=indata); 
 
Count is the count of the variable, 
Days is the number of days in trial, 
Trt is the Randomized treatment group, 
Incidens is the number of incidences, 
Indata is the name of the data set containing analysis data. 
 
 
The variance under the null (HYPOTH=NULL) will be used for computing p-values, 
while the variance under the alternative (HYPOTH=ALT) will be used for computing 
confidence intervals. 
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17.3 
Sensitivity Analyses for the Primary Efficacy Endpoint 
17.3.1 
Imputation for the Second Co-primary Efficacy Endpoint 
1- Control-based Imputation method 
A control-based multiple imputation approach will be used as a sensitivity analysis to 
consider the Missingness Not At Random (MNAR) mechanism for monotone missing 
data. The mean change from baseline in LDH level at Week 26 will be analyzed based on 
the data observed while the subject remains on study treatment as well as the data 
imputed using multiple imputation (MI) methodology for the time points with missing 
values. Imputation of outcome values in the SOC group will rely on the MAR 
assumption. Imputation of the primary outcome values in the pegcetacoplan group will be 
done as if the subject had been on SOC. Imputed values in the pegcetacoplan group will 
be sampled using the imputation model of the SOC, i.e., conditional on the outcome 
values observed at the time points prior to discontinuation. This approach does not 
assume a sustained benefit of pegcetacoplan after discontinuation but rather assumes a 
post-discontinuation effect like that of SOC and time effects based the estimated 
correlations among the time points in the SOC group. The number of imputations will be 
500 (NIMPUTE=500) and the random seed will be 123876 for both partial imputation 
and sequential regression imputation detailed in Steps 1 and 2. The approach will be 
implemented as follows: 
• Step 1: Non-monotone missing data will be imputed first based on the MAR 
assumption and a multivariate joint Gaussian imputation model using the Markov 
chain Monte Carlo (MCMC) method using the MCMC statement in PROC MI. 
As a result, each imputed data set will only have missing data at the end of each 
subject’s record, i.e., a monotone missing data pattern. The MCMC method in 
PROC MI will be invoked with multiple chains (CHAIN=MULTIPLE), 200 burn- 
in iterations and a non-informative prior. A separate imputation model will be 
used for each treatment group. The imputation models will represent a simplified 
version of the primary analysis model and will include the following terms: 
stratification variables, baseline LDH level and LDH levels at each time point. In 
case of non-convergence or other issues, a ridge prior and a single imputation 
model will be considered with the treatment term added to the model. 
• Step 2: The resulting monotone missing data for all subjects who discontinue 
study treatment early will be imputed using a sequential regression multiple 
imputation model estimated based on the data from the SOC group only. Each 
sequential regression model for imputation of outcome values at a given time 
point will include the following terms: stratification variables, baseline Hb level 
and Hb levels at all previous time points. Missing values at a given time point in 
both treatment groups will be imputed from the same imputation model, 
conditional on the subject values observed or imputed at previous time points. 
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• Step 3: The change from baseline in Hb level to each scheduled post-baseline visit 
will be calculated based on the observed and imputed data. Each of the 1000 
imputed complete data sets from Step 2 will be analyzed using the primary 
analysis model. 
• Step 4: The results obtained in each imputed data set, including the treatment 
differences and their standard errors, will be combined using Rubin’s imputation 
rules (Rubin, 1987) to produce a pooled estimate of the treatment differences, 
corresponding 95% confidence interval and a pooled treatment effect P-value 
using PROC MIANALYZE. 
2- Imputation based on the delta-adjusted stress testing method 
In addition to the control-based imputation method, sensitivity to departures from the 
MAR assumption will also be investigated using a tipping point analysis based on the 
delta-adjusted stress testing method. Departures from MAR in the pegcetacoplan group 
will be evaluated assuming that subjects who discontinue study treatment have, on 
average, efficacy outcomes after discontinuation that are worse by a pre-defined amount 
(delta) compared to the value which would have been assumed under an MAR model. 
A series of analyses based on this method will be performed with increasing values of the 
delta until the treatment difference is no longer statistically significant. The smallest 
value of the delta parameter that overturns the primary conclusions is known as a tipping 
point. An interpretation of clinical plausibility of the assumptions underlying the tipping 
point will be provided. 
The mean change from baseline in LDH level at Week 26 will be analyzed based on the 
data observed while a subject remains on study treatment as well as the data imputed 
using MI methodology for the time points with missing primary outcome values. Imputed 
values in the pegcetacoplan group will first be sampled from an MAR-based multiple 
imputation model and then the delta-adjusted method described will be applied as 
described below. The analyses will be performed using the delta starting from 0 with 
decrement of 0.2 until the null hypothesis can no longer be rejected. 
As with the control-based imputation method, this approach uses MCMC for partial 
imputation of non-monotone data under MAR followed by sequential MI regression for 
monotone data. 
• Step 1: The step is equivalent to the corresponding step for the control-based 
imputation method for non-monotone missing data (see Step 1). 
