Clinical trial NCT04115293
Conditions: Myasthenia Gravis, Generalized
Sponsor: Ra Pharmaceuticals, Inc.
Start date: 2019-09-17; Completion date: 2021-12-30
Enrollment: 174 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The RAISE study is a multicenter, randomized, double-blind, placebo controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with generalized Myasthenia Gravis. Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: zilucoplan (RA101495) intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous (SC) injection intervention 2: Daily subcutaneous (SC) injection

Protocol documents:
Prot_000.pdf: 
Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 1 of 79 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Confirm the Safety, Tolerability, and Efficacy of Zilucoplan in 
Subjects with Generalized Myasthenia Gravis 
 
Protocol Number:  RA101495-02.301 (RAISE) (UCB study MG0010) 
Protocol Version/Date: Version 2.0/18.Dec.2020 
Indication Studied: Generalized Myasthenia Gravis 
Developmental Phase of Study: 3 
EudraCT Number: 2019-001564-30 
Sponsor Address: Ra Pharmaceuticals, Inc. (now part of UCB) 
87 Cambridge Park Drive 
Cambridge, MA, 02140 | USA 
This study will be conducted by Ra Pharmaceuticals, Inc. and affiliates in compliance 
with the protocol, Good Clinical Practice, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior 
written consent of Ra Pharmaceuticals, Inc. is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 2 of 79 
CENTER INVESTIGATOR SIGNATURE PAGE 
I have read this protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated. This trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and International Council for Harmonisation guidelines. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by the Sponsor or its representative 
and will fulfill all responsibilities for submitting pertinent information to the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) responsible for this study. 
I agree that the Sponsor or its representatives shall have access to any source documents 
from which case report form information may have been generated. I agree that 
regulatory authorities [Food and Drug Administration (FDA), European Medicines 
Agency (EMA), and other local and country-related agencies] can audit and review 
source documents. 
I further agree not to originate or use the name of Ra Pharmaceuticals, Inc. or any of its 
employees, in any publicity, news release, or other public announcement, written or oral, 
whether to the public, press, or otherwise, relating to his protocol, to any amendment 
hereto, or to the performance hereunder, without the prior written consent of Ra 
Pharmaceuticals, Inc. 
 
 
________________________________________________ 
_________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
________________________________________________ 
Name of Investigator (Typed or Printed) 
 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 3 of 79 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Protocol Version 
Date 
Original Protocol (Canada, US) 
1.0 
08 Apr 2019 
Protocol Amendment (United Kingdom) 
GB.1.1 
02 Oct 2019 
Protocol Amendment (Japan) 
JP.1.1 
29 Oct 2019 
Protocol Amendment (Germany) 
DE.1.1 
13 Nov 2019 
Protocol Amendment (Norway) 
NO.1.1 
13 Nov 2019 
Protocol Amendment (Italy) 
IT.1.1 
26 Nov 2019 
Protocol Amendment (Japan) 
JP.1.2 
06 Dec 2019 
Protocol Amendment (France) 
FR.1.1 
06 Feb 2020 
Protocol Amendment (Germany) 
DE.1.2 
26 Jun2020 
Protocol Amendment (global)  
2.0 
18 Dec 2020 
 
PROTOCOL AMENDMENT (GLOBAL) VERSION 2.0 (18 DEC 2020) 
The purpose of this protocol amendment is to make the following changes to the original 
protocol (Version 1.0 dated 08 Apr 2019): 
• The total sample size has been increased from 130 subjects (65 subjects per 
treatment group) to 156 subjects (78 subjects per treatment group). This increase 
was made to account for higher variability in the primary endpoint than originally 
assumed, and to maintain the power of the study. 
• An unblinded interim analysis has been added to be performed after the final 
subject has completed the Week 12 visit, or after the final subject has prematurely 
discontinued prior to reaching Week 12. The purpose of this interim analysis is to 
perform a comprehensive evaluation of all available double-blind data to prepare 
regulatory submissions for approval of the MG target indication. 
• Changes made in earlier country-specific protocol amendments (France, 
Germany, Italy, Japan, Norway, United Kingdom) have been consolidated into a 
single global protocol. 
• The objectives and endpoints were revised to reflect current UCB practices for the 
categorization and description of study objectives, estimands, and endpoints. 
• The protocol was updated to include provisions for the COVID-19 pandemic. 
• Additional administrative updates were made in the protocol. 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 4 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated version number 
and date; added UCB study 
number 
Updates 
Section 1, Synopsis, 
Study Population 
Provided specific age range 
of study population 
Clarification 
Section 1, Synopsis, 
Planned Number of 
Subjects 
Revised sample size 
Update 
Section 1, Synopsis, 
Study Design 
Revised sample size 
Update 
Section 1, Synopsis, 
Study Design 
Added enrollment rate for 
Japanese sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Study Design 
Added overnight 
hospitalization following 
Day 1 dose for Japanese 
sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Study Design 
Added information on the 
use of eculizumab as rescue 
therapy for German sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Inclusion/Exclusion 
Criteria 
Updated inclusion 
criterion 12 (contraception) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Inclusion/Exclusion 
Criteria 
Updated exclusion 
criterion 12 (treatment with 
rituximab) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Inclusion/Exclusion 
Criteria 
Added exclusion 
criterion 18 
(hypersensitivity to study 
drug) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 1, Synopsis, 
Study Objectives and 
Endpoints 
Revised objectives and 
endpoints 
Updated to reflect UCB 
practices for categorization 
and description of study 
objectives, estimands, and 
endpoints 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 5 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1, Synopsis, 
Statistical 
Considerations, Efficacy 
Analyses 
Minor revisions to 
description of efficacy 
analyses 
Update and clarification 
Section 1, Synopsis, 
Statistical 
Considerations, 
Determination of Sample 
Size 
Increased total sample size 
to 156 subjects (78 subjects 
per treatment group) 
Update to account for 
higher variability in the 
primary endpoint than the 
original assumption, and to 
maintain the power of the 
study 
Section 2, Time and 
Events Table 
Added table row for 
“Hospitalization” 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 2, Time and 
Events Table, footnote h 
Revised to indicate 
collection of information for 
concomitant medications 
taken during the 30 days 
prior to Screening 
Clarification 
Section 2, Time and 
Events Table, footnote u 
Added footnote u 
(COVID-19 provisions) 
Update to include 
provisions for the 
COVID-19 pandemic 
Section 2, Time and 
Events Table, footnote v 
Added footnote v (overnight 
hospitalization in Japan) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 2, Time and 
Events Table, footnote w 
Added to footnote w 
(analysis for neutralizing 
antibodies included in ADA 
analysis) 
Clarification 
Section 4, List of 
Abbreviations and 
Definitions 
Added additional 
abbreviations 
Update 
Section 5, Introduction 
Added reference to 
benefit/risk analysis 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 5.1, Overview of 
Generalized Myasthenia 
Gravis, paragraph 3 
Update of treatments for 
gMG 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
CONFIDENTIAL 
 
