A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With Cold Agglutinin Disease (CAD)
Phase: PHASE3
Conditions: Cold Agglutinin Disease
Sponsor: Swedish Orphan Biovitrum

Pegcetacoplan/CAD 
Clinical Study No: Sobi.PEGCET-101 
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A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study 
to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients with Cold 
Agglutinin Disease (CAD)  
Final Protocol Number: Sobi.PEGCET-101 
EudraCT Number: 2021-003160-27 
Type of Study: Therapeutic Confirmatory 
Original Protocol: 02 Aug 2021 
Protocol version 2.0 (including Protocol Amendment 1): 08 Oct 2021 
Sponsor’s Medical Director 
 
Medical Director 
 
 
Signature
Date
Confidential 
This protocol contains confidential information belonging to Swedish Orphan Biovitrum. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified. 
NCT Number:  05096403

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Investigator statement 
I have read the protocol entitled “A Phase 3, Randomized, Double-blind, Placebo-controlled 
Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients with Cold 
Agglutinin Disease (CAD)” and the accompanying current investigator’s brochure. I agree to 
conduct the clinical investigation in compliance with the Final Protocol, Version <version 
number>, <insert date>, the International Council for Harmonisation (ICH) harmonised 
guideline E6(R2): Guideline for Good Clinical Practice (GCP) [1], applicable 
regulatory/government regulations, and in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki [2]. I will not implement any changes to study procedures or 
conduct without prior approval from the sponsor and, when applicable, the independent ethics 
committee/institutional review board/research ethics board and regulatory authority. I will 
supervise any individual or party to whom I delegate study-related duties and functions 
conducted at the study site and ensure qualification of individuals or parties who perform 
delegated tasks.  
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB (publ). 
My site has implemented risk minimization and the mitigation plan for COVID-19 in line with 
local regulations and best practices, including precautions such as the use of personal protective 
equipment for patients, site staff and other visitors, site staff health-check and the disinfection of 
site premises. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 

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Table of contents 
1 
Synopsis .......................................................................................................................... 12 
Study schematic ............................................................................................................................. 21 
Schedule of assessments ................................................................................................................ 22 
2 
Abbreviations and definition of terms............................................................................. 29 
2.1 
List of abbreviations and definitions .......................................................................... 29 
3 
Ethics ............................................................................................................................... 32 
3.1 
Independent ethics committee and/or institutional review board ............................... 32 
3.2 
Ethical conduct of the study ....................................................................................... 32 
3.3 
Patient information and consent ................................................................................. 32 
4 
Introduction ..................................................................................................................... 32 
4.1 
Background ................................................................................................................ 32 
4.1.1 
Cold agglutinin disease and unmet medical need .................................................. 33 
4.1.2 
Summary of clinical experience with pegcetacoplan ............................................ 33 
4.1.2.1 Study APL2 CP AIHA-208 .............................................................................. 34 
4.2 
Study rationale ............................................................................................................ 34 
4.3 
Potential risks and benefits ......................................................................................... 35 
4.3.1 
COVID-19 risk mitigation measures ..................................................................... 36 
5 
Study objectives and endpoints ....................................................................................... 37 
5.1 
Primary objective ....................................................................................................... 37 
5.1.1 
Primary endpoint ................................................................................................... 37 
5.2 
Secondary objectives .................................................................................................. 38 
5.2.1 
Secondary endpoints supporting the secondary objectives ................................... 38 
5.2.1.1 Key secondary efficacy endpoints .................................................................... 38 
5.2.1.2 Secondary efficacy endpoints ........................................................................... 38 
5.2.1.3 Tertiary efficacy endpoints ............................................................................... 39 
5.2.1.4 Safety endpoints ................................................................................................ 40 
5.3 
Exploratory objectives ................................................................................................ 40 
5.3.1 
Exploratory endpoints ............................................................................................ 40 
6 
Investigational plan ......................................................................................................... 41 
6.1 
Overall study design and plan .................................................................................... 41 
6.1.1 
Screening period (up to 4 weeks) .......................................................................... 41 
6.1.1.1 Retesting and rescreening ................................................................................. 42 
6.1.1.2 Screen failures ................................................................................................... 42 
6.1.2 
Double-blind treatment period (24 weeks): Part A................................................ 42 

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6.1.3 
Open-label treatment period (24 weeks): Part B ................................................... 43 
6.1.4 
Open-label maintenance period (up to additional 48 weeks or until the product 
becomes commercially available): Part C ............................................................. 43 
6.1.5 
Follow-up period (6 weeks) ................................................................................... 43 
6.1.6 
Unscheduled visits ................................................................................................. 43 
6.2 
Discussion of study design, including the choice of control groups .......................... 43 
6.3 
Selection of study population ..................................................................................... 44 
6.3.1 
Inclusion criteria .................................................................................................... 44 
6.3.2 
Exclusion criteria ................................................................................................... 45 
6.3.3 
Withdrawal of patients from treatment or study .................................................... 46 
6.3.3.1 Withdrawal from treatment ............................................................................... 46 
6.3.3.2 Withdrawal from study ..................................................................................... 47 
6.3.3.3 Lost to follow-up ............................................................................................... 47 
6.3.4 
Replacement of withdrawn patients....................................................................... 47 
6.3.5 
Specific restrictions/requirements ......................................................................... 47 
6.3.5.1 Acceptable methods of contraception ............................................................... 47 
6.3.5.2 Vaccination and preventive antibiotic requirements ......................................... 48 
6.3.6 
Study stopping criteria ........................................................................................... 48 
6.4 
Treatments .................................................................................................................. 49 
6.4.1 
Treatments administered ........................................................................................ 49 
6.4.1.1 Investigational medicinal products ................................................................... 49 
6.4.1.2 Vaccination and preventive antibiotics ............................................................. 49 
6.4.2 
Identity of investigational medicinal products ...................................................... 50 
6.4.2.1 IMP packaging and labeling ............................................................................. 51 
6.4.2.2 IMP storage and handling ................................................................................. 51 
6.4.3 
Method of assigning patients to treatment groups ................................................. 51 
6.4.4 
Selection of doses .................................................................................................. 52 
6.4.5 
Selection and timing of doses for each patient ...................................................... 52 
6.4.6 
Dose modification .................................................................................................. 53 
6.4.7 
Treatment stopping criteria .................................................................................... 53 
6.4.8 
Infusion supplies .................................................................................................... 54 
6.4.9 
Blinding and unblinding ........................................................................................ 54 
6.4.9.1 IMP blinding ..................................................................................................... 54 
6.4.9.2 IMP unblinding ................................................................................................. 54 
6.4.10 
Prior and concomitant therapy ............................................................................... 55 
6.4.10.1 Permitted concomitant therapy ......................................................................... 55 

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6.4.10.2 Prohibited medications ...................................................................................... 56 
6.4.11 
Treatment compliance ........................................................................................... 56 
6.4.12 
IMP accountability................................................................................................. 56 
6.4.13 
IMP disposal .......................................................................................................... 57 
6.5 
Efficacy, safety, pharmacokinetic, pharmacodynamic and other assessments .......... 57 
6.5.1 
Medical history ...................................................................................................... 57 
6.5.2 
Demography .......................................................................................................... 57 
6.5.3 
Efficacy assessments ............................................................................................. 58 
6.5.3.1 Hb level and other laboratory efficacy assessments ......................................... 58 
6.5.3.2 Transfusions ...................................................................................................... 58 
6.5.3.3 Health-related quality of life ............................................................................. 58 
6.5.3.4 Appropriateness of efficacy measurements ...................................................... 58 
6.5.4 
Safety assessments ................................................................................................. 59 
6.5.4.1 Adverse events .................................................................................................. 59 
6.5.4.2 Laboratory assessments .................................................................................... 64 
6.5.4.3 Anti–pegcetacoplan peptide antibody and anti-PEG antibody assessments ..... 66 
6.5.4.4 Vital signs ......................................................................................................... 67 
6.5.4.5 Weight and height ............................................................................................. 67 
6.5.4.6 Physical examination ........................................................................................ 67 
6.5.4.7 Electrocardiograms ........................................................................................... 67 
6.5.4.8 Infusion-site reactions/pump-safety assessments ............................................. 68 
6.5.4.9 Appropriateness of safety measurements .......................................................... 68 
6.5.5 
Pharmacokinetic assessments ................................................................................ 68 
6.5.6 
Pharmacodynamic assessments ............................................................................. 69 
6.5.7 
Other study assessments ........................................................................................ 69 
6.5.7.1 MYD88 mutation testing .................................................................................. 69 
6.5.7.2 Actigraph ........................................................................................................... 69 
7 
Quality control and quality assurance ............................................................................. 69 
8 
Statistical plan ................................................................................................................. 70 
8.1 
Determination of sample size ..................................................................................... 70 
8.2 
Definition of study populations .................................................................................. 71 
8.2.1 
Screened set ........................................................................................................... 71 
8.2.2 
Safety set ................................................................................................................ 71 
8.2.3 
Intent-to-treat set .................................................................................................... 71 
8.2.4 
Modified intent-to-treat set .................................................................................... 71 
8.2.5 
Per-protocol set ...................................................................................................... 71 

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8.2.6 
Pharmacokinetic set ............................................................................................... 71 
8.2.7 
Pharmacodynamic set ............................................................................................ 71 
8.3 
Overall statistical and analytical plan ......................................................................... 72 
8.3.1 
General statistical issues ........................................................................................ 72 
8.3.2 
Demographics and baseline characteristics ........................................................... 72 
8.3.3 
Analysis related to primary objective .................................................................... 72 
8.3.4 
Analysis related to secondary objectives ............................................................... 73 
8.3.4.1 Analysis of key secondary efficacy endpoints .................................................. 73 
8.3.4.2 Analysis of secondary efficacy endpoints: Part A ............................................ 73 
8.3.4.3 Analysis of secondary efficacy endpoints: Part B ............................................ 74 
8.3.4.4 Analysis of tertiary efficacy endpoints: Part C ................................................. 75 
8.3.4.5 Analysis of exploratory endpoints. ................................................................... 75 
8.3.5 
Analysis of safety and tolerability data ................................................................. 75 
8.3.5.1 Adverse events .................................................................................................. 75 
8.3.6 
Analysis of pharmacokinetic and pharmacodynamic ............................................ 76 
8.3.6.1 Pharmacokinetic analysis .................................................................................. 76 
8.3.6.2 Pharmacodynamic analysis ............................................................................... 76 
8.3.7 
Interim analysis ...................................................................................................... 77 
8.3.8 
Multiple comparison/multiplicity .......................................................................... 77 
8.3.9 
Handling of missing data ....................................................................................... 77 
9 
Data collection, handling and record keeping ................................................................. 77 
9.1 
Data standards ............................................................................................................ 77 
9.2 
Case report form ......................................................................................................... 77 
9.3 
Source data ................................................................................................................. 78 
9.4 
Protocol deviations ..................................................................................................... 78 
9.5 
Database closure ......................................................................................................... 79 
9.6 
Record retention ......................................................................................................... 79 
10 
End of study .................................................................................................................... 79 
11 
Sponsor’s discontinuation criteria ................................................................................... 79 
12 
Dissemination and publication of results ........................................................................ 80 
13 
Confidentiality ................................................................................................................ 80 
14 
Reference list ................................................................................................................... 81 
Appendix 1 
Additional protocol signatures ............................................................................... 82 
Appendix 2 
Functional Assessment of Cancer Therapy–Anemia/Fatigue................................ 83 
Appendix 3 
12-Item Short Form Survey ................................................................................... 86 
Appendix 4 
EuroQol-5 Dimension-5 Level .............................................................................. 87 

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Appendix 5 
Protocol changes to be followed during COVID-19 restrictions ........................... 90 
 
Table of tables 
Table 1 
Schedule of assessments: Screening to Week 24 ‒ Part A ...................... 22 
Table 2 
Schedule of assessments: Part B, Part C and Follow-up period .............. 26 
Table 3 
Investigational medicinal products .......................................................... 49 
Table 4 
Laboratory assessments ........................................................................... 65 
Table 5 
Revised COVID-19 minimum schedule of assessments: Screening to 
Week 24 ‒ Part A .................................................................................... 92 
Table 6 
Revised COVID-19 minimum schedule of assessments: Part B, Part C 
and Follow-up period .............................................................................. 96 
 
Table of figures 
Figure 1 
Study design ............................................................................................ 21 
 
1 
Synopsis .......................................................................................................................... 12 
Study schematic ............................................................................................................................. 21 
Schedule of assessments ................................................................................................................ 22 
2 
Abbreviations and definition of terms............................................................................. 29 
2.1 
List of abbreviations and definitions .......................................................................... 29 
3 
Ethics ............................................................................................................................... 32 
3.1 
Independent ethics committee and/or institutional review board ............................... 32 
3.2 
Ethical conduct of the study ....................................................................................... 32 
3.3 
Patient information and consent ................................................................................. 32 
4 
Introduction ..................................................................................................................... 32 
4.1 
Background ................................................................................................................ 32 
4.1.1 
Cold agglutinin disease and unmet medical need .................................................. 33 
4.1.2 
Summary of clinical experience with pegcetacoplan ............................................ 33 
4.1.2.1 Study APL2 CP AIHA-208 .............................................................................. 34 
4.2 
Study rationale ............................................................................................................ 34 
4.3 
Potential risks and benefits ......................................................................................... 35 
4.3.1 
COVID-19 risk mitigation measures ..................................................................... 36 

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5 
Study objectives and endpoints ....................................................................................... 37 
5.1 
Primary objective ....................................................................................................... 37 
5.1.1 
Primary endpoint ................................................................................................... 37 
5.2 
Secondary objectives .................................................................................................. 38 
5.2.1 
Secondary endpoints supporting the secondary objectives ................................... 38 
5.2.1.1 Key secondary efficacy endpoints .................................................................... 38 
5.2.1.2 Secondary efficacy endpoints ........................................................................... 38 
5.2.1.3 Tertiary efficacy endpoints ............................................................................... 39 
5.2.1.4 Safety endpoints ................................................................................................ 40 
5.3 
Exploratory objectives ................................................................................................ 40 
5.3.1 
Exploratory endpoints ............................................................................................ 40 
6 
Investigational plan ......................................................................................................... 41 
6.1 
Overall study design and plan .................................................................................... 41 
6.1.1 
Screening period (up to 4 weeks) .......................................................................... 41 
6.1.1.1 Retesting and rescreening ................................................................................. 42 
6.1.1.2 Screen failures ................................................................................................... 42 
6.1.2 
Double-blind treatment period (24 weeks): Part A................................................ 42 
6.1.3 
Open-label treatment period (24 weeks): Part B ................................................... 43 
6.1.4 
Open-label maintenance period (up to additional 48 weeks or until the product 
becomes commercially available): Part C ............................................................. 43 
6.1.5 
Follow-up period (6 weeks) ................................................................................... 43 
6.1.6 
Unscheduled visits ................................................................................................. 43 
6.2 
Discussion of study design, including the choice of control groups .......................... 43 
6.3 
Selection of study population ..................................................................................... 44 
6.3.1 
Inclusion criteria .................................................................................................... 44 
6.3.2 
Exclusion criteria ................................................................................................... 45 
6.3.3 
Withdrawal of patients from treatment or study .................................................... 46 
6.3.3.1 Withdrawal from treatment ............................................................................... 46 
6.3.3.2 Withdrawal from study ..................................................................................... 47 
6.3.3.3 Lost to follow-up ............................................................................................... 47 
6.3.4 
Replacement of withdrawn patients....................................................................... 47 
6.3.5 
Specific restrictions/requirements ......................................................................... 47 
6.3.5.1 Acceptable methods of contraception ............................................................... 47 
6.3.5.2 Vaccination and preventive antibiotic requirements ......................................... 48 
6.3.6 
Study stopping criteria ........................................................................................... 48 
6.4 
Treatments .................................................................................................................. 49 

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6.4.1 
Treatments administered ........................................................................................ 49 
6.4.1.1 Investigational medicinal products ................................................................... 49 
6.4.1.2 Vaccination and preventive antibiotics ............................................................. 49 
6.4.2 
Identity of investigational medicinal products ...................................................... 50 
6.4.2.1 IMP packaging and labeling ............................................................................. 51 
6.4.2.2 IMP storage and handling ................................................................................. 51 
6.4.3 
Method of assigning patients to treatment groups ................................................. 51 
6.4.4 
Selection of doses .................................................................................................. 52 
6.4.5 
Selection and timing of doses for each patient ...................................................... 52 
6.4.6 
Dose modification .................................................................................................. 53 
6.4.7 
Treatment stopping criteria .................................................................................... 53 
6.4.8 
Infusion supplies .................................................................................................... 54 
6.4.9 
Blinding and unblinding ........................................................................................ 54 
6.4.9.1 IMP blinding ..................................................................................................... 54 
6.4.9.2 IMP unblinding ................................................................................................. 54 
6.4.10 
Prior and concomitant therapy ............................................................................... 55 
6.4.10.1 Permitted concomitant therapy ......................................................................... 55 
6.4.10.2 Prohibited medications ...................................................................................... 56 
6.4.11 
Treatment compliance ........................................................................................... 56 
6.4.12 
IMP accountability................................................................................................. 56 
6.4.13 
IMP disposal .......................................................................................................... 57 
6.5 
Efficacy, safety, pharmacokinetic, pharmacodynamic and other assessments .......... 57 
6.5.1 
Medical history ...................................................................................................... 57 
6.5.2 
Demography .......................................................................................................... 57 
6.5.3 
Efficacy assessments ............................................................................................. 58 
6.5.3.1 Hb level and other laboratory efficacy assessments ......................................... 58 
6.5.3.2 Transfusions ...................................................................................................... 58 
6.5.3.3 Health-related quality of life ............................................................................. 58 
6.5.3.4 Appropriateness of efficacy measurements ...................................................... 58 
6.5.4 
Safety assessments ................................................................................................. 59 
6.5.4.1 Adverse events .................................................................................................. 59 
6.5.4.2 Laboratory assessments .................................................................................... 64 
6.5.4.3 Anti–pegcetacoplan peptide antibody and anti-PEG antibody assessments ..... 66 
6.5.4.4 Vital signs ......................................................................................................... 67 
6.5.4.5 Weight and height ............................................................................................. 67 
6.5.4.6 Physical examination ........................................................................................ 67 

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6.5.4.7 Electrocardiograms ........................................................................................... 67 
6.5.4.8 Infusion-site reactions/pump-safety assessments ............................................. 68 
6.5.4.9 Appropriateness of safety measurements .......................................................... 68 
6.5.5 
Pharmacokinetic assessments ................................................................................ 68 
6.5.6 
Pharmacodynamic assessments ............................................................................. 69 
6.5.7 
Other study assessments ........................................................................................ 69 
6.5.7.1 MYD88 mutation testing .................................................................................. 69 
6.5.7.2 Actigraph ........................................................................................................... 69 
7 
Quality control and quality assurance ............................................................................. 69 
8 
Statistical plan ................................................................................................................. 70 
8.1 
Determination of sample size ..................................................................................... 70 
8.2 
Definition of study populations .................................................................................. 71 
8.2.1 
Screened set ........................................................................................................... 71 
8.2.2 
Safety set ................................................................................................................ 71 
8.2.3 
Intent-to-treat set .................................................................................................... 71 
8.2.4 
Modified intent-to-treat set .................................................................................... 71 
8.2.5 
Per-protocol set ...................................................................................................... 71 
8.2.6 
Pharmacokinetic set ............................................................................................... 71 
8.2.7 
Pharmacodynamic set ............................................................................................ 71 
8.3 
Overall statistical and analytical plan ......................................................................... 72 
8.3.1 
General statistical issues ........................................................................................ 72 
8.3.2 
Demographics and baseline characteristics ........................................................... 72 
8.3.3 
Analysis related to primary objective .................................................................... 72 
8.3.4 
Analysis related to secondary objectives ............................................................... 73 
8.3.4.1 Analysis of key secondary efficacy endpoints .................................................. 73 
8.3.4.2 Analysis of secondary efficacy endpoints: Part A ............................................ 73 
8.3.4.3 Analysis of secondary efficacy endpoints: Part B ............................................ 74 
8.3.4.4 Analysis of tertiary efficacy endpoints: Part C ................................................. 75 
8.3.4.5 Analysis of exploratory endpoints. ................................................................... 75 
8.3.5 
Analysis of safety and tolerability data ................................................................. 75 
8.3.5.1 Adverse events .................................................................................................. 75 
8.3.6 
Analysis of pharmacokinetic and pharmacodynamic ............................................ 76 
8.3.6.1 Pharmacokinetic analysis .................................................................................. 76 
8.3.6.2 Pharmacodynamic analysis ............................................................................... 76 
8.3.7 
Interim analysis ...................................................................................................... 77 
8.3.8 
Multiple comparison/multiplicity .......................................................................... 77 

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8.3.9 
Handling of missing data ....................................................................................... 77 
9 
Data collection, handling and record keeping ................................................................. 77 
9.1 
Data standards ............................................................................................................ 77 
9.2 
Case report form ......................................................................................................... 77 
9.3 
Source data ................................................................................................................. 78 
9.4 
Protocol deviations ..................................................................................................... 78 
9.5 
Database closure ......................................................................................................... 79 
9.6 
Record retention ......................................................................................................... 79 
10 
End of study .................................................................................................................... 79 
11 
Sponsor’s discontinuation criteria ................................................................................... 79 
12 
Dissemination and publication of results ........................................................................ 80 
13 
Confidentiality ................................................................................................................ 80 
14 
Reference list ................................................................................................................... 81 
Appendix 1 
Additional protocol signatures ............................................................................... 82 
Appendix 2 
Functional Assessment of Cancer Therapy–Anemia/Fatigue................................ 83 
Appendix 3 
12-Item Short Form Survey ................................................................................... 86 
Appendix 4 
EuroQol-5 Dimension-5 Level .............................................................................. 87 
Appendix 5 
Protocol changes to be followed during COVID-19 restrictions ........................... 90 

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1 
Synopsis 
STUDY IDENTIFIERS 
 
Title of study: 
A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to 
Evaluate the Efficacy and Safety of Pegcetacoplan in Patients with Cold 
Agglutinin Disease (CAD)  
Clinical study number: 
Sobi.PEGCET-101 
 
 
 
 
Type of study: 
Therapeutic confirmatory  
STUDY OBJECTIVES 
 
Primary objective: 
To demonstrate the efficacy of twice-weekly subcutaneous (s.c.) 1080-mg 
infusions of pegcetacoplan compared with that of placebo in patients with CAD. 
Secondary objectives: 
Key secondary objectives: 
 
To demonstrate the effect of pegcetacoplan on the number of packed red 
blood cell (PRBC) transfusions in patients with CAD. 
 