• Step 2: The resulting monotone missing data will be imputed using sequential 
regression multiple imputation, where a separate regression model is estimated for 
imputation of outcome values at each time point. Each regression model will 
include the following terms: stratification variables, baseline Hb level and Hb 
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levels at all previous time points. The delta adjustment will be imposed on all 
imputed values at each visit after generating all imputations under the MAR 
assumption. 
• Steps 3 and 4: The steps are equivalent to the corresponding steps for the control- 
based imputation method (see Steps 3 and 4). 
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17.4 
COVID-19 Changes 
The COVID-19 pandemic may impact the conduct of clinical trials such as site or 
laboratory closures, travel limitations, interruptions to the supply chain for the 
investigational product, or other considerations if site personnel or trial subjects become 
infected with COVID-19. Therefore, there is a possibility that we will have several missed 
visits by subjects and/or subjects might be referred to a certified local laboratory for blood 
works instead of central laboratory. 
As a result of the COVID-19 global pandemic, Apellis issued an Urgent Safety Measure 
to safeguard the rights, welfare, and safety of APL2-308 study subjects and investigative 
site staff. These measures align with current guidance issued by global regulatory health 
authorities in regards to the impact of COVID-19 on the management of clinical trials. 
The urgent safety measures are minimum study requirements and are reflected in the 
Schedule of Events table below and it supersedes the Schedule of Events table sent on 26 
March 2020. A subject cannot be considered for screening using the minimum study 
requirements. The screening and baseline assessments must remain unchanged and must 
be completed in their entirety. 
Where feasible, sites should continue to follow the full schedule of assessments (based on 
their treatment group assignment). 
All assessments missed as a result of COVID-19 will be captured in the CRFs. 
TRANSITION TO STUDY APL2-307 
As per protocol, any subject that is able to travel to the study site and complete 
Week 26 of the APL2-308 study should transition over to Study APL2-307. However, the 
following modifications are allowed: 
• Any subject that is not able to perform the Week 26 assessments on site due 
to COVID-19-related travel restrictions and/or site limitations, can remain on 
Study APL2-308 until such time as the restrictions are lifted or other options 
become available. Any subject that remains on Study APL2-308 should 
continue to follow the Week 26 visit schedule procedures and perform at least 
the minimum study requirements, in accordance with the Urgent Safety 
Measures, every 2 weeks until the transition to Study APL2-307 is possible. 
• Any subject that is within 2 weeks of the Week 26 visit and is not 
subject to travel restrictions and/or study site limitations is encouraged 
to complete the Week 26 visit as soon as possible. 
The CRA and medical monitor must be made aware of any subject who will not be able 
to complete the study transition or will be performing the Week 26 visit early. 
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While this decision may require subjects to stay in the APL2-308 study longer than 
anticipated, this decision will reduce subjects’ need to travel during the ongoing 
pandemic. 
This modification is also intended to ensure adequate study-related safety 
monitoring, continuity of investigational drug supply, reduction of subject travel and in- 
clinic time, and also to provide for more scheduling flexibility while maintaining study 
and data integrity. 
Minimum Study Requirements 
The following are the minimum study requirements for Study APL2-308 during the 
COVID-19 pandemic and should be used as guidance when the full protocol 
requirements cannot be conducted: 
1. Maintain dosing schedules, considerations for escalation, and management per 
protocol 
2. Obtain key safety laboratory assessments: 
a. All laboratory assessments should be drawn at the frequency required by 
the minimized Schedule of Events (provided below): 
i. Includes (at minimum): hematology with differential, reticulocyte 
count, chemistry, LDH, coagulation profile, and urine pregnancy 
test (only for women of childbearing potential) 
b. In the event that the clinical investigative site is closed and/or subjects are 
unable/unwilling to travel, subjects should be referred to a certified local 
laboratory that can perform the required safety testing (see Schedule of 
Events below). The investigator should collect the local laboratory reports, 
which must be redacted (eg, name and other local requirements), 
laboratory reference ranges, and file with the study records. 
3. Perform minimal medical safety assessments: 
a. If the subject is unable to have an in-person assessment, the investigator 
(or delegated site staff) should have a telephone and/or video contact at a 
frequency noted in the protocol (at minimum) to solicit adverse events 
(including SAEs), transfusion requirements, and concomitant medications. 
The appropriate forms in the eCRF should be completed. 
b. All serious adverse events are still required to be reported to Apellis 
immediately and within 24 hours of the investigator becoming aware. 
4. Document appropriate contact with the subject: 
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a. Earnest and reasonable attempts must be made to solicit adverse events 
and concomitant medications. The CRA and medical monitor must be 
notified of any subjects lost to follow-up. 
b. All communication with the subject (including failed attempts at contact) 
must be documented in the study records. 
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Signature Adoption: Pre-selected Style 
Signature ID: 
 