Page 6 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6, Study 
Objectives and Endpoints 
Revised objectives and 
endpoints 
Updated to reflect UCB 
practices for categorization 
and description of study 
objectives, estimands, and 
endpoints 
Section 7.1, Overview of 
Study Design, 
paragraph 1 
Increased total sample size 
to 156 subjects (78 subjects 
per treatment group) 
Update to account for 
higher variability in the 
primary endpoint than the 
original assumption, and to 
maintain the power of the 
study 
Section 7.1, Overview of 
Study Design, 
paragraph 3 
Added enrollment rate for 
Japanese sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 7.1, Overview of 
Study Design, 
paragraph 6 
Added overnight 
hospitalization following 
Day 1 dose for Japanese 
sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 7.1, Overview of 
Study Design, 
paragraph 7 
Added information on the 
use of eculizumab as rescue 
therapy for German sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 7.2.1.1, 
Screening and 
Enrollment, bullet point 
regarding concomitant 
medications 
Revised to indicate 
collection of information for 
concomitant medications 
taken during the 30 days 
prior to Screening 
Clarification and 
consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 7.2.1.1, 
Screening and 
Enrollment, bullet point 
regarding ADA testing 
Revised to indicate that 
ADA testing also includes 
neutralizing antibody 
testing 
Clarification 
Section 7.2.1.2, 
Randomization and 
Blinding, paragraph 3 
Added information on 
database locks, including 
interim database lock after 
the final subject has 
completed Week 12 
Update 
Section 7.2.2, Treatment 
Period, paragraph 2 
Added information on 
overnight hospitalization 
following Day 1 dose for 
Japanese sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
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Page 7 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.3, Early 
Termination, paragraph 1 
Added sentence addressing 
termination of study based 
on new or emerging safety 
information 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 7.4, Study 
Conduct During 
COVID-19 
Added new section 
Update to include 
provisions for the 
COVID-19 pandemic 
Section 8.1, Inclusion 
Criteria, Inclusion 
Criterion 12 
Updated inclusion 
criterion 12 (contraception) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 8.2, Exclusion 
Criteria, Exclusion 
Criterion 12 
Updated exclusion 
criterion 12 (treatment with 
rituximab) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 8.2, Exclusion 
Criteria, Exclusion 
Criterion 18 
Added exclusion 
criterion 18 
(hypersensitivity to study 
drug) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 8.3.2, Premature 
Discontinuation 
Updated reasons for 
discontinuation 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 9.1.1, 
Investigational Medicinal 
Product and Placebo, 
paragraph 2 
Added information for the 
BD Ultrasafe Plus device 
(compliance with European 
regulations) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 9.1.2, Dosing 
Schedule, paragraph 1 
Added text to clarify that 
study medication is 
self-administered 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 9.1.3, Dose 
Presentation, paragraph 2 
Added information 
regarding composition of 
placebo 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 9.1.3, Dose 
Presentation, paragraph 3 
Added text referring to 
subjects with lower body 
weight (<43 kg) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 9.1.3.1, Missed 
Doses, paragraph 1 
Added text regarding timing 
of administration of study 
drug (Japan)  
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
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Page 8 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 9.2.1.1, 
Alternative Study 
Treatment Supply due to 
COVID-19 Pandemic 
Added new section 
Update to include 
provisions for the 
COVID-19 pandemic 
Section 9.2.3, Disposal, 
Return, or Retention of 
Unused Drugs, 
paragraph 1 
Added clarification for 
return of unused study drug 
and containers 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.1.3, Prior and 
Concomitant 
Medications, paragraph 1 
Revised to indicate 
collection of information for 
concomitant medications 
taken during the 30 days 
prior to Screening 
Clarification and 
consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.1.3, Prior and 
Concomitant 
Medications, paragraph 3 
Added reference to 
Appendix 2 (Prohibited 
Concomitant Medications) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.1.3.1, Rescue 
Therapy, paragraph 2 and 
paragraph 3 
Added information on the 
use of eculizumab as rescue 
therapy  
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.2.4.1, 
Hematology, Chemistry, 
and Coagulation, Table 4 
Added RBC to tabular list 
of clinical laboratory tests 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.2.4.3, 
Pregnancy Testing and 
Contraception 
Revised information on 
contraception 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 10.2.6, 
Immunogenicity 
Revised to indicate that 
ADA testing also includes 
neutralizing antibody 
testing 
Clarification 
Section 10.2.8, Overnight 
Observational 
Hospitalization in Japan 
Added new section 
describing overnight 
hospitalization following 
Day 1 dose for Japanese 
sites 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 11.1.1.1, 
Occurrence of 
COVID-19 
Added section regarding 
reporting cases of 
COVID-19 
Update to include 
provisions for the 
COVID-19 pandemic 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
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Page 9 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 11.1.2, Serious 
Adverse Events, final 
paragraph 
Added text regarding 
overnight hospitalization 
(Japan) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 11.4.1.2, Serious 
Adverse Events, final 
paragraph 
Added text regarding 
reporting of SUSARs 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 11.4.3, 
Emergency Unblinding, 
final paragraph 
Added text regarding safety 
follow-up 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 12.2.1, General 
Methods 
Added text regarding 
interim and final database 
locks, and analyses to 
explore impact of 
COVID-19 
Update 
Section 12.2.5.1, Primary 
Efficacy Endpoint 
Analysis, paragraph 1 
Deleted interaction terms 
baseline QMG Scorevisit 
and geographical 
regionvisit 
Update 
Section 12.2.5.2, 
Secondary Endpoint 
Analyses, paragraph 1 
and paragraph 2 
Revised text regarding 
analyses of secondary 
efficacy endpoints 
Update 
Section 12.2.6, Handling 
of Missing and Censored 
Data 
Added bullet point 
regarding the expected 
impact of the COVID-19 
pandemic on MG-ADL 
Update 
Section 12.2.6, Handling 
of Missing and Censored 
Data 
Added reference to 
eculizumab as potential 
rescue therapy 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 12.2.6, Handling 
of Missing and Censored 
Data, final sentence 
Added sentence referring to 
protocol deviations related 
to COVID-19 
Update 
Section 12.2.8.1, 
Pharmacokinetic and 
Pharmacodynamic 
Analyses 
Added text describing 
population PK, PD, and 
PK/PD analyses 
Update 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
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Page 10 of 79 
Section # and Name 
Description of Change 
Brief Rationale 
Section 12.2.9, Interim 
Analysis 
Revised with addition of 
description of interim 
analysis based on interim 
database lock after the final 
subject has completed 
Week 12 
Update 
Section 12.3, Sample 
Size Determination 
Increased total sample size 
to 156 subjects (78 subjects 
per treatment group) 
Update to account for 
higher variability in the 
primary endpoint than the 
original assumption, and to 
maintain the power of the 
study 
Section 13.2, Informed 
Consent of Study 
Subjects, paragraph 5 
Added text regarding age of 
adulthood in Japan 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Section 16, Appendices, 
Appendix 2 
Added Appendix 2 
(Prohibited Concomitant 
Medications) 
Consolidation of earlier 
country-specific protocol 
amendments into global 
protocol 
Sponsor Signature Page 
Moved sponsor signature 
page to end of document 
Alignment with UCB 
document practices, 
including the use of 
electronic sponsor 
signatures 
 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.301 
18.Dec.2020 
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1 SYNOPSIS 
Protocol Title 
A Phase 3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Confirm the Efficacy, Safety, 
and Tolerability of Zilucoplan in Subjects with Generalized 
Myasthenia Gravis 
Protocol Number 
RA101495-02.301 (RAISE) (UCB study MG0010) 
Phase of Clinical Development 
Phase 3 
Investigational Medicinal 
Product (IMP) 
Zilucoplan (RA101495) administered by daily subcutaneous 
(SC) injection (0.3 mg/kg) 
Study Population 
Male or female ≥18 years and <75 years with generalized 
myasthenia gravis (gMG) 
Investigative Sites 
Approximately 100 centers are planned worldwide 
Planned Number of Subjects  
Approximately 156 subjects (78 per treatment arm) 
Study Objectives 
• To confirm the efficacy of zilucoplan in subjects with gMG  
• To confirm the safety and tolerability of zilucoplan in subjects with gMG  
Study Design 
Study RA101495-02.301 is a multicenter, randomized, double-blind, placebo-controlled study to 
confirm the efficacy, safety, and tolerability of zilucoplan in subjects with gMG.  
The planned enrollment is approximately 156 subjects. Subjects will be randomized in a 1:1 ratio 
to receive daily SC doses of 0.3 mg/kg zilucoplan or placebo. Randomization will be stratified 
based on the baseline MG-Activities of Daily Living (MG-ADL) Score (≤9 versus ≥10), 
Quantitative Myasthenia Gravis (QMG) Score (≤17 versus ≥18), and geographical region. 
In order to ensure a gradual initiation of the study in Japan, each Japanese site will be capped to 
an enrollment rate of no more than one subject per site per week). 
The study includes a Screening Period of up to 4 weeks and a 12-week Treatment Period. During 
the Treatment Period, subjects will return to the clinic at Week 1, Week 2, Week 4, Week 8, and 
Week 12 to evaluate efficacy, safety, and tolerability. Additional assessments will include 
questionnaires, biomarker samples, pharmacokinetics, pharmacodynamics, and optional 
pharmacogenomics. Safety assessments will include physical examinations, vital signs, 
electrocardiogram (ECG), clinical laboratory tests, adverse event (AE) monitoring, 
immunogenicity, and Columbia-Suicide Severity Rating Scale (C-SSRS). 
Randomized subjects will receive 0.3 mg/kg zilucoplan or matching placebo administered SC at 
the Day 1 visit. Following in-clinic education and training, all subjects will self-inject daily SC 
doses of blinded study drug, according to randomized treatment allocation, for the subsequent 
12 weeks. Single-use pre-filled syringes in injection devices will be provided for use during the 
study. 
In Japan, following their Day 1 dose, subjects will be hospitalized overnight for observation to 
ensure safety of study drug administration. Prior to discharge, subjects will be asked to self-
administer their Day 2 dose under supervision to ensure that their technique for self-injection is 
adequate and appropriate, and to answer any additional questions. These pre-scheduled overnight 
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Zilucoplan  
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18.Dec.2020 
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observational hospitalizations will not be considered SAEs in this study (even if hospital stay is 
extended, provided that the sole purpose of the extension is improvement of the injection 
technique). Subjects will continue to self-inject daily SC doses of blinded study drug, according 
to randomized treatment allocation, for the subsequent 12 weeks. 
Subjects are expected to remain on stable doses of all medications unless medically indicated 
changes become necessary. All standard of care (SOC) therapy medications for gMG should be 
kept at the same dose throughout the 12-week study, including corticosteroids and 
immunosuppressant therapy (IST) drugs. If escalation of gMG therapy (i.e., ‘rescue therapy’) 
becomes necessary due to major deterioration of a subject’s clinical status, or risk of myasthenia 
gravis (MG) crisis as per the investigator’s judgment, the subject may receive intravenous 
immunoglobulin G (IVIG) or plasma exchange (PLEX) treatment as ‘rescue therapy’. In 
Germany, the choice of eculizumab as ‘rescue therapy’ will not be withheld, if the investigator 
considers this to be the best course of action. 
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must be 
vaccinated against meningococcal infections (with a quadrivalent vaccine and, where available 
and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, or at the time of, 
initiating study drug. Subjects who initiate study drug treatment less than 2 weeks after receiving 
a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics (e.g., 
Penicillin V 500mg twice daily, third generation cephalosporin, etc.) until at least 2 weeks after 
the initial dose of vaccine(s). The use of fluoroquinolone or macrolide antibiotics is not 
recommended due to the potential for exacerbation of MG. Booster vaccinations should be 
administered in accordance with SOC.   
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled and 
reminded of the early signs and symptoms of Neisseria meningitidis infection. A patient safety 
card detailing the signs and symptoms of infection, with instructions to seek immediate medical 
attention if any such symptoms occur, will be provided to each subject. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an unblinded 
data review should become necessary to ensure subject safety, a Safety Monitoring Committee 
(SMC) will convene and evaluate study data as appropriate.  
At the end of the Treatment Period, all subjects will have the option to receive zilucoplan in a 
separate Extension Study, provided they meet the Extension Study inclusion criteria.  
If a subject discontinues study drug treatment prior to the Week 12 visit for any reason, he/she 
will not be eligible for the Extension Study. For subjects who permanently discontinue study 
drug, a Safety Follow-up Visit will be performed at 40 days after the last dose of study drug, to 
collect information on any ongoing AEs or new serious adverse events (SAE) since the last 
study visit. 
Duration of Study Participation 
The duration of study participation will include a Screening Period of up to 4 weeks and a 12-
week Treatment Period for a total of approximately 16 weeks. 
Inclusion/Exclusion Criteria 
To be eligible for this study, subjects must meet ALL the following inclusion criteria: 
1. Male or female 18 years and <75 years 
2. Able to provide informed consent, including signing and dating the informed consent form 
(ICF) 
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Zilucoplan  
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3. Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IV] at 
Screening 
4. Positive serology for acetylcholine receptor (AChR) binding autoantibodies 
5. MG-ADL Score of ≥6 at Screening and Baseline 
6. QMG Score of ≥12 at Screening and Baseline (off acetylcholinesterase inhibitor therapy for 
at least 10 hours) 
7. 4 or more of the QMG test items must be scored at ≥2 at Screening and Baseline 
8. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur 
during the 12-week treatment period 
9. No change in immunosuppressive therapy, including dose, for at least 30 days prior to 
Baseline or anticipated to occur during the 12-week treatment period 
10. Vaccination with a quadrivalent meningococcal vaccine and, where available, meningococcal 
serotype B vaccine at least 14 days prior to the first dose of study drug at the Day 1 visit. A 
booster vaccination should also be administered as clinically indicated, according to the local 
SOC, for subjects who have been previously vaccinated against Neisseria meningitidis 
11. Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test within 24 hours prior to the first dose of study 
drug 
12. Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation) and all male subjects (who have not been surgically sterilized by vasectomy) 
must agree to use effective contraception during the study and during the safety follow-up 
period of 40 days after the last dose of study drug. Postmenopausal women are, for the 
purposes of this protocol, defined as women who have not had menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
Subjects who meet ANY of the following exclusion criteria must be excluded from the study: 
1. Thymectomy within 12 months prior to baseline or scheduled to occur during the 12-week 
study 
2. Abnormal thyroid function as determined by local standard 
3. Known positive serology for muscle-specific kinase (MuSK)  
4. Minimal Manifestation Status of MG based on the clinical judgement of the investigator 
5. Fixed weakness (‘burnt out’ MG) based on the clinical judgement of the investigator 
6. History of meningococcal disease 
7. Current or recent systemic infection within 2 weeks prior to Baseline or infection requiring 
intravenous (IV) antibiotics within 4 weeks prior to Baseline 
8. Pregnant, planning to become pregnant, or nursing female subjects 
9. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or expected to 
have surgery requiring general anesthesia during the 12-week Treatment Period 
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10. Prior treatment with a complement inhibitor  
11. Treatment with an experimental drug within 30 days or 5 half-lives of the experimental drug 
(whichever is longer) prior to Baseline 
12. Treatment with rituximab within 12 months prior to Baseline or planned to occur during the 
12-week study (this exclusion criterion is implemented out of an abundance of caution, in the 
absence of data showing that complement inhibition in the context of B-cell elimination by 
rituximab is safe) 
13. Treatment with IVIG, SC immunoglobulin, or PLEX within 4 weeks prior to Baseline 
14. Active malignancy (except curatively resected squamous or basal cell carcinoma of the skin) 
requiring surgery, chemotherapy, or radiation within the prior 12 months (subjects with a 
history of malignancy who have undergone curative resection or otherwise not requiring 
treatment for at least 12 months prior to Screening with no detectable recurrence are allowed) 
15. History of or current significant medical disorder, psychiatric disorder, or laboratory 
abnormality that in the opinion of the investigator would make the subject unsuitable for 
participation in the study 
16. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is permitted) 
17. Unable or unwilling to comply with the requirements of the study 
18. Hypersensitivity to zilucoplan or any of its excipients, or to placebo 
Study Objectives and Endpoints 
Objectives 
Estimands/Endpoints 
Primary Efficacy Objective:  
To confirm the efficacy of 
zilucoplan in subjects with gMG 
Primary Estimand: 
Treatment: Zilucoplan administered by daily subcutaneous (SC) 
injection (0.3 mg/kg) vs Placebo 
Target Population: Adults with generalized myasthenia gravis 
(gMG) with inclusion/exclusion criteria provided in Section 8.1 and 
Section 8.2 of the protocol. 
Endpoint: Change from Baseline (CFB) in Week 12 in Myasthenia 
Gravis-Activities of Daily Living (MG-ADL) Score 
Intercurrent event handling: 
If a subject experiences any of the following intercurrent events, 
then data at and after the point of the intercurrent event will be 
treated as missing using a hypothetical strategy: 
A participant receiving rescue therapy: The study is interested in 
the treatment effect assuming that the treatment effect is null, and 
no rescue effect occurs after a subject receives rescue medication.  
A subject discontinuing the study: For subjects that discontinue due 
to AEs related to study drug, it is assumed that the treatment effect 
is null. For subjects that discontinue for other reasons (i.e., 
unrelated to study drug) it is assumed that the subject had remained 
on their treatment throughout the study (i.e., a "Hypothetical 
strategy" assuming subjects did not discontinue the study and 
remained on treatment).  
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Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the mean CFB in the Week 12 
MG-ADL. 
As described in Section 10.3.1, the MG-ADL is a brief 8-item 
survey designed to evaluate MG symptom severity. Higher scores 
are associated with more severe symptoms of MG.  
Appendix 1: MG-Activities of Daily Living Scale presents the 8 
items with corresponding response scale, each scored on a 0-3 point 
scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total 
score is the sum of the 8 individual scores and range 0–24.  
Secondary Efficacy Objective:  
To confirm the efficacy of 
zilucoplan in subjects with gMG 
Secondary Efficacy Endpoints:  
• 
CFB to Week 12 in the Quantitative Myasthenia Gravis 
(QMG) Score 
• 
CFB to Week 12 in the Myasthenia Gravis Composite (MGC) 
Score 
• 
CFB to Week 12 in the Myasthenia Gravis – Quality of Life 
revised (MG-QOL15r) Score  
• 
Time to first receipt of rescue therapy over the 12-week 
Treatment Period 
• 
Achieving Minimal Symptom Expression (MSE), defined as 
an MG-ADL of 0 or 1 at Week 12 without rescue therapy 
• 
Achieving a ≥ 3-point reduction in MG-ADL Score at Week 
12 without rescue therapy  
• 
Achieving a ≥5-point reduction in QMG Score without rescue 
therapy at Week 12 
Secondary Safety Objective:  
To confirm the safety and 
tolerability of zilucoplan in 
subjects with gMG 
Secondary Safety Endpoint: 
• 
Incidence of treatment-emergent AEs 
Other Safety Objective:  
To confirm the safety and 
tolerability of zilucoplan in 
subjects with gMG 
Other Safety Endpoints: 
• 
Physical Examination 
• 
Vital Signs 
• 
ECG 
• 
Clinical Laboratory Tests 
• 
Immunogenicity 
• 
C-SSRS 
Exploratory Objectives 
To assess the PK of zilucoplan 
• 
Plasma concentrations of zilucoplan and its major metabolites  
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To assess the PD of zilucoplan 
• 
Sheep red blood cell (sRBC) lysis assay for evaluation of 
classical complement pathway activation 
• 
Complement component 5 (C5) levels 
To explore the efficacy on 
additional efficacy endpoints 
• 
Achievement of Minimal Manifestation Status per MGFA 
Post-Intervention Status (MGFA-PIS) at Week 12 without 
rescue therapy 
• 
CFB to Week 12 in Work Productivity and Activity 
Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP)  
• 
CFB to Week 12 in EQ-5D-5L [5-item questionnaire and 
visual analog scale (VAS)]  
• 
CFB to Week 12 in QMG sub-scores: ocular, bulbar, 
respiratory, limb  
• 
CFB to Week 12 in Neuro-QOL Short Form Fatigue Scale 
• 
Responder analysis for changes in QMG, MG-ADL, 
MG-QOL15r, and MG Composite Scores from baseline 
without rescue therapy 
To evaluate the emergence of 
antidrug antibodies (ADAs) of 
zilucoplan 
• 
ADAs and neutralizing antibodies at each scheduled 
assessment 
To assess the effect on biomarkers • 
Mechanistic biomarkers pertinent to MG pathophysiology 
[e.g., complement fixation, complement function, complement 
pathway proteins, autoantibody characterization (titer and 
immunoglobulin class) and inflammatory markers] 
Statistical Considerations 
Study Populations: The following study populations are defined: 
• Intention-to-Treat (ITT) Population: All randomized subjects  
• Per Protocol Population: All subjects in the ITT Population who completed the 12-week 
Treatment Period and have no major protocol deviations  
• Safety Population: All subjects who received at least 1 dose of study drug with subjects to be 
analyzed based on the actual study treatment received  
General Considerations: A disposition of subjects will be provided and will include a 
breakdown of subjects who were randomized, were treated, discontinued treatment, were lost to 
follow-up, or withdrew consent. 
Continuous variables will be summarized using the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. 
Randomization: Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 
0.3 mg/kg zilucoplan or placebo. Randomization will be stratified on the baseline MG-ADL 
Score (≤9 versus 10), baseline QMG Score (≤17 versus 18), and geographical region.  
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Efficacy Analyses:  
Primary Efficacy Analysis:  
For the primary efficacy endpoint, CFB to Week 12 in MG-ADL Score, treatment group 
differences will be assessed using a mixed model with repeated measures (MMRM) analysis of 
covariance (ANCOVA) with treatment, baseline MG-ADL Score, baseline QMG Score, 
geographical region, treatmentvisit (interaction term), and baseline MG-ADL Scorevisit 
(interaction term) as fixed effects and subject as a random effect. The MMRM ANCOVA will 
include Weeks 1, 2, 4, 8, and 12. 
The primary efficacy analysis will be the comparison of the 0.3 mg/kg zilucoplan dose group 
versus placebo in CFB to Week 12 in MG-ADL Score at a 2-sided 0.05 significance level based 
on the ITT population.  
Secondary Efficacy Analyses:  
The continuous secondary efficacy endpoints: Week 12 CFB in QMG, MGC, and MG-QOL15r 
Survey will be analyzed by an MMRM ANCOVA model similar to the primary endpoint 
analysis. 
The dichotomous secondary efficacy endpoints: received rescue therapy over the 12-week 
Treatment Period, achieving MSE, defined as an MG-ADL of 0 or 1, at Week 12 without rescue 
therapy, a ≥3-point reduction in MG-ADL Score at Week 12 without rescue therapy, and a ≥5-
point reduction in QMG Score at Week 12 without rescue therapy will be analyzed by a logistic 
regression with treatment as a factor and baseline MG-ADL Score, baseline QMG Score, and 
geographical region as covariates.  
For each of the secondary endpoints, the analysis will be the Week 12 comparison of the 
0.3 mg/kg zilucoplan dose group versus placebo at a 2-sided 0.05 significance level based on the 
ITT population.  
Multiplicity: 
The primary efficacy endpoint will be tested at the 2-sided 0.05 significance level. The secondary 
endpoints will be tested using a fixed-sequential testing procedure in the following order:  
• CFB to Week 12 in the QMG Score 
• CFB to Week 12 in the MGC  
• CFB to Week 12 in the MG-QOL15r Survey 
• Received rescue therapy over the 12-week Treatment Period  
• Achieving MSE, defined as an MG-ADL of 0 or 1, at Week 12 without rescue therapy  
• Achieving a ≥3-point reduction in MG-ADL Score at Week 12 without rescue therapy 
• Achieving a ≥5-point reduction in QMG Score at Week 12 without rescue therapy 
Each secondary endpoint will be tested at the 2-sided 0.05 significance level. A secondary 
endpoint analysis will be considered statistically significant if the 2-sided p-value is ≤0.05 for the 
endpoint analysis and the primary efficacy endpoint analysis and all the secondary endpoint 
analyses occurring earlier in the fixed-sequence are also statistically significant (i.e., have a 
2-sided p-value ≤0.05).  
Safety: AEs will be coded using the Medical Dictionary for Regulatory (MedDRA). Incidence 
rates for treatment-emergent AEs (TEAEs) will be summarized overall, by maximum severity, 
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and by relationship to study drug for each treatment group. SAEs will also be summarized by 
treatment group.  
Quantitative laboratory endpoints will be summarized by treatment group at each scheduled 
assessment time point using descriptive statistics. 
Descriptive statistics for ECG parameters [i.e., heart rate (HR), PR interval, RR interval, QRS 
interval, and QT interval] at each assessment time point will be presented by treatment group. 
Descriptive statistics for vital signs (HR, body temperature, and blood pressure) will be presented 
by treatment group. 
Clinically significant physical examination abnormalities will be reported as AEs, when 
appropriate. 
Pharmacokinetics: Individual PK results will be presented in listings and summarized using 
descriptive statistics. 
Pharmacodynamics: Pharmacodynamic endpoints will be summarized by treatment group. 
Determination of Sample Size: For the primary efficacy endpoint, CFB to Week 12 in MG-
ADL Score, assuming a difference in treatment group least squares means of 2.3, a SD of 3.7, 
and 78 subjects per group, the study has approximately 94% power to detect a difference between 
an active and placebo treatment group based on a 2-sided alpha of 0.05. This assumes rates of 
rescue and dropout of up to 10% and 5%, respectively. 
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2 TIME AND EVENTS TABLE 
Table 1: Time and Events Table 
 
 
 
Week 1 
Week 2 
Week 4 
Week 8 
Week 12 
 
 
 
Study Procedure 
Screening 
Days -28 to -1 
Day 1u 
(‘Baseline’) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 57 
(± 7 days) 
Day 84a  
End of Study 
 (± 2 days) 
Safety Follow-up 
Visitb 
(40 days ± 7 days) 
 
Rescue Therapy 
Visitc 
(if applicable) 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
Review eligibilityd 
X 
 
 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
 
 
Medical history and demographicsf 
X 
 
 
 
 
 
 
 
 
 
Height and weightg 
X 
 
 
 
 
 
X 
 
 
 
Prior and concomitant medicationsh 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
X 
 
 
 
Neisseria meningitidis vaccinationj 
X 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC 
 
 
 
Hematology/Chemistryk 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Coagulationl 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy testm 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsn 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Anti-drug antibodyw 
X 
X 
X 
 
X 
 
X 
X 
 
X 
C-SSRSo 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hospitalizationv 
 
X 
 
 
 
 
 
 
 
 
Efficacyp 
 
 
 
 
 
 
 
 
 
 
MG-ADL 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
QMG Score 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
MG-QOL15r 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
MGC 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pharmacokinetic/Pharmacodynamicq 
 
 
 
 
 
 
 
 
 
 
Zilucoplan plasma PK 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Pharmacodynamic analysis 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Additionalr 
 
 
 
 
 
 
 
 
 
 
Biomarker samples 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Auto-antibodies 
 
X 
 
 
X 
 
X 
 
 
X 
IgG subclasses 
 
X 
 
 
X 
 
X 
 
 
X 
Pharmacogenomic analysis (optional) s 
X 
 
 
 
 
 
 
 
 
 
WPAI:SHP 
 
X 
X 
X 
X 
X 
X 
 
 
X 
EQ-5D-5L 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Neuro-QOL 
 
X 
X 
X 
X 
X 
X 
 
 
X 
MGFA Post-Intervention Status 
 
 
X 
X 
X 
X 
X 
 
 
X 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Zilucoplan or placebo administrationt 
 
X 
X 
X 
X 
X 
X 
 
 
X 
See footnotes on following page. 
 