To demonstrate the effect of pegcetacoplan on health-related quality of 
life in patients with CAD. 
Other secondary objectives: 
 
To assess the effect of pegcetacoplan on clinical laboratory markers of 
hemolysis and transfusion dependence in patients with CAD. 
 
To determine the durability of response in patients with CAD receiving 
pegcetacoplan. 
 
To assess tolerability, safety and immunogenicity of pegcetacoplan in 
patients with CAD. 
 
To describe long-term effect of pegcetacoplan in patients with CAD. 
Exploratory objectives: 
 
To evaluate the pharmacokinetics (PK) of pegcetacoplan following 
twice-weekly s.c. infusions. 
 
To evaluate the effect of pegcetacoplan in complement biomarkers.  
 
To evaluate change in patient activity level and energy expenditure. 
STUDY ENDPOINTS 
 
Primary endpoint: 
Response to treatment at Week 24. 
Response is defined as:  
 
An increase in hemoglobin (Hb) of ≥ 1.5 g/dL from Baseline or Hb 
normalization at Week 16; AND 
 
Maintenance of this effect from Week 16 to Week 24; AND 
 
The absence of PRBC transfusions (between Week 5 and Week 24). 
Note: Hb normalization is defined as within normal range (between the defined 
upper and lower limits of normal [ULN and LLN]), as set by the testing 
laboratory. 
Key secondary endpoints: 
 
Transfusion avoidance (Yes/No) from Week 5 to Week 24. 
 
Change from Baseline to Week 24 in Hb level. 
 
Change from Baseline to Week 24 in the Functional Assessment of 
Cancer Therapy–Anemia/Fatigue (FACT-An) score. 

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Secondary efficacy 
endpoints: 
 
Part A: 
 
Number of PRBC transfusions from Week 5 to Week 24. 
 
Change from Baseline to Week 24 in the following: 
• 
Lactate dehydrogenase (LDH) level. 
• 
Haptoglobin level. 
• 
Indirect bilirubin level. 
• 
Absolute reticulocyte counts (ARC). 
• 
D-dimer level. 
 
Normalization of markers of hemolysis at Week 24, specifically: 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Time to normalization from Baseline to Week 24 for the following: 
• 
Hb level. 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Number of PRBC units transfused from Week 5 to Week 24. 
 
Change from Baseline to Week 24 in the following:  
• 
12-Item Short Form Survey (SF-12) score. 
• 
5-Level EuroQol 5-Dimension (EQ-5D-5L) score. 
Part B: 
 
Change from Baseline to Week 48 in the following: 
• 
Hb level. 
• 
LDH level. 
• 
Haptoglobin level. 
• 
Indirect bilirubin level. 
• 
ARC. 
• 
D-dimer level. 
 
Normalization of markers of hemolysis at Week 48, specifically: 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Time to normalization from Baseline to Week 48 for the following: 
• 
Hb level. 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Durability of response for patients randomized to pegcetacoplan who 
achieve the primary endpoint at Week 24 (patients are considered to 
maintain response until they receive a blood transfusion or they 
experience Hb decrease by at least 1.5 g/dL from the highest level 
achieved or to below 10.0 g/dL). 
 
Change from Baseline to Week 48 in the following:  
• 
FACT-An score. 

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• 
SF-12 score. 
• 
EQ-5D-5L score. 
Tertiary efficacy 
endpoints:  
Part C: 
 
Change from Baseline to Week 96 in the following: 
• 
Hb level. 
• 
LDH level. 
• 
Haptoglobin level. 
• 
Indirect bilirubin level. 
• 
ARC. 
• 
D-dimer level. 
 
Normalization of markers of hemolysis at Week 96, specifically: 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Time to normalization from Baseline to Week 96 for the following: 
• 
Hb level. 
• 
LDH level. 
• 
Indirect bilirubin level. 
• 
ARC. 
 
Change from Baseline to Week 96 in the following:  
• 
FACT-An score. 
• 
SF-12 score. 
• 
EQ-5D-5L score. 
Safety endpoints: 
 
Adverse events (AEs) up to 6 weeks after end of treatment (EOT). 
 
Serious adverse events (SAEs) up to 6 weeks after EOT. 
 
AEs leading to premature discontinuation of the investigational 
medicinal product (IMP). 
 
Clinically meaningful laboratory abnormalities up to 6 weeks after EOT. 
 
Changes from Baseline in laboratory parameters markers (Baseline will 
be taken as the last measurement prior to the first dose of IMP). 
 
Clinically meaningful ECG abnormalities up to 6 weeks after EOT. 
 
Clinically meaningful changes in vital signs (blood pressure and pulse 
rate and body weight) from Baseline up to 6 weeks after EOT.  
 
Immunogenicity: presence of antibodies (Ab) to polyethylene glycol and 
pegcetacoplan peptide throughout treatment and follow-up periods. 

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Exploratory endpoints: 
 
Pegcetacoplan PK concentrations at Week 24 and Week 48. 
 
Changes from Baseline to Week 24 and Week 48 in complement 
biomarkers (C3 levels, functional assays for classical and alternative 
complement pathways). 
 
Changes from Baseline to Week 24 and Week 48 in inflammatory 
biomarkers: TNFα, IL-6, IL-10, IFNγ and IL-1β. 
 
Change from Baseline to Week 24 and Week 48 in activity levels 
(assessed by Actigraph). 
 
Normalization of haptoglobin level at Week 24, Week 48 and Week 96. 
 
Time to normalization from Baseline to Week 24, Week 48 and Week 96 
for haptoglobin level. 
STUDY DESIGN AND METHODS 
 
Study design: 
This is a phase 3, randomized, double-blind, placebo-controlled multicenter study 
of s.c. pegcetacoplan 1080 mg twice weekly or placebo conducted in 57 patients 
with CAD.  
Patients will be randomized in a ratio of 2:1 to receive either pegcetacoplan or 
placebo, respectively. The randomization will be stratified by transfusion history 
(number of transfusions during the 6-month period prior to randomization ≥ 1; 0). 
Every effort should be made to enroll patients in both subgroups. 
The planned length of participation in the study for each patient is a maximum of 
102 weeks. This study will consist of 5 periods: 
 
Screening period: up to 4 weeks. 
 
Double-blind treatment period: 24 weeks (Part A). 
 
Open-label treatment period: 24 weeks (Part B). 
 
Open-label maintenance period: up to additional 48 weeks or until the 
product becomes commercially available (Part C). 
 
Follow-up period: 6 weeks. 
Screening period (up to 4 weeks) 
Informed consent will be obtained during a screening visit prior to any 
study-related procedures being conducted. Some screening assessments, 
including laboratory tests and quality of life questionnaires, will be performed 
within 7 days before randomization. Patients will be screened to confirm that the 
patient selection criteria for the study have been met. Key inclusion and exclusion 
criteria will be reviewed by the study medical monitor and eligibility will be 
confirmed prior to the enrollment. Patients experiencing acute hemolytic crisis 
may receive blood cell transfusions during the screening period. 
Double-blind treatment period (24 weeks): Part A 
A total of 57 patients who meet all of the inclusion criteria and none of the 
exclusion criteria will be randomized in a 2:1 ratio to either pegcetacoplan or 
placebo. Safety and efficacy will be assessed.  
Patients randomized into the study will receive s.c. IMP (pegcetacoplan or 
placebo) twice weekly for 24 weeks.  
All standard-of-care medications can be continued, with the exception of 
protocol-defined prohibited medications. 
During the double-blind treatment period, patients will receive a blood 
transfusion if Hb level is ever shown to be < 7.0 g/dL. During this study period, 
transfusion will be considered, at the investigator’s discretion, in symptomatic 
patients with Hb levels ≥ 7.0 and < 9.0 g/dL.  

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Open-label treatment period (24 weeks): Part B 
All patients who complete the 24-week double-blind treatment will be eligible to 
enter the open-label treatment period, in which they will receive pegcetacoplan 
1080 mg s.c. twice weekly for up to 24 weeks (Week 48). 
Open-label maintenance period (up to additional 48 weeks or until the product 
becomes commercially available): Part C 
After completion of the open-label treatment period, patients who benefit from 
therapy without significant side effects will continue receiving pegcetacoplan 
1080 mg s.c. twice weekly for a maximum of 48 additional weeks or until the 
product is commercially available. 
Follow-up period (6 weeks) 
After completion of the open-label maintenance period, or if patients discontinue 
pegcetacoplan treatment early, an EOT visit will be performed, followed by an 
end of study visit 6 weeks later. 
No formal interim analyses are planned. However, data will be reported for 
Part A (double-blind treatment period) once all patients have completed their 
Week 24 visit (or have early discontinued) and the database has been cleaned and 
verified for all visits up to and including Week 24. Similarly, data will be 
reported after Part B. 
Number of patients 
planned: 
57 patients. 
Diagnosis and main 
criteria for inclusion: 
Patients with a diagnosis of primary CAD. 
Inclusion criteria: 
1. 
Age18 years or older.  
2. 
Diagnosis of primary CAD on the basis of the presence of all the 
following criteria: 
a. 
Signs of hemolysis with abnormal values by at least 2 of the 
following hemolytic markers: 
i. Reduced haptoglobin level (< LLN). 
ii. Elevated LDH level (> ULN). 
iii. Elevated indirect bilirubin level (> ULN; > 3 x ULN 
for patients with Gilbert-Meulengracht Syndrome). 
iv. Increased ARC (above the ULN). 
b. 
Monospecific direct antiglobulin test strongly positive for C3d. 
c. 
Cold agglutinin titer ≥ 64 at 4 °C. 
3. 
Hb level ≤ 9 g/dL. 
4. 
Documented results from bone marrow biopsy within 1 year of 
screening with lymphoproliferative infiltration ≤ 20 %. Patients who 
have not received a bone marrow biopsy within 1 year of their 
screening visit or those patients for whom bone marrow biopsy 
reports are incomplete or unavailable will be required to receive a 
bone marrow biopsy to determine eligibility. 
5. 
Body weight ≤ 100 kg. 
6. 
Either have vaccination against Streptococcus pneumoniae, 
Neisseria meningitidis (Types A, C, W, Y, and B), and 
Haemophilus influenzae (Type B) within 2 years prior to screening 
or agree to receive vaccination during screening as follows:  

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o 
First dose of vaccine against N. meningitidis Types A, C, W, 
and Y at least 2 weeks prior to start of study drug with second 
dose 2 months later (Study Day 57), and then boosters every 
5 years. 
o 
First dose of the vaccine against N. meningitidis Type B at least 
2 weeks prior to start of study drug with a second dose after at 
least 1 month (Study Day 29). First booster dose 1 year later, 
and then additional booster doses every 2 to 3 years. 
o 
S. pneumoniae: pneumococcal polysaccharide vaccine 23 
(PCV13) and/or pneumococcal polysaccharide vaccine 23 
(PPSV23) as per Advisory Committee on Immunization 
Practices (ACIP) guidelines for adults or children with 
immunocompromising conditions. 
o 
H. influenzae Type B: 1 dose at least 2 weeks prior to start of 
study drug. 
Vaccination is mandatory, unless documented evidence exists that 
patients are nonresponders to vaccination. Patients who were not 
previously vaccinated should not receive multiple vaccines on the 
same day.  
7. 
Women of childbearing potential (WOCBP), defined as any women 
who have experienced menarche and who are NOT permanently 
sterile or postmenopausal, must have a negative pregnancy test at 
screening and agree to use protocol-defined methods of 
contraception for the duration of the study and 8 weeks after their 
last IMP dose. 
Note: Postmenopausal is defined as having had 12 consecutive 
months with no menses without an alternative medical cause. 
8. 
Men must agree to the following for the duration of the study and 
8 weeks after their last IMP dose: 
a. 
Avoid fathering a child. 
b. Use protocol-defined methods of contraception. 
c. 
Refrain from donating sperm. 
9. 
Willing and able to give written informed consent. 
Exclusion criteria: 
1. 
Have received other anticomplement therapies (approved or 
investigational) within 5 half-lives of the agent prior to 
randomization (e.g., eculizumab within 10 weeks, ravulizumab 
within 36 weeks or sutimlimab within 4 weeks) and are not able or 
willing to refrain from using them during the study. 
2. 
Treatment with rituximab monotherapy within 12 weeks prior to 
randomization, or rituximab combination therapies (e.g., with 
bendamustine, fludarabine, other cytotoxic drugs or ibrutinib) 
within 16 weeks prior to randomization. 
3. 
Use of prohibited medications as described in the protocol. The list 
of acceptable medications and required stable regimen periods are 
outlined in the study protocol.  
4. 
Diagnosis of systemic lupus erythematosus or other autoimmune 
diseases with antinuclear antibodies. 
5. 
History of an aggressive lymphoma or presence of a lymphoma 
requiring therapy. 

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6. 
Have received an organ transplant. 
7. 
Cold agglutinin syndrome secondary to Mycoplasma pneumoniae, 
Epstein-Barr virus or other specific causative infection. 
8. 
HIV or hepatitis C virus detectable by polymerase chain reaction at 
screening or documented in the patient’s medical record. 
9. 
Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL 
(> 5000 copies/mL) at screening or documented in the patient’s 
medical record. Eligible patients who are chronic active carriers 
(≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., 
entecavir, tenofovir, lamivudine) according to local country 
guidelines. 
10. 
Presence of an active malignant disease within the last 12 months 
other than skin basal cell carcinoma or in situ carcinoma of the 
cervix. A low-grade lymphoproliferative bone marrow disorder not 
requiring therapy by itself is not defined as a malignant disease in 
this context. 
11. 
A monospecific direct antiglobulin test result of IgG > 1+. 
12. 
Presence or suspicion of liver dysfunction as indicated by elevated 
alanine aminotransferase (ALT) > 2.5 x ULN, or direct bilirubin 
levels > 2 x ULN. 
13. 
Presence or suspicion of severe recurrent or chronic infections that, 
in the opinion of the investigator, increase the patient’s risk by 
participating in the study. 
14. 
Participation in any other investigational drug trial or exposure to 
other investigational agent, device or procedure within 30 days prior 
to screening period. 
15. 
If breastfeeding, is unwilling to discontinue for the duration of study 
and for at least 8 weeks after the final IMP dose. 
16. 
Inability to cooperate with study procedures. 
17. 
Any disease(s), psychiatric condition, metabolic dysfunction, or 
findings from a physical examination or clinical laboratory test 
result that would cause reasonable suspicion of a disease or 
condition that may jeopardize the patient’s wellbeing, that may 
increase the risk associated with study participation, that may affect 
the interpretation of the results, or that would make the patient 
unsuitable for this study. 
Assessments: 
Refer to the schedule of assessments (Table 1 and Table 2). 
Test product; dose and 
mode of administration: 
Pegcetacoplan, 1080 mg twice weekly, s.c. infusion (20 mL). 
Reference product; dose 
and mode of 
administration: 
Placebo, twice weekly, s.c. infusion. 
Duration of treatment(s): 
Up to 96 weeks (Part A ‒ double-blind treatment period: 24 weeks; Part B ‒ 
open-label treatment period: 24 weeks; Part C – open-label maintenance period: 
up to  48 weeks). 

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Determination of sample 
size: 
The primary endpoint is response at Week 24. Under the assumption that the 
response rate is 55 % for pegcetacoplan and 10 % for placebo, 54 patients 
(36 treated with pegcetacoplan and 18 with placebo) are required to reject the null 
hypothesis of no difference between the treatment groups at a significance level 
of 5 % and a power of 90 % using a 2-sided Fisher’s exact test with a 2:1 
allocation to treatment groups. To account for potential drop out prior to first dose 
of IMP, 57 patients will be enrolled in the study.  
Statistical methods: 
The primary efficacy endpoint is a responder analysis, where response is defined 
as an increase in Hb level of ≥1.5 g/dL from Baseline or Hb normalization, and 
maintenance of this effect from Week 16 to Week 24, in the absence of PRBC 
transfusions (between Week 5 and Week 24). The estimand will be a composite 
where patients having an intercurrent event will be considered as nonresponders. 
The intercurrent events of interest are: 
 
Withdrawal from treatment or lost to follow-up before end of the 
double-blind period. 
 
Use of prohibited medications (any therapy for CAD including rituximab 
alone or in combination; any other complement inhibitor; any other 
investigational drug and plasma exchange). 
The number and percentage of patients who respond will be tabulated by 
treatment group and compared between treatment groups using a Fisher’s exact 
test. The odds ratio of being a responder for the pegcetacoplan treatment group 
versus the placebo group and associated 95 % confidence interval (CI) will be 
provided. 
Transfusion avoidance will be tabulated by treatment group and compared 
between treatment groups using Fisher’s exact test. The odds ratio of showing 
transfusion avoidance from Week 5 to Week 24 for the pegcetacoplan treatment 
group versus the placebo group and associated 95 % CI will be provided. The 
composite strategy is used as estimand where patients meeting any of the 
intercurrent events defined for primary endpoint will be considered as failures. 
The change from Baseline to Week 24 in Hb will be analyzed using mixed-model 
for repeated measures (MMRM) with the fixed effects of treatment, strata, visit, 
visit-by-treatment interaction and Hb level at Baseline as covariate, using an 
unstructured covariance matrix and the Kenward-Roger method for calculating 
the degrees of freedom. The difference between treatment groups will be 
estimated, along with its 95 % CI and p-value. 
The change from Baseline at Week 24 in the FACT-An score will be analyzed 
using MMRM with the fixed effects of treatment, strata, visit, visit-by-treatment 
interaction and the FACT-An score at Baseline as covariate, using an 
unstructured covariance matrix and the Kenward rogers method for calculating 
the degrees of freedom. The difference between treatment groups will be 
estimated, along with its 95 % CI and p-value. 
To preserve the Type 1 error, a fixed-sequence testing strategy will be used; 
hence, statistical significance with the first key secondary endpoint will only be 
concluded if statistical significance is achieved with the primary analysis of the 
primary endpoint. The order of testing the key secondary endpoints will be: 
 
Transfusion avoidance (Yes/No) from Week 5 to Week 24. 
 
Change from Baseline to Week 24 in Hb level. 
 
Change from Baseline to Week 24 in the FACT-An score. 
All efficacy (primary and secondary) analyses will be conducted on the 
intent-to-treat set. 

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All safety analyses will be carried out descriptively on the safety set, consisting of 
all patients who received at least 1 dose of IMP. 
 