With Signing Authentication via DocuSign password 
With Signing Reasons (on each tab): 
I approve this document 
 
 
 
 
 
 
Signature Adoption: Pre-selected Style 
Signature ID: 
 
With Signing Authentication via DocuSign password 
With Signing Reasons (on each tab): 
I approve this document 
Sent: 4/28/2021 9:44:24 AM 
Viewed: 4/28/2021 9:59:37 AM 
Signed: 4/28/2021 10:00:07 AM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sent: 4/28/2021 9:44:23 AM 
Viewed: 4/28/2021 11:10:53 AM 
Signed: 4/28/2021 11:11:24 AM 
Signer Events 
Signature 
Timestamp 
CCI
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Signer Events 
Signature 
Timestamp 
 
Apellis 
Security Level: Email, Account Authentication 
(Required) 
 
 
 
 
 
 
 
Electronic Record and Signature Disclosure: 
Not Offered via DocuSign 
 
 
 
Signature Adoption: Pre-selected Style 
Signature ID: 
 
With Signing Authentication via DocuSign password 
With Signing Reasons (on each tab): 
I approve this document 
Sent: 4/28/2021 9:44:23 AM 
Viewed: 4/28/2021 9:54:09 AM 
Signed: 4/28/2021 9:55:44 AM 
 
Apellis Pharmaceuticals, Inc. 
Security Level: Email, Account Authentication 
(Required) 
Signature Adoption: Pre-selected Style 
Signature ID: 
Sent: 4/28/2021 9:44:23 AM 
Viewed: 4/28/2021 9:45:09 AM 
Signed: 4/28/2021 9:45:30 AM 
 
 
 
 
 
Electronic Record and Signature Disclosure: 
With Signing Authentication via DocuSign password 
With Signing Reasons (on each tab): 
I approve this document 
 
Apellis Pharmaceuticals, Inc. 
Security Level: Email, Account Authentication 
(Required) 
 
 
 
 
 
 
 
Electronic Record and Signature Disclosure: 
 
 
 
Signature Adoption: Pre-selected Style 
Signature ID: 
Signed using mobile 
With Signing Authentication via DocuSign password 
With Signing Reasons (on each tab): 
I approve this document 
Sent: 4/28/2021 9:44:23 AM 
Viewed: 4/28/2021 12:04:24 PM 
Signed: 4/28/2021 12:05:15 PM 
 
In Person Signer Events 
Signature 
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Editor Delivery Events 
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Agent Delivery Events 
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Intermediary Delivery Events 
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Certified Delivery Events 
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Carbon Copy Events 
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Witness Events 
Signature 
Timestamp 
 
 
Notary Events 
Signature 
Timestamp 
Envelope Summary Events 
Status 
Timestamps 
Envelope Sent 
Hashed/Encrypted 
4/28/2021 9:44:24 AM 
Certified Delivered 
Security Checked 
4/28/2021 12:04:24 PM 
Signing Complete 
Security Checked 
4/28/2021 12:05:15 PM 
Completed 
Security Checked 
4/28/2021 12:05:15 PM 
Payment Events 
Status 
Timestamps 
Electronic Record and Signature Disclosure 


 
Electronic Record and Signature Disclosure created on: 6/29/2018 12:31:59 PM 
Parties agreed to: 
 
 
 