 
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a. 
If a subject prematurely discontinues study drug prior to completion of the Week 12 Visit, the subject should return to clinic for an End of Study Visit.  
b. 
Subjects who choose not to enter the Extension Study or who terminate the study prior to Week 12 will be required to return to the clinic 40 ±7 days after their last dose to gather 
information on ongoing AEs and report any new SAEs since the last study visit. 
c. 
For subjects who require rescue therapy (see Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue Therapy Visit 
coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
d. 
Procedures performed as SOC during the Screening Period may be used to determine eligibility. Informed consent must be obtained prior to performing any study-specific procedures 
that are not SOC.  
e. 
Eligibility must be confirmed prior to randomization on Day 1. 
f. 
Screening includes disease history with diagnosis of gMG by the MGFA criteria (Class II-IV) and serology for AChR autoantibodies.  
g. 
Height will be measured only at Screening. 
h. 
All prescriptions and over-the-counter medications taken during the 30 days prior to Screening through the last study visit will be documented.  
NOTE: A complete history of medications taken for the treatment of gMG will be collected. 
i. 
The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
j. 
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must be vaccinated against meningococcal infections (with a quadrivalent vaccine and, where 
available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, or at the time of, initiating study drug. Subjects who initiate study drug treatment less than 2 
weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics (e.g., Penicillin V 500mg twice daily, third generation cephalosporin, 
etc.) until at least 2 weeks after the initial dose of vaccine(s). The use of fluoroquinolone or macrolide antibiotics is not recommended due to the potential for exacerbation of MG. 
Booster vaccinations should be administered in accordance with SOC. 
k. 
All laboratory samples should be obtained prior to administration of study drug at applicable visits.  
l. 
Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
m. For all female subjects of childbearing potential, a negative serum pregnancy test must be documented at Screening. All other pregnancy tests will be performed via urine.  
n. 
All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the procedures 
outlined in the protocol.  
o. 
In accordance with the draft FDA Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials Guidance for Industry (FDA 2012) subjects will be asked to 
complete the C-SSRS at study visits as specified. 
p. 
The MG-ADL, QMG, MG-QOL15r, and MGC should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained 
evaluator (e.g., neurologist, physical therapist, or other study staff) in the same order at each visit throughout the study.  
NOTE: If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 10 hours prior to the QMG test.  
q. 
Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). If Rescue Therapy is administered at a location separate from the 
clinical site, then there is no need to collect blood samples for PK/PD. For local Rescue Therapy visits, PK and PD samples will be collected at the following time points: 
During Rescue Therapy 
ONLY at sites where rescue therapy is administered locally 
Within 1 hour before administration of each round of rescue therapy 
For PLEX only: PK will be measured in the exchanged plasma 
Within 1 hour after administration of each round of rescue therapy 
r. 
Blood samples for the additional tests will be obtained prior to administration of study drug (within 1 hour of dosing).  
s. 
The pharmacogenomic sample is noted at Screening, however it may be collected at any study visit. 
t. 
Dosing on study visit days should be held until all assessments (e.g., MG-ADL, QMG, MG-QOL15r, MGC, questionnaires, sample collection, etc.) have been completed. On days when 
rescue therapy is concurrently administered, study drug dosing should be held until after administration of rescue therapy and PK/PD sampling. 
u. 
In circumstances where COVID-19 disruptions lead to subject being unable to return for Day 1 within 28 days of screening, additional days may be included in the screening period.  
Contact with the medical monitor is requested in such situations. 
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v. 
In Japan, following their Day 1 dose, subjects will be hospitalized overnight for observation to ensure safety of study drug administration. Prior to discharge, subjects will be asked to 
self-administer their Day 2 dose under supervision to ensure that their technique for self-injection is adequate and appropriate, and to answer any additional questions. These 
pre-scheduled overnight observational hospitalizations will not be considered SAEs in this study (even if hospital stay is extended, provided that the sole purpose of the extension is 
improvement of the injection technique). Subjects will continue to self-inject daily SC doses of blinded study drug, according to randomized treatment allocation, for the subsequent 
12 weeks. 
w. Anti-drug antibody analysis also includes analysis for neutralizing antibodies. 
 
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3 TABLE OF CONTENTS 
1 
SYNOPSIS ......................................................................................................11 
2 
TIME AND EVENTS TABLE ......................................................................19 
3 
TABLE OF CONTENTS ..............................................................................22 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................26 
5 
INTRODUCTION..........................................................................................27 
5.1 
OVERVIEW OF GENERALIZED MYASTHENIA GRAVIS ........................................27 
5.2 
ETIOLOGY OF GENERALIZED MYASTHENIA GRAVIS AND THE 
ROLE OF COMPLEMENT .....................................................................................28 
5.3 
RATIONALE FOR COMPLEMENT INHIBITION IN MYASTHENIA 
GRAVIS .............................................................................................................29 
5.4 
MECHANISM OF ACTION OF ZILUCOPLAN .........................................................29 
5.5 
CLINICAL TRIAL EXPERIENCE WITH ZILUCOPLAN .............................................30 
5.5.1 
ZILUCOPLAN PHASE 1 EXPERIENCE ..................................................................30 
5.5.2 
ZILUCOPLAN EXPERIENCE IN GMG ...................................................................31 
5.6 
RATIONALE FOR THE CURRENT STUDY .............................................................32 
5.6.1 
RATIONALE FOR BLINDING AND PLACEBO CONTROL ........................................33 
5.6.2 
DOSE SELECTION AND PRESENTATION ..............................................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................34 
7 
STUDY DESIGN ............................................................................................36 
7.1 
OVERVIEW OF STUDY DESIGN ..........................................................................36 
7.2 
STUDY PERIODS ................................................................................................38 
7.2.1 
SCREENING PERIOD ...........................................................................................38 
7.2.2 
TREATMENT PERIOD .........................................................................................40 
7.3 
EARLY STUDY TERMINATION ...........................................................................41 
7.4 
STUDY CONDUCT DURING COVID-19 .............................................................42 
8 
SELECTION OF STUDY POPULATION .................................................43 
8.1 
INCLUSION CRITERIA ........................................................................................43 
8.2 
EXCLUSION CRITERIA .......................................................................................44 
8.3 
REMOVAL OF SUBJECTS IN THE STUDY .............................................................45 
8.3.1 
WITHDRAWAL OF CONSENT ..............................................................................45 
8.3.2 
PREMATURE DISCONTINUATION .......................................................................45 
8.3.3 
REPLACEMENT OF SUBJECTS .............................................................................46 
9 
INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENTS
..........................................................................................................................46 
9.1 
STUDY TREATMENT ADMINISTRATION .............................................................46 
9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO ..................................46 
9.1.2 
DOSING SCHEDULE ...........................................................................................46 
9.1.3 
DOSE PRESENTATION ........................................................................................46 
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9.2 
STUDY TREATMENT MANAGEMENT ..................................................................47 
9.2.1 
PREPARATION AND DISPENSING ........................................................................47 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING ...........................................48 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ....................................48 
9.2.4 
DRUG ACCOUNTABILITY ...................................................................................48 
10 
STUDY ASSESSMENTS ..............................................................................48 
10.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS .......................................48 
10.1.1 
MEDICAL HISTORY AND DEMOGRAPHICS .........................................................48 
10.1.2 
HEIGHT AND WEIGHT .......................................................................................49 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................49 
10.2 
SAFETY ASSESSMENTS ......................................................................................50 
10.2.1 
PHYSICAL EXAMINATION ..................................................................................50 
10.2.2 
VITAL SIGNS .....................................................................................................50 
10.2.3 
ELECTROCARDIOGRAM .....................................................................................51 
10.2.4 
LABORATORY SAFETY ASSESSMENTS ...............................................................51 
10.2.5 
ADVERSE EVENT RECORDING ...........................................................................53 
10.2.6 
IMMUNOGENICITY .............................................................................................53 
10.2.7 
COLUMBIA-SUICIDE SEVERITY RATING SCALE .................................................53 
10.2.8 
OVERNIGHT OBSERVATIONAL HOSPITALIZATION IN JAPAN ..............................53 
10.3 
EFFICACY ASSESSMENTS ..................................................................................53 
10.3.1 
PRIMARY EFFICACY ASSESSMENTS ...................................................................53 
10.3.2 
SECONDARY EFFICACY ASSESSMENTS ..............................................................54 
10.4 
PHARMACOKINETIC ASSESSMENTS/PHARMACODYNAMIC 
ASSESSMENTS ...................................................................................................54 
10.5 
ADDITIONAL ASSESSMENTS ..............................................................................55 
10.5.1 
MGFA POST-INTERVENTION STATUS ...............................................................55 
10.5.2 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE ...............................................................................................55 
10.5.3 
EQ-5D-5L ........................................................................................................55 
10.5.4 
NEURO-QOL FATIGUE SHORT FORM ................................................................56 
10.5.5 
BIOMARKERS ....................................................................................................56 
10.5.6 
PHARMACOGENOMIC ASSESSMENTS .................................................................56 
11 
SAFETY REPORTING.................................................................................57 
11.1 
DEFINITIONS .....................................................................................................57 
11.1.1 
ADVERSE EVENTS .............................................................................................57 
11.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................57 
11.2 
MONITORING OF INFECTION ..............................................................................58 
11.3 
EVALUATION AND CLASSIFICATIONS ................................................................58 
11.3.1 
SEVERITY ..........................................................................................................58 
11.3.2 
CAUSALITY .......................................................................................................59 
11.4 
RECORDING, REPORTING, AND MONITORING ....................................................59 
11.4.1 
RECORDING AND REPORTING ............................................................................59 
11.4.2 
SAFETY MONITORING .......................................................................................61 
11.4.3 
EMERGENCY UNBLINDING ................................................................................62 
11.5 
SPECIAL CIRCUMSTANCES ................................................................................63 
11.5.1 
PREGNANCY ......................................................................................................63 
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11.5.2 
OTHER ..............................................................................................................63 
12 
STATISTICAL AND ANALYTICAL PLANS ...........................................64 
12.1 
ANALYSIS POPULATIONS ..................................................................................64 
12.1.1 
INTENTION-TO-TREAT POPULATION .................................................................64 
12.1.2 
PER PROTOCOL POPULATION ............................................................................64 
12.1.3 
SAFETY POPULATION ........................................................................................64 
12.2 
ANALYSIS METHODS ........................................................................................64 
12.2.1 
GENERAL METHODS .........................................................................................64 
12.2.2 
SUBJECT DISPOSITION .......................................................................................64 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..............................65 
12.2.4 
ESTIMANDS .......................................................................................................65 
12.2.5 
EFFICACY ANALYSIS .........................................................................................65 
12.2.6 
HANDLING OF MISSING AND CENSORED DATA .................................................66 
12.2.7 
SAFETY ANALYSIS ............................................................................................68 
12.2.8 
CLINICAL PHARMACOLOGY ANALYSIS .............................................................69 
12.2.9 
INTERIM ANALYSIS ...........................................................................................69 
12.3 
SAMPLE SIZE DETERMINATION .........................................................................69 
13 
ETHICAL CONSIDERATIONS ..................................................................69 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE COMMUNICATIONS .......................................................................70 
13.1.1 
PROGRESS REPORTS ..........................................................................................70 
13.1.2 
FINAL INVESTIGATOR REPORT ..........................................................................70 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS ........................................................70 
13.3 
PROTOCOL COMPLIANCE ..................................................................................71 
13.4 
PROTECTION OF CONFIDENTIALITY ...................................................................71 
13.5 
DISCLOSURE OF STUDY RESULTS ......................................................................72 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .........72 
14.1 
QUALITY ASSURANCE .......................................................................................72 
14.1.1 
MONITORING ....................................................................................................72 
14.1.2 
AUDIT ...............................................................................................................72 
14.2 
CLINICAL RESEARCH ORGANIZATIONS .............................................................72 
14.3 
DATA MANAGEMENT ........................................................................................73 
14.3.1 
CASE REPORT FORMS .......................................................................................73 
14.3.2 
SOURCE DOCUMENTS .......................................................................................73 
14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY .............................74 
14.5 
CLINICAL STUDY REPORT .................................................................................74 
14.6 
PUBLICATION POLICY .......................................................................................74 
15 
REFERENCES ...............................................................................................75 
16 
APPENDICES ................................................................................................77 
APPENDIX 1: MG-ACTIVITIES OF DAILY LIVING SCALE .....................................................77 
APPENDIX 2: PROHIBITED CONCOMITANT MEDICATIONS ...................................................78 
 
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LIST OF TABLES 
TABLE 1: TIME AND EVENTS TABLE ...................................................................................19 
TABLE 2: CLINICAL EFFICACY OUTCOMES IN STUDY RA101495-02.201 AT 
WEEK 12 (ANCOVA) ......................................................................................32 
TABLE 3: ZILUCOPLAN DOSE PRESENTATIONS BY WEIGHT BRACKETS ..............................47 
TABLE 4: CHEMISTRY, HEMATOLOGY, AND COAGULATION ANALYTES .............................51 
 
LIST OF FIGURES 
FIGURE 1: MECHANISM OF ACTION OF ZILUCOPLAN IN THE COMPLEMENT 
SYSTEM .............................................................................................................30 
 
 
 
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4 LIST OF ABBREVIATIONS AND DEFINITIONS 
 
AChR acetylcholine receptor 
 
ADA anti-drug antibody 
 
AE adverse event 
 
ALP alkaline phosphatase 
 
ALT alanine aminotransferase 
 ANCOVA analysis of covariance 
 
aPTT activated partial thromboplastin time 
 
AST aspartate aminotransferase 
 
BUN blood urea nitrogen 
 
C5 complement component 5 
 
CFB change from baseline 
 
CFB change from baseline 
COVID-19  corona virus disease 2019 
 
CPK creatine phosphokinase  
 
CRO clinical research organization 
 
CRP c-reactive protein 
 
CSR complete stable remission  
 
C-SSRS Columbia-Suicide Severity Rating 
Scale 
 
CTCAE Common Terminology Criteria for 
Adverse Events 
 
DAP Data Analysis Plan 
 
DNA deoxyribonucleic acid 
 
ECG electrocardiogram 
 
eCRF electronic case report form 
 
EMA European Medicines Agency 
 
FDA Food and Drug Administration 
 
GCP Good Clinical Practice  
 
GGT gamma-glutamyl transferase 
 
gMG generalized myasthenia gravis 
 
HR heart rate 
 
IB Investigator’s Brochure 
 
ICF informed consent form 
 
IEC Independent Ethics Committee 
 
IMP investigational medicinal product 
 
INR international normalized ratio 
 
IRB Institutional Review Board 
 
ISR injection site reaction 
 
IST immunosuppressant therapy 
 
ITT Intention-to-Treat 
 
IV intravenous 
 
IVIG intravenous immunoglobulin G 
 
LFT liver function test 
 
LOCF last observation carried forward 
 
LSLV last subject last visit 
 
MAC membrane attack complex 
 
MCH mean corpuscular hemoglobin 
 
MCHC mean corpuscular hemoglobin 
concentration 
 
MCV mean corpuscular volume 
 
MedDRA Medical Dictionary for Regulatory 
Activities 
 
MG myasthenia gravis  
 MG-ADL Myasthenia Gravis-Activities of Daily 
Living  
MGC  Myasthenia Gravis Composite 
 
MGFA Myasthenia Gravis Foundation of 
America 
 MGFA-PIS MGFA Post-Intervention Status 
MI  multiple imputation  
MMRM  mixed model with repeated measures 
MG-QOL15r Myasthenia Gravis-Quality of Life 
Revised 
MNAR missing not at random 
 
MSE minimal symptom expression 
 
MuSK muscle-specific kinase 
 
NMJ neuromuscular junction 
 
PD pharmacodynamic(s) 
 
PK pharmacokinetic(s) 
 
PLEX plasma exchange 
 
PNH paroxysmal nocturnal hemoglobinuria 
 
PR pharmacologic remission 
 
PT prothrombin time 
 
PTT partial thromboplastin time 
 
RBC red blood cell 
 
QMG Quantitative Myasthenia Gravis  
 
SAE serious adverse event 
 
SAP statistical analysis plan 
 
SAS Statistical Analysis System 
 
SC subcutaneous(ly) 
 