 

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Study schematic 
Figure 1 
Study design 
Pegcetacoplan 1080 mg 2x week
Pegcetacoplan 1080 mg 2x week
Pegcetacoplan 1080 mg 2x week
Placebo
Screening
Week
-4                         2      4           8           12            16           20             24
  32                            40                              48
Part A
24-week Double-blind Treatment Period
Part B
24-week Open-label Treatment Period
Part C
Open-label Maintenance Period a
End of 
Treatment
2:1 Randomization
Pegcetacoplan:Placebo
Follow-
up 
Period
a Open-label maintenance for a maximum of 48 weeks or 
until the product becomes commercially available
--------------------------- every 8 weeks ---------------------------    96           102
 

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Schedule of assessments 
Table 1 
Schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
-4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
Study Day 
-28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
RBC transfusions collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Actigraph 
 
X 
 
 
 
 
 
 
 
 
 
Vaccination b 
X 
 
 
 
X 
 
 
X 
 
 
 
Preventive antibiotic administration c  
At the discretion of the investigator 
Full physical examination d 
X 
 
X 
 
 
 
 
 
 
 
X 
Brief physical examination e 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Weight and height f 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (prior to venipuncture) 
X 
 
X 
 
 
 
 
 
 
 
X 
IMP administration g 
 
Twice weekly------------------------------------------------------------------------------------ 
Infusion-site assessment h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine studies 
X 
 
 
X 
X 
X 
X 
X 
X 

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Table 1 
Schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
-4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
Study Day 
-28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
Blood k  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics m 
X 
 
X 
X 
X 
X 
X 
Anti–pegcetacoplan peptide and 
anti-PEG Ab assay n 
 
X 
 
X 
X 
X 
 
X 
 
 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile o 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
TNFα, IL-6, IL-10, IFNγ and IL-1β 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, functional 
assays for classical and alternative 
complement pathways) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry for C3 deposition 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin, vitamin B12/folate 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Iron 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
DAT monospecific C3 and IgG 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins quantitative (IgG, IgM, 
and IgA) p 
X 
 
 
 
 
X 
 
 
X 
 
X 
Serum cold agglutinin titer (at 4 °C) p 
X 
 
 
 
X 
X 
X 
HIV, HCV-RNA, HBV-DNA 
X 
 
 
EBV, Mycoplasma pneumoniae 
X 
 
 
 
 
 
 
 
 
 
 

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Table 1 
Schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
-4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24 
Study Day 
-28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
MYD88 Mutation Testing (only in 
patients requiring a bone marrow biopsy 
or if already done per local institution 
practice) 
X 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies for SLE and other 
autoimmune diseases 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy (B-HCG and FSH) 
X 
 
 
Urine pregnancy test q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACT-An  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy for eligibility (as 
needed) r 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation for home administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: Ab, Antibody(ies); AE, Adverse event; B-HCG, Beta human chorionic gonadotropin; C3, Complement component 3; CAD, Cold agglutinin disease; 
DAT, Direct antiglobulin test; DNA, Deoxyribonucleic acid; EBV, Epstein-Barr virus; ECG, Electrocardiogram; EQ-5D-5L, EuroQol 5-Dimension 5-Level Questionnaire; 
FACT-An, Functional Assessment of Cancer Therapy-Anemia/Fatigue; FSH, Follicle-stimulating hormone; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human 
immunodeficiency virus; ICF, Informed consent form; IFNγ, Interferon-gamma; Ig, Immunoglobulin; IL, Interleukin; IMP, Investigational medicinal product; 
PEG, Polyethylene glycol; PK, Pharmacokinetic; RBC, Red blood cell; RNA, Ribonucleic acid; s.c., Subcutaneous; SF-12, 12-Item Short Form Survey; SLE, Systemic lupus 
erythematosus; TNFα, tumor necrosis factor-alpha; WOCBP, Women of childbearing potential. 

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a Screening period is up to 4 weeks before randomization, but certain assessments, including some laboratory assessments and quality of life questionnaires, are to be performed 
within 7 days before randomization. 
b The status of vaccination against Neisseria meningitidis Types A, C, W, Y, and B, Streptococcus pneumoniae, and Haemophilus influenzae Type B should be confirmed and 
any required vaccinations or boosters are to be administered as described in Section 6.4.1.2.  
c To receive treatment with IMP, patients who are documented nonresponders to vaccination or cannot be vaccinated prior to IMP initiation will require preventive antibiotics at 
the discretion of the investigator, and should take into consideration the level of immunosuppression, complement levels, and timing of vaccination relative to IMP start, as well 
as local practices.  
d Full physical examination will include assessment of the following items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; chest; lungs; 
abdomen; skin; extremities; back/neck; musculoskeletal system and lymph nodes. 
e Brief physical examination will include general appearance, heart, lungs, abdomen and extremities. 
f Both height and weight measurements should be done without shoes on. Height will be recorded at screening only. 
g Patients will self-administer s.c. IMP, after receiving appropriate training by research personnel. IMP will be dosed at the clinical site on Day 1. Dosing diaries will be used for study 
treatment and are to be completed for each dose administered at the clinic or at home. On dosing days that coincide with clinic visits, doses will be administered at the clinic visit.  
h Between site visits, patients will be instructed to report any infusion-site reaction to the investigator or other study personnel. 
i On clinic dosing days, vital signs will be measured within 2 hours before dosing and venipuncture (and ECG, if applicable), and at 30 minutes (± 5 minutes) post dose (see 
Section 6.5.4.4). All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes, except when supine or semi-reclined because of 
study procedures and/or AEs or if deemed necessary by the investigator.  
k Baseline laboratory assessments within 7 days before Day 1. If IMP is administered at study visit, blood samples will be taken before dosing. 
m PK samples will be taken 15 minutes predose at each visit. 
n For patients with positive anti–pegcetacoplan peptide or anti-PEG Ab in last dose sample, additional samples will be collected every 6 months from last dose until Ab levels 
return to baseline. 
o The use of silica reagents in coagulation panels should be avoided in all patients. 
p Serum samples for immunoglobulins quantitative and CAD titer assessment to be kept at 37 ºC to 38 ºC (until serum has been removed from the clot, after which the sample 
can be handled at room temperature). 
q Urine pregnancy test will be completed for WOCBP prior to dosing on days where dosing coincides with clinic visits.  
r Bone marrow biopsy only needed if biopsy not previously undertaken within 1 year prior to ICF signature. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at the unscheduled 
visit at the discretion of the investigator. 
 
 

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Table 2 
Schedule of assessments: Part B, Part C and Follow-up period 
Study Period 
Part B: 
Open-label treatment period 
Part C: 
Open-label maintenance period 
Follow-up period o 
EOT/ET 
EOS 
Study Week 
32 
40 
48 
56 
64 
72 
80 
88 
96 
102 
Study Day 
225 
281 
337 
393 
449 
505 
561 
617 
673 
715 
Study Visit 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Visit window (± days) 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
RBC transfusions collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Actigraph 
 
 
 
 
 
 
 
 
X 
X 
Recommended preventive antibiotic 
administration a  
At the discretion of the 
investigator 
At the discretion of the investigator 
 
 
Full physical examination (including weight) b 
 
 
 
 
 
 
 
 
X 
X 
Brief physical examination (including weight) c 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG (prior to venipuncture) 
X 
 
 
 
 
 
 
 
X 
X 
IMP administration d 
Twice weekly--------------- 
Twice weekly--------------------------------------------- 
 
 
Infusion-site assessment e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications/treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements f  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine studies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood g  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics h 
X 
 
 
 
 
 
X 
X 
Anti–pegcetacoplan peptide and anti-PEG 
Ab assay i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table 2 
Schedule of assessments: Part B, Part C and Follow-up period 
Study Period 
Part B: 
Open-label treatment period 
Part C: 
Open-label maintenance period 
Follow-up period o 
EOT/ET 
EOS 
Study Week 
32 
40 
48 
56 
64 
72 
80 
88 
96 
102 
Study Day 
225 
281 
337 
393 
449 
505 
561 
617 
673 
715 
Study Visit 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Visit window (± days) 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
TNFα, IL-6, IL-10, IFNγ and IL-1β 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, functional assays 
for classical and alternative complement 
pathways) 
X 
X 
X 
 
 
 
 
 
X 
X 
Flow cytometry for C3 deposition 
X 
X 
X 
 
 
 
 
 
X 
X 
Ferritin, vitamin B12/folate 
X 
X 
X 
 
 
 
 
 
X 
X 
Iron 
X 
X 
X 
 
 
 
 
 
X 
X 
DAT monospecific C3 and IgG 
X 
X 
X 
 
 
 
 
 
X 
X 
Immunoglobulins quantitative (IgG, IgM, 
and IgA) m 
 
 
X 
 
 
 
 
 
X 
X 
Serum cold agglutinin titer (at 4 °C) m 
X 
 
 
 
 
 
X 
X 
Urine pregnancy test n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACT-An  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events and serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation for home administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: Ab, Antibody(ies); B-HCG, Beta human chorionic gonadotropin; C3, Complement component 3; CAD, Cold agglutinin disease; DAT, Direct antiglobulin test; 
DNA, Deoxyribonucleic acid; ECG, Electrocardiogram; EOS, End of study; EOT, End of treatment; EQ-5D-5L, EuroQol 5-Dimension 5-Level Questionnaire; ET, Early 
termination; FACT-An, Functional Assessment of Cancer Therapy-Anemia/Fatigue; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; 

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IFNγ, Interferon-gamma; Ig, Immunoglobulin; IL, Interleukin; IMP, Investigational medicinal product; PEG, Polyethylene glycol; PK, Pharmacokinetic; RBC, Red blood cell; 
RNA, Ribonucleic acid; s.c., Subcutaneous; SF-12, 12-Item Short Form Survey; TNFα, tumor necrosis factor-alpha; WOCBP, Women of childbearing potential. 
a To receive treatment with IMP, patients who are documented nonresponders to vaccination or cannot be vaccinated prior to IMP initiation will require preventive antibiotics at 
the discretion of the investigator, and should take into consideration the level of immunosuppression, complement levels, and timing of vaccination relative to IMP start, as well 
as local practices.  
b Full physical examination will include assessment of the following items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; chest; lungs; 
abdomen; skin; extremities; back/neck; musculoskeletal system and lymph nodes. Weight will also be recorded at each physical examination. 
c Brief physical examination will include general appearance, heart, lungs, abdomen and extremities. Weight will also be recorded at each physical examination. 
d Patients will self-administer s.c. IMP, after receiving appropriate training by research personnel. Dosing diaries will be used for study treatment and are to be completed for each 
dose administered at the clinic or at home. On dosing days that coincide with clinic visits, doses will be administered at the clinic visit.  
e Between site visits, patients will be instructed to report any infusion-site reaction to the study coordinator. 
f On clinic dosing days, vital signs will be measured within 2 hours before dosing and venipuncture (and ECG, if applicable), and at 30 minutes (± 5 minutes) post dose (see 
Section 6.5.4.4). 
g If IMP is administered at study visit, blood samples will be taken before dosing. 
h PK samples will be taken 15 minutes predose at each visit. 
i For patients with positive anti–pegcetacoplan peptide or anti-PEG Ab in last dose samples, additional samples will be collected every 6 months from last dose until Ab levels 
returns to baseline. 
k The use of silica reagents in coagulation panels should be avoided in all patients. 
m Serum samples for immunoglobulins quantitative and CAD titer assessment to be kept at 37 ºC to 38 ºC (until serum has been removed from the clot, after which the sample 
can be handled at room temperature). 
n Urine pregnancy test will be completed for WOCBP prior to dosing on days where dosing coincides with clinic visits.  
o After completion of the maintenance period, patients will complete an EOT visit. Patients who discontinue early should complete an ET visit. An EOS visit will be performed 
6 weeks (± 7 days) after treatment discontinuation for any reason. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at the unscheduled 
visit at the discretion of the investigator. 
 
 
 

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2 
Abbreviations and definition of terms 
2.1 
List of abbreviations and definitions 
Term 
Definition 
Ab 
Antibodies 
ACIP 
Advisory Committee on Immunization Practices 
ADA 
Antidrug antibodies 
AE 
Adverse event 
AIHA 
Autoimmune hemolytic anemia 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ARC 
Absolute reticulocyte counts 
AST 
Aspartate aminotransferase 
AxMP 
Auxiliary medicinal product 
B-HCG 
Beta human chorionic gonadotropin 
C3 
Complement component 3 
CAD 
Cold agglutinin disease 
CDASH 
Clinical data acquisition standards harmonization 
CDISC 
Clinical data interchange standards consortium 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CP 
Classical pathway of complement 
CRO 
Contract Research Organization 
CSR  
Clinical Study Report 
DAT 
Direct antiglobulin test 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 

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eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol–5 Dimension–5 Level 
FACIT-F 
Functional Assessment of Chronic Illness Therapy–Fatigue 
FACT-An 
Functional Assessment of Cancer Therapy–Anemia/Fatigue 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IFNγ 
Interferon-gamma 
IgA, IgG, IgM 
Immunoglobulin A, immunoglobulin G, immunoglobulin M 
IL-1β, IL-6, IL-10 
Interleukin 1-beta, interleukin 6, interleukin 10 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology  
ITT 
Intent-to-treat 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 

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mITT 
Modified intent-to-treat 
MMRM 
Mixed-model for repeated measures 
PCV13 
Pneumococcal conjugate vaccine 13 
PD 
Pharmacodynamic 
PEG 
Polyethylene glycol 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PP 
Per-protocol 
PPSV23 
Pneumococcal polysaccharide vaccine 23 
PRBCs 
Packed red blood cells 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous 
SOC 
System organ class 
SF-12 
12-Item Short Form Survey 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 

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3 
Ethics 
3.1 
Independent ethics committee and/or institutional review board  
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written patient information and ICF from the IEC/IRB. The investigator 
should file all correspondence with the IEC/IRB. Copies of IEC/IRB correspondence and 
approvals should be forwarded to Swedish Orphan Biovitrum (Sobi). 
3.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the ICH GCP [1], applicable 
regulatory requirements, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki [2]. 
3.3 
Patient information and consent 
It is the responsibility of the investigator to give each patient, prior to any study-related 
activities, full and adequate verbal and written information regarding the objective and 
procedures of the study and the possible risks involved. The patients must be informed about 
their right to withdraw from the study at any time. The written patient information and/or ICF 
must not be changed without prior discussion with Sobi. Before any revisions are implemented, 
the revised written patient information and/or ICF must be approved by the IEC/IRB. 
It is the responsibility of the investigator to obtain signed informed consent from all patients 
prior to any study-related activities. The patients should receive a copy of the written information 
and the signed ICF. 
4 
Introduction 
4.1 
Background 
AIHA is defined as the increased destruction of RBCs in the presence of anti-RBC 
autoantibodies, with or without complement activation. Autoantibodies are produced by both 
tissue and circulating self-reactive B lymphocytes, following cooperation with T-helper 
lymphocytes. A third key player in anti-RBC autoimmunity is the complement system, which 
can induce a direct erythrocyte osmotic lysis through the sequential activation of the membrane 
attack complex or an extravascular hemolysis through Ab-dependent cellular cytotoxicity and 
phagocytosis occurring preferentially in the spleen and lymphoid organs [3].  
AIHA occurs uncommonly with estimates of 1 to 3 in 100 000 population annually. The ability 
of the autoantibody to bind to the erythrocyte antigen at speciﬁc temperatures is fundamental to 

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the diagnosis in terms of whether it is designated as warm (reacts maximally at 37 °C) or cold 
(reacts maximally at 4 °C) AIHA. The pathologic and clinical features of AIHA relate to the 
autoantibody class, thermal amplitude and their efﬁciency in activating complement [4]. 
AIHAs consist of warm-, cold-, and mixed-reactive Ab types that are directed against antigens 
on the RBC surface. The autoantibodies may be idiopathic (primary) or related to an underlying 
condition such as infection, malignancy, or immune disease (secondary) [5]. Cold-antibody 
AIHAs are further characterized into CAD, whose patients will be focused on this study.  
4.1.1 
Cold agglutinin disease and unmet medical need 
Primary chronic CAD is an uncommon form of AIHA in which hemolysis is thought to be 
entirely complement-dependent. CAD accounts for about 15 % of AIHAs and is deﬁned as an 
AIHA mediated by cold agglutinins, without any obvious underlying disease such as aggressive 
lymphoma, other overt malignancies or speciﬁc infections. Cold agglutinins are autoantibodies 
that can agglutinate RBCs at an optimum temperature of 3 to 4 ºC [6]. 
Cold antibodies (IgM) temporarily bind to the RBC membrane, which in turn activates 
complement, and leads to the deposition of C3b on the cell surface. These C3b-coated RBCs are 
cleared slowly by the macrophages of the liver through extravascular hemolysis. To a lesser 
extent, the complete complement cascade may be activated at the cell surface, ultimately 
resulting in the insertion of membrane attack complex C5b to C9 and intravascular hemolysis. 
Various therapeutic approaches have been used in treating these patients, including RBC 
transfusions, off-label use of rituximab, rituximab-based combination therapy or bortezomib [7]. 
However, a substantial unmet medical need still exists. 
4.1.2 
Summary of clinical experience with pegcetacoplan 
Clinical data from studies with pegcetacoplan in patients with PNH indicate that pegcetacoplan 
is an effective complement modulating agent resulting in broad control of intravascular and 
extravascular hemolysis.  
To date, pegcetacoplan, at doses of ≤ 360 mg/day, has been well tolerated when administered via 
s.c. infusion, including to patients with warm AIHA and CAD (Study APL2-CP-AIHA-208 [8]; 
see Section 4.1.2.1). 
Available safety data from completed and ongoing clinical studies have not indicated any serious 
safety concern in patients treated with pegcetacoplan. 
Please refer to the latest version of the pegcetacoplan IB for the overall risk/benefit assessment 
and the most accurate and current information regarding the drug metabolism, PK, efficacy and 
safety of pegcetacoplan. 

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4.1.2.1 
Study APL2 CP AIHA-208 
This was a Phase 2, open-label, prospective pilot study of pegcetacoplan conducted in subjects 
with a primary diagnosis of warm AIHA or CAD in parallel [8]. The study included 24 patients, 
11 patients with a primary diagnosis of warm AIHA in Cohort 1 and 13 patients with a primary 
diagnosis of CAD in Cohort 2. Patients in each cohort were to be randomly (1:1) assigned to 
receive either 270 mg/day or 360 mg/day of pegcetacoplan treatment for up to 12 months 
(Part A, the core study phase). Seven patients in Cohort 1 (warm AIHA) and 10 patients in 
Cohort 2 (CAD) completed the study per the protocol. 
Safety data demonstrated the tolerability of pegcetacoplan; s.c. pegcetacoplan was well tolerated 
in both cohorts. Most TEAEs were mild, and most (81%) were deemed by the principal 
investigator to be unlikely related/unrelated to study drug. No SAEs were considered related to 
pegcetacoplan. The most common possibly treatment-related TEAE in Cohort 2 (CAD) was 
headache, reported in 3 patients (23.1%). 
Antidrug antibody responses observed in the study had no noticeable impact on the PK/PD, 
efficacy, or safety profile of pegcetacoplan. 
This study also demonstrated that pegcetacoplan rapidly increased Hb values, an effect that 
persisted for 48 weeks. This result was more prominent in patients with CAD (Cohort 2). In 
addition, transfusion avoidance during the 12 months of the core study phase was observed in 
Cohort 2 in 77% of patients after treatment with pegcetacoplan. Improvements in hemolysis by 
reduction in ARCs, LDH and indirect bilirubin were observed in both cohorts. 
Persistent inhibition of the alternative complement pathway was demonstrated without affecting 
classical complement activation. Increases in C3 levels were also observed in both dosage 
groups (270 mg/day and 360 mg/day). There was also a trend of reduction of C3 deposition on 
RBCs (% Type I) in both cohorts, which suggests that pegcetacoplan protects RBCs from 
complement-mediated attack. 
Serum pegcetacoplan concentrations reached steady state between Week 4 and Week 8. After 
reaching steady state, mean trough concentrations of pegcetacoplan were generally higher in the 
360 mg/day group, supporting that exposure increased in a dosage-dependent manner. 
In summary, pegcetacoplan produced consistent, meaningful, and prolonged effects on most 
relevant clinical efficacy measures along with an acceptable safety profile in patients with warm 
AIHA and CAD. 
4.2 
Study rationale 
Aberrant complement pathway activation has been demonstrated in many autoimmune disorders, 
particularly in diseases associated with pathogenic autoantibodies [9]. Binding of C1 complex, 
the triggering mechanism of the CP, to an immune complex containing a self-antigen and an 
autoantibody results in the formation of the CP C3 convertase, C4b2a. Subsequent cleavage of 
complement proteins C3 and C5 results in generation of C3a and C5a, anaphylatoxins that attract 
and activate effector immune cells to the site of Ab binding/complement activation; deposition of 