 
ELECTRONIC RECORD AND SIGNATURE DISCLOSURE 
From time to time, Apellis Pharmaceuticals, Inc. - Part 11 (we, us or Company) may be required 
by law to provide to you certain written notices or disclosures. Described below are the terms 
and conditions for providing to you such notices and disclosures electronically through your 
DocuSign, Inc. (DocuSign) Express user account. Please read the information below carefully 
and thoroughly, and if you can access this information electronically to your satisfaction and 
agree to these terms and conditions, please confirm your agreement by clicking the 'I agree' 
button at the bottom of this document. 
Getting paper copies 
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. For such copies, as long as you are an authorized user of the 
DocuSign system you will have the ability to download and print any documents we send to you 
through your DocuSign user account for a limited period of time (usually 30 days) after such 
documents are first sent to you. After such time, if you wish for us to send you paper copies of 
any such documents from our office to you, you will be charged a $0.00 per-page fee. You may 
request delivery of such paper copies from us by following the procedure described below. 
Withdrawing your consent 
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
Consequences of changing your mind 
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. To indicate to us that you are changing your mind, you must 
withdraw your consent using the DocuSign 'Withdraw Consent' form on the signing page of your 
DocuSign account. This will indicate to us that you have withdrawn your consent to receive 
required notices and disclosures electronically from us and you will no longer be able to use your 
DocuSign Express user account to receive required notices and consents electronically from us 
or to sign electronically documents from us. 
All notices and disclosures will be sent to you electronically 
Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through your DocuSign user account all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
How to contact Apellis Pharmaceuticals, Inc. - Part 11: 
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You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: 
 
 
To advise Apellis Pharmaceuticals, Inc. - Part 11 of your new e-mail address 
 
To let us know of a change in your e-mail address where we should send notices and disclosures 
electronically to you, you must send an email message to us at 
and in the 
body of such request you must state: your previous e-mail address, your new e-mail address. We 
do not require any other information from you to change your email address.. 
 
In addition, you must notify DocuSign, Inc to arrange for your new email address to be reflected 
in your DocuSign account by following the process for changing e-mail in DocuSign. 
 
To request paper copies from Apellis Pharmaceuticals, Inc. - Part 11 
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an e-mail to 
 and in the body 
of such request you must state your e-mail address, full name, US Postal address, and telephone 
number. We will bill you for any fees at that time, if any. 
To withdraw your consent with Apellis Pharmaceuticals, Inc. - Part 11 
 
To inform us that you no longer want to receive future notices and disclosures in electronic 
format you may: 
 
i. decline to sign a document from within your DocuSign account, and on the subsequent 
page, select the check-box indicating you wish to withdraw your consent, or you may; 
 
ii. send us an e-mail to
 and in the body of such request you must 
state your e-mail, full name, IS Postal Address, telephone number, and account number. 
We do not need any other information from you to withdraw consent.. The consequences 
of your withdrawing consent for online documents will be that transactions may take a 
longer time to process.. 
 
Required hardware and software 
Operating Systems: 
Windows2000? or WindowsXP? 
Browsers (for 
SENDERS): 
Internet Explorer 6.0? or above 
Browsers (for 
SIGNERS): 
Internet Explorer 6.0?, Mozilla FireFox 1.0, NetScape 7.2 (or above) 
Email: 
Access to a valid email account 
Screen Resolution: 
800 x 600 minimum 
Enabled Security 
Settings: 
• Allow per session cookies 
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• Users accessing the internet behind a Proxy Server must enable HTTP 
1.1 settings via proxy connection 
** These minimum requirements are subject to change. If these requirements change, we will 
provide you with an email message at the email address we have on file for you at that time 
providing you with the revised hardware and software requirements, at which time you will have 
the right to withdraw your consent. 
Acknowledging your access and consent to receive materials electronically 
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please verify that you were 
able to read this electronic disclosure and that you also were able to print on paper or 
electronically save this page for your future reference and access or that you were able to e-mail 
this disclosure and consent to an address where you will be able to print on paper or save it for 
your future reference and access. Further, if you consent to receiving notices and disclosures 
exclusively in electronic format on the terms and conditions described above, please let us know 
by clicking the 'I agree' button below. 
By checking the 'I Agree' box, I confirm that: 
 
• 
I can access and read this Electronic CONSENT TO ELECTRONIC RECEIPT OF 
ELECTRONIC RECORD AND SIGNATURE DISCLOSURES document; and 
• 
I can print on paper the disclosure or save or send the disclosure to a place where I can 
print it, for future reference and access; and 
• 
Until or unless I notify Apellis Pharmaceuticals, Inc. - Part 11 as described above, I 
consent to receive from exclusively through electronic means all notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided 
or made available to me by Apellis Pharmaceuticals, Inc. - Part 11 during the course of 
my relationship with you.