SD standard deviation 
 
SMC Safety Monitoring Committee 
 
SOC standard of care 
 
SOP standard operating procedure 
 
sRBC sheep red blood cell 
 
SUSAR suspected unexpected serious adverse 
reactions 
 
TEAE treatment-emergent adverse event 
 
TMF trial master file 
 
TSH thyroid stimulating hormone 
 
VAS visual analog scale 
 
WBC white blood cell 
WPAI:SHP Work Productivity and Activity 
Impairment Questionnaire: Specific 
Health Problem 
 
 
 
 
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5 INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing zilucoplan, a SC self-administered 15-amino acid 
cyclic peptide that binds to, and inhibits, the cleavage of C5.  
Please refer to the Investigator’s Brochure (IB) for additional information on the 
chemistry, toxicology, pharmacology, safety, and benefit/risk analysis of zilucoplan.  
5.1 
 Overview of Generalized Myasthenia Gravis 
MG is a rare complement-mediated autoimmune disease characterized by the production 
of autoantibodies targeting proteins that are critical for the normal transmission of 
neurotransmitter signals from nerves to muscles. The prevalence of MG in the United 
States and European Union is estimated at approximately 60,000 and 191,000 cases, 
respectively. In 15% of patients with MG, symptoms remain confined to the ocular 
muscles. In approximately 85% of patients MG progresses beyond the ocular muscles to 
affect multiple muscle groups throughout the body, a condition that is typically referred 
to as generalized MG (Gilhus 2016).  
Patients with gMG present with muscle weakness that characteristically becomes more 
severe with repeated use and recovers with rest. Symptoms are typically at their mildest 
in the morning, when overnight inactivity enables replenishment of acetylcholine levels 
in presynaptic motor nerve terminals and worsen during the course of the day. Muscle 
weakness can be localized to specific muscles, but often progresses to more diffuse 
muscle weakness (Chamanza et al. 2010; Gilhus & Verschuuren 2015; Gilhus 2016). 
gMG symptoms can become life-threatening when muscle weakness involves the 
diaphragm and intercostal muscles in the chest wall that are responsible for breathing. 
The most dangerous complication of gMG, known as myasthenic crisis, requires 
hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of 
patients with gMG will experience a myasthenic crisis within two years of diagnosis 
(Ramizuddin 2014). 
The most common target of autoantibodies in gMG is the nicotinic AChR, located at the 
neuromuscular junction (NMJ), the point at which a motor neuron transmits chemical 
signals to a skeletal muscle fiber. Most therapies for gMG focus on either augmenting the 
AChR signal or nonspecifically suppressing the autoimmune response. First-line therapy 
for symptomatic gMG is treatment with acetylcholinesterase inhibitors such as 
pyridostigmine. Although sometimes adequate for control of mild ocular symptoms, 
pyridostigmine monotherapy is usually insufficient for the treatment of generalized 
weakness, and dosing is often limited by cholinergic side effects. Therefore, in patients 
who remain symptomatic despite pyridostigmine therapy, corticosteroids with or without 
systemic ISTs are used off-label (Riedemann et al. 2002; Sanders et al. 2016). ISTs used 
frequently in gMG include azathioprine and mycophenolate mofetil. Cyclosporine, 
methotrexate, tacrolimus, cyclophosphamide, and rituximab are also used occasionally. 
Well-controlled, randomized, efficacy data for these agents are sparse and no steroidal or 
IST has been approved for the treatment of gMG, with the exception of Japan where 
tacrolimus and cyclosporine are approved for gMG (Farmakidis et al. 2018). Moreover, 
all of these agents are associated with well-documented short-term as well as long-term 
toxicities. Surgical removal of the thymus may be recommended in patients with non-
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thymomatous gMG and moderate to severe symptoms, in an effort to reduce the 
production of AChR autoantibodies (Wachtman 2012; Wolfe et al. 2016). IVIG and 
PLEX are invasive therapies, typically used short-term to manage worsening MG 
symptoms and in patients with myasthenic crisis or life-threatening signs such as 
respiratory insufficiency or dysphagia (Riedemann et al. 2002; Sanders et al. 2016). 
However, some patients with severe disease and multiple exacerbations may eventually 
require chronic IVIG or PLEX. 
5.2 
Etiology of Generalized Myasthenia Gravis and the Role of Complement  
MG is caused by the failure of signal transmission from nerve terminals to muscle fibers. 
The structures that mediate this neuromuscular signal transmission are NMJs, sometimes 
also called neuromuscular synapses. NMJs are specialized regions of contact between 
nerve cells and muscle fibers that consist of the nerve terminal, the synaptic cleft and the 
post-synaptic membrane with the latter being a highly specialized region of the muscle 
fiber membrane itself. The postsynaptic membrane of the NMJ is characterized by deep 
folds and densely packed AChR at the top of the folds. 
When an action potential originating from a motor neuron arrives at the nerve terminal of 
the NMJ, it triggers release of the acetylcholine. Only once a sufficiently high 
concentration of acetylcholine is reached in the synaptic cleft, are enough AChRs bound 
and activated to surpass the excitability threshold required for successful propagation of a 
muscle action potential and ensuing contraction of the muscle fiber. 
In patients with MG, the process of signal transmission at the NMJ is inhibited by 
antibodies directed against proteins of the postsynaptic membrane. Most frequently (in 
approximately 80% of MG patients) such antibodies are specific for AChR. 
There is substantial pre-clinical and clinical evidence supporting a role for the terminal 
complement cascade in the pathogenesis of gMG (Howard 2017; Kusner et al. 2018). The 
most common target of autoantibodies in gMG is the AChR. Among AChR 
autoantibodies, there is a predominance of IgG1 and IgG3 immunoglobulin subclasses 
which efficiently activate the classical pathway of complement. Therefore, binding of 
anti-AChR autoantibodies to AChR results in uncontrolled and inappropriate activation 
of the classical complement cascade at the NMJ. The immune complex formed by the 
autoantibody-antigen interaction is recognized by the initiating component of the 
classical complement pathway, the C1 complex. Binding of the C1 complex leads to a 
series of enzymatic cleavage steps culminating in the cleavage of C5 into C5a and C5b 
and deposition of membrane attack complex (MAC) onto the post-synaptic membrane of 
the NMJ with subsequent injury and electrochemical disruption of the neuromuscular 
endplate. As a result, NMJs in MG patients show complement-mediated tissue damage 
characterized by a marked disruption of cytoarchitecture and loss of membrane folds (i.e., 
decrease in overall area of the postsynaptic membrane) and a decrease in AChR density. 
The net effect of this complement-mediated attack is to make it less likely that a 
sufficient number of AChRs can be simultaneously activated to trigger a muscle action 
potential. Deposition of the terminal complement complex in the NMJ is a universal 
finding in gMG patients (Nakan & Engel 1993; Engel et al. 1977) and in rodent models 
of disease (Solyts et al. 2009). 
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5.3 
Rationale for Complement Inhibition in Myasthenia Gravis 
Terminal complement pathway inhibition is expected to rapidly restore the membrane 
potential at NMJs by eliminating the large hydrophilic pores that are formed when MAC 
is deposited in excitable membranes (Jackson et al. 1981). The reduced electrical leakage 
is expected to rapidly improve the safety factor of NMJs (Conti-Fine et al. 2006) and 
improve neuromuscular signal transmission. Sustained complement inhibition is expected 
to lead to restoration of the microanatomy of NMJs including normalization of the 
cytoarchitecture and restoration of the postsynaptic membrane folds, as has been 
observed in animal models of experimental autoimmune MG that were depleted of 
complement C5 with cobra venom (Lennon et al. 1978). From a clinical perspective, the 
persistent clinical benefit over several weeks after treatment discontinuation seen with the 
complement C5 inhibitor eculizumab in a Phase 2 crossover study (Howard et al. 2013) is 
consistent with, although not conclusive of, structural improvement in the NMJ rather 
than a rapidly reversible symptomatic treatment effect as is seen with 
acetylcholinesterase inhibitors (e.g., pyridostigmine). 
Inhibition of C5 for the treatment of gMG has already been shown to be effective in two 
clinical studies with the C5-blocking antibody, eculizumab (Howard et al. 2013; Howard 
2017), which established that inhibition of the terminal complement cascade by blocking 
cleavage of C5 is a clinically validated approach for treating gMG. These data are 
consistent with the beneficial clinical effect observed with zilucoplan in patients with 
gMG in Phase 2 (see Section 5.5.2.1). 
5.4 
 Mechanism of Action of Zilucoplan 
Zilucoplan targets C5, a component of the terminal complement activation pathway. 
Zilucoplan binds to C5 with high affinity and prevents its cleavage by C5 convertases 
into the cleavage products C5a and C5b. Inhibition of C5 cleavage prevents the 
downstream assembly and cytolytic activity of the MAC. 
Using surface plasmon resonance and analysis of a high-resolution co-crystal structure, 
zilucoplan has been shown to bind to a specific site on C5 and to exhibit a strong and 
rapid association with C5, coupled with a slow dissociation rate. Zilucoplan binds to the 
portion of C5 which corresponds to C5b. In binding to this region of C5, should any C5b 
be formed, it will be blocked from binding to C6 by zilucoplan, which further prevents 
the subsequent assembly of the MAC (C5b-9). 
Thus, zilucoplan inhibits MAC formation by a dual mechanism (Figure 1): 
1. Prevention of downstream complement activation by allosterically inhibiting C5 
cleavage. 
2. Direct inhibition of the first step in MAC assembly: C5b-C6-binding. 
 
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Figure 1: Mechanism of Action of Zilucoplan in the Complement System 
Abbreviations: AP: Alternative Pathway of the Complement Cascade; CP: Classical Pathway of the Complement 
Cascade; MBL: Mannose binding Lectin pathway of the complement cascade; MAC: membrane attack complex; 
Complement components are shown using their standard abbreviations. 
The binding site of zilucoplan on the C5 protein is distinct from that of the complement 
C5 inhibitory monoclonal antibody eculizumab. Nishimura and colleagues have 
described 11 patients in Japan (≈3.2% of the PNH population) who carry mutations in the 
C5 gene that prevent the binding of eculizumab to C5 and who are resistant to treatment 
with the antibody (Nishimura et al. 2014). Zilucoplan has been shown to effectively bind 
to C5 from blood samples from patients with this mutation, and to inhibit complement 
activation in vitro. 
Pharmacologically, zilucoplan has demonstrated dose-dependent inhibition of C5a and 
C5b formation following activation of classical or alternative complement pathways, as 
well as inhibition of red blood cell (RBC) lysis in the serum/plasma from various species. 
Zilucoplan is a potent complement inhibitor in humans and primates and a poor inhibitor 
in most other laboratory animal species. 
5.5 
 Clinical Trial Experience with Zilucoplan 
Zilucoplan is currently under clinical development by Ra Pharmacueticals, Inc. for the 
treatment of patients with gMG and paroxysmal nocturnal hemoglobinuria (PNH).  
5.5.1 Zilucoplan Phase 1 Experience 
RA101495-1001 was a randomized, double-blind, placebo-controlled, single-ascending 
dose (SAD) and multiple-dose (MD) study in healthy volunteers. The study was 
conducted to evaluate the safety, tolerability, PK, and PD of single-ascending doses of 
zilucoplan at dose levels of 
 administered by SC 
injection, and multiple-doses of 
 administered SC once daily for 7 days. 
Zilucoplan displayed a dose-proportional and predictable pharmacokinetic profile that 
was tightly correlated with the intended pharmacodynamic effect, suppression of the 
terminal complement pathway. 
Study RA101495-03.101 was an open-label, single dose Phase 1 pharmacokinetic study 
of zilucoplan in subjects with severe renal impairment (as defined by a creatinine 
clearance < 30 ml/min) and healthy controls who received a single dose of 0.3 mg/kg 
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zilucoplan SC. A total of 16 subjects were enrolled into this study: 8 subjects with severe 
renal impairment and 8 healthy controls. Based on the data from this study, there is no 
significant impact of reduced creatinine clearance on the elimination of zilucoplan, and 
therefore no dose adjustment is needed for the use of zilucoplan in patients with renal 
impairment. 
Study RA101495-01.102 was a double-blind, single- and multiple-dose Phase 1 study 
evaluating safety and tolerability of zilucoplan in healthy Japanese subjects in 
comparison to healthy Caucasian subjects. A total of 36 subjects were enrolled in this 
study: 18 Japanese subjects and 18 Caucasian subjects. There were two single dose 
cohorts (0.1 mg/kg and 0.3 mg/kg zilucoplan SC) and one multiple dose cohort (0.3 
mg/kg zilucoplan SC for 14 days). Dose proportionality and metabolite profile were 
similar between the Caucasian and Japanese subjects. Based on the data from this study, 
there is no significant difference between Caucasian and Japanese subjects with respect to 
the pharmacokinetic, pharmacodynamic and safety profiles of zilucoplan. 
A complete overview of results from these Phase 1 studies, including details of PK and 
PD measurements, is provided in the zilucoplan IB. 
5.5.2 Zilucoplan Experience in gMG 
5.5.2.1 Completed Phase 2 Study in gMG  
The safety and efficacy of zilucoplan was evaluated in gMG subjects in the Phase 2 study 
RA101495-02.201. A total of 44 subjects were enrolled in Study RA101495-02.201 and 
randomized to receive placebo, 0.1 mg/kg or 0.3 mg/kg zilucoplan SC daily for 12 weeks. 
Thereafter, subjects randomized to active zilucoplan continue receiving their assigned 
dose, while subjects randomized to placebo were re-randomized to receive active 
zilucoplan at either the 0.1 mg/kg or 0.3 mg/kg dose level. 
The following clinical assessments were performed in Study RA101495-02.201 to 
evaluate efficacy: The QMG scale was the primary outcome measure, and the secondary 
outcome measures included the MG-ADL, the MGC, and the MG-QOL15r. The study 
met its primary endpoint, showing a statistically significant and clinically meaningful 
difference on the QMG between the 0.3 mg/kg zilucoplan and placebo groups, favoring 
zilucoplan. Additional analyses supported the primary analysis and showed a consistent 
clinical benefit of zilucoplan over placebo. The results for the primary and secondary 
analyses are presented in Table 2. 
 
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Table 2: Clinical Efficacy Outcomes in Study RA101495-02.201 at Week 12 (ANCOVA) 
 