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C3 opsonins that mediate phagocytosis and lymphocyte activation and, ﬁnally, the formation of 
the membrane attack complex, a lytic pore that disrupts the cellular membrane and leads to 
cellular destruction [10]. Thus, complement components have long been an attractive target for 
drug development.  
Pegcetacoplan, the active ingredient in pegcetacoplan solution for s.c. infusion 1080 mg/20 mL, 
is a pentadecapeptide (a bioactive cyclic tridecapeptide C3-inhibiting moiety and a 2–amino acid 
linker) covalently coupled to each end of a linear 40-kDa PEG chain, so that there are 2 active 
peptide moieties per molecule of pegcetacoplan. The peptide portion of the drug binds to 
complement C3 and is a broad modulator of the complement cascade, a biological process that is 
part of innate immunity and is involved in multiple inflammatory processes. The PEGylation of 
the molecule imparts slower elimination from mammalian systems following administration (see 
the pegcetacoplan IB). 
On the basis of scientific and clinical evidence on the role of complement activation in CAD, it 
can be concluded that pegcetacoplan, which acts through modulation of the complement system, 
has the potential to prevent C3-mediated extravascular and intravascular hemolysis in CAD 
patients. 
Pegcetacoplan was able to rapidly increase Hb values in 10 patients with CAD treated in the 
phase 2 APL2 CP AIHA-208 study, reducing both intravascular and extravascular hemolysis (as 
shown by reduction and normalization of LDH, indirect bilirubin and ARCs) and leading to 
transfusion independency in the majority of them, being well tolerated. 
Thus, this phase 3 study is being conducted to confirm the safety and efficacy of pegcetacoplan 
in patients with CAD. 
Pegcetacoplan will be compared to the standard of care as per local institution in a 
double-blinded, randomized fashion. The treatment duration will be 24 weeks for both treatment 
groups to ensure capturing a durable treatment effect. At the end of the randomized portion of 
the study, all enrolled patients will be offered a 24-week treatment with pegcetacoplan in an 
open-label fashion, and 48 additional weeks to allow treatment continuity until the product is 
commercially available. 
4.3 
Potential risks and benefits 
Cumulatively, up to 10 July 2020, 322 subjects have been systematically exposed (via 
intravenous and s.c. route) to pegcetacoplan in completed and ongoing studies across multiple 
indications. The administration of pegcetacoplan was well tolerated and the safety data did not 
indicate any significant safety concern. Nonetheless, a number of safety monitoring practices are 
being employed by this protocol to ensure patient safety, including physical examination, vital 
signs monitoring, ECGs, hematology (including coagulation), serum chemistry, urinalysis and 
prompt reporting of AEs. 
As with other complement-inhibiting drugs, there is a potential increased risk of infections with 
encapsulated pathogens including Streptococcus pneumoniae, Neisseria meningitidis (serogroups 
A, C, W, Y, and B), and Haemophilus influenzae Type B. There have been no reports of 

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meningococcal infection or other severe infections potentially related to encapsulated bacteria. 
There was only 1 treatment-related SAE of hypersensitivity pneumonitis that led to study 
discontinuation and may have been better classified as interstitial lung disease (i.e., 
pneumonitis). All other serious infections that were observed were manageable and did not 
require discontinuation from pegcetacoplan. A review of all TEAEs (i.e., not limited to the 
infections and infestations SOC) revealed no additional potential severe infections with the 
exception of the case of pneumonitis (SOC respiratory, thoracic and mediastinal disorders). 
Therefore, the data do not support an increased risk of serious infections attributable to 
pegcetacoplan treatment. 
Thus, patients will be required to have documented evidence of vaccination against these 
pathogens within 2 years before study initiation, or will be required to receive vaccination upon 
initiation of IMP.  
Prophylactic antibiotic therapy is mandated for any patient who is required to receive a 
vaccination in the study. Chronic administration of prophylactic antibiotic therapy is 
recommended, at the discretion of the treating investigator and in accordance with local 
treatment guidelines.  
Body temperature and other vital signs will be monitored at all clinic visits, and relevant blood 
parameters will be monitored throughout the study to assess for signs of infection. Patients will 
be provided with emergency study cards that list symptoms associated with infections caused by 
encapsulated organisms. This study card also guides patients 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 should provide 
guidance on appropriate action to be taken. 
Infusion-site/pump safety will be assessed during clinical visits, and any significant finding from 
the assessment will be reported as an AE (see Section 6.5.4.1).  
Hemolysis occurring in study subjects after sudden pegcetacoplan withdrawal has been observed 
in 2 patients with PNH. Abrupt discontinuation of pegcetacoplan treatment may render PNH red 
blood cells unprotected against complement activation, potentially resulting in hemolysis leading 
to severe anemia. 
Whenever possible, the study medical monitor will be contacted before interrupting or 
discontinuing treatment with IMP. 
4.3.1 
COVID-19 risk mitigation measures 
The sponsor is not currently aware of any evidence associating pegcetacoplan use with specific 
risks or complications of COVID-19. The sponsor recognizes the need to consider the public 
health risks of the COVID-19 pandemic within the context of conducting a clinical study. 
Because these risks may change as the pandemic evolves and may vary on the basis of 
geographic location, the sponsor will continue to evaluate the risk/benefit around study conduct 
on an ongoing and patient-by-patient basis. 

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In the event that an investigative site is closed or a patient is unable/unwilling to attend a study 
visit because of COVID-19 restrictions and, in the opinion of the investigator, it is in the 
patient’s best interest to continue in the study, the following mitigation measures may be 
implemented for the study and utilized if deemed necessary and authorized by the sponsor, 
including but not limited to:  
 In locations where home nursing services may be utilized, a home nursing vendor may be 
set up to complete assessments at a patient’s home.  
 Collection of AEs or SAEs should be done over the phone and documented in the source 
documents and in the correct eCRF page.  
 If a patient has been tested for COVID-19, the results, if available, will be documented in 
the eCRF. 
 Minimized schedule of assessment can be followed during COVID-19 restrictions 
(Table 5 and Table 6), including the use of certified local laboratory. 
 The EDC system will capture any missed assessments related to COVID-19. 
 Where applicable, relevant study documentation will be updated and communicated to 
Health Authorities and/or IRBs/IECs as required. 
COVID-19 vaccination is permitted during the course of the study as per local standard of care. 
Details of the deployed vaccine should be recorded in the medical notes and study visits should 
continue as planned if possible and appropriate. 
5 
Study objectives and endpoints 
5.1 
Primary objective  
The primary objective of this study is to demonstrate the efficacy of twice-weekly s.c. 1080-mg 
infusions of pegcetacoplan compared with that of placebo in patients with CAD. 
5.1.1 
Primary endpoint 
The primary efficacy endpoint is response to treatment at Week 24. 
Response is defined as:  
 An increase in Hb of ≥ 1.5 g/dL from Baseline or Hb normalization at Week 16; AND 
 Maintenance of this effect from Week 16 to Week 24 AND 
 The absence of PRBC transfusions (between Week 5 and Week 24). 
Note: Hb normalization is defined as within normal range (between the defined ULN and LLN), 
as set by the testing laboratory. 

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5.2 
Secondary objectives  
The following are the key secondary objectives of this study: 
 To demonstrate the effect of pegcetacoplan on the number of PRBC transfusions in 
patients with CAD.  
 To demonstrate the effect of pegcetacoplan on health-related quality of life in patients 
with CAD. 
The following are the other secondary objectives of this study: 
 To assess the effect of pegcetacoplan on clinical laboratory markers of hemolysis and 
transfusion dependence in patients with CAD. 
 To determine the durability of response in patients with CAD receiving pegcetacoplan. 
 To assess tolerability, safety and immunogenicity of pegcetacoplan in patients with CAD. 
 To describe long-term effect of pegcetacoplan in patients with CAD. 
5.2.1 
Secondary endpoints supporting the secondary objectives 
5.2.1.1 
Key secondary efficacy endpoints 
The following are the key secondary endpoints for this study: 
 Transfusion avoidance (Yes/No) from Week 5 to Week 24. 
 Change from Baseline to Week 24 in Hb level. 
 Change from Baseline to Week 24 in the FACT-An score. 
5.2.1.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints are as follows: 
Part A: 
 Number of PRBC transfusions from Week 5 to Week 24. 
 Change from Baseline to Week 24 in the following: 
o LDH level. 
o Haptoglobin level. 
o Indirect bilirubin level. 
o ARC. 
o D-dimer level. 
 Normalization of markers of hemolysis at Week 24, specifically: 
o LDH level. 
o Indirect bilirubin level. 
o ARC. 
 Time to normalization from Baseline to Week 24 for the following: 
o Hb level. 
o LDH level. 

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o Indirect bilirubin level. 
o ARC. 
 Number of PRBC units transfused from Week 5 to Week 24. 
 Change from Baseline to Week 24 in the following:  
o SF-12 score. 
o EQ-5D-5L score. 
Part B: 
 Change from Baseline to Week 48 in the following: 
o Hb level. 
o LDH level. 
o Haptoglobin level. 
o Indirect bilirubin level. 
o ARC. 
o D-dimer level. 
 Normalization of markers of hemolysis at Week 48, specifically: 
o LDH level. 
o Indirect bilirubin level. 
o ARC. 
 Time to normalization from Baseline to Week 48 for the following: 
o Hb level. 
o LDH level. 
o Indirect bilirubin level. 
o ARC. 
 Durability of response for patients randomized to pegcetacoplan who achieve the primary 
endpoint at Week 24 (patients are considered to maintain response until they receive a 
blood transfusion or they experience Hb decrease by at least 1.5 g/dL from the highest 
level achieved or to below 10.0 g/dL). 
 Change from Baseline to Week 48 in the following:  
o FACT-An score. 
o SF-12 score. 
o EQ-5D-5L score. 
5.2.1.3 
Tertiary efficacy endpoints 
The tertiary efficacy endpoints are as follows: 
Part C: 
 Change from Baseline to Week 96 in the following: 
o Hb level. 
o LDH level. 
o Haptoglobin level. 
o Indirect bilirubin level. 
o ARC. 

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o D-dimer level. 
 Normalization of markers of hemolysis at Week 96, specifically: 
o LDH level. 
o Indirect bilirubin level. 
o ARC. 
 Time to normalization from Baseline to Week 96 for the following: 
o Hb level. 
o LDH level. 
o Indirect bilirubin level. 
o ARC. 
 Change from Baseline to Week 96 in the following:  
o FACT-An score. 
o SF-12 score. 
o EQ-5D-5L score. 
5.2.1.4 
Safety endpoints 
The safety endpoints are as follows: 
 AEs up to 6 weeks after EOT. 
 SAEs up to 6 weeks after EOT. 
 AEs leading to premature discontinuation of IMP. 
 Clinically meaningful laboratory abnormalities up to 6 weeks after EOT. 
 Changes from Baseline in laboratory parameters markers (Baseline will be taken as the 
last measurement prior to the first IMP dose). 
 Clinically meaningful ECG abnormalities up to 6 weeks after EOT. 
 Clinically meaningful changes in vital signs (blood pressure and pulse rate and body 
weight) from Baseline up to 6 weeks after EOT. 
 Immunogenicity: presence of Ab to polyethylene glycol and pegcetacoplan peptide 
throughout treatment and follow-up periods. 
5.3 
Exploratory objectives  
 To evaluate the PK of pegcetacoplan following twice-weekly s.c. infusions. 
 To evaluate the effect of pegcetacoplan in complement biomarkers. 
 To evaluate change in patient activity level and energy expenditure. 
5.3.1 
Exploratory endpoints 
The exploratory endpoints are as follows: 
 Pegcetacoplan PK concentrations at Week 24 and Week 48. 
 Changes from Baseline to Week 24 and Week 48 in complement biomarkers (C3 levels, 
functional assays for classical and alternative complement pathways). 

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 Changes from Baseline to Week 24 and Week 48 in inflammatory biomarkers: TNFα, 
IL-6, IL-10, IFNγ and IL-1β. 
 Change from Baseline to Week 24 and Week 48 in activity levels (assessed by 
Actigraph). 
 Normalization of haptoglobin level at Week 24, Week 48 and Week 96. 
 Time to normalization from Baseline to Week 24, Week 48 and Week 96 for haptoglobin 
level. 
6 
Investigational plan 
6.1 
Overall study design and plan 
This is a phase 3, randomized, double-blind, placebo-controlled multicenter study of 
pegcetacoplan (1080 mg) or placebo, administered twice weekly by s.c. infusion in patients with 
CAD.  
A total of 57 patients with CAD will be enrolled in this study. Patients will be randomized in a 
ratio of 2:1 to receive either pegcetacoplan or placebo, respectively. The randomization will be 
stratified by transfusion history (number of transfusions during the 6-month period prior to 
randomization ≥ 1; 0). Every effort should be made to enroll patients in both subgroups. 
The planned length of participation in the study for each patient is a maximum of 102 weeks. 
This study will consist of 5 periods: 
 Screening period: up to 4 weeks. 
 Double-blind treatment period: 24 weeks (Part A). 
 Open-label treatment period: 24 weeks (Part B). 
 Open-label maintenance period: up to additional 48 weeks or until the product becomes 
commercially available (Part C). 
 Follow-up period: 6 weeks. 
The study design is outlined in Figure 1, and the visit schedule and planned assessments at each 
visit are detailed in Table 1 and Table 2. 
No formal interim analyses are planned. However, data will be reported for Part A (double-blind 
treatment period) once all patients have completed their Week 24 visit (or have early 
discontinued) and the database has been cleaned and verified for all visits up to and including 
Week 24. Similarly, data will be reported after Part B (see Section 8.3.7).  
6.1.1 
Screening period (up to 4 weeks) 
Informed consent will be obtained during a screening visit prior to any study-related procedures 
being conducted. Some screening assessments, including laboratory tests and quality of life 
questionnaires, will be performed within 7 days before randomization. Patients will be screened 
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will be reviewed by the study medical monitor and eligibility will be confirmed prior to the 
enrollment. Patients experiencing acute hemolytic crisis may receive blood cell transfusions 
during the screening period. For Hb level qualification, the latest post-transfusion value will be 
used as Baseline, and the threshold of ≤ 9.0 g/dL must be met. 
6.1.1.1 
Retesting and rescreening 
Patients who fail to qualify for the study on the basis of certain laboratory parameters may be 
retested and/or rescreened at the discretion of the investigator.  
 
Retesting 
Retesting is defined as repeating laboratory tests within the same screening period.  
Patients who initially fail to qualify for the study on the basis of laboratory test results not 
meeting inclusion criteria or due to technical issues (e.g., hemolysis, clotting) may have, at the 
discretion of the investigator, any individual laboratory parameter retested 1 time within the 
4-week screening period. Retesting within the 4-week screening period does not constitute 
rescreening; however, if retesting falls outside of the 4-week screening period, it should be 
considered rescreening (see below).  
In case of retesting for Hb level qualification, the last measured value will be used as Baseline. 
 
Rescreening 
Rescreening is permitted for patients who consent to participate in the study but who do not 
initially meet all the requirements as outlined in the inclusion and exclusion criteria. In this case, 
additional screening visits and/or repeat screening assessments may be conducted, as needed, to 
establish eligibility. 
Screening is limited to 3 attempts (screening and 2 additional rescreening attempts).  
In the event that rescreening occurs and the patient has not remained in the screening period, the 
individual is required to reconsent and must be assigned a new identification number.  
6.1.1.2 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study but who do 
not meet 1 or more criterion required for participation and are not subsequently entered in the 
study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects, to meet the Consolidated Standards of Reporting Trials publishing 
requirements, and to respond to queries from regulatory authorities. Minimal information 
includes demography and reason for screen failure. 
6.1.2 
Double-blind treatment period (24 weeks): Part A 
A total of 57 patients who meet all of the inclusion criteria and none of the exclusion criteria will 
be randomized in a 2:1 ratio to receive either pegcetacoplan or placebo.  

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Patients randomized into the study will receive IMP (pegcetacoplan or placebo) twice weekly for 
24 weeks.  
All standard-of-care medications can be continued, with the exception of protocol-defined 
prohibited medications (see Section 6.4.10.2). 
During the double-blind treatment period, patients will receive a blood transfusion if their Hb 
level is ever shown to be < 7.0 g/dL. During this study period, transfusions will be considered, at 
the investigator’s discretion, in symptomatic patients with Hb levels ≥ 7.0 and < 9.0 g/dL.  
6.1.3 
Open-label treatment period (24 weeks): Part B 
All patients who complete the 24-week double-blind treatment period will be eligible to enter the 
open-label treatment period, in which they will receive pegcetacoplan 1080 mg twice weekly for 
up to 24 weeks (Week 48). 
6.1.4 
Open-label maintenance period (up to additional 48 weeks or until the 
product becomes commercially available): Part C 
After completion of the open-label treatment period, patients who benefit from therapy without 
significant side effects will continue receiving pegcetacoplan 1080 mg s.c. twice weekly for a 
maximum of 48 additional weeks or until the product is commercially available. 
6.1.5 
Follow-up period (6 weeks) 
After completion of the open-label maintenance period, or if patients discontinue pegcetacoplan 
treatment early, an EOT visit will be performed, followed by an EOS visit 6 weeks later. See 
Figure 1 for the study schematic illustrating the study periods as a function of time. 
6.1.6 
Unscheduled visits 
Unscheduled additional visits may be performed at the investigator’s judgment. Any of the 
study procedures or other assessments may be performed at the unscheduled visit at the 
discretion of the investigator. 
6.2 
Discussion of study design, including the choice of control groups 
In this double-blinded, randomized, phase 3 study, patients will be randomized in a ratio of 2:1 
to receive pegcetacoplan or placebo. The study will enroll patients affected by CAD who have an 
Hb level ≤ 9 g/dL. There are no currently approved therapies for patients with CAD in need of 
treatment; therefore, the choice of placebo as comparator is fully justified. 

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The primary endpoint of the study is a composite endpoint aimed at demonstrating a significant 
effect of pegcetacoplan on hemoglobin levels that is durable and effective in reducing 
transfusion requirement. 
The treatment duration will be 24 weeks for both treatment groups to ensure capturing a durable 
treatment effect, with an extended 24-week open-label treatment period offered to all patients 
enrolled in the study, and 48 additional weeks to allow treatment continuity until the product is 
commercially available.  
Those patients randomized to the placebo group requiring a rescue blood transfusion according 
to the study-specified criteria for transfusion or those who receive a prohibited concomitant 
medication during the treatment period will be considered as nonresponders. 
6.3 
Selection of study population 
6.3.1 
Inclusion criteria 
A patient must fulfill the following criteria to be included in the study: 
1. Age 18 years or older. 
2. Diagnosis of primary CAD on the basis of the presence of all the following criteria: 
a. Signs of hemolysis with abnormal values for at least 2 of the following hemolytic 
markers: 
i. Reduced haptoglobin level (< LLN). 
ii. Elevated LDH level (> ULN). 
iii. Elevated indirect bilirubin level (> ULN; > 3 x ULN for patients with 
Gilbert-Meulengracht syndrome). 
iv. Increased ARC (above the ULN). 
b. Monospecific direct antiglobulin test strongly positive for C3d. 
c. Cold agglutinin titer ≥ 64 at 4 °C. 
3. Hb level ≤ 9 g/dL. 
4. Documented results from bone marrow biopsy within 1 year of screening with 
lymphoproliferative infiltration ≤ 20 %. Patients who have not received a bone marrow 
biopsy within 1 year of their screening visit or for whom bone marrow biopsy reports are 
incomplete or unavailable will be required to receive a bone marrow biopsy to determine 
eligibility.  
5. Body weight ≤ 100 kg. 
6. Either have vaccination against S. pneumoniae, N. meningitidis (Types A, C, W, Y, and 
B), and H. influenzae (Type B) within 2 years prior to screening or agree to receive 
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 First dose of vaccine against N. meningitidis Types A, C, W, and Y at least 2 weeks 
prior to start of study drug with second dose 2 months later (Study Day 57), and then 
boosters every 5 years. 
 First dose of the vaccine against N. meningitidis Type B at least 2 weeks prior to start 
of study drug with a second dose after at least 1 month (Study Day 29). First booster 
dose 1 year later, and then additional booster doses every 2 to 3 years. 
 S. pneumoniae: PCV13 and/or PPSV23 as per ACIP guidelines for adults or children 
with immunocompromising conditions. 
 H. influenzae Type B: 1 dose at least 2 weeks prior to start of study drug.  
Vaccination is mandatory unless documented evidence exists that patients are 
nonresponders to vaccination. Patients who were not previously vaccinated should not 
receive multiple vaccines on the same day. 
7. WOCBP, defined as any women who have experienced menarche and who are NOT 
permanently sterile or postmenopausal, must have a negative pregnancy test at screening 
and agree to use protocol-defined methods of contraception for the duration of the study 
and 8 weeks after their last IMP dose. 
Note: Postmenopausal is defined as having had 12 consecutive months with no 
menses without an alternative medical cause. 
8. Men must agree to the following for the duration of the study and 8 weeks after their last 
IMP dose: 
a. Avoid fathering a child. 
b. Use protocol-defined methods of contraception. 
c. Refrain from donating sperm. 
9. Willing and able to give written informed consent. 
6.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Have received other anticomplement therapies (approved or investigational) within 
5 half-lives of the agent prior to randomization (e.g., eculizumab within 10 weeks, 
ravulizumab within 36 weeks or sutimlimab within 4 weeks) and are not able or willing 
to refrain from using them during the study. 
2. Treatment with rituximab monotherapy within 12 weeks prior to randomization, or 
rituximab combination therapies (e.g., with bendamustine, fludarabine, other cytotoxic 
drugs or ibrutinib ) within 16 weeks prior to randomization. 
3. Use of prohibited medications as described in Section 6.4.10.2. Refer to Section 6.4.10.1 
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4. Diagnosis of systemic lupus erythematosus or other autoimmune disease with antinuclear 
antibodies. 
5. History of an aggressive lymphoma or presence of a lymphoma requiring therapy. 
6. Have received an organ transplant. 
7. Cold agglutinin syndrome secondary to Mycoplasma pneumoniae, Epstein-Barr virus or 
other specific causative infection. 
8. HIV or hepatitis C virus detectable by polymerase chain reaction at screening or 
documented in the patient’s medical record. 
9. Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at 
screening or documented in the patient’s medical record. Eligible patients who are 
chronic active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment 
(e.g., entecavir, tenofovir, lamivudine) according to local country guidelines. 
10. Presence of an active malignant disease within the last 12 months other than skin basal 
cell carcinoma or in situ carcinoma of the cervix. A low-grade lymphoproliferative bone 
marrow disorder not requiring therapy by itself is not defined as a malignant disease in 
this context. 
11. A monospecific direct antiglobulin test result of IgG > 1+. 
12. Presence or suspicion of liver dysfunction as indicated by elevated ALT > 2.5 x ULN, or 
direct bilirubin levels > 2 x ULN. 
13. Presence or suspicion of severe recurrent or chronic infections that, in the opinion of the 
investigator, increase the patient’s risk by participating in the study. 
14. Participation in any other investigational drug trial or exposure to other investigational 
agent, device, or procedure within 30 days prior to screening period. 
15. If breastfeeding, is unwilling to discontinue for the duration of study and for at least 
8 weeks after the final IMP dose. 
16. Inability to cooperate with study procedures. 
17. Any disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical 
examination or clinical laboratory test result that would cause reasonable suspicion of a 
disease or condition that may jeopardize the patient’s wellbeing, that may increase the 
risk associated with study participation, that may affect the interpretation of the results, or 
that would make the patient unsuitable for this study. 
6.3.3 
Withdrawal of patients from treatment or study  
6.3.3.1 
Withdrawal from treatment 
A patient should be withdrawn from the study treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient. Specific treatment stopping criteria are 
provided in Section 6.4.7. 