QMG 
MG-ADL 
MG-QOL15r 
MGC 
0.3 mg/kg zilucoplan CFB LS mean(se) 
-6.0 (1.2) 
-3.4 (0.9) 
-5.9 (1.7) 
-7.4 (1.6) 
0.1 mg/kg zilucoplan CFB LS mean (se) 
-5.5 (1.2) 
-3.3 (0.9) 
-7.4 (1.7) 
-5.3 (1.5) 
Placebo LS mean CFB (se) 
-3.2 (1.2) 
-1.1 (0.9) 
-2.1 (1.7) 
-3.3 (1.6) 
0.3 mg/kg zilucoplan CFB LS mean 
difference vs. placebo 
-2.8 (1.7) 
-2.3 (1.3) 
-3.7 (2.4) 
-4.1 (2.2) 
p- value* 
0.05 
0.04 
0.06 
0.04 
0.1 mg/kg zilucoplan CFB LS mean 
difference vs. placebo (se) 
-2.3 (1.7) 
-2.2 (1.3) 
-5.3 (2.4) 
-2.0 (2.2) 
p- value* 
0.09 
0.05 
0.02 
0.19 
* p-values are one-sided based on an ANCOVA model with baseline values as a covariate and using LOCF 
for subjects who received rescue therapy 
LS = least squares; CFB = Change from Baseline, se=standard error 
Please refer to the zilucoplan IB for additional information regarding the results from 
studies RA101495-02.201. 
5.6 
Rationale for the Current Study 
Zilucoplan is being developed to treat patients with gMG. Based on the data in Study 
RA101495-02.201, zilucoplan has the potential to provide several advantages over the 
currently approved therapy for gMG, eculizumab.  
As detailed in Section 5.5.2.1 in Study RA101495-02.201, 0.3 mg/kg zilucoplan showed 
a statistically significant and clinically meaningful benefit as measured by improvement 
on the primary endpoint, the QMG, compared to placebo over 12 weeks as well as on the 
MG-ADL, MG-QOL15r, and MGC.  
The clinical benefit of zilucoplan seen in the Phase 2 study compares favorably with 
published data on unapproved SOC therapies such as corticosteroids, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, cyclophosphamide, rituximab, 
PLEX, and IVIG for which only small investigator-initiated trials with positive data 
(cyclosporine, cyclophosphamide, IVIG), circumstantial evidence (azathioprine, PLEX), 
or negative clinical trial data (mycophenolate mofetil, methotrexate, rituximab) are 
available to support efficacy (Farmakidis et al. 2018). 
Moreover, the placebo-corrected clinical efficacy of 0.3 mg/kg zilucoplan daily SC as 
measured by the QMG and MG-ADL at Week 12 is similar to the efficacy observed in 
Phase 3 (Howard et al. 2017) with the approved complement C5 inhibitor eculizumab at 
Week 26 after treatment initiation. Unlike eculizumab, zilucoplan provides patients with 
the advantages of SC self-administration at home and is being evaluated in a broad gMG 
population rather than being restricted to patients who are refractory to all other therapies. 
Given the positive results of the Phase 2 gMG study with zilucoplan, confirmation of 
these findings in a pivotal Phase 3 trial is warranted.  
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5.6.1 Rationale for Blinding and Placebo Control 
The primary objective of Study RA101495-02.301 is the evaluation of efficacy based on 
functional assessment of weakness measured by the MG-ADL Score, as well as 
additional clinical endpoints. Such clinical assessments are prone to placebo effects and 
may be influenced by knowledge of treatment assignment by the clinical evaluator and/or 
subject. Moreover, the evaluation of potential adverse effects may also be influenced by 
knowledge of treatment assignment. To enable rigorous efficacy and safety evaluation 
without the potential bias caused by knowledge of treatment assignment, this study was 
designed as a double-blind placebo-controlled study.  
Subjects entering the study will be allowed to continue their SOC therapy, including 
escalation of treatment as medically necessary (see Section 10.1.3.1). Therefore, subjects 
receiving placebo will not be subject to increased risk due to withholding of medically 
necessary interventions. In addition, the placebo study drug contains substances that are 
known to be well-tolerated (phosphate buffered saline) and are delivered in a small 
volume < 1 mL; therefore, placebo administration by daily SC injection over the 12-week 
study period is expected to be well-tolerated. Consequently, administration of a placebo 
in Study RA101495-02.301 is not anticipated to cause undue burden or risk for study 
subjects. 
Following the completion of the 12-week Treatment Period, all subjects will have the 
option to receive zilucoplan in a separate Extension Study, provided they meet the 
Extension Study inclusion criteria. Therefore, subjects originally randomized to placebo 
will eventually have the opportunity to receive active study drug.  
5.6.2 Dose Selection and Presentation 
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6 STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Estimands/Endpoints 
Primary Efficacy Objective:  
To confirm the efficacy of 
zilucoplan in subjects with gMG 
Primary Estimand: 
Treatment: Zilucoplan administered by daily subcutaneous 
(SC) injection (0.3 mg/kg) vs Placebo 
Target Population: Adults with generalized myasthenia 
gravis (gMG) with inclusion/exclusion criteria provided in 
Section 8.1 and Section 8.2 of the protocol. 
Endpoint: Change from Baseline (CFB) in Week 12 in 
Myasthenia Gravis-Activities of Daily Living (MG-ADL) 
Score 
Intercurrent event handling: 
If a subject experiences any of the following intercurrent 
events, then data at and after the point of the intercurrent 
event will be treated as missing using a hypothetical 
strategy: 
A participant receiving rescue therapy: The study is 
interested in the treatment effect assuming that the treatment 
effect is null, and no rescue effect occurs after a subject 
receives rescue medication.  
A subject discontinuing the study: For subjects that 
discontinue due to AEs related to study drug, it is assumed 
that the treatment effect is null. For subjects that discontinue 
for other reasons (i.e., unrelated to study drug) it is assumed 
that the subject had remained on their treatment throughout 
the study (i.e., a "Hypothetical strategy" assuming subjects 
did not discontinue the study and remained on treatment).  
Population level summary: The difference between the 
zilucoplan and placebo treatment groups in the mean CFB in 
the Week 12 MG-ADL. 
As described in Section 10.3.1, the MG-ADL is a brief 
8-item survey designed to evaluate MG symptom severity. 
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Objectives 
Estimands/Endpoints 
Higher scores are associated with more severe symptoms of 
MG.  
Appendix 1: MG-Activities of Daily Living Scale presents 
the 8 items with corresponding response scale, each scored 
on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 
3=severe). The total score is the sum of the 8 individual 
scores and range 0–24.  
Secondary Efficacy Objective:  
To confirm the efficacy of 
zilucoplan in subjects with gMG 
Secondary Efficacy Endpoints:  
• 
CFB to Week 12 in the Quantitative Myasthenia Gravis 
(QMG) Score 
• 
CFB to Week 12 in the Myasthenia Gravis Composite 
(MGC) Score 
• 
CFB to Week 12 in the Myasthenia Gravis – Quality of 
Life revised (MG-QOL15r) Score  
• 
Time to first receipt of rescue therapy over the 12-week 
Treatment Period 
• 
Achieving Minimal Symptom Expression (MSE), 
defined as an MG-ADL of 0 or 1 at Week 12 without 
rescue therapy 
• 
Achieving a ≥ 3-point reduction in MG-ADL Score at 
Week 12 without rescue therapy  
• 
Achieving a ≥5-point reduction in QMG Score without 
rescue therapy at Week 12 
Secondary Safety Objective:  
To confirm the safety and 
tolerability of zilucoplan in 
subjects with gMG 
Secondary Safety Endpoint: 
• 
Incidence of treatment-emergent AEs 
Other Safety Objective:  
To confirm the safety and 
tolerability of zilucoplan in 
subjects with gMG 
Other Safety Endpoints: 
• 
Physical Examination 
• 
Vital Signs 
• 
ECG 
• 
Clinical Laboratory Tests 
• 
Immunogenicity 
• 
C-SSRS 
Exploratory Objectives 
To assess the PK of zilucoplan 
• 
Plasma concentrations of zilucoplan and its major 
metabolites  
To assess the PD of zilucoplan 
• 
Sheep red blood cell (sRBC) lysis assay for evaluation 
of classical complement pathway activation 
• 
Complement component 5 (C5) levels 
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Objectives 
Estimands/Endpoints 
To explore the efficacy on 
additional efficacy endpoints 
• 
Achievement of Minimal Manifestation Status per 
MGFA Post-Intervention Status (MGFA-PIS) at Week 
12 without rescue therapy 
• 
CFB to Week 12 in Work Productivity and Activity 
Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP)  
• 
CFB to Week 12 in EQ-5D-5L [5-item questionnaire 
and visual analog scale (VAS)]  
• 
CFB to Week 12 in QMG sub-scores: ocular, bulbar, 
respiratory, limb  
• 
CFB to Week 12 in Neuro-QOL Short Form Fatigue 
Scale 
• 
Responder analysis for changes in QMG, MG-ADL, 
MG-QOL15r, and MG Composite Scores from baseline 
without rescue therapy 
To evaluate the emergence of 
antidrug antibodies (ADAs) of 
zilucoplan 
• 
ADAs and neutralizing antibodies at each scheduled 
assessment 
To assess the effect on biomarkers • 
Mechanistic biomarkers pertinent to MG 
pathophysiology [e.g., complement fixation, 
complement function, complement pathway proteins, 
autoantibody characterization (titer and 
immunoglobulin class) and inflammatory markers] 
 
7 STUDY DESIGN 
7.1 
Overview of Study Design  
Study RA101495-02.301 is a multicenter, randomized, double-blind, placebo-controlled 
study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with gMG. 
The planned enrollment is approximately 156 subjects.  
Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg 
zilucoplan or placebo. Randomization will be stratified based on the baseline MG-ADL 
Score (≤9 versus ≥10), QMG Score (≤17 versus ≥18), and geographical region. 
In order to ensure a gradual initiation of the study in Japan, each Japanese site will be 
capped to an enrollment rate of no more than one subject per site per week). 
The study includes a Screening Period of up to 4 weeks and a 12-week Treatment Period. 
During the Treatment Period, subjects will return to the clinic at Week 1, Week 2, and 
monthly visits at Week 4, Week 8, and Week 12 to evaluate efficacy, safety, and 
tolerability. Additional assessments will include questionnaires, biomarker samples, 
pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety 
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assessments will include physical examinations, vital signs, ECG, clinical laboratory 
tests, AE monitoring, immunogenicity, and C-SSRS. 
Randomized subjects will receive 0.3 mg/kg zilucoplan or placebo administered SC at the 
Day 1 visit. Following in-clinic education and training, all subjects will self-inject daily 
SC doses of blinded study drug, according to randomized treatment allocation, for the 
subsequent 12 weeks. Single use pre-filled syringes in injection devices will be provided 
for use during the study. 
In Japan, following their Day 1 dose, subjects will be hospitalized overnight for 
observation to ensure safety of study drug administration. Prior to discharge, subjects will 
be asked to self-administer their Day 2 dose under supervision to ensure that their 
technique for self-injection is adequate and appropriate, and to answer any additional 
questions. These pre-scheduled overnight observational hospitalizations will not be 
considered SAEs in this study (even if hospital stay is extended, provided that the sole 
purpose of the extension is improvement of the injection technique). Subjects will 
continue to self-inject daily SC doses of blinded study drug, according to randomized 
treatment allocation, for the subsequent 12 weeks. 
Subjects are expected to remain on stable doses of all medications unless medically 
indicated changes become necessary. All SOC therapy medications for gMG should be 
kept at the same dose throughout the study, including corticosteroids and IST drugs. If 
escalation of gMG therapy (i.e., ‘rescue therapy’) becomes necessary due to major 
deterioration of a subject’s clinical status, or risk of MG crisis as per the investigator’s 
judgment, the subject may receive IVIG or PLEX treatment as ‘rescue therapy’. In 
Germany, the choice of eculizumab as ‘rescue therapy’ will not be withheld, if the 
investigator considers this to be the best course of action. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an 
unblinded data review should become necessary to ensure subject safety, a SMC will 
convene and evaluate study data as appropriate (see Section 11.4.2.1).  
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must 
be vaccinated against meningococcal infections (with a quadrivalent vaccine and, where 
available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, 
or at the time of, initiating study drug. Subjects who initiate study drug treatment less 
than 2 weeks after receiving a meningococcal vaccine must receive treatment with 
appropriate prophylactic antibiotics (e.g., Penicillin V 500mg twice daily, third 
generation cephalosporin, etc.) until at least 2 weeks after the initial dose of vaccine(s). 
The use of fluoroquinolone or macrolide antibiotics is not recommended due to the 
potential for exacerbation of MG. Booster vaccinations should be administered in 
accordance with SOC.   
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
seek immediate medical attention if any such symptoms occur, will be provided to each 
subject. 
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At the conclusion of the Treatment Period, all subjects will have the option to receive 
zilucoplan in a separate Extension Study, provided they meet the Extension Study 
inclusion criteria.  
If a subject discontinues study drug treatment prior to the Week 12 visit for any reason, 
he/she will not be eligible for the Extension Study. For subjects who permanently 
discontinue study drug, a Safety Follow-up Visit will be performed at 40 days after the 
last dose of study drug, to collect information on any ongoing AEs or new SAEs since the 
last study visit. 
7.2 
Study Periods 
The total duration of study participation for all subjects will be up to approximately 
16 weeks, including a Screening Period of up to 4 weeks and a 12-week Treatment 
Period. For subjects who permanently discontinue study drug at any time, a Safety 
Follow-up Visit will be performed at 40 days after the last dose of study drug, to collect 
information on any ongoing AEs or new SAEs since the last study visit. 
At the conclusion of the Treatment Period of the study, all subjects will have the option 
to receive zilucoplan in a separate Extension Study, provided they meet the Extension 
Study inclusion criteria. In the Extension Study, zilucoplan will be provided by the 
Sponsor until zilucoplan is approved and available in the territory, or the Sponsor 
terminates development of zilucoplan for gMG. In countries where zilucoplan is not 
approved or marketed, but in which sponsored clinical studies have been conducted, 
subjects may continue to receive zilucoplan through a compassionate use pathway. 
7.2.1 Screening Period  
The Screening visit(s) will occur no more than 28 days prior to the first dose of study 
drug on Day 1.  
Subjects that do not meet the entry criteria for the study may rescreen after 8 weeks. 
Subjects may be rescreened no more than 2 times.  
7.2.1.1 Screening and Enrollment 
Procedures performed as SOC during the Screening Period may be used to determine 
eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC. 
At the Screening visit, subjects will be assigned a unique subject number. The following 
assessments will be performed during Screening: 
• Informed consent 
• Completion of the following efficacy assessments: 
o MG-ADL 
o QMG 
o MG-QOL15r 
o MGC 
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• Review of eligibility criteria 
• Review of medical history and demographics, including collection of disease history 
with diagnosis of gMG according to MGFA criteria (Class II-IV), and confirmation 
of serology for AChR autoantibodies  
• Measurement of height and weight 
• Review and documentation of prior and concomitant medications 
NOTE: A complete history of medications taken for the treatment of gMG will be 
collected. All medications taken during 30 days prior to Screening will be recorded. 
• Full physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• 12-lead ECG  
• Neisseria meningitidis vaccination: To reduce the risk of meningococcal infection 
(Neisseria meningitidis), all subjects must be vaccinated against meningococcal 
infections (with a quadrivalent vaccine and, where available and in accordance with 
local SOC, serogroup B vaccine) within 3 years prior to, or at the time of, initiating 
study drug. Subjects who initiate study drug treatment less than 2 weeks after 
receiving a meningococcal vaccine must receive treatment with appropriate 
prophylactic antibiotics (e.g., Penicillin V 500mg twice daily, third generation 
cephalosporin, etc.) until at least 2 weeks after the initial dose of vaccine(s). The use 
of fluoroquinolone or macrolide antibiotics is not recommended due to the potential 
for exacerbation of MG. Booster vaccinations should be administered in accordance 
with SOC. 
• Collection of blood samples for laboratory testing: hematology, chemistry, and 
coagulation (if applicable) 
• Collection of urine sample for urinalysis 
• Serum pregnancy testing for females of childbearing potential only 
• Collection of blood sample for anti-drug antibody (ADA) testing (including 
neutralizing antibody testing) 
• Collection of blood sample for pharmacogenomic analysis (optional)  
NOTE: If the pharmacogenomic analysis sample is not collected at the Screening 
visit, it may also be collected on any other visit during the study 
7.2.1.2 Randomization and Blinding 
Subjects who meet all entry criteria will be randomized in a 1:1 ratio to receive daily SC 
doses of 0.3 mg/kg zilucoplan or placebo. Subjects will be assigned to study arms in a 
blinded fashion using a computerized randomization algorithm. Randomization will be 
stratified based on the baseline MG-ADL Score (≤9 versus ≥10), and QMG Score (≤17 
versus ≥18), and geographical region. 
This is a double-blind study. Subjects and study staff will remain blinded to treatment 
assignments until after the data have been cleaned, locked, and unblinded. 
To facilitate a comprehensive evaluation of all available double-blind data to prepare 
regulatory submissions for approval of the MG target indication, two database locks are 
planned for this study. The first interim lock will occur once the last subject has 
completed Week 12, or after the last subject has prematurely discontinued prior to 
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reaching Week 12. A copy of the randomization list will then be sent to the responsible 
statistician after the first database lock. Only study staff involved in data analysis and 
review will have access to unblinded results. Investigators and site personnel will not be 
unblinded to treatment assignments after the first database lock. A final database lock 
will occur after all data (through to the SFU visit) have been collected. If all the subjects 
have completed the study at the interim look (the last participants entered the extension 
study), then the interim database lock will be the final lock. 
Instructions for emergency unblinding, if warranted, for safety reasons are provided in 
Section 11.4.3. 
7.2.2 Treatment Period  
Subjects will receive treatment with 0.3 mg/kg zilucoplan or placebo, according to 
randomization, from Day 1 to Week 12 during the Treatment Period. 
In Japan, following their Day 1 dose, subjects will be hospitalized overnight for 
observation to ensure safety of study drug administration. Prior to discharge, subjects will 
be asked to self-administer their Day 2 dose under supervision to ensure that their 
technique for self-injection is adequate and appropriate, and to answer any additional 
questions. These pre-scheduled overnight observational hospitalizations will not be 
considered SAEs in this study (even if hospital stay is extended, provided that the sole 
purpose of the extension is improvement of the injection technique). Subjects will 
continue to self-inject daily SC doses of blinded study drug, according to randomized 
treatment allocation, for the subsequent 12 weeks. 
In consultation with the treating physician, subjects who complete the Week 12 Visit 
(including those randomized to the placebo arm) will have the option to continue 
treatment with zilucoplan in a separate Extension Study.  
If a subject chooses not to participate in the Extension Study, the subject will complete an 
End of Study Visit (see Section 7.2.2.1) and receive standard-of-care treatment off-study, 
as recommended by the treating physician. For subjects who permanently discontinue 
study drug at any time, a Safety Follow-up Visit will be performed at 40 days after the 
last dose of study drug, to collect information on any ongoing AEs or new SAEs since the 
last study visit. 
Please refer to Table 1 for details regarding assessments that must be completed at visits 
during the Treatment Period.  
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7.2.2.1 Discontinuation of Investigational Medicinal Product 
If a subject discontinues study drug after the Treatment Period and does not enter the 
Extension Study, the Week 12 Visit and the End of Study Visit are one and the same.  
If a subject prematurely discontinues study drug at any time prior to Week 12 (see 
Section 8.3.2), the subject should return to clinic for a stand-alone End of Study Visit.  
For subjects who permanently discontinue study drug at any time, a Safety Follow-up 
Visit will be performed at 40 days after the last dose of study drug, to collect information 
on any ongoing AEs or new SAEs since the last study visit. 
The following procedures will be completed at the End of Study/Week 12 visit:  
• Completion of the following efficacy assessments: 
o MG-ADL 
 
 o  MG-QOL15r 
o QMG 
 
 o   MGC  
• Completion of the following additional assessments: 
o MGFA-PIS 
 
 o  EQ-5D-5L 
        
o WPAI:SHP 
 
 o  Neuro-QOL 
• Measurement of weight 
• Review and documentation of concomitant medications 
• Full physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• 12-lead ECG 
• Collection of blood samples for laboratory testing: hematology, chemistry, and 
coagulation (if applicable)  
• Collection of urine sample for urinalysis 
• Urine pregnancy testing for females of childbearing potential only 
• Record AEs 
• C-SSRS 
• Collection of blood samples for the following assessments: 
o ADA sampling       o   Biomarker analysis 
o PK analysis 
         o   Auto-antibodies 
o PD analysis 
         o   IgG Subclasses 
• Return of all used and unused study drug syringes to site  
7.3 
Early Study Termination  
The Sponsor may terminate this study early (in its entirety, in part, or at 1 or more study 
sites) for reasonable cause provided that written notice is submitted in advance of the 
intended termination. The investigator may also terminate the study at the site for 
reasonable cause, after providing written notice to the Sponsor in advance of the intended 
termination. Advance notice is not required by either party if the study is stopped due to 
safety concerns. The Sponsor may terminate the study for new or emerging safety 
information that affects the benefit/risk assessment of the product or the clinical trial 
negatively. If the Sponsor terminates the study for safety reasons, the Sponsor will 
immediately notify the investigator and subsequently provide written instructions for  
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If the Sponsor terminates or suspends the study, all applicable Competent Regulatory 
Authorities will be informed as per applicable legislation. 
The end of study, or study termination, is defined as the time at which the last subject has 
performed their last visit (LSLV). Following LSLV, all remaining data will be collected 
in the appropriate case report forms (see Section 14.3.1) and the study results will be 
summarized in the clinical study report (see Section 14.5). 
7.4 
Study Conduct During COVID-19 
The protocol-mandated visit schedule should be followed to the extent possible, based on 
the judgment of the investigator. However, during the COVID-19 outbreak or under other 
exceptional circumstances, remote follow-up will be conducted and the subjects will be 
contacted by telephone/video contact to assess as many details as possible, according to 
the protocol scheduling, to verify that the subject is suitable for continuing study 
treatment. Some procedures may be collected by other remote means if feasible. Study 
sites should make efforts to inform the sponsor or the CRO in the event that procotol 
procedures cannot be completed due to COVID-19. 
In those situations when the subject cannot return to the study site, the investigators will 
assess the subject’s safety by telephone/video contact. Based on information gathered 
from the telephone/video contact, investigators will confirm whether the subject could 
continue the current IMP treatment after the assessment. If the subject is suitable for 
study treatment continuation, the investigator or designee will assess if the subject agrees 
to provide name, address, telephone number and email to the appointed courier. The 
subject will confirm his/her consent by email or verbally in order to receive IMP via 
courier. If the email option is not possible, the site must obtain consent via phone and 
document it in the medical record. 
If the shipment is agreed, the investigator or designee will clearly explain to the subject 
everything needed regarding the handling (in case of inconsistencies at delivery) and 
administration of the study drug and how to return all unused IMP to the study site at the 
next on-site visit. Only after approval by the study staff for the correct shipment, the 
subject will start taking the treatment. The whole process and communication with 
subject will be documented in the subject’s medical source record. Changes in the study 
treatment supply in this situation are described in Section 9.2.1.1. 
Ad hoc subject contact may be warranted to understand the current health status of the 
subjects, to follow up on AEs, and inform them of any protective measures taken by the 
clinical site as a result of the COVID-19 pandemic (eg, any measures that may limit 
access to the site or may require additional actions by the subject prior to entry to the 
site). 
If a subject needs to be discontinued and cannot come into the clinic, a visit will be 
scheduled to perform final safety assessments as soon as possible. 
If a subject visits another facility for a medical issue, the investigator should request 
contact with the physician providing care to provide a detailed explanation of the 
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subject’s condition and his/her participation in the clinical study. Subjects or caregivers 
shall be reminded to completely collect and keep records of this visit. 
Deviations to data collection including inability to perform some assessments, or 
alternative methods of assessment, such as phone calls, should be recorded in the source 
documentation and notated as “not done” in the eCRF. 
8 SELECTION OF STUDY POPULATION 
8.1 
Inclusion Criteria  
To be eligible for this study, subjects must meet ALL of the following inclusion criteria: 
1. Male or female 18 years and <75 years 
2. Able to provide informed consent, including signing and dating the informed consent 
form (ICF) 
3. Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IV] 
at Screening 
4. Positive serology for acetylcholine receptor (AChR) binding autoantibodies 
5. MG-ADL Score of ≥6 at Screening and Baseline 
6. QMG Score of ≥12 at Screening and Baseline (off acetylcholinesterase inhibitor 
therapy for at least 10 hours) 
7. 4 or more of the QMG test items must be scored at ≥2 at Screening and Baseline 
8. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated 
to occur during the 12-week treatment period 
9. No change in immunosuppressive therapy, including dose, for at least 30 days prior to 
Baseline or anticipated to occur during the 12-week treatment period 
10. Vaccination with a quadrivalent meningococcal vaccine and, where available, 
meningococcal serotype B vaccine at least 14 days prior to the first dose of study 
drug at the Day 1 visit. A booster vaccination should also be administered as 
clinically indicated, according to the local SOC, for subjects who have been 
previously vaccinated against Neisseria meningitidis 
11. Female subjects of childbearing potential must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test within 24 hours prior to the first 
dose of study drug 
12. Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation) and all male subjects (who have not been surgically sterilized 
by vasectomy) must agree to use effective contraception during the study and during 
the safety follow-up period of 40 days after the last dose of study drug. 
Postmenopausal women are, for the purposes of this protocol, defined as women who 
have not had menses for 12 months without an alternative medical cause. A high 
follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
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8.2 
Exclusion Criteria 
Subjects who meet ANY of the following exclusion criteria must be excluded from the 
study:  
1. Thymectomy within 12 months prior to baseline or scheduled to occur during the 12-
week study 
2. Abnormal thyroid function as determined by local standard 
3. Known positive serology for muscle-specific kinase (MuSK)  
4. Minimal Manifestation Status of MG based on the clinical judgement of the 
investigator 
5. Fixed weakness (‘burnt out’ MG) based on the clinical judgement of the investigator 
6. History of meningococcal disease 
7. Current or recent systemic infection within 2 weeks prior to Baseline or infection 
requiring intravenous (IV) antibiotics within 4 weeks prior to Baseline 
8. Pregnant, planning to become pregnant, or nursing female subjects 
9. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or 
expected to have surgery requiring general anesthesia during the 12-week Treatment 
Period 
10. Prior treatment with a complement inhibitor  
11. Treatment with an experimental drug within 30 days or 5 half-lives of the 
experimental drug (whichever is longer) prior to Baseline 
12. Treatment with rituximab within 12 months prior to Baseline or planned to occur 
during the 12-week study (this exclusion criterion is implemented out of an 
abundance of caution, in the absence of data showing that complement inhibition in 
the context of B-cell elimination by rituximab is safe) 
13. Treatment with IVIG, SC immunoglobulin, or PLEX 4 weeks prior to Baseline 
14. Active malignancy (except curatively resected squamous or basal cell carcinoma of 
the skin) requiring surgery, chemotherapy, or radiation within the prior 12 months 
(subjects with a history of malignancy who have undergone curative resection or 
otherwise not requiring treatment for at least 12 months prior to Screening with no 
detectable recurrence are allowed) 
15. History of or current significant medical disorder, psychiatric disorder, or laboratory 
abnormality that in the opinion of the investigator would make the subject unsuitable 
for participation in the study 
16. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is 
permitted) 
17. Unable or unwilling to comply with the requirements of the study 
18. Hypersensitivity to zilucoplan, any of its excipients, or to placebo 
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8.3 
Removal of Subjects in the Study 
8.3.1 Withdrawal of Consent 
A subject may withdraw consent to participate in this study at any time without penalty 
or loss of benefits to which the subject is otherwise entitled to. When a subject wishes to 
withdraw consent, it is important to distinguish between withdrawing his/her consent for 
a particular study procedure or visit versus withdrawing his/her consent from the study 
entirely (i.e., premature discontinuation). 
When a subject withdraws consent from the study (or study procedure), the reason(s) for 
withdrawal will be recorded by the investigator or designee on the relevant page of the 
electronic case report form (eCRF). 
8.3.2 Premature Discontinuation 
Every reasonable effort should be made to encourage retention of subjects in the study, 
maximize compliance with study drug, and facilitate attendance at all scheduled study 
visits/assessments.  
All subjects have the right to refuse further participation in the study at any time and for 
any reason. A subject’s participation must, therefore, be terminated immediately upon 
his/her request. 
The investigator will make every attempt to ascertain the reason(s) for discontinuation 
and to document this in detail in the source documentation and the appropriate sections of 
the eCRF. A subject must be withdrawn from the study for any of the following reasons:  
• Withdrawal by subject 
• Protocol Violation/Noncompliance (defined as refusal or inability to adhere to the 
study procedures) 
• Pregnancy while receiving study drug 
• At the request of the Sponsor, regulatory agencies, or IRB/IEC 
• Physician decision 
• Loss to follow-up 
• Death 
• Safety/best interest of the subject as determined by the investigator or Sponsor 
• Intolerability of study medication 
Dosing of a subjects may be interrupted or permanently discontinued if, in the opinion of 
the investigator and / or Sponsor, it is unsafe for the subject to continue dosing with study 
medication. Subjects diagnosed with meningococcal disease will be discontinued 
immediately and permanently. 
All subjects who prematurely discontinue study treatment (i.e., prior to Week 12 visit) for 
any reason will not be eligible to participate in the Extension Study. 
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8.3.3 Replacement of Subjects 
Subjects who prematurely discontinue participation prior to the Day 84 visit may be 
replaced to obtain an adequate number of subjects that complete the study (see 
Section 12.3), additional subjects may be enrolled into the study, at the discretion of the 
Sponsor. 
9 INVESTIGATIONAL MEDICINAL PRODUCTS AND 
TREATMENTS 
9.1 
Study Treatment Administration 
9.1.1 Investigational Medicinal Product and Placebo 
 
 
 