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Study treatment must be discontinued if a female patient becomes pregnant. 
When a patient is withdrawn from treatment, the study site must immediately notify the study 
medical monitor, and the date of last IMP dose and the date and reason for treatment withdrawal 
should be clearly described in the relevant sections of the eCRF. If a patient is removed from 
treatment because of an AE, the reason for treatment withdrawal should always be stated as 
‘adverse event’ irrespective of whether this was the investigator’s or the patient’s decision. 
The patient will continue to participate in the study without taking study treatment. Patients who 
stop study treatment prior to the exit visit should undergo all follow-up visits and procedures 
through study completion, unless they are unwilling or unable or consent has been withdrawn. 
Patients who wish to fully withdraw from the study before completion should be encouraged to 
complete the Early termination visit (see Table 2). 
6.3.3.2 
Withdrawal from study 
A patient may withdraw from the study at any time at his/her own request or at the request of 
their legally authorized representative, or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is expected to be 
uncommon. Whenever possible and irrespective of the reason for withdrawal, the patient should 
be examined as soon as possible. Relevant samples should be obtained and all relevant 
assessments should be completed. The eCRF should be completed as far as possible. Date and 
reason for the study withdrawal should be clearly described in the eCRF. 
Once a patient leaves the study, he/she may not reenter the study. 
6.3.3.3 
Lost to follow-up 
A minimum of 3 documented attempts must be made to contact any patient lost to follow-up at 
any 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 patient’s last known 
address via courier or mail (with an acknowledgment of receipt request) asking that the patient 
return to the site for final safety evaluations and to return any IMP. 
Should the patient continue to be unreachable, they will be considered to have withdrawn from 
the study. 
6.3.4 
Replacement of withdrawn patients 
Withdrawn patients will not be replaced. 
6.3.5 
Specific restrictions/requirements  
6.3.5.1 
Acceptable methods of contraception 
Acceptable methods of contraception include: 

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 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral, intravaginal or transdermal. 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral, injectable or implantable. 
 Intrauterine device. 
 Intrauterine hormone-releasing system. 
 Bilateral tubal occlusion. 
 Vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP 
study patient and the vasectomized partner has received medical assessment of the 
surgical success). 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with study treatments). 
 Male condom, with or without spermicide (for male study patients with female partners 
of childbearing potential only). 
Not all methods of contraception may be available in all of the countries in which the study is 
being conducted. 
Note: Sexual abstinence is accepted only when it is the preferred and usual lifestyle of the 
patient. 
Patients must agree to use an acceptable method of contraception during the study and for 
8 weeks after their last dose of IMP.  
Male patients will be counseled to avoid donating semen during the time between the first 
screening and the final exit visit and for the 8 weeks after their last dose of IMP. 
6.3.5.2 
Vaccination and preventive antibiotic requirements 
Details about required vaccination against N. meningitidis (Types A, C, W, Y, and B), 
S. pneumoniae (with a PCV13 or PPSV23 vaccine), and H. influenzae Type B (Hib) and 
required/recommended preventive antibiotics are provided in Section 6.4.1.2. 
6.3.6 
Study stopping criteria 
The study enrollment will be suspended if:  
 Two patients from 2 different investigational sites experience a Grade 4 AE assessed as 
related to the IMP by the investigator.  
 One patient experiences a Grade 5 AE assessed as related to the IMP by the investigator. 
The sponsor will thoroughly evaluate the reported adverse reactions and will resume the study 
only if an alternative explanation of the reported events is identified. In case the decision to stop 
the study is made, the sponsor will communicate the appropriate action for enrolled patients who 
are on treatment with the active drug based on the risk-benefit assessment. The sponsor or 
designee will also promptly inform the relevant regulatory authorities of the 

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suspension/termination along with the reasons for such action, when applicable. Where required 
by applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC. 
6.4 
Treatments 
6.4.1 
Treatments administered  
6.4.1.1 
Investigational medicinal products 
Table 3 
Investigational medicinal products 
Investigational 
product 
Dosage form 
Route 
Dose 
Dosage regimen 
Pegcetacoplan 
Sterile solution in 
stoppered glass vials 
Subcutaneous 
1080 mg 
Twice weekly 
Placebo 
Sterile solution in 
stoppered glass vials 
Subcutaneous 
Not 
applicable 
Twice weekly 
The pegcetacoplan treatment group will receive a dosage of 1080 mg twice weekly via s.c. 
infusion (20 mL) during the double-blind treatment period (24 weeks).  
The placebo group will receive placebo s.c. infusion twice weekly during the double-blind 
treatment period. 
Following the double-blind treatment period, patients from both treatment groups may enter the 
open-label treatment period (24 weeks) and will receive pegcetacoplan 1080 mg twice weekly 
via s.c. infusion (20 mL) (equivalent to 308 mg/day).  
The open-label treatment period will be followed by an open-label maintenance period 
(maximum of additional 48 weeks or until the product becomes commercially available), and 
patients who benefited from therapy without significant side effects during the double-blind 
treatment period will continue receiving pegcetacoplan 1080 mg twice weekly via s.c. infusion 
(20 mL). 
6.4.1.2 
Vaccination and preventive antibiotics 
 
Vaccination  
To receive treatment with IMP, patients will be required to be vaccinated as per ACIP 
recommendations for adults or children with complement deficiencies and/or 
immunocompromising conditions (available at 
https://www.cdc.gov/vaccines/schedules/hcp/index.html) as follows: 
Patients previously vaccinated will have documented evidence of vaccination against the 
following within 2 years of screening: N. meningitidis Types A, C, W, Y, and B (administered as 

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2 separate vaccinations), S. pneumoniae (with a PCV13 or PPSV23 vaccine), and H. influenzae 
Type B (Hib) vaccine (see Section 6.3.1, Inclusion Criterion #6). 
Patients not previously vaccinated will have to receive vaccines during screening as follows: 
 First dose of vaccine against N. meningitidis Types A, C, W, and Y at least 2 weeks prior 
to start of study drug with second dose 2 months later (study Day 57), and then boosters 
every 5 years. 
 First dose of the vaccine against N. meningitidis Type B at least 2 weeks prior to start of 
study drug with a second dose after at least 1 month (study Day 29). First booster dose 
1 year later, and then additional booster doses every 2 to 3 years. 
 S. pneumoniae: PCV13 and/or PPSV23 as per ACIP guidelines for adults or children 
with immunocompromising conditions. 
 H. influenzae Type B: 1 dose at least 2 weeks prior to start of study drug.  
Vaccination is mandatory, unless documented evidence exists that patients are nonresponders to 
vaccination. The investigator will discuss with the sponsor regarding individual patient 
circumstances. Patients who were not previously vaccinated should not receive multiple vaccines 
on the same day.  
Vaccines will be sourced locally by the study sites and reimbursed by the sponsor, or sourced by 
the sponsor if local sourcing is not feasible. 
An AxMP is a medicinal product used for the needs of a clinical study as described in the 
protocol, but not as an IMP. In this study, the described mandatory vaccines are considered as 
AxMP and safety reporting applies for them, see Sections 6.5.4.1.3.1 and 6.5.4.1.4.1.  
 
Preventive antibiotics  
To receive treatment with IMP, patients who are documented nonresponders to vaccination or 
cannot be vaccinated prior to IMP initiation will require preventive antibiotics at the discretion 
of the investigator, and should take into consideration the level of immunosuppression, 
complement levels, and timing of vaccination relative to IMP start, as well as local practices.   
6.4.2 
Identity of investigational medicinal products 
The IMP is pegcetacoplan, which will be provided as a sterile solution of pegcetacoplan at 
54 mg/mL (1080 mg/20 mL) in 10 mM acetate buffer, pH 5.0, containing 4.1 % sorbitol, 
provided in single-use stoppered glass vials. Additional information is provided in the 
pegcetacoplan IB.  
Placebo will be provided as a sterile solution of 10 mM sodium acetate, pH 5.0, containing 4.1 % 
sorbitol supplied in stoppered glass vials. 
Possible deficiencies related to the handling and quality of the IMP(s) should be reported to the 
study medical monitor and also directly to complaints@sobi.com. 

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6.4.2.1 
IMP packaging and labeling 
The IMP is supplied in 20-cc glass vials. Please refer to the pharmacy manual for details.  
All IMP will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice guidelines. 
Changes to sponsor-supplied packaging prior to administration may not occur without full 
agreement, in advance, by the sponsor. 
6.4.2.2 
IMP storage and handling 
The IMP should be stored refrigerated at 2 °C to 8 °C, both at home and in the clinic. 
Temperature monitoring is required at the investigator site (or documented storage location) to 
ensure that the IMP is maintained within an established temperature range.  
The investigator or appropriately qualified site staff will be responsible for the following 
activities: 
 Ensuring that the IMP is stored in a secure, limited-access location at the site. 
 Ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained. 
Limited responsibility may be delegated to the pharmacy or to another member of the study 
team, but this delegation must be documented. 
A pharmacist or appropriately qualified designated person will be responsible for the following: 
 Storing the IMP appropriately. 
 Dispensing the IMP vials to the patient and entering the unique subject identifier as 
appropriate. 
When the patient receives the IMP from the site, it should be transported in a sponsor-approved 
bag or box containing previously temperature-conditioned cold plates to ensure that the storage 
temperature (2 °C to 8 °C) is maintained. Temperature monitoring will not be required during 
transport or at the patient’s residence. It is required for the patient to complete the diary, 
confirming that all IMP was kept refrigerated at 2°C to 8°C (35.6°F to 46.4°F) prior to removing 
from refrigerator for use. 
6.4.3 
Method of assigning patients to treatment groups 
Randomization will occur through the IRT system.  
All patients who meet all the inclusion criteria and none of the exclusion criteria will be enrolled 
in the study after eligibility review the study medical monitor, until such time that 57 patients 
have been enrolled in the study. Patients will then be randomly assigned through the IRT system 
to either pegcetacoplan or placebo in a 2:1 ratio. The randomization will be stratified according 
to number of transfusions during the 6-month period prior to randomization ≥ 1; 0. Every effort 
should be made to enroll patients in both subgroups. 

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Blinded IMP supplies labeled with kit numbers and other information as per Master Label and in 
line with regulatory requirements will be provided to each study site. IMP dosing will be 
initiated at the site after randomization. At each visit when IMP is administered and dispensed, 
the study staff will contact the IRT to obtain appropriate kit numbers. 
For the open-label treatment and maintenance periods, all patients will receive pegcetacoplan 
open-label.  
Please refer to the study manuals for further details of randomization and unblinding. 
6.4.4 
Selection of doses 
A twice-weekly dose of 1080 mg was selected as the dosing regimen on the basis of PK 
modeling, which predicts a pegcetacoplan serum level for this regimen between those observed 
for the 270-mg and 360-mg daily dose regimens. The pegcetacoplan serum concentration 
predicted for 1080-mg twice-weekly s.c. administration was confirmed in a study of healthy 
subjects (e.g., Study 101; refer to the pegcetacoplan IB). 
Population PK modeling based on pooled data from 10 clinical studies, including data up to 
Week 16 from Study APL2-302, confirmed that the pegcetacoplan exposure achieved at a 
dosage of 1080 mg s.c. twice weekly is intermediate to those predicted for dosages of 270 mg 
and 360 mg s.c. once daily (refer to the pegcetacoplan IB).  
The exposure-response model for Hb provides support for the hypothesis that the phase 3 dose 
regimen of 1080 mg twice weekly will be effective in increasing Hb levels to normal or near-
normal levels. Indeed, steady-state pegcetacoplan serum concentrations are expected to reach 
99 % of the maximal predicted Hb response. Similarly, the exposure-response model for LDH 
also provides support for the hypothesis that the phase 3 dose regimen of 1080 mg twice weekly 
will be an effective dosage for LDH response. Steady-state pegcetacoplan serum concentrations 
are expected to reach 95 % of the maximal predicted LDH response. 
6.4.5 
Selection and timing of doses for each patient 
Patients will self-administer s.c. IMP, after receiving appropriate training by research personnel. 
IMP will be dosed at the clinical site on Day 1. On dosing days that coincide with clinic visits, 
doses will be administered at the clinic visit. 
Patients will be instructed to self-administer their IMP only as prescribed and to contact the 
investigator immediately for guidance in the event of any missed doses. 
Dosing diaries will be used for study treatment and are to be completed for each dose 
administered at the clinic or at home. Patients should not deviate from the IMP dosing schedule: 
Day 1 and Day 4 of each treatment week (e.g., Monday/Thursday/Monday/Thursday). 
The preferred site of infusion will be the abdomen. If administration into the abdomen is not 
feasible, alternative appropriate sites are acceptable (see the Pump Instructions for Use document 
for more details).  

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The typical s.c. infusion time for pegcetacoplan is approximately 30 minutes if using 2 sites, or 
approximately 60 minutes if using 1 site. 
During initial qualification, the research nurse or other appropriately qualified and trained 
research personnel will administer the s.c. infusions (as needed) and will qualify and supervise 
the self-administration or caregiver administration. These qualified research personnel will be 
made available for a minimum of 6 days on treatment (2 doses) to ensure the patient has been 
qualified to conduct self-administration; the duration can be shortened if qualification happens 
sooner. During qualification, the patient or caregiver must demonstrate to the research personnel 
their ability to safely and effectively administer the IMP using the infusion pump. 
Following self-administration or caregiver administration qualification, patients or caregivers 
may self-administer the s.c. infusions without supervision. Once qualified, the patient or 
caregiver will continue to administer infusions at the clinic on those days when a clinic visit 
occurs and at an off-site location convenient to the patient on all other days. Self-administration 
or caregiver administration conducted at the clinic will be supervised to ensure that the patient or 
caregiver continues to remain compliant with the administration guidelines.  
Missed doses will be handled on a case-by-case basis between the investigator and the study 
medical monitor, with the general approach being to administer a missed dose as soon as noticed, 
unless the next dose has already been administered. 
NOTE: If the patient or caregiver requires further training, the self-administration qualification 
period may be extended beyond 6 days on treatment (2 doses). Caregiver administration may be 
conducted by a member of the patient’s household, a family member, etc, who will undergo the 
same qualification criteria (qualification is not intended to be restricted to the patient).  
6.4.6 
Dose modification 
Any dose modification (treatment interruption/discontinuation) necessary to manage AEs should 
be discussed with the study medical monitor. 
6.4.7 
Treatment stopping criteria 
Pegcetacoplan will be discontinued in an individual patient if any of the following laboratory 
abnormalities and/or AEs are observed that are assessed as causally related to the IMP (i.e., no 
alternative explanation is identified) by the investigator: 
 Any Grade ≥ 3 nonhematological laboratory abnormality (other than Grade 3 
hypoglycemia; Grade 3 AST, GGT, and total bilirubin caused by unconjugated bilirubin 
elevation). 
 Grade 4 thrombocytopenia for ≥ 7 days, or Grade ≥ 3 thrombocytopenia associated with 
bleeding. 
 Grade 4 neutropenia for ≥ 7 days, or Grade ≥ 3 neutropenia associated with infection. 
 Febrile neutropenia of any grade. 

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 Any Grade ≥ 3 nonhematological toxicity (other than Grade 3 nausea, vomiting, or 
diarrhea ≤ 72 hours in duration with adequate prophylactic and supportive care). 
6.4.8 
Infusion supplies  
The sponsor will supply syringes, vial adapters, infusion sets, ambulatory syringe infusion 
pumps, and any other supplies needed for the safe home IMP administration as required. Refer to 
the pharmacy manual for further details. 
6.4.9 
Blinding and unblinding 
6.4.9.1 
IMP blinding 
Active and placebo product will be of identical appearance.  
The IMP blind will be maintained through the Week 24 primary endpoint analysis. Patients, the 
sponsor, investigators, CROs and all study site personnel involved with the study, carrying out 
study procedures, evaluating patients, entering study data, and/or evaluating study data will 
remain blinded to treatment allocations until all patients have completed the Week 24 
assessments and the database has been locked for the analysis at Week 24.  
After Week 24, all patients will receive open-label pegcetacoplan. 
6.4.9.2 
IMP unblinding 
 
Emergency unblinding 
Unblinding, i.e., breaking the code for an individual patient during the study, is restricted to 
emergency situations and should only be used under circumstances where knowledge of the 
treatment is necessary for the proper handling of the patient. Emergency unblinding will be 
performed through IRT system.  
In situations in which knowledge of the patient’s IMP is necessary for clinical management, the 
investigator must first attempt to contact the study medical monitor or designee, to discuss the 
need for unblinding to occur. The study medical monitor or designee will answer calls 24 hours a 
day/7 days a week. In situations in which the investigator has tried but is unable to reach the 
medical monitor or designee, the investigator should use best judgment, based on the nature and 
urgency of the clinical situation, and may proceed with unblinding through IRT without having 
successfully reached and discussed the situation with the medical monitor or designee. Once a 
patient’s treatment assignment has been unblinded, the study medical monitor and study 
coordinator should be notified within 24 hours of unblinding of the treatment. Information 
relating to unblinding (e.g., date and time of the call to the medical monitor by the investigator, 
reason for unblinding, and date and time of unblinding) shall be clearly recorded in the patient’s 
study file and in the EDC system as part of relevant standard operating procedures. In addition, 
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considered an AE or SAE according to the criteria for AEs or SAEs (see Section 6.5.4.1.1), and 
if so, such event shall be reported accordingly (see Section 6.5.4.1.2). 
 