Table 3. 
The BD Ultrasafe Plus device complies with applicable European requirements for a 
Class I medical device under Rule 1 of Annex IX of the Directive; a Declaration of 
Conformity per Annex VII of the EU Medical Device Directive (Council Directive 
93/42/EEC concerning medical devices) is available for this device. 
9.1.2 Dosing Schedule 
All eligible subjects will be randomized 1:1 to receive 0.3 mg/kg zilucoplan or placebo 
administered SC at the Day 1 visit, which will be performed by the subject while 
observed by the site staff at the study visit. Following in-clinic education and training, all 
subjects will self-inject daily SC doses of study drug at approximately the same time each 
day for the remainder of the Treatment Period.  
Dosing on study visit days should be held until all assessments (e.g., MG-ADL, QMG, 
MG-QOL15r, MGC, questionnaires, sample collection, etc.) have been completed. On 
days when rescue therapy is concurrently administered, study drug dosing should be held 
until after administration of rescue therapy and PK/PD sampling.  
At each study visit, dosing should be supervised to ensure correct injection technique. 
9.1.3 Dose Presentation  
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Subjects who present with a higher body weight (≥150 kg) or a lower body weight 
(<43 kg) will be accommodated on a case-by-case basis, in consultation with the medical 
monitor. 
9.1.3.1 Missed Doses  
In Japan, subjects will be instructed to self-inject SC doses daily at approximately the 
same time each day. A missed dose will be defined as a dose missed 36 hours from the 
previous dose. 
Study personnel will assess study drug compliance at every visit to record whether any 
doses were missed. If a subject misses 1 dose (i.e., 1 day) of study drug, he/she should 
take the next planned dose as scheduled and the investigator should be contacted as soon 
as possible. If a subject misses 2 or more doses, he/she must notify the investigator 
immediately and the medical monitor should be consulted.  
If a subject misses 10 or more consecutive doses, he/she must notify the investigator 
immediately, the medical monitor should be consulted, and this will be considered a 
major protocol deviation. 
9.2 
Study Treatment Management 
9.2.1 Preparation and Dispensing 
Prefilled syringes will be dispensed to each subject at each study visit, beginning on 
Day 1 of the Treatment Period.  
Subjects will be provided with training and detailed instructions on the administration of 
study drug using the single use pre-filled syringes in injection devices. 
9.2.1.1 Alternative Study Treatment Supply Due to COVID-19 Pandemic 
In circumstances where the subject is not allowed to visit the site, the IMP may be 
delivered directly to the subject via qualified courier that will act as a liaison between 
sites and subjects to deliver the drug during the outbreak. 
If the shipment of the drug directly to the subject is agreed, the investigator or designee 
will clearly explain proper handling and administration of the study drug. Subjects will be 
instructed to return all unused IMP at the next on-site visit. 
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9.2.2 Study Drug Supply, Storage, and Handling 
Zilucoplan and placebo should be stored at 2°C to 8°C at the study site. Once dispensed 
to subjects, zilucoplan and placebo may be stored at room temperature [20°C to 25°C 
(68°F to 77°F)] for up to 45 days protected from sources of heat, light, and damage. 
Storage of zilucoplan and placebo outside of room temperatures should be avoided. 
Please refer to the study Pharmacy Manual for additional details. 
Subjects will be instructed to self-inject SC doses daily at approximately the same time 
each day. The subject may inject study drug into the abdomen (preferred site), thigh, or 
upper arm. 
All subjects will receive study drug kits, each of which will include 7 single-dose, 
prefilled syringes (pre-loaded into self-injection devices) containing study drug, alcohol 
wipes, and adhesive dressings, as well as a syringe disposal container. 
9.2.3 Disposal, Return, or Retention of Unused Drug 
Subjects will receive secure containers to dispose of used syringes while at home. At 
each visit, the subject should return the container containing all used syringes to the site. 
The unused study drug (i.e., unused syringes) and containers should be returned by the 
subject at each study visit.  
All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the last study visit (i.e., End of Study Visit). 
9.2.4 Drug Accountability 
It is the responsibility of the pharmacist to ensure that a current record of inventory/drug 
accountability is maintained. Inventory records must be readily available for inspection 
by the study monitor and are open to inspection by regulatory authorities at any time. For 
further details, please consult the Pharmacy Manual.  
10 STUDY ASSESSMENTS 
Please refer to Table 1 for the timing of study assessments. All assessments are to be 
completed in the same order and approximately at the same time at each visit, starting 
with efficacy assessments, additional clinical and safety assessments, laboratory 
evaluations and study drug administration. 
10.1 Subject and Baseline Disease Characteristics 
10.1.1 Medical History and Demographics 
Relevant medical history (including surgical history) will be documented at the Screening 
visit to assess subject eligibility. The following demographic data will be collected: date 
of birth, gender, ethnicity, and race.  
The Screening assessment will also include disease history with documentation of the 
diagnosis of gMG by MGFA criteria (Class II-IV), serology for AChR autoantibodies, 
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and efficacy assessments (i.e., MG-ADL, QMG, MG-QOL15r, and MGC) (see Section 
10.3.1 for additional instructions).  
10.1.2 Height and Weight  
Height (cm) will be collected at the Screening visit only. Weight (kg) will be measured at 
the study visits indicated in Table 1. 
10.1.3 Prior and Concomitant Medications 
All prescriptions and over-the-counter medications taken during the 30 days prior to 
Screening through the last study visit will be documented. NOTE: A complete history of 
medications taken for the treatment of gMG will be collected.  
Concomitant medications include any prescription or over-the-counter medication that is 
ongoing on Day 1 or that is initiated following the first dose of study drug on Day 1.  
Medications, including over the counter therapeutics, natural products, and vitamins, 
should not be changed during the Screening or Treatment Periods, unless medically 
necessary. Please refer to Appendix 2: Prohibited Concomitant Medications for a list of 
prohibited concomitant medications. 
Subjects are expected to remain on stable doses of SOC therapy for gMG throughout the 
study, including corticosteroids and IST drugs. The pyridostigmine dose may be reduced 
if the investigator identifies intolerable side effects clearly related to pyridostigmine. 
Prior to altering the dose of pyridostigmine, the investigator should contact the medical 
monitor. Any pyridostigmine, regardless of the dosing regimen, is to be withheld for a 
minimum of 10 hours prior to clinical evaluation. 
Dose of SOC treatment should not be increased during the study. Instead, rescue therapy 
as described in Section 10.1.3.1 should be administered.  
Medications will be recorded on the subject’s source documents and entered on the 
appropriate eCRF. Any changes to concomitant medications will be recorded in the 
eCRF. Physical therapy interventions and medical devices are considered concomitant 
interventions and will be captured in the procedures eCRF.  
10.1.3.1 Rescue Therapy 
Subjects are expected to remain on stable doses of all medications unless medically 
indicated changes become necessary. All SOC therapy medications for gMG should be 
kept at the same dose throughout the study, including corticosteroids and IST drugs. If 
escalation of gMG therapy (i.e., ‘rescue therapy’) becomes necessary due to major 
deterioration of a subject’s clinical status, or risk of MG crisis as per the investigator’s 
judgment, the subject may receive IVIG or PLEX treatment as ‘rescue therapy’.  
In Germany, the choice of eculizumab as ‘rescue therapy’ will not be withheld, if the 
investigator considers this to be the best course of action. In subjects with refractory 
gMG, the use of eculizumab (according to its marketing authorization) may only be 
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waived if the use of eculizumab is contraindicated, ineffective, or not tolerated. Upon 
initiation of eculizumab, subjects will discontinue study drug, but will otherwise 
complete the study as planned. Initiation of eculizumab is considered ‘rescue therapy’ as 
per protocol. 
If such rescue therapy becomes necessary, the choice of IVIG vs. PLEX vs eculizumab, 
as well as the frequency and duration of such therapy, will be determined by the 
investigator. Escalation of doses of corticosteroids or IST drugs (other than initiation of 
eculizumab) for rescue is not permitted. The Sponsor should be notified immediately 
upon determination that rescue therapy is necessary in any given subject. 
A Rescue Therapy Visit should be performed prior to initiation of rescue therapy (see 
Table 1 for a list of applicable study procedures).  
Unblinding of treatment assignment prior to initiation of rescue therapy will not be 
allowed, unless critical for reasons of subject safety. The subject will continue their 
blinded treatment and complete all study-specified assessments while undergoing rescue 
therapy and through the end of the study if the investigator, in consultation with the 
medical monitor, considers this course of action in the best interest of the subject. Details 
on the rescue therapy, as well as reasons for initiation of rescue therapy, will be collected. 
10.2 Safety Assessments 
10.2.1 Physical Examination  
A physical examination will be performed on all subjects at the visits listed in Table 1 
and will include the following assessments: 
• Abdomen 
• Cardiac 
• Eyes, Ears, Nose & Throat 
• General appearance 
• Head & Neck 
• Musculoskeletal 
• Neurological 
• Respiratory 
• Skin/Mucosal 
Clinically significant physical examination abnormalities will be reported as AEs, when 
appropriate.  
Physical examinations should also include an examination of the injection site(s). If an 
injection site reaction (ISR) is observed or reported by the subject, it should be recorded 
as an AE in the eCRF.  
10.2.2 Vital Signs 
Vital signs (HR, body temperature, and blood pressure) will be measured in the sitting 
position. If blood samples are scheduled at the same time, vital signs should be measured 
before the blood draw. Blood pressure may be measured manually or by automated 
device, preferably using the non-dominant arm. The same measurement technique should 
be used throughout the study for the same subjects.  
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10.2.3 Electrocardiogram  
12-lead ECGs will be assessed as normal or abnormal by the investigator or delegate; any 
abnormal findings will be described in the eCRF and the investigator will assess clinical 
significance. The ECG recording strip will be signed and dated by the investigator and 
stored in the medical records. 
Subjects should be in the supine position for at least 5 minutes prior to and during the 
ECG measurement. ECGs should be performed prior to blood draws when both 
assessments are required at the same visit. 
10.2.4 Laboratory Safety Assessments 
Safety laboratory tests for this study [chemistry, hematology, coagulation (for applicable 
subjects), and urinalysis] are to be performed by a central laboratory, and only values 
from the central laboratory are to be entered into the laboratory section of the study 
database. Values from local laboratories may be used to determine eligibility for study 
enrollment and as the basis for clinical decisions. 
10.2.4.1 Hematology, Chemistry, and Coagulation 
Hematology, chemistry, and coagulation analytes that will be assessed during the study 
are identified in Table 4 and should be performed as specified in Table 1. 
All laboratory samples should be collected prior to the administration of study drug at 
applicable visits.  
Coagulation tests should only be performed in subjects receiving anticoagulant therapy.  
Table 4: Chemistry, Hematology, and Coagulation Analytes 
Chemistry 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Bilirubin (total) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lipase 
Potassium 
Sodium 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count and differential (%) 
Basophils (% and absolute) 
Eosinophils (% and absolute) 
Lymphocytes (% and absolute) 
Monocytes (% and absolute) 
Neutrophils (% and absolute) 
Coagulation 
International normalized ratio (INR)/prothrombin time (PT) 
Partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) 
Other 
C-reactive protein (CRP) 
Thyroid Stimulating Hormone (TSH) – screening only 
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10.2.4.2 Urinalysis 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), 
glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult 
blood, hemoglobin, and cells. A microscopic examination will be performed, if 
necessary.  
10.2.4.3 Pregnancy Testing and Contraception 
A serum pregnancy test for human chorionic gonadotropin will be performed on female 
subjects of childbearing potential at Screening.  
A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on 
female subjects of childbearing potential at all other study visits as specified in Table 1. 
Negative pregnancy tests must be documented for all female subjects of childbearing 
potential prior to dosing at applicable study visits.  
Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation) and all male subjects (who have not been surgically sterilized by 
vasectomy) must agree to use effective contraception during the study and during the 
safety follow-up period of 40 days after the last dose of study drug. Postmenopausal 
women are, for the purposes of this protocol, defined as women who have not had 
menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. Effective contraception is defined as: 
• Hormonal contraception (e.g., oral contraceptive, transdermal contraceptive, 
contraceptive implant, or injectable hormonal contraceptive) for at least 3 months 
prior to study drug administration, throughout the study, and for 40 days after the 
last dose of study drug. 
• In countries other than Germany and Norway, double-barrier birth control (e.g., a 
combination of male condom with either cap, diaphragm, or sponge together with 
spermicide) starting at the Screening visit, throughout the study, and for at least 
40 days after the last dose of study drug. 
NOTE: Use of a male and female condom simultaneously is NOT an acceptable 
method of double-barrier birth control.  
• Intrauterine contraception/device starting at the Screening visit, throughout the 
study, and for 40 days after the last dose of study drug. 
• Total abstinence from sexual intercourse (only acceptable if it is the preferred and 
usual lifestyle of the subject) for at least 1 complete menstrual cycle prior to the 
Screening visit, throughout the study, and for 40 days after the last dose of study 
drug. 
• Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy. 
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NOTE: Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are 
not acceptable methods of contraception. 
10.2.5 Adverse Event Recording  
Guidance on the identification, monitoring, and reporting of AEs is provided in 
Section 11.  
10.2.6 Immunogenicity 
Blood samples for ADA and neutralizing antibody assessment will be collected as 
specified in Table 1 in all enrolled subjects. These samples will be banked and used to 
investigate and characterize any ADA and neutralizing antibody response over time in the 
general study population.  
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.2.7 Columbia-Suicide Severity Rating Scale 
In accordance with the draft FDA Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials Guidance for Industry (FDA 2012) subjects 
will be asked to complete the C-SSRS at study visits as specified in Table 1. 
10.2.8 Overnight Observational Hospitalization in Japan 
In Japan, following their Day 1 dose, subjects will be hospitalized overnight for 
observation to ensure safety of study drug administration. Prior to discharge, subjects will 
be asked to self-administer their Day 2 dose under supervision to ensure that their 
technique for self-injection is adequate and appropriate, and to answer any additional 
questions. These pre-scheduled overnight observational hospitalizations will not be 
considered SAEs in this study (even if hospital stay is extended, provided that the sole 
purpose of the extension is improvement of the injection technique). Subjects will 
continue to self-inject daily SC doses of blinded study drug, according to randomized 
treatment allocation, for the subsequent 12 weeks. 
10.3 Efficacy Assessments  
10.3.1 Primary Efficacy Assessments 
The primary efficacy endpoint is the CFB to Week 12 in MG-ADL Score. 
The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. 
Higher scores are associated with more severe symptoms of MG. A 2-point change in 
MG-ADL Score is considered clinically meaningful (Wolfe et al. 1999; Muppidi et al. 
2011). 
Clinical Evaluators must be adequately trained prior to conducting any efficacy 
assessments. The MG-ADL assessment will be performed at Screening to assess subject 
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eligibility and at each study visit according to Table 1. The MG-ADL assessment must be 
performed at approximately the same time of day (preferably in the morning) and 
administered by the same well-trained evaluator (e.g., neurologist, physical therapist, or 
other study staff experienced in clinical assessments) at each visit throughout the study. If 
a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 10 
hours prior to the assessment. Detailed instructions regarding the administration of the 
MG-ADL test will be provided to sites.  
10.3.2 Secondary Efficacy Assessments 
Detailed instructions regarding the administration of the secondary efficacy assessments 
will be provided to sites. 
10.3.2.1 Quantitative Myasthenia Gravis 
The QMG is a standardized and validated quantitative strength scoring system that was 
developed specifically for MG. If a subject is receiving a cholinesterase inhibitor, the 
dose must be withheld for at least 10 hours prior to the assessment. Higher scores are 
representative of more severe impairment. A change in the QMG Score of 3 points or 
more may be considered clinically meaningful, in a typical clinical trial population of 
MG patients (Barohn et al. 1998; Katzberg et al. 2014).  
10.3.2.2 MG Composite  
The MGC is a 10-item scale that has been used to measure the clinical status of patients 
with MG, both in the practice setting and in clinical trials, in order to evaluate treatment 
response. Higher scores in the MGC indicate more severe impairment due to the disease. 
A 3-point change in this assessment is considered clinically meaningful (Benatar et al. 
2012; Sadjadi 2012).  
10.3.2.3 MG-QOL15r 
The MG-QOL15r is a 15-item survey that was designed to assess quality of life in 
patients with MG. Higher scores indicate more severe impact of the disease on aspects of 
the patient’s life (Burns et al. 2010; Burns et al. 2016). 
10.3.2.4 Minimal Symptom Expression  
MSE is designed to assess how many subjects become free or virtually free of MG 
symptoms as measured by achieving an MG-ADL total score of 0 or 1 on therapy 
(Vissing et al. 2018). 
10.4 Pharmacokinetic Assessments/Pharmacodynamic Assessments 
Blood samples for PK/PD assessments will be collected from all subjects and include 
measurements of: 
• Plasma concentration of zilucoplan and its major metabolites 
• sRBC lysis assay for evaluation of classical complement pathway activation 
• C5 levels 
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Blood samples for PK and PD analysis will be obtained prior to administration of study 
drug (within 1 hour of dosing). If Rescue Therapy is administered at a location separate 
from the clinical site, then there is no need to collect blood samples for PK/PD. For local 
Rescue Therapy visits, PK and PD samples will be collected at the following time points:  
 