Unblinding for suspected unexpected serious adverse reactions 
When a SUSAR occurs for a patient participating in the study, Sobi Global Pharmacovigilance & 
Patient Safety will request the unblinding of the treatment assignment. The randomization code 
will not be communicated to the site staff, or to the Sobi study team; unblinded SUSAR 
information will be provided to respective Health Authorities. 
Please refer to the study manuals for further details of randomization and unblinding. 
6.4.10 
Prior and concomitant therapy 
6.4.10.1 
Permitted concomitant therapy 
All medications administered and procedures performed within 12 weeks before ICF signature 
will be recorded as prior medications and procedures. Medications administered and procedures 
performed from the time of informed consent through the EOS visit are regarded as concomitant 
and will be documented as such.  
Concomitant medications refer to all treatment taken between the dates of the first dose of IMP 
and the end of the follow-up period, inclusive. Concomitant medication information must be 
recorded on the appropriate eCRF page. With the exception of prohibited medications any 
concomitant medications deemed necessary for the patient’s standard of care or wellbeing during 
the study or for the treatment of any AE 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 patient’s eCRF.  
The following concomitant medications are permitted only if administration is continued on a 
stable regimen (i.e., the dose has not changed for specific period defined below and is likely to 
remain unchanged during the study): 
 Stable dosage for at least 4 weeks prior to randomization: 
o Bortezomib monotherapy. 
o Erythropoietin. 
o Corticosteroids. If a patient, per the investigator’s opinion, requires 
corticosteroids initiation during the study for reasons other than CAD, a 
discussion with the study medical monitor is required before starting treatment. 
Topical, inhalation or intraarticular use of corticosteroids is permitted. 
o Vitamin K antagonists (e.g., warfarin) with a stable INR.  
o Direct oral anticoagulants. 
o Iron supplements, vitamin B12 or folic acid. 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 study medical monitor. 
o Low-molecular-weight heparin. 
 Stable dosage for at least 8 weeks prior to randomization: 

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o Immunosuppressants 
 Stable dosage for at least 14 weeks prior to randomization: 
o Belimumab monotherapy. 
If clinically indicated and deemed in the best interest of the patient, the frequency or dose level 
of any of the above may be adjusted by the investigator in consultation with the study medical 
monitor. 
6.4.10.2 
Prohibited medications 
Other than pegcetacoplan, any therapy for CAD is prohibited during patient’s participation in the 
study, including: 
 Rituximab (alone or in combination). 
 Any other complement inhibitor (e.g., eculizumab, ravulizumab, or sutimlimab). 
 Any other investigational drug. 
 Plasma exchange. 
Phlebotomy/venesection for iron overload is also prohibited. 
6.4.11 
Treatment compliance 
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. Patients should not deviate from 
their dosing schedule. 
When patients are dosed at the site, they will receive pegcetacoplan directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in eCRF. The dose of pegcetacoplan and 
study patient identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention. 
When patients self-administer pegcetacoplan at home, compliance will be assessed at each visit. 
Patients must be instructed to bring their empty/partially used/unused IMP packaging to every 
visit following randomization. Compliance will be assessed during the site visits and 
documented in the source documents and eCRF.  
The pharmacist/designee will record details on the drug accountability form. Refer to the 
pharmacy manual for further details. 
6.4.12 
IMP accountability 
Accountability and maintenance of the IMP at the study center is the responsibility of the 
investigator. The investigator will ensure that the IMP is used only in accordance with this study 
protocol. Where allowed, the investigator may choose to delegate drug accountability 
responsibilities to a pharmacist or other appropriate individual. 

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Investigators will be provided with the IMP to carry out this protocol for the agreed number of 
patients. The investigator/designee will acknowledge receipt of the IMP, and documenting 
shipment content and condition. Accurate records of all IMP dispensed, used/unused, returned, 
and/or destroyed must be maintained. Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and patient numbers. The sponsor/designee 
will review IMP accountability at the study center on an ongoing basis during monitoring visits. 
The IMP must not be used for any purpose other than the present study. IMP that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
The investigator is responsible for ensuring the retrieval of all returnable study supplies from 
patients. 
6.4.13 
IMP disposal 
All unused and used IMP vials should be retained at the center until accountability and 
reconciliation has been performed by the study monitor. At the conclusion of the study, any 
unused IMP will either be destroyed at the investigator site or be returned to the 
sponsor/designee for destruction, and destruction will be documented appropriately. If no 
supplies remain, this fact will be documented appropriately. 
6.5 
Efficacy, safety, pharmacokinetic, pharmacodynamic and other 
assessments 
6.5.1 
Medical history 
Medical history will be recorded at screening. Investigators should document the occurrence, 
signs, and symptoms of the patient’s preexisting conditions, including all prior significant 
illnesses, up to and including 1 year before screening. Additional preexisting conditions, present 
at the time when informed consent is given, up to the time of first dosing, are to be regarded as 
concomitant. The number of transfusions received during the 12-month period prior to 
randomization in this study will be recorded. Medical history will also include alcohol 
consumption and smoking history, if applicable. 
Illnesses first occurring or detected during the study and worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 6.5.4.1.2. 
6.5.2 
Demography 
Demographic data, including age, sex, race and ethnicity, will be collected for all patients, as 
allowed, per applicable regulations and recorded in the eCRF.  

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6.5.3 
Efficacy assessments 
6.5.3.1 
Hb level and other laboratory efficacy assessments 
The primary and other secondary efficacy assessments (i.e., Hb and LDH, haptoglobin, indirect 
bilirubin, ARC and D-dimer) are based on laboratory parameters and are described in 
Section 6.5.4.2. 
For the primary efficacy assessment, response is defined as an increase in Hb level of ≥ 1.5 g/dL 
from Baseline or Hb normalization defined as change to within normal range (between the 
defined ULN and LLN) and maintenance of this effect from Week 16 to Week 24. 
6.5.3.2 
Transfusions 
All the RBC transfusions performed during the study period from screening until end of the 
study will be recorded. 
6.5.3.3 
Health-related quality of life 
The FACT-An is a useful measure of quality of life in cancer patients that adds focus to the 
widespread clinical problems of anemia [11]. It is a 5-point Likert-type scale and consists of 
47 items: 27 items related to general quality of life (including physical, social, emotional and 
functional wellbeing) and 20 items related to the impact of fatigue and other anemia-related 
symptoms (see Appendix 2 for informative purpose).  
The SF-12 is a self-reported outcome measure assessing the impact of health on an individual’s 
everyday life [12]. It is based on a subset of 12 items from the 36-Item Short Form Survey and 
assesses the same 8 health domains as its predecessor, with 1 or 2 questions per domain: physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional 
and mental health (see Appendix 3 for informative purpose).  
The EQ-5D-5L is a standardized instrument for measuring generic health status [13]. It consists 
of 2 pages: the descriptive system (comprising 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression, with 5 levels for each dimension) and a visual analog 
scale (to record the patient’s self-rated health) (see Appendix 4 for informative purpose). 
6.5.3.4 
Appropriateness of efficacy measurements 
The methods and measurements used for efficacy during the study (Hb and other laboratory 
parameters, number of transfusions and health-related quality of life tools) were used to 
determine responses to IMP and were appropriate measures to assess the efficacy objectives. 

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6.5.4 
Safety assessments 
6.5.4.1 
Adverse events 
 
Definitions 
Adverse event  
An AE is any untoward medical occurrence in a patient or study subject during the course of the 
study (after signing of the informed consent), whether or not considered by the investigator as 
related to study treatment. 
AEs include the following: 
 Abnormal test findings, as specified below. 
 Changes in physical examination findings. 
 Progression/worsening of underlying disease. 
 Signs and symptoms resulting from overdose, withdrawal of treatment, drug-drug 
interactions, abuse and misuse. 
 Increase in frequency or intensity of a preexisting episodic disease or medical condition. 
 Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
 Continuous persistent disease or symptoms present at study start that worsen following 
the start of the study. 
For pregnancies and breastfeeding, see Section 6.5.4.1.5. 
Abnormal test findings 
An abnormal test finding, e.g. abnormal laboratory analysis results, vital signs or ECG, should be 
recorded as an AE in any of the following situations: 
 The investigator considers the abnormal test finding to be clinically significant. 
 The abnormal test finding leads to a medical/surgical intervention including withdrawal 
of IMP(s) or discontinuation from the study. Repeat/confirmatory testing is not 
considered a medical intervention. 
Preexisting conditions  
A preexisting condition (i.e., a disorder present before the AE reporting period started and noted 
on the pretreatment medical history/physical examination form) should not be reported as an AE 
unless the condition worsens or episodes increase in frequency during the AE reporting period.  

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AEs diagnosis versus signs/symptoms 
For any AE, a diagnosis should be recorded rather than individual signs and symptoms or 
abnormal laboratory findings. However, if at the time of AE reporting a diagnosis is not 
available, each individual sign/symptom should be recorded. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be removed and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds to 
the start date of the first symptom of the eventual diagnosis. This approach also applies to signs 
and symptoms of CAD worsening, which should be reported as “CAD worsening/progression” 
or similar (e.g., relapse, flare progression or exacerbation), as appropriate. 
Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE and the resulting appendectomy 
entered in the comments section of the eCRF. 
Treatment-emergent adverse event 
A treatment-emergent AE is any AE temporally associated with the use of study treatment, i.e., 
from study treatment initiation until 6 weeks after study treatment discontinuation. 
Serious adverse event  
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
 Results in death. 
 Is life threatening (i.e., at immediate risk of death). 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect (i.e., in an offspring to the study patient). 
 Is a medically important AE. 
Medically important AEs are events that may not result in death, be life threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
may jeopardize the patient or subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
Serious also includes any other event that the investigator or company judges to be serious. Any 
suspected transmission of an infectious agent via IMP shall also be considered serious. 

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Hospitalization 
In general, hospitalization means that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
The following situations are not considered hospitalizations (although other SAE criteria may 
still apply): 
 Outpatient procedures/ambulatory care. 
 Emergency department visits. 
Hospitalization in the absence of an AE occurring during the study should not be considered an 
SAE. This includes: 
 Pre-planned hospitalization due to a preexisting condition not associated with a 
worsening of the preexisting condition. 
 Protocol specified admission. 
 Elective admission, e.g., due to cosmetic surgery. 
 Social admittance (e.g., stay overnight due to travel reasons). 
Complications that occur during hospitalization should not be considered SAEs unless the 
complication prolongs hospitalization. 
Suspected unexpected serious adverse reaction  
A SUSAR is an untoward and unintended response to a study drug that is not listed in the 
reference safety information of the IB, meets at least 1 of the seriousness criteria, and is assessed 
as causally related to the IMP. 
 
Adverse event reporting period 
The AE/SAE reporting period will be as follows:  
Screening period: Any SAEs occurring between signing of the ICF and the first IMP dose should 
be reported to Sobi. 
Treatment, maintenance and follow-up period: All AEs (including SAEs) occurring upon 
receiving the first IMP dose up to 6 weeks after last IMP administration must be recorded in the 
AE pages of the eCRF. In addition, SAEs should be reported to Sobi (see Section 6.5.4.1.4). 
After follow-up period: New SAEs occurring at any time after the 6-week AE follow-up period 
should be reported to Sobi only if considered causally related to previous exposure to the IMP by 
the investigator. These SAEs are only entered in the drug safety database and, hence, will not 
affect study closure. 

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Obtaining and recording adverse event information 
The investigator obtains AE information that is directly observed or solicited from the patient or 
patient relative during the course of the study. All AEs must be recorded in the eCRF using 
concise medical terminology.  
The investigator is responsible for obtaining sufficient information to determine seriousness, 
causality and outcome of each AE. 
Severity assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum severity of the AE. For the purpose of consistency, these severity grades are defined 
as follows:  
MILD 
Does not interfere with patient’s usual function 
MODERATE  
Interferes to some extent with patient’s usual function 
SEVERE 
 
Interferes significantly with patient’s usual function 
Note the distinction between the gravity (seriousness) and the severity of an AE. Severe is a 
measure of intensity; thus, a severe event is not necessarily a serious event. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed above. 
Causality assessment 
For each AE, the investigator must make a causality assessment to determine if there is a 
reasonable possibility that the IMP(s) caused the AE. The AE is assessed as related or 
not related to the IMP(s).  
6.5.4.1.3.1 
Reporting of adverse event to an auxiliary medicinal product 
All AEs occurring after initiation of AxMP should also be reported in line with the reporting 
requirements stated above. Relationship to AxMp should be stated. 
 
Serious adverse event reporting 
Both serious and nonserious AEs are to be reported on the AE page of the eCRF as specified in 
the eCRF instructions. 
In addition, all SAEs must be reported by the investigator to the Sobi Global Pharmacovigilance 
& Patient Safety within 24 hours of the investigator’s first knowledge of the event. 
If an SAE occurs, it is to be notified by e-mail (e-mail address is indicated on the SAE form) 
using the designated Serious Adverse Event form. 
The SAE collection form is not always the same as the AE eCRF form. The forms must be 
completed in a consistent manner. For example, the same AE term should be used on both forms. 

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All new information obtained, relevant to an SAE report, should be forwarded to Sobi Global 
Pharmacovigilance & Patient Safety within the same timeframe as the initial information. 
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and documentation. 
New SAEs occurring after the 6-week AE follow-up period must be reported to Sobi Global 
Pharmacovigilance & Patient Safety within 24 hours of the investigator’s knowledge of the 
event, only if considered causally related to previous exposure to the study treatment by the 
investigator. 
The investigator shall provide Sobi Global Pharmacovigilance & Patient Safety with sufficient 
information to enable a complete medical assessment of the reported event. Best efforts shall be 
made by the investigator to provide Sobi Global Pharmacovigilance & Patient Safety with 
additional information related to any SAE as requested. 
The reference safety document to assess expectedness of a suspect serious adverse reaction and 
reported by the sponsor to Health Authorities, IRBs/IECs, and investigators is the reference 
safety information section of the IB. 
6.5.4.1.4.1 
Reporting of serious adverse event to an auxiliary medicinal product 
All SAEs occurring after initiation of AxMP should also be reported in line with the reporting 
requirements stated above. Relationship to AxMp should be stated. 
 
Exposure during pregnancy and breastfeeding 
If a woman becomes pregnant while on study treatment, study treatment must be discontinued. 
The investigator must counsel the patient and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. 
Any pregnancy occurring after study initiation (i.e., signing of ICF) up to 6 weeks following 
study treatment discontinuation must be reported within 24 hours of the investigator’s 
knowledge of the event. This includes all situations where a woman is or has been found to be 
pregnant after being exposed to IMP ‒ directly, indirectly or via her partner (paternal exposure). 
All events of exposure to the IMP during pregnancy (female patient or male patient’s partner) or 
breastfeeding, whether the exposure is associated with an AE or not, shall be reported to Sobi 
Global Pharmacovigilance & Patient Safety by e-mail using pregnancy notification form by 
e-mail (e-mail address is indicated on the pregnancy notification form).  
In all reported situations of exposure during pregnancy, Sobi will provide the investigator with a 
Pregnancy report form that shall be completed and returned by the investigator. The investigator 
is responsible for monitoring the outcome of the pregnancy and to inform Sobi Global 
Pharmacovigilance & Patient Safety of relevant information and any information requested 
related to the outcome of the pregnancy.  
Any AEs and SAEs observed during and in relation to pregnancy, delivery or breastfeeding 
should be recorded in the eCRF and, as applicable, be reported to Sobi Global 
Pharmacovigilance & Patient Safety as described previously in this section. 

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Follow-up of unresolved adverse events 
All AEs should be followed until they are resolved or the investigator assesses them as chronic 
or stable, or the patient’s participation in the study ends, i.e., until the last scheduled visit. How 
to report changes in an ongoing AE during a patient's participation in the study is described in 
the eCRF instructions.  
In addition, all serious and nonserious AEs assessed by the investigator as related to the IMP 
should continue to be followed until they resolve or until the investigator assesses them as 
“chronic” or “stable,” even after the patient's participation in the study is over, but without 
further recordings into the eCRF.  
6.5.4.2 
Laboratory assessments 
Laboratory assessment samples (Table 4) are to be obtained at designated visits as detailed in the 
schedule of assessments (Table 1 and Table 2). 

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Table 4 
Laboratory assessments 
Hematology 
Hb 
ARC 
Haptoglobin 
 
Hematocrit 
Platelet count 
RBC count 
WBC count with differential 
Serum chemistry 
Albumin 
ALT 
ALP 
AST 
Bilirubin (total, direct, and indirect) 
BUN 
Calcium 
Chloride 
Creatinine 
Creatine kinase  
Estimated glomerular filtration rate 
(using CKD-EPI formula) 
GGT 
Glucose 
LDH 
Phosphorus 
Potassium 
Sodium 
Uric acid 
Urine studies 
Urinalysis 
Bile 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Pregnancy, when applicable 
Protein 
Specific gravity 
Urobilinogen 
Albumin-to-creatinine ratio 
Coagulation a 
aPTT 
D-dimer  
Fibrinogen 
INR 
Thrombin-antithrombin complex 
Additional 
Serum pregnancy test  
FSH (postmenopausal women) 
HBV-DNA 
HCV-RNA 
HIV 
Mycoplasma pneumoniae 
EBV DNA 
Folate 
Vitamin B12 
Ferritin  
Iron 
TNFα, IL-6, IL-10, IFNγ and IL-1β 
Complement activation tests: C3, 
functional assays for classical and 
alternative complement pathways 
Anti–pegcetacoplan peptide/anti-PEG 
Ab  
Immunoglobulins quantitative (IgG, 
IgM and IgA) 
DAT monospecific C3 and IgG 
Flow cytometry for C3 deposition on 
RBC 
Serum cold agglutinin titer (at 4 °C) 
Antinuclear antibodies for SLE and 
other autoimmune diseases 
Abbreviations: Ab, Antibody; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; aPTT, Activated partial 
thromboplastin time; ARC, Absolute reticulocyte counts; AST, Aspartate aminotransferase; BUN, Blood urea 
nitrogen; C3, Complement component 3; CKD-EPI, Chronic Kidney Disease – Epidemiology Collaboration; 
DAT, Direct antiglobulin test; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; FSH, Follicle-stimulating 
hormone; GGT, Gamma-glutamyltransferase; Hb, Hemoglobin; HBV, Hepatitis B virus; HCV, Hepatitis C virus; 
HIV, Human immunodeficiency virus; IFNγ, Interferon-gamma; Ig, Immunoglobulin; IL, Interleukin; 
INR, International normalized ratio; LDH, Lactate dehydrogenase; PEG, Polyethylene glycol; RBC, Red blood 
cells; RNA, ribonucleic acid; SLE, Systemic lupus erythematosus; TNFα, tumor necrosis factor-alpha; WBC, White 
blood cells. 

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a The use of silica reagents in coagulation panels should be avoided in all patients. 
Blood and urine samples will be analyzed at a central laboratory unless a local laboratory facility 
is necessary, as defined in the laboratory manual. Urine samples will be analyzed by dipstick and 
microscopic analysis. All laboratory reports must be reviewed, signed, and dated by the 
investigator. A legible copy of all reports must be filed with both the patient’s eCRF and medical 
record (source document) for that visit.  
Any laboratory test result considered by the investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention), see 
Section 6.5.4.1.1 for details. Clinically significant abnormal values occurring during the study 
will be followed up until repeat test results return to normal, stabilize, or are no longer clinically 
significant. 
The use of silica reagents in coagulation panels should be avoided. The sponsor previously 
conducted an investigation into prolonged 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. 
If a patient has been tested for COVID-19, the results, if available, will be documented in the 
eCRF. 
 
Pregnancy tests 
For WOCBP, a serum pregnancy test will be performed at screening. A urine pregnancy test will 
also be performed at all subsequent study visits through the end of the study, including the 
Follow-up visit. Patients with positive results will be excluded or discontinued from the study. 
Urine pregnancy test will be completed prior to dosing on days where dosing coincides with 
clinic visits.  
6.5.4.3 
Anti–pegcetacoplan peptide antibody and anti-PEG antibody assessments 
Patients will have anti–pegcetacoplan peptide Ab and anti-PEG Ab samples collected as outlined 
in the schedule of assessments (Table 1 and Table 2). The proposed ADA sampling schedule was 
established to capture the ADA signal at Baseline, any potential early onset and the dynamic 
profile (transient or persistent) of Ab formation while minimizing pegcetacoplan level in the 
sample.  
Patients who are confirmed as having positive results for anti–pegcetacoplan peptide or anti-PEG 
Ab in the last dosed sample will be followed up with ADA samples being collected every 
6 months until the Ab levels return to baseline. Specific Ab titers will be determined in all 
samples that are confirmed positive for anti–pegcetacoplan peptide or anti-PEG Ab. Any 
samples that are confirmed positive for anti–pegcetacoplan peptide Ab will be further 
characterized with a neutralizing Ab assay. 

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6.5.4.4 
Vital signs 
Vital signs (body temperature, respiration rate, heart rate and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the schedule of assessments 
(Table 1 and Table 2). All vital signs will be measured after the patient has been resting in a 
sitting position for at least 5 minutes, except when supine or semi-reclined because of study 
procedures and/or AEs or if deemed necessary by the investigator. Blood pressure measurements 
are to be taken in the same arm for the duration of the study.  
When the IMP is administered at the study site, vital signs will be measured within 2 hours 
before dosing and venipuncture (and ECG, if applicable) and at 30 minutes (± 5 minutes) 
post dose.  
Vital signs measurements will be repeated, if clinically significant or if machine/equipment 
errors occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be 
repeated at the investigator’s discretion. Any confirmed, clinically significant vital signs 
measurements must be reported as AEs (see Section 6.5.4.1.1 for details).   
6.5.4.5 
Weight and height 
Body weight and height (both assessed without shoes on) will be recorded at screening. Weight 
will also be recorded at each physical examination. 
6.5.4.6 
Physical examination 
Full physical examinations performed by the investigator/designee will include assessment of the 
following items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; 
chest; lungs; abdomen; skin; extremities; back/neck; musculoskeletal system and lymph nodes.  
Brief physical examinations will include general appearance, heart, lungs, abdomen and 
extremities, and are to be performed at all visits where a full physical examination does not 
occur.  
See the schedule of assessments (Table 1 and Table 2) for the details regarding which type of 
physical examination should be performed at each visit. 
If any abnormalities are reported at screening, they should be recorded as medical history. New 
or worsening of abnormalities after first IMP dosing should be reported as AEs (see 
Section 6.5.4.1.1 for details). 
6.5.4.7 
Electrocardiograms 
Single 12-lead ECGs will be measured prior to dosing at the time points outlined in the schedule 
of assessments (Table 1 and Table 2). The ECG will be taken after the patient has been resting in 
the supine position for 5 minutes in a quiet environment and prior to any blood sampling 
procedures, unless specified at time points after timed blood sampling procedures. 
The ECGs will be classified as normal, having a not clinically significant abnormality or having 
a clinically significant abnormality.  

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Any significant ECG finding present prior to the start of study drug is to be documented in the 
medical history section of the eCRF. Any significant ECG finding with an onset time after study 
drug initiation and that were not present at screening, or worsened during the study, is to be 
reported as AEs (see Section 6.5.4.1.1 for details). 
6.5.4.8 
Infusion-site reactions/pump-safety assessments 
If the scheduled dosing day coincides with a clinical visit, the patient or their caregiver should 
perform their injection/infusion at the clinic in presence of the investigator or other trained and 
qualified site staff. Patients or their caregivers will be trained to administer at home. 
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. 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 patient 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 
eCRFs. 
Patients will be instructed to notify the investigator 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 (see Section 6.5.4.1.1 for details). 
6.5.4.9 
Appropriateness of safety measurements 
The methods and measurements used for safety during the study are standard and were 
appropriate for the clinical evaluation of the patients with CAD treated with pegcetacoplan. 
6.5.5 
Pharmacokinetic assessments 
Blood sampling and processing blood samples for the PK assessment of pegcetacoplan will be 
collected via direct venipuncture at the time points outlined in the schedule of assessments 
(Table 1 and Table 2). PK samples will be taken 15 minutes predose at each visit.  
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation. 
Serum sample analysis will be performed using validated LC-MS/MS methods. The methods 
used and the results obtained will be included in the CSR as an appendix. 
Population PK and exposure-response modeling of the safety and efficacy data will be described 
in a pegcetacoplan Population PK/PD Analysis Plan and reported in a separate population PK 
report.  

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6.5.6 
Pharmacodynamic assessments 
Blood samples for PD assessment of hemolytic complement activation through functional assays 
for classical and alternative complement pathways will be collected on study days designated in 
the schedule of assessments (Table 1 and Table 2). Blood samples to measure C3 levels will also 
be collected. Instructions for collection, handling, processing, storage, and shipping of samples 
will be provided in a separate laboratory sample handling manual prior to study initiation. 
The PD measurements in this study are widely used, generally recognized and accepted as 
reliable, accurate, relevant and consistent with those used in several other studies of 
pegcetacoplan. 
6.5.7 
Other study assessments 
6.5.7.1 
MYD88 mutation testing 
Bone marrow biopsy will be performed at screening only if a biopsy was not previously 
undertaken within 1 year prior to ICF signature. 
In those patients requiring a bone marrow biopsy for study purposes, genetic mutation testing of 
the MYD88 gene will be performed on aspirate during screening. If the MYD88 genetic 
mutation testing has been already performed according to the local institutional standard of care, 
the result will be collected at screening. 
6.5.7.2 
Actigraph 
The following will be collected via the Actigraph:  
 Total activity/movement volume. 
 Time spent in physical activity intensity categories (sedentary, light and 
moderate -to -vigorous physical activity). 
 Step accumulation. 
 Best 6-minute effort (defined as the peak 6-minute stepping effort within each day). 
 Prolonged stepping bouts. 
 Preference cadence. 
The patients will wear the device for data collection for approximately 1 week at Baseline and 
again for approximately 1 week at Week 24 and at Week 48. 
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, Sobi 
SOPs, CRO SOPs, the ICH Guideline for GCP [1], and applicable regulatory requirements. 
The sponsor will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data that would affect patient safety and reliability of 
study data. 

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The sponsor will establish a systematic, prioritized, risk-based approach to monitoring and has 
chosen a combination of on-site and centralized monitoring. 
Monitoring visits to the study site will be performed periodically during the study, to help ensure 
compliance with the protocol, study specific procedures and applicable regulatory requirements.  
In case of new waves of restricted access to study sites due to the unforeseeable evolution of the 
COVID-19 pandemic, to ensure ongoing patients’ rights, safety and wellbeing, and control risks 
to study critical processes, the sponsor might decide to apply alternative mechanisms of 
oversight and monitoring. Among these mechanisms, remote source data verification would be 
implemented only if allowed by country regulations and within the limits established. 
Source documents will be reviewed for verification of agreement with data in eCRFs. All patient 
ICFs will be reviewed. The investigator or institution guarantees access to source documents by 
Sobi, its representatives, and appropriate regulatory agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as well 
as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits/inspections, and that sufficient time is devoted to the 
process. 
8 
Statistical plan 
A formal SAP will be developed and finalized prior to locking the database and unblinding of 
the study data. 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 CSR. 
8.1 
Determination of sample size 
The primary endpoint is response at Week 24. Under the assumption that the response rate is 
55 % for pegcetacoplan and 10 % in placebo, 54 patients (36 treated with pegcetacoplan and 
18 with placebo) are required to reject the null hypothesis of no difference between the treatment 
groups at a significance level of 5 % and a power of 90 % using a 2-sided Fisher’s exact test with 
a 2:1 allocation to treatment groups. To account for potential drop out prior to first dose of IMP, 
57 patients will be enrolled in the study.  

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8.2 
Definition of study populations 
8.2.1 
Screened set 
The screened set will include all patients who provide written informed consent. This set will be 
used only for the purpose of describing patient disposition. 
8.2.2 
Safety set 
The safety set will include all patients who receive at least 1 dose of IMP. Patients will be 
analyzed according to the treatment they received. 
8.2.3 
Intent-to-treat set 
The ITT set will include all randomized patients. Patients will be analyzed according to their 
assigned treatment, regardless of the treatment actually received.  
8.2.4 
Modified intent-to-treat set 
The mITT set will include all patients in the ITT set who continue IMP beyond Week 4. 
8.2.5 
 Per-protocol set 
The PP set will include all patients 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 patients from the PP analysis set will be made 
and documented prior to database lock. 
8.2.6 
Pharmacokinetic set 
The PK set will include all patients in the ITT set who receive IMP and have at least 1 evaluable 
post dose PK measurement.  
8.2.7 
Pharmacodynamic set 
The PD set will include all patients in the ITT set who receive IMP and have at least 1 evaluable 
post dose PD measurement.  

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8.3 
Overall statistical and analytical plan 
All details of the statistical analyses for primary and secondary endpoints will be described in the 
SAP, which will be finalized and signed off prior to breaking the blind after Part A.  
8.3.1 
General statistical issues 
All statistical tests will be 2-sided and performed at a significance level of 5 % unless otherwise 
stated. 
8.3.2 
Demographics and baseline characteristics 
Demographics, baseline characteristics, concomitant medications/treatments, medical history, 
and IMP exposure will be summarized by treatment group. 
The WHO and MedDRA coding dictionaries will be used for the concomitant 
medications/treatments and medical histories, respectively. 
8.3.3 
Analysis related to primary objective 
The primary efficacy endpoint is a responder analysis, where response is defined as an increase 
in Hb level of ≥ 1.5 g/dL from Baseline or Hb normalization and maintenance of this effect from 
Week 16 to Week 24, in the absence of PRBC transfusions (between Week 5 and Week 24). Hb 
normalization is defined as within normal range (between the defined ULN and LLN), as set by 
the testing laboratory. The primary efficacy analysis will be conducted on the ITT set.  
The estimand will be a composite where patients having an intercurrent event will be considered 
as nonresponders. The intercurrent events of interest are: 
 Withdrawal from treatment or lost to follow-up before end of the double-blind period. 
 Use of prohibited medications (rituximab alone or in combination, any other complement 
inhibitor, any other investigational drug and plasma exchange). 
The number and percentage of patients who respond will be tabulated by treatment group and 
compared between treatment groups using a Fisher’s exact test. The odds ratio of being a 
responder for the pegcetacoplan treatment group versus the placebo group and associated 
95 % CI will be provided. 
The following will be included as a sensitivity analysis: 
 Analyses will be repeated using the PP set and mITT set. 
 Other sensitivity analyses will be explored, and details will be provided in the SAP.  
Subgroup analyses on the primary endpoint will be conducted for: 
 The strata with ≥ 1 / 0 transfusions during the 6 months prior to randomization.   
 The subgroups of patients previously treated with rituximab / rituximab-naïve patients. 

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Other potential subgroups of interest will be described in the SAP. 
Baseline will be taken at Day 1 prior to the start of IMP treatment. 
8.3.4 
Analysis related to secondary objectives  
8.3.4.1 
Analysis of key secondary efficacy endpoints 
The key secondary efficacy endpoints are described in Section 5.2.1.1. 
Transfusion avoidance (Yes/No) from Week 5 to Week 24 (total population) will be tabulated by 
treatment group and compared between treatment groups using Fisher’s exact test. The odds 
ratio of showing transfusion avoidance from Week 5 to Week 24 for the pegcetacoplan treatment 
group versus the placebo group and associated 95 % CI will be provided. The composite strategy 
is used as estimand where patients meeting any of the intercurrent events defined for primary 
endpoint will be considered as failures. 
The change from Baseline to Week 24 in Hb will be analyzed using MMRM with the fixed 
effects of treatment, strata, visit, visit-by-treatment interaction and Hb level at Baseline as 
covariate using an unstructured covariance matrix and the Kenward-Roger method for 
calculating the degrees of freedom. Should the model fail to converge with an unstructured 
covariance matrix other covariance structures will be explored. Details will be described in the 
SAP. The difference between treatment groups will be estimated, along with its 95 % CI and 
p-value. 
The change from Baseline at Week 24 in the FACT-An score will be analyzed using MMRM 
with the fixed effects of treatment, strata, visit, visit-by-treatment interaction and the FACT-An 
score at Baseline as covariate using an unstructured covariance matrix and the Kenward rogers 
method for calculating the degrees of freedom. Should the model fail to converge with an 
unstructured covariance matrix other covariance structures will be explored. Details will be 
described in the SAP. The difference between treatment groups will be estimated, along with its 
95 % CI and p-value. 
To preserve the Type 1 error, a fixed-sequence testing strategy will be used; hence, statistical 
significance with the first key secondary endpoint will only be concluded if statistical 
significance is achieved with the primary analysis of the primary endpoint. The ordering of the 
key secondary endpoints in this testing strategy will match the order in which they are presented 
in Section 5.2.1.1, i.e., transfusion avoidance (Yes/No) from Week 5 to Week 24, change from 
Baseline to Week 24 in Hb level and change from Baseline to Week 24 in the FACT-An score.  
For both key secondary endpoints, subgroup analyses will be conducted for the strata 
(≥ 1 / 0 transfusions during the 6 months prior to randomization) and for the subgroups of 
patients previously treated with rituximab / rituximab-naïve patients.. Other potential subgroups 
of interest will be described in the SAP. 
8.3.4.2 
Analysis of secondary efficacy endpoints: Part A 
Baseline measurements will be taken at Day 1, prior to the start of IMP treatment.  

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All secondary efficacy analyses will be analyzed with the ITT set.  
The number of PRBC transfusions from Week 5 to Week 24 in each treatment group will be 
compared using a negative binomial regression model. The model-based estimate and 
corresponding 95 % CI will be calculated.  
Transfusion avoidance (Yes/No) from Week 5 to Week 24 for those patients with at least 
3 transfusions in the last year prior to screening will be tabulated by treatment group and 
compared between treatment groups using Fisher’s exact test.  
The change from Baseline at Week 24 in LDH, haptoglobin, indirect bilirubin, ARC and 
D-dimer will be analyzed using MMRM analysis with the fixed effects of treatment, strata, visit, 
visit-by-treatment interaction, and the respective Baseline level as covariate, using an 
unstructured covariance matrix and the Kenward-Roger method for calculating the degrees of 
freedom. Should the model fail to converge with an unstructured covariance matrix, other 
covariance structures will be explored. Details will be described in the SAP. The difference 
between treatment groups will be estimated, along with its 95 % CI and p-value.  
For the endpoint regarding the normalization of markers of hemolysis (LDH, indirect bilirubin 
and ARC), at Week 24, the number and percentage of patients who respond will be tabulated by 
treatment group and compared between treatment groups using a Fisher’s exact test.  
Kaplan-Meier plots will be presented for the time-to-event endpoints of time to normalization 
from Baseline to Week 24 for LDH, Hb, indirect bilirubin and ARC for each treatment group at 
Week 24, and survival estimates will be provided. 
The number of units of PRBCs transfused from Week 5 to Week 24 in each treatment group will 
be compared using a Wilcoxon rank-sum test. The difference between the medians will be 
estimated along with its 95 % CI. Patients who withdraw before Week 24 will have the number 
of units estimated from the duration that they were in the study.  
The change from Baseline at Week 24 in SF-12 and EQ-5D-5L will be analyzed using MMRM 
with the fixed effects of treatment, strata, visit, visit-by-treatment interaction and the respective 
Baseline level as covariate, using an unstructured covariance matrix and the Kenward-Roger 
method for calculating the degrees of freedom. Should the model fail to converge with an 
unstructured covariance matrix other covariance structures will be explored. Details will be 
described in the SAP. The difference between treatment groups will be estimated, along with its 
95 % CI and p-value.  
Summary statistics by treatment groups will be presented at each assessment visit during the 
24-week double-blind treatment period. 
8.3.4.3 
Analysis of secondary efficacy endpoints: Part B 
Baseline measurements will be taken at Day 1, prior to the start of IMP treatment. 
All Part B secondary efficacy analyses will be analyzed with the ITT set, and data presentations 
will be by randomized treatment group in Part A as well as combined.  

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The change from Baseline at Week 48 in Hb, LDH, indirect bilirubin, ARC and D-dimer will be 
analyzed using descriptive statistics. 
Durability of response will be analyzed with descriptive statistics. 
For the endpoint regarding the normalization of markers of hemolysis (LDH, indirect bilirubin 
and ARC), at Week 48, the number and percentage of patients who respond will be tabulated in 
frequency tables by randomized treatment group in Part A as well as combined.  
The change from Baseline at Week 48 in FACT-An, SF-12 and EQ-5D-5L will be analyzed 
using descriptive statistics. 
8.3.4.4 
Analysis of tertiary efficacy endpoints: Part C 
Baseline measurements will be taken at Day 1, prior to the start of IMP treatment. 
All tertiary efficacy analyses will be analyzed with the ITT set and data presentations will be by 
randomized treatment group in Part A as well as combined.  
The change from Baseline at Week 96 in Hb, LDH, haptoglobin, indirect bilirubin, ARC and 
D-dimer will be analyzed using descriptive statistics.  
For the endpoint regarding the normalization of markers of hemolysis (LDH, indirect bilirubin 
and ARC), at Week 96, the number and percentage of patients who respond will be tabulated in 
frequency tables by randomized treatment group in Part A as well as combined.  
The change from Baseline at Week 96 in FACT-An, SF-12 and EQ-5D-5L will be analyzed 
using descriptive statistics. 
8.3.4.5 
Analysis of exploratory endpoints. 
All exploratory endpoints will be summarized descriptively. Further details will be described in 
the SAP. 
8.3.5 
Analysis of safety and tolerability data 
8.3.5.1 
Adverse events 
All safety analyses will be carried out descriptively on the safety set, consisting of all patients 
who received at least 1 dose of IMP. 
In general, the evaluation of safety and tolerability is carried out separately for the double-blind 
placebo-controlled period and the open-label period. Other analyses are detailed in the SAP.  
Pretreatment AEs are those occurring between ICF signature and the first IMP administration. 
TEAEs are defined as those AEs that develop or worsen after the first dose of IMP and up to 
6 weeks after the last dose of study medication.  
All AEs will be coded using the MedDRA. Pretreatment AEs will be summarized by SOC and 
PT. TEAEs will be summarized by SOC, PT, treatment group for number of patients and 
proportion reporting the event. A similar summary will be produced for SAEs, AEs leading to 

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premature discontinuation of IMP and AEs related to the IMP. The intensity of AEs and the 
relationship to the IMP will be summarized for each SOC and PT by treatment group.  
Reasons for premature discontinuation of IMP will be summarized by frequency tables. 
The results of laboratory assessments, anti–pegcetacoplan peptide/anti-PEG Ab assessments and 
ECGs will be summarized by treatment group using appropriate descriptive statistics. 
The AE summaries will be presented across all patients. All AEs will be listed by patient, along 
with information regarding onset, duration, relationship to IMP, severity, action taken with IMP, 
treatment of event and outcome.  
Changes from Baseline in clinical laboratory test results will be summarized, using descriptive 
statistics, by visit and nominal time post dose. Baseline will be taken as the measurement closest, 
but prior, to randomization. Out-of-range values will be flagged in data listings.  
Changes in physical examinations will be described in a data listing. 
Safety data will include all data up to Week 24 for reporting Part A, all data up to Week 48 for 
reporting Part B, and all data for reporting Part C. 
8.3.6 
Analysis of pharmacokinetic and pharmacodynamic 
8.3.6.1 
Pharmacokinetic analysis 
The PK concentrations will be evaluated using the PK set. 
Concentrations will be summarized, using descriptive statistics, over time, in the randomized 
treatment groups. 
Individual patient 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.  
8.3.6.2 
Pharmacodynamic analysis 
The PD endpoints will be evaluated using the PD set. 
Absolute values, changes from Baseline and percentage changes from Baseline will be 
summarized using descriptive statistics, over time by treatment group. 
Individual patient time profiles will be plotted against actual sampling time. Median profiles, 
over time, using nominal sampling time, will also be presented. 
The PD endpoints in each treatment group will be compared using mixed effect repeated 
measures analyses. 

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8.3.7 
Interim analysis  
No formal interim analyses are planned for the primary endpoint. Data will be reported for 
Part A (double-blind treatment period) once all patients have completed their Week 24 visits (or 
have early discontinued) and the database has been cleaned and verified for all visits up to and 
including Week 24. Similarly, data will be reported after Part B. 
8.3.8 
Multiple comparison/multiplicity 
Adjustments for multiple testing will be done among key secondary endpoints as described in 
Section 8.3.4.1. 
8.3.9 
Handling of missing data 
Imputation of missing data (e.g., partial or missing dates) will be described in the SAP. 
9 
Data collection, handling and record keeping 
9.1 
Data standards 
Collection of data should be performed in the CDASH format, according to the CDISC. The 
standards should be used to the extent possible and/or required for the specific study/project. The 
minimum requirement of the CDISC standard is to collect all core variables specified as 
‘Required’ in the Study Data Tabulation Model format.  
9.2 
Case report form 
An eCRF is required and should be completed for each included patient. In this study, a web 
based, password protected, EDC software tool will be used to collect, clean and process the 
study data. The EDC system will be provided and managed by the independent CRO. The 
designated investigator site staff will only be given access to the EDC system upon completion 
of the user training.  
The data should be entered by site users into the EDC system on an ongoing basis. In principle, it 
is recommended to perform data entry within 5 working days from the visit date. To ensure data 
quality within EDC, an automated edit check will be triggered to verify the completeness and 
accuracy of input data. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these eCRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the 
eCRFs.  

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The completed original eCRFs are the sole property of Sobi and should not be made available in 
any form to third parties, except for authorized representatives of appropriate regulatory 
authorities, without written permission from Sobi. 
9.3 
Source data 
Patient source documents are the patient’s medical records maintained at the study site. In most 
cases, the source documents will be the hospital’s or the physician’s chart. In those cases, the 
information collected on the eCRFs must match those charts. In some cases, a portion of the 
source documents for a given patient may be the eCRF.  
A separate source document location agreement will be completed and signed by the principal 
investigator and the site monitor before study start. 
Source data should be attributable, legible, contemporaneous, original, accurate, complete, 
consistent, enduring and available (ALCOA+). Changes to source data should be traceable, 
should not obscure the original entry, and should be explained if necessary (e.g. via an audit 
trail). 
9.4 
Protocol deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of patients. The investigator should not 
implement any deviation from, or changes to, the protocol, unless it is necessary to eliminate an 
immediate hazard to study patients. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
When a deviation from the protocol is identified, the investigator or designee must ensure that 
the study medical monitor is notified. The study medical monitor will follow up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the patient to determine patient continuation in the study. 
The investigator and CRO must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human subject protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IEC/IRB and applicable regulatory requirements.  

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9.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before breaking of the blind and 
before generation of any results. The database lock will be approved by relevant study personnel, 
and all edit accesses will be removed. The study database can only be unlocked in cases where 
critical errors, affecting the main conclusions of the study, are discovered.   
9.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential documents 
as defined in the ICH GCP Guideline [1] including source documents and should have control of 
and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study.  
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search and retrieval. The data will be available for evaluation and/or audits from Health 
Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g. source documents, eCRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline [1].  
The records should be retained by the investigator as specified in the Clinical Trial Agreement 
and in accordance with local regulations.  
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. Archiving on behalf of the investigator can also be delegated to Sobi.   
10 
End of study 
The end of study is when all randomized patients have terminated the 6-week safety follow-up 
period and performed the EOS visit or the Early termination visit in case of discontinuation for 
any reason from the study before completion. 
11 
Sponsor’s discontinuation criteria 
Specific study stopping criteria are described in Section 6.3.6. Sobi reserves the right to 
discontinue the study prior to inclusion of the intended number of patients, but intends only to 
exercise this right for valid scientific or administrative reasons. After such a decision, the 
investigator must contact all participating patients within 30 days. All study materials must be 
collected, and all the eCRFs must be completed to the greatest extent possible. 

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12 
Dissemination and publication of results 
A CSR will be prepared for the primary analysis once all patients have completed their Week 24 
visits and the database has been cleaned for all visits up to and including Week 24 (Part A). CSR 
addenda will be prepared to include open-label (Part B), maintenance (Part C) and follow-up 
data. 
Sobi will register the study by posting study information and post study results regardless of 
outcome on a publicly accessible website in accordance with applicable laws and regulations, 
e.g., on www.clinicaltrials.gov and EudraCT. The results of this study will be published within 
12 months of the EOS. 
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent and 
timely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors (ICMJE) recommendations for the conduct, reporting, editing and publication of 
scholarly work in medical journals including criteria for authorship [14]. 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The sponsor will be responsible for these activities and will 
work with the investigators to determine how the publication is written, the number and order of 
authors, the journal or scientific meeting to which it will be submitted and other related issues. 
The results of the study, or any part thereof, shall not be published without the prior written 
consent and approval of Sobi; such consent and approval shall not to be unreasonably withheld. 
13 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from the sponsor. However, authorized regulatory officials, IRB/IEC personnel, the 
sponsor and its authorized representatives are allowed full access to the records. 
All study patients must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient, who will be required to give consent for their data to be used as 
described in the ICF. The patients must be informed that their medical records may be examined 
by auditors or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
Identification of patients and eCRFs shall be by unique subject identification numbers only. All 
personal identifiers according to applicable regulations (eg, name, phone number) must be 
redacted permanently by the site personnel and replaced with the subject’s unique identification 
number in all records and data before transfer to the sponsor (or designee). 
All personal details will be treated as confidential by the investigator and sponsor’s or designated 
staff. 

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14 
Reference list 
1  
ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1), Guideline for Good 
Clinical Practice E6(R2) Current Step 4 version dated 9 November 2016. Available from: 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html   
2 
World Medical Association Declaration of Helsinki; Ethical Principles for Medical 
Research Involving Human Subjects. Available from:  
https://www.wma.net/publications/wma-doh-1964-2014/  
3 
Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. 
Transfus Med Hemother. 2015;42(5):287-293.  
4  
Go R, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 
2017;129(22):2971-2979.  
5  
Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 
2013;122(7):1114-1121.  
6  
Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ Program. 
2016;(1):226-231.  
7  
Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, et al. 
Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic 
prospective multicenter trial. Blood. 2017;130(4):537-541.  
8  
APL2-CP-AIHA-208 CLINICAL STUDY REPORT (PART A DATA ONLY). An open 
label, prospective, study to assess the safety, tolerability, efficacy and pharmacokinetics 
of pegcetacoplan in patients with warm antibody autoimmune hemolytic anemia 
(wAIHA) or cold agglutinin disease (CAD). Apellis Pharmaceuticals, Inc. 
16 November 2020. 
9  
Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol. 
2008;4(9):491-498.  
10  
Lyubchenko T, Dal Porto JM, Holers VM, Cambier JC. Cutting edge: Complement 
(C3d)-linked antigens break B cell anergy. J Immunol. 2007;179(5):2695-2699.  
11  
Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale: a 
new tool for the assessment of outcomes in cancer anemia and fatigue. Seminars in 
Hematology. 1997, 34(3, Suppl 2):13-19. 
12  
Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care. 
1996 Mar;34(3):220-233. 
13  
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L) Qual Life Res. 2011 Dec;20(10):1727-1736. 
14  
International Committee of Medical Journal Editors. Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals: updated 
December 2016 [Internet]. ICMJE; 2016. [cited 2017 Jan 12]. Available from: 
http://www.icmje.org/recommendations/   
 

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Appendix 1 
Additional protocol signatures 
 
 
Sponsor’s Clinical Program Leader  
 
Clinical Program Leader 
E-mail
  
Signature 
 
Date
 
 
Sponsor’s Statistician 
 
Statistical Science Director 
E-mail
 
Signature
Date
 

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Appendix 2 
Functional Assessment of Cancer Therapy–
Anemia/Fatigue 
 

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Appendix 3 
12-Item Short Form Survey  
 

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Appendix 4 
EuroQol-5 Dimension-5 Level  
 

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Appendix 5 
Protocol changes to be followed during 
COVID-19 restrictions 
OVERVIEW 
In response to the COVID-19 crisis, to ensure the safety of study patients and investigative sites 
as well as proper conduct of the study, TEMPORARY changes to the protocol have been 
implemented. These changes should be followed only during COVID-19 restrictions and include 
extended IMP administration windows, rescreening instructions, and a revised schedule of 
assessments. These changes will be reported as COVID-19-related protocol deviations. 
Where feasible, sites could continue to follow the full schedule of assessments. 
In case of new waves of restricted access to study sites due to the unforeseeable evolution of the 
COVID-19 pandemic, to ensure ongoing patients’ rights, safety and wellbeing, and control risks 
to study critical processes, the sponsor might decide to apply alternative mechanisms of 
oversight and monitoring. Among these mechanisms, remote source data verification would be 
implemented only if allowed by country regulations and within the limits established. 
MINIMUM SCHEDULE OF ACTIVITIES 
Where feasible, sites could continue to follow the full schedule of activities (based on their 
treatment group assignment). The minimum assessment tables, only to be followed during this 
COVID-19 effort and if determined necessary to use on the basis of the investigator’s clinical 
judgment, are provided below to reduce the time required for each study visit. Assessments not 
performed (even those that have been removed in the minimum assessment table) should be 
documented.  
Patients who are not able to come into the clinic for a study visit because of COVID-19-related 
restrictions, should be contacted via the phone for the collection of AEs (including SAEs) and 
concomitant medications. All SAEs are still required to be reported within 24 hours of site 
awareness, even if reported via phone call. All communications via phone call should also be 
documented in the source documentation and in the respective eCRF page. In addition, these 
patients should be instructed to self-monitor their symptoms at home and report any changes in 
symptoms or their overall health via phone call. The site must inform the sponsor of any patients 
lost to follow-up.  
It is critical that local, country, and regional governance regarding COVID-19 is followed along 
with your best clinical judgment when managing this situation. All visits or assessments missed 
as a result of COVID-19 will be captured in the case report forms.  
MINIMUM STUDY REQUIREMENTS 
The following are the minimum study requirements for Study Sobi.PEGCET-101 during the 
COVID-19 pandemic and should be used as guidance when the full protocol requirements cannot 
be conducted.  
1. Obtain key safety laboratory assessments. 

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a. All laboratory assessments should be drawn at the frequency required by 
the minimized schedule of events (Table 5 and Table 6). 
i. Includes (at minimum): hematology with differential, reticulocyte count, 
chemistry including LDH, haptoglobin and bilirubin total, coagulation 
profile, and urine pregnancy test (only for women 
of childbearing potential). 
b. In the event that the clinical investigative site is closed or patients are 
unable/unwilling to travel, patients 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 (e.g., name and other local requirements) and added to the study 
records.  
2. Perform minimal medical safety assessments.  
a. If the patient is unable to have an in-person assessment, the investigator (or 
delegated site staff) should have a telephone contact at a frequency noted in the 
protocol (at minimum) to solicit AEs (including SAEs), concomitant medications 
and transfusions. The appropriate forms in the eCRF should be completed.  
3. Document appropriate contact with the patient. 
a. Earnest and reasonable attempts must be made to solicit AEs and concomitant 
medications. The CRA/medical monitor must be notified of any patients lost to 
follow-up.  
b. All communication with the patient (including failed attempts at contact) must be 
documented in the study records.  
 
The modified schedule of activities is shown in Table 5 and Table 6. 
 

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Table 5 
Revised COVID-19 minimum schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
–4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24o 
Study Day 
–28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
RBC transfusions collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Actigraph 
 
X 
 
 
 
 
 
 
 
 
 
Vaccination b 
X 
 
 
 
X 
 
 
X 
 
 
 
Preventive antibiotic administration c  
At the discretion of the investigator 
Full physical examination d 
X 
 
X 
 
 
 
 
 
 
 
X 
Brief physical examination e 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Weight and height f 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (prior to venipuncture) 
X 
 
X 
 
 
 
 
 
 
 
X 
IMP administration g 
 
Twice weekly----------------------------------------------------------------------------- 
Infusion-site assessment h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine studies 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood k  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics m 
X 
 
X 
X 
X 
X 
X 

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Table 5 
Revised COVID-19 minimum schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
–4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24o 
Study Day 
–28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
Anti–pegcetacoplan peptide and 
anti-PEG Ab assay n 
 
X 
 
X 
X 
X 
 
X 
 
 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile o 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
TNFα, IL-6, IL-10, IFNγ and IL-1β 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, functional 
assays for classical and alternative 
complement pathways) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry for C3 deposition 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin, vitamin B12/folate 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Iron 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
DAT monospecific C3 and IgG 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins quantitative (IgG, IgM, 
and IgA) p 
X 
 
 
 
 
X 
 
 
X 
 
X 
Serum cold agglutinin titer (at 4 °C) p 
X 
 
 
 
X 
X 
X 
HIV, HCV-RNA, HBV-DNA 
X 
 
 
EBV, Mycoplasma pneumoniae 
X 
 
 
 
 
 
 
 
 
 
 

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Table 5 
Revised COVID-19 minimum schedule of assessments: Screening to Week 24 ‒ Part A 
Study Period 
Screening a 
Part A: Double-blind treatment period 
Study Week 
–4 to -1 
-1 
0 
1 
2 
4 
8 
12 
16 
20 
24o 
Study Day 
–28 to -1 
-7 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit window (± days) 
0 
0 
1 
2 
7 
7 
7 
7 
7 
7 
MYD88 Mutation Testing (only in 
patients requiring a bone marrow biopsy 
or if already done per local institution 
practice) 
X 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies for SLE and other 
autoimmune diseases 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy (B-HCG and FSH) 
X 
 
 
Urine pregnancy test q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACT-An  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy for eligibility (as 
needed) r 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation for home administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: Ab, Antibody(ies); AE, Adverse event; B-HCG, Beta human chorionic gonadotropin; C3, Complement component 3; CAD, Cold agglutinin disease; 
DAT, Direct antiglobulin test; DNA, Deoxyribonucleic acid; EBV, Epstein-Barr virus; ECG, Electrocardiogram; EQ-5D-5L, EuroQol 5-dimension 5-level questionnaire; 
FACT-An, Functional Assessment of Cancer Therapy-Anemia/Fatigue; FSH, Follicle-stimulating hormone; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human 
immunodeficiency virus; ICF, Informed consent form; IFNγ, Interferon-gamma; Ig, Immunoglobulin; ; IL, Interleukin; IMP, Investigational medicinal product; 
PEG, Polyethylene glycol; PK, Pharmacokinetic; RBC, Red blood cell; RNA, Ribonucleic acid; s.c., Subcutaneous; SF-12, 12-Item Short Form Survey; SLE, Systemic lupus 
erythematosus; TNFα, tumor necrosis factor-alpha; WOCBP, Women of childbearing potential. 

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a Screening period is up to 4 weeks before randomization, but certain assessments, including some laboratory assessments and quality of life questionnaires, are to be performed 
within 7 days before randomization. 
b The status of vaccination against Neisseria meningitidis Types A, C, W, Y, and B, Streptococcus pneumoniae, and Haemophilus influenzae Type B should be 
confirmed and any required vaccinations or boosters are to be administered as described in Section 6.4.1.2.  
c To receive treatment with IMP, patients who are documented nonresponders to vaccination or cannot be vaccinated prior to IMP initiation will require preventive antibiotics at 
the discretion of the investigator, and should take into consideration the level of immunosuppression, complement levels, and timing of vaccination relative to IMP start, as well 
as local practices.  
d Full physical examination will include assessment of the following items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; chest; lungs; 
abdomen; skin; extremities; back/neck; musculoskeletal system and lymph nodes. 
e Brief physical examination will include general appearance, heart, lungs, abdomen and extremities. 
f Both height and weight measurements should be done without shoes on. Height will be recorded at screening only. 
g Patients will self-administer s.c. IMP, after receiving appropriate training by research personnel. Dosing diaries will be used for study treatment and are to be completed for each 
dose administered at the clinic or at home. IMP will be dosed at the clinical site on Day 1. On dosing days that coincide with clinic visits, doses will be administered at the clinic visit.  
h Between site visits, patients will be instructed to report any infusion-site reaction to the investigator or other study personnel. 
i On clinic dosing days, vital signs will be measured within 2 hours before dosing and venipuncture (and ECG, if applicable), and at 30 minutes (± 5 minutes) post dose. (see 
Section 6.5.4.4). All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes, except when supine or semi-reclined because of 
study procedures and/or AEs or if deemed necessary by the investigator.   
k Baseline laboratory assessments within 7 days before Day 1. If IMP is administered at study visit, blood samples will be taken before dosing. 
m PK samples will be taken 15 minutes predose at each visit. 
n For patients with positive anti–pegcetacoplan peptide or anti-PEG Ab in last dose sample, additional samples will be collected every 6 months from last dose until Ab levels 
returns to baseline. 
o The use of silica reagents in coagulation panels should be avoided in all patients. 
p Serum samples for immunoglobulins quantitative and CAD titer assessment to be kept at 37 ºC to 38 ºC (until serum has been removed from the clot, after which the sample 
can be handled at room temperature). 
q Urine pregnancy test will be completed for WOCBP prior to dosing on days where dosing coincides with clinic visits.  
r Bone marrow biopsy only needed if biopsy not previously undertaken within 1 year prior to ICF signature. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at the unscheduled 
visit at the discretion of the investigator. 

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Table 6 
Revised COVID-19 minimum schedule of assessments: Part B, Part C and Follow-up period 
Study Period 
Part B: 
Open-label treatment period 
Part C: 
Open-label maintenance period 
Follow-up period o 
EOT/ET 
EOS 
Study Week 
32 
40 
48 
56 
64 
72 
80 
88 
96 
102 
Study Day 
225 
281 
337 
393 
449 
505 
561 
617 
673 
715 
Study Visit 
11 
12 
13 
14 
15 
16 
17 
18 
19 
21 
Visit window (± days) 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
RBC transfusions collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Actigraph 
 
 
 
 
 
 
 
 
X 
X 
Recommended preventive antibiotic 
administration a  
At the discretion of the 
investigator 
At the discretion of the investigator 
 
 
Full physical examination (including weight) b 
 
 
 
 
 
 
 
 
X 
X 
Brief physical examination (including weight) c 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG (prior to venipuncture) 
X 
 
 
 
 
 
 
 
X 
X 
IMP administration d 
Twice weekly--------------- 
Twice weekly--------------------------------------------- 
 
 
Infusion-site assessment e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications/treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements f  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine studies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood g  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics h 
X 
 
 
 
 
 
X 
X 
Anti–pegcetacoplan peptide and anti-PEG 
Ab assay i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Sobi 
 
Pegcetacoplan/CAD 
Clinical Study No: Sobi.PEGCET-101 
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Table 6 
Revised COVID-19 minimum schedule of assessments: Part B, Part C and Follow-up period 
Study Period 
Part B: 
Open-label treatment period 
Part C: 
Open-label maintenance period 
Follow-up period o 
EOT/ET 
EOS 
Study Week 
32 
40 
48 
56 
64 
72 
80 
88 
96 
102 
Study Day 
225 
281 
337 
393 
449 
505 
561 
617 
673 
715 
Study Visit 
11 
12 
13 
14 
15 
16 
17 
18 
19 
21 
Visit window (± days) 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
TNFα, IL-6, IL-10, IFNγ and IL-1β 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, functional assays 
for classical and alternative complement 
pathways) 
X 
X 
X 
 
 
 
 
 
X 
X 
Flow cytometry for C3 deposition 
X 
X 
X 
 
 
 
 
 
X 
X 
Ferritin, vitamin B12/folate 
X 
X 
X 
 
 
 
 
 
X 
X 
Iron 
X 
X 
X 
 
 
 
 
 
X 
X 
DAT monospecific C3 and IgG 
X 
X 
X 
 
 
 
 
 
X 
X 
Immunoglobulins quantitative (IgG, IgM, 
and IgA) m 
 
 
X 
 
 
 
 
 
X 
X 
Serum cold agglutinin titer (at 4 °C) m 
X 
 
 
 
 
 
X 
X 
Urine pregnancy test n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACT-An  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events and serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation for home administration 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: Ab, Antibody(ies); C3, Complement component 3; CAD, Cold agglutinin disease; DAT, Direct antiglobulin test; ECG, Electrocardiogram; EOS, End of study; 
EOT, End of treatment; EQ-5D-5L, EuroQol 5-dimension 5-level questionnaire; ET, Early termination; FACT-An, Functional Assessment of Cancer Therapy-Anemia/Fatigue; 

Sobi 
 
Pegcetacoplan/CAD 
Clinical Study No: Sobi.PEGCET-101 
Confidential 
Page 98 of 98 
Version 2.0 Final Date 08 Oct 2021 
 
IFNγ, Interferon-gamma; Ig, Immunoglobulin; IL, Interleukin; IMP, Investigational medicinal product; PEG, Polyethylene glycol; PK, Pharmacokinetic; RBC, Red blood cell; 
s.c., Subcutaneous; SF-12, 12-Item Short Form Survey; TNFα, tumor necrosis factor-alpha; WOCBP, Women of childbearing potential. 
a To receive treatment with IMP, patients who are documented nonresponders to vaccination or cannot be vaccinated prior to IMP initiation will require preventive antibiotics at 
the discretion of the investigator, and should take into consideration the level of immunosuppression, complement levels, and timing of vaccination relative to IMP start, as well 
as local practices.  
b Full physical examination include assessment of the following items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; chest; lungs; abdomen; 
skin; extremities; back/neck; musculoskeletal system and lymph nodes. Weight will also be recorded at each physical examination. 
c Brief physical examination will include general appearance, heart, lungs, abdomen and extremities. Weight will also be recorded at each physical examination. 
d Patients will self-administer s.c. IMP, after receiving appropriate training by research personnel. Dosing diaries will be used for study treatment and are to be completed for each 
dose administered at the clinic or at home. On dosing days that coincide with clinic visits, doses will be administered at the clinic visit.  
e Between site visits, patients will be instructed to report any infusion-site reaction to the study coordinator. 
f On clinic dosing days, vital signs will be measured within 2 hours before dosing and venipuncture (and ECG, if applicable), and at 30 minutes (± 5 minutes) post dose. (see 
Section 6.5.4.4). 
g If IMP is administered at study visit, blood samples will be taken before dosing. 
h PK samples will be taken 15 minutes predose at each visit. 
i For patients with positive anti–pegcetacoplan peptide or anti-PEG Ab in last dose samples, additional samples will be collected every 6 months from last dose until Ab levels 
returns to baseline. 
k The use of silica reagents in coagulation panels should be avoided in all patients. 
m Serum samples for immunoglobulins quantitative and CAD titer assessment to be kept at 37 ºC to 38 ºC (until serum has been removed from the clot, after which the sample 
can be handled at room temperature). 
n Urine pregnancy test will be completed for WOCBP prior to dosing on days where dosing coincides with clinic visits.  
o After completion of the maintenance period, patients will complete an EOT visit. Patients who discontinue early should complete an ET visit. An EOS visit will be performed 
6 weeks (± 7 days) after treatment discontinuation for any reason. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at the unscheduled 
visit at the discretion of the investigator.