During Rescue Therapy 
ONLY at sites where rescue therapy is administered locally 
Within 1 hour before administration of each round of rescue therapy 
For PLEX only: PK will be measured in the exchanged plasma 
Within 1 hour after administration of each round of rescue therapy 
All samples will be sent to an accredited laboratory for analysis, and results will remain 
blinded until after database lock. Detailed instructions regarding PK/PD sample 
collection, processing, and shipping will be provided to sites. 
10.5 Additional Assessments  
10.5.1 MGFA Post-Intervention Status 
The MGFA-PIS is a physician-determined assessment of a clinical symptoms of MG 
after initiation of MG specific therapy. Minimal Manifestation is defined as follows: 
‘The patient has no symptoms of functional limitations from MG but has some weakness 
on examination of some muscles. This class recognizes that some patients who otherwise 
meet the definition of Complete Stable Remission (CSR) or Pharmacologic Remission 
(PR) do have weakness that is only detectable by careful examination.’ 
For the purpose of the current study, Minimal Manifestation will be determined at each 
timepoint after treatment initiation (rather than after 1 year). Change in status (improved, 
unchanged, worse, exacerbation, or died of MG) will also be determined.  
10.5.2 Work Productivity and Activity Impairment Questionnaire 
The WPAI:SHP is a standardized 6-item questionnaire for assessing the amount of both 
absenteeism (work time missed) and presenteeism (reduced on-the-job effectiveness) due 
to health problems (Reilly et al. 1993). All subjects will be asked to complete the 
WPAI:SHP questionnaire in accordance with Table 1. 
10.5.3 EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for measuring generic health status. The EQ-
5D which consists of the EQ-5D descriptive system and the EQ VAS. The EQ-5D 
descriptive system is comprised of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression; each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, extreme problems 
(EuroQOL Group 1990). Subjects answer questions based on symptoms and health status 
on the day the questionnaire is completed. All subjects will be asked to complete the EQ-
5D-5L in accordance with Table 1. 
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10.5.4 Neuro-QOL Fatigue Short Form 
The Neuro-QOL Fatigue Short Form is part of the Neuro-QOL battery of measures that 
quantify the physical, mental, and social effects experienced by patients with 
neurological conditions. The Neuro-QOL Scales were developed with National Institutes 
of Health (NIH) funding to standardize assessments of these evaluations across patients 
with neurological diseases. Fatigue is a frequent complaint in subjects with MG but has 
rarely been formally assessed to date. The Neuro-QOL Short Form will be used to 
explore any potential effect of treatment of zilucoplan on fatigue. All subjects will be 
asked to complete the Neuro-QOL Fatigue Short Form in accordance with Table 1. 
10.5.5 Biomarkers 
Blood samples for mechanistic biomarker testing [e.g., complement fixation, complement 
function, complement pathway proteins, autoantibody characterization (titer and 
immunoglobulin class), and inflammatory markers] will be obtained prior to 
administration of study drug (within 1 hour of dosing) in accordance with Table 1. 
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
The analysis of biomarkers pertaining to the pathophysiology of MG [e.g., complement 
fixation, complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class), and inflammatory markers] may 
provide further insight into the clinical efficacy and safety of zilucoplan in subjects with 
gMG. Complement protein levels and complement activity will be tested to evaluate 
response to zilucoplan and to understand subject characteristics related to variations in 
response to drug. Markers of inflammation may be tested to assess correlation with 
complement function and clinical response to zilucoplan. A list of analytes will be 
created through review of the literature, ongoing clinical studies, and ongoing exploratory 
work and may be finalized after completion of the study.  
The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the biomarker analysis may be reported separately from the main 
clinical study report. 
10.5.6 Pharmacogenomic Assessments 
Participation in the pharmacogenomic assessment is optional, and subjects must provide 
additional consent for the pharmacogenomic analysis. 
For subjects who choose to participate in pharmacogenomic studies, a blood sample will 
be obtained. All genomic analyses will be performed at an accredited laboratory. Detailed 
instructions regarding sample collection, processing, and shipping will be provided to 
sites. 
Genomic studies (e.g., deoxyribonucleic acid (DNA) sequencing) including exploration 
of whether specific genomic features correlate with response or resistance to study drug, 
may be performed. 
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The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the genomic investigations may be reported separately from the 
main clinical study report. 
11 SAFETY REPORTING 
11.1 Definitions 
11.1.1 Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with study treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The following are not considered to be AEs despite requiring hospitalization: 
• Pre-existing conditions that, in the opinion of the investigator, did not worsen or 
progress during study participation 
• Routinely scheduled procedures or treatment 
• Elective procedures that were scheduled prior to study participation (i.e., signing of 
the ICF) 
All AEs should be appropriately recorded according to the instructions in Section 11.4. 
11.1.1.1 Occurrence of COVID-19 
Occurrence of COVID-19 in subjects should be reported as either “suspected 
COVID-19” or “confirmed COVID-19” along with all available relevant data, including 
diagnostic and laboratory data. For subjects where COVID-19 is still suspected despite a 
negative viral test, please report as “suspected COVID-19” and provide relevant data to 
support the diagnosis as well as the test results. 
11.1.2 Serious Adverse Events 
An SAE is any AE that: 
• Results in death 
• Is life-threatening (note that this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe) 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
An SAE may also be any other important medical event that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or 
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require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events include intensive treatment in an emergency room or at home 
for bronchospasm, hyperkalemia, or convulsions that do not result in a formal 
hospitalization. 
Elective hospitalizations that were scheduled prior to study participation (i.e., signing of 
the ICF) are not considered to be SAEs and should not be reported.  
Also, in Japan, overnight observational hospitalizations to ensure to ensure safety of 
study drug administration will not be considered SAEs in this study (even if extended, 
provided that the sole purpose of the extension is improvement of the injection 
technique). 
11.2 Monitoring of Infection 
All subjects will be monitored at every study visit for signs and symptoms of Neisseria 
meningitidis infection. 
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must 
be vaccinated against meningococcal infections (with a quadrivalent vaccine and, where 
available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, 
or at the time of, initiating study drug. Subjects who initiate study drug treatment less 
than 2 weeks after receiving a meningococcal vaccine must receive treatment with 
appropriate prophylactic antibiotics (e.g., Penicillin V 500mg twice daily, third 
generation cephalosporin, etc.) until at least 2 weeks after the initial dose of vaccine(s). 
The use of fluoroquinolone or macrolide antibiotics is not recommended due to the 
potential for exacerbation of MG. Booster vaccinations should be administered in 
accordance with SOC.  
To mitigate the risk of infection, subjects will be counseled and reminded of the early 
signs and symptoms of Neisseria meningitidis infection. A patient safety card detailing 
the signs and symptoms of infection, with instructions to seek immediate medical 
attention if any such symptoms occur, will be provided to each subject. 
11.3 Evaluation and Classifications 
11.3.1 Severity 
The investigator should determine the severity of the reported AE by using the Common 
Terminology Criteria for Adverse Events (CTCAE).  
For any reported AE not described in the CTCAE, the following guidelines must be 
considered for severity evaluation: 
Adverse Event Severity 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s). 
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Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
11.3.2 Causality 
The causal relationship of the AE to study drug will be assessed by both the investigator 
and the Sponsor. The assessment of causal relationship to study drug should be evidence-
based, and not based on the premise that all AEs are causally related to study drug until 
proven otherwise. Default categorization of ‘related’ without supportive evidence for a 
causal relationship to study drug is generally uninformative and does not contribute to 
understanding of the safety profile of the drug with respect to the intended population. 
Examples of evidence that would suggest a causal relationship between the study drug 
and the AE include the occurrence of an AE that is known to be strongly associated with 
drug exposure (e.g., ISRs) or an AE that is otherwise uncommon in the study population. 
Lack of efficacy of study drug, in isolation, leading to unmasking of underlying 
symptoms and signs of disease, should NOT be considered evidence of relatedness. 
The causal relationship of each AE is assessed using a binary system, with all AEs 
classified as either ‘related’ or ‘not related’. 
Related: There is ‘reasonable possibility’ that the study drug caused the AE. The AE 
follows a reasonable temporal association from the time of study drug administration. 
There is supportive evidence to suggest a possible causal relationship, irrespective of the 
degree of certainty, between the observed AE and the study drug. There is no alternative 
more likely explanation for the AE. Lack of study drug efficacy is not considered, by 
itself, to be evidence of relatedness.  
Not Related: Lack of a reasonable temporal or causal association from the administration 
of the study drug and the occurrence of the AE. There is evidence of an alternative 
explanation that is more likely the cause of the AE. 
11.4 Recording, Reporting, and Monitoring 
11.4.1 Recording and Reporting 
The investigator must make every effort to properly evaluate all information relevant to 
the reported AE in such a way that a diagnosis can be confidently made and reported. For 
example, it is preferable to report ‘pneumonia’ as the AE rather than its symptoms (e.g., 
‘rales’ or ‘fever’) as separate AEs. 
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When recording and/or reporting AEs or SAEs, the following elements must be included: 
• The fulfilled criteria for seriousness as presented in Section 11.1.2 
• The severity of the event as defined in Section 11.3.1 
• The relationship of the event to study treatment as defined in Section 11.3.2 
Actions taken in relation to the AE will be recorded as drug discontinued, drug 
interrupted, concomitant medication, other action (e.g., diagnostic testing), or no action. 
Any medication given to treat the AE will be recorded separately in the concomitant 
medication list of the eCRF. 
The outcome of the AE will be recorded as date ended, ongoing, or resulting in death 
with date of death. 
11.4.1.1 Adverse Events 
Pre-existing conditions that are detected prior to administration of the first dose of study 
drug will be recorded as part of the medical history. For all subjects, the AE reporting 
period will start with the first administration of study drug on Day 1 and will end with the 
last study visit (i.e., End of Study Visit, Week 12 Visit), after which no new non-serious 
AEs are to be reported. The subjects will be monitored throughout the study for any AEs, 
including clinically significant findings at vital signs measurements, spontaneous reports 
by study subjects, and observations by the study personnel. 
When possible, ongoing AEs assessed as related to the study drug will be followed until 
resolved or stabilized. Sites will call subjects 40 days after their last dose to gather 
information on ongoing AEs and report any new SAEs since the last study visit (see 
Section 11.4.1.2 for SAE reporting instructions).  
All AEs will be recorded in the eCRF. The investigator will assess and record any AE in 
detail including the date and time of onset, event diagnosis (if known) or sign/symptom, 
severity, time course (end date or ongoing), relationship of the AE to study drug, and 
action(s) taken. All AEs should be reported separately (i.e., 1 record per event). 
Reporting of AEs is event-based (i.e., an ongoing event will not be closed until resolved 
or at the end of study). For the AE description, a diagnosis is preferred over symptoms. If 
no diagnosis can be made, each symptom will be reported as a separate AE. 
Abbreviations should be avoided. Descriptive words should be used for ongoing 
conditions as applicable (e.g., worsening of eczema).  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) after 
the eCRFs have been monitored and signed by the investigator. 
11.4.1.2 Serious Adverse Events 
Any SAE experienced by the subject from signing the ICF through to 40 days after the 
last dose of study drug, regardless of severity or causality, must be recorded on the eCRF 
and SAE forms. Sites will call subjects 40 days after their last dose to gather information 
on ongoing AEs and report any new SAEs since the last study visit.  
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The study site must formally notify the Sponsor (or delegate) of the SAE within 24 hours 
from the time the study site becomes aware of the SAE. A formal notification must be 
submitted to the Sponsor regardless of the following: 
• Severity 
• Causality 
• Whether or not the subject received study treatment or underwent study related 
procedures  
The IRB/IEC will be notified as required by local regulations. The investigator will be 
responsible for submitting the required safety information to the appropriate IRB/IEC, 
including any safety reports received from the Sponsor as well as any SAEs occurring at 
his/her site.  
The Sponsor, or designee, will prepare any required safety reports for Competent 
Regulatory Authorities and all active investigators. These reports will be provided as 
addenda to the IB, and the investigator will place these with the IB. All Competent 
Regulatory Authorities will be informed as per applicable legislation. Reporting of 
suspected unexpected serious adverse reactions (SUSARs) will be in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
11.4.1.3 Death 
Any event with an outcome of death should be appropriately recorded in the eCRF. All 
identified causes of death, including an assessment of the possible relationship of each to 
study treatment, must be reported as SAEs as outlined in Section 11.4.1.2. Any autopsy 
or other postmortem findings (including a coroner’s report) should be provided if 
available. 
11.4.1.4 Abnormal Laboratory Values 
All central laboratory data generated during the study will be included in standard 
Statistical Analysis System (SAS) datasets. Throughout this study, subjects will have 
samples sent to local laboratories and to the central laboratory. Only the values from the 
central laboratory will be captured in the database and used for the safety analysis. 
Investigators may report AEs based upon local laboratory values, if clinically relevant. In 
this event, the actual value and the normal range for the local laboratory should be 
recorded on the AE eCRF. 
11.4.2 Safety Monitoring 
All AEs should be monitored by the investigator until resolution or stabilization.  
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11.4.2.1 Safety Monitoring Committee 
The safety of study subjects will be monitored throughout the study on an ongoing basis. 
Given the double blind, placebo-controlled design of Study RA101495.02.301, this 
standard safety data review will be performed while blinded to treatment assignment.  
If an unblinded data review should become necessary to ensure subject safety, a separate 
SMC will convene and evaluate study data as appropriate. To ensure the scientific 
integrity of the study, members of the SMC will not be directly involved in management 
of the study. The composition, duties, and purview of the SMC will be outlined in a 
separate SMC Charter.  
11.4.2.2 Post-study Events 
Any SAE that was continuing at the time of subject discontinuation or study completion 
should be monitored by the investigator until resolution or stabilization. 
SAEs that occur within 40 days after the subject discontinues from or completes the study 
should be reported using the same procedures outlined in Section 11.4.1.2. These SAEs 
should be recorded in the eCRF. Subjects will visit the clinic 40 days after their last dose 
of study drug to gather information on ongoing AEs and report any new SAEs since the 
last study visit (see Section 11.4.1.2 for SAE reporting instructions). All SAEs will be 
followed to resolution or stabilization. 
11.4.3 Emergency Unblinding 
The study drug treatment assignment may be unblinded only in emergency situations 
when knowledge of the treatment assignment is considered absolutely necessary for 
medical management of the subject or for clinical decision-making (i.e., when knowledge 
of the treatment assignment would impact a treatment decision). The investigator will 
have unrestricted and immediate access to unblind the treatment code in the IXRS. The 
instructions for unblinding a subject in the IXRS can be found in the IXRS User Guide. 
In the event unblinding is necessary, the investigator is strongly encouraged, but not 
required, to contact the appropriate medical monitor to discuss the situation and the 
subject’s medical status prior to unblinding. 
When a subject’s treatment assignment is unblinded, a comprehensive source note must 
be completed by the unblinding investigator that includes the date and time and the 
reason(s) the subject’s treatment code was unblinded. In the event the investigator 
chooses to discuss the unblinding with the medical monitor, the source note must also 
include a record of the discussion.  
It is mandatory that all personnel who are involved in the unblinding and who have 
access to the unblinded treatment assignment information maintain the confidentiality of 
the information by not divulging the treatment assignment. 
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Following emergency unblinding, the subject’s further participation in the study should 
be discussed with the medical monitor. Unblinded subjects will receive the same safety 
follow-up as required by non-unblinded study subjects. 
11.5 Special Circumstances 
11.5.1 Pregnancy 
Subjects and their partners should avoid pregnancy throughout the course of the study. 
Pregnancy in a study subject or partner must be reported to the Sponsor within 24 hours 
of the study site becoming aware of the pregnancy. Subjects with a positive pregnancy 
test before study drug dosing must not be dosed. 
Information regarding a pregnancy occurrence in a study subject or partner and the 
outcome of the pregnancy will be collected. 
Pregnancy in a study subject or partner is not, in itself, considered an AE. However, the 
medical outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly 
is considered an SAE and must be reported to the Sponsor within 24 hours of the site 
becoming aware of the event. The procedure of elective abortion should not be reported 
as an AE.  
11.5.2 Other 
Certain safety events, called ‘Special Situations’, that occur in association with study 
drug(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
• Overdose of the medicinal product, where ‘overdose’ is defined as a subject receiving 
≥ 2 times the intended dose for any given SC injection 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
• Medication error involving study drug (with or without subject exposure to the 
Sponsor’s medicinal product, e.g., name confusion) 
Special situations should be reported on the Special Situations form whether they result 
in an AE/SAE or not. Special Situations associated with an AE/SAE should also be 
reported on the corresponding AE/SAE forms. 
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12 STATISTICAL AND ANALYTICAL PLANS 
12.1 Analysis Populations 
12.1.1 Intention-to-Treat Population 
The Intention-to-Treat (ITT) Population will include all randomized subjects.  
12.1.2 Per Protocol Population 
The Per Protocol Population will include all subjects in the ITT Population who have 
completed the 12-week Treatment Period and have no major protocol deviations. 
12.1.3 Safety Population 
The Safety Population will include all subjects who received at least 1 dose of study drug 
with subjects to be analyzed based on the actual study treatment received. 
12.2 Analysis Methods 
12.2.1 General Methods 
Details of the statistical analysis methodology will be provided in a statistical analysis 
plan (SAP), which will be finalized prior to study unblinding. 
Continuous variables will be summarized using the number of observations, mean, SD, 
median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages. 
Once all subjects have completed the Day 84 visit, the study database will be locked 
(interim database lock), unblinded, and the analyses for the study will be performed. If 
necessary, all TFLs will be produced again after final database lock once all the subjects 
have completed the study (after SFU visit). 
Additional statistical summaries will be provided to explore the impact of COVID-19 on 
this study. More details will be provided in the SAP. 
12.2.2 Subject Disposition 
A disposition of subjects will be provided and will include a breakdown of subjects who 
were randomized, were treated, and discontinued treatment, were lost to follow up, or 
withdrew consent. Additionally, a summary of subjects included in each of the analysis 
populations defined in Section 12.1 will be provided. 
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12.2.3 Demography and Baseline Disease Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment group 
and overall.  
12.2.4 Estimands 
The estimand corresponding to the primary objective and efficacy endpoint analysis for 
this study is described below.  
A. Population: The population is characterized by the inclusion/exclusion criteria 
provided in Section 8.1 and Section 8.2. 
B. Endpoint: The endpoint is the CFB in the Week 12 MG-ADL Score. 
C. Intercurrent Events: The intercurrent events considered in this trial are: 
1. A subject receiving rescue therapy: The study is interested in the treatment effect 
assuming that the treatment effect is null, and no rescue effect occurs after a 
subject receives rescue medication.  
2. A subject discontinuing the study: For subjects that discontinue due to AEs 
related to study drug, it is assumed that the treatment effect is null. For subjects 
that discontinue for other reasons (i.e., unrelated to study drug) it is assumed that 
the subject had remained on their treatment throughout the study (i.e., a 
“Hypothetical-strategy” assuming subjects did not discontinue the study and 
remained on treatment).  
D. Population-level summary: The population summary is the difference between the 
zilucoplan and placebo treatment groups in the mean CFB in the Week 12 MG-ADL. 
12.2.5 Efficacy Analysis 
12.2.5.1 Primary Efficacy Endpoint Analysis 
For the primary efficacy endpoint, CFB to Week 12 in MG-ADL Score, treatment group 
differences will be assessed using a MMRM ANCOVA with treatment, baseline 
MG-ADL Score, baseline QMG Score, geographical region, treatmentvisit (interaction 
term), and baseline MG-ADL Scorevisit (interaction term) as fixed effects and subject 
as a random effect. The MMRM ANCOVA will include Weeks 1, 2, 4, 8, and 12. 
The visit, treatment, and geographical region terms in the MMRM model will be treated 
as categorical, and the baseline MG-ADL and QMG Scores will be treated as continuous.  
The primary efficacy analysis will be the comparison of the 0.3 mg/kg zilucoplan dose 
group versus placebo in CFB to Week 12 in MG-ADL Score at a 2-sided 0.05 
significance level based on the ITT population using least squares means. 
Sensitivity analyses for the primary efficacy endpoint analysis will be provided in the 
SAP.  
12.2.5.2 Secondary Endpoint Analyses 
The continuous secondary efficacy endpoints: Week 12 CFB in QMG, MGC, and MG-
QOL15r survey will be analyzed by an MMRM ANCOVA model similar to the primary 
endpoint analysis. More details will be provided in the SAP. 
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The dichotomous secondary efficacy endpoints: received rescue therapy over the 12-
week Treatment Period, achieving MSE, defined as an MG-ADL of 0 or 1, at Week 12 
without rescue therapy, a ≥3-point reduction in MG-ADL Score at Week 12 without 
rescue therapy, and a ≥5-point reduction in QMG Score at Week 12 without rescue 
therapy will be analyzed by a logistic regression with treatment as a factor and baseline 
MG-ADL Score, baseline QMG Score, and geographical region as covariates.  
For each of the secondary endpoints, the analysis will be the Week 12 comparison of the 
0.3 mg/kg zilucoplan dose group versus placebo at a 2-sided 0.05 significance level based 
on the ITT population. 
12.2.6 Handling of Missing and Censored Data 
It is anticipated that: 
• 
Approximately 5% of subjects will be missing MG-ADL data during the 12-week 
treatment period.  
 
This is based on the results of the zilucoplan Phase 2 study (RA101495-02.201) 
where 2.3% of subjects (n=1 out of 44) were missing their Week 12 visit MG-ADL 
Score, and, from the eculizumab Phase 3 study, where 5.5% (7/126) of subjects did 
not complete the 26-week treatment period (Howard et al. 2017). 
• 
Approximately 10% of subjects will receive rescue therapy during the 12-week 
treatment period.  
 
This is based on the results of the zilucoplan Phase 2 study (see Section 5.5.2.1) 
where 9.1% of subjects (n=4 out of 44, n=0 subjects on the 0.3 mg/kg dose) received 
rescue therapy during the 12-week treatment period and, from the eculizumab Phase 3 
study where 14.3% (18/126) of subjects received rescue therapy during the 26-week 
treatment period (6 subjects in the eculizumab group and 12 subjects in the placebo 
group). 
• 
The amount of non-monotonic missing data will be minimal  
 
This is based on the results of the zilucoplan Phase 2 study (RA101495-02.201) 
where, across the scheduled treatment visits during the 12-Week treatment period, 
there was no non-monotonic missing data for MG-ADL (i.e., the one subject who was 
missing MG-ADL at the Week 8 visit also had a missing value MG-ADL value at the 
Week 12 visit). 
• 
The impact of the COVID-19 pandemic on MG-ADL will be minimal because this 
assessment can be conducted remotely. 
Based on these estimates from the zilucoplan Phase 2 study (RA101495-02.201) and the 
eculizumab Phase 3 study, it is anticipated that the percentage of subjects with 
missing/censored data during the 12-week treatment period will be approximately 15%. 
The missing data pattern for the secondary endpoints is anticipated to be similar to the 
primary endpoint. 
For the primary efficacy endpoint analysis, multiple imputation (MI) methods will be 
used to handle missing data and data after rescue therapy use (i.e., data collected after a 
subject has used rescue therapy will be censored and treated as missing data for the 
primary efficacy analysis). The following is a summary of the imputation method. 
For the primary efficacy analysis, 100 imputed datasets will be created using monotone 
linear regression imputation methods which will impute the subjects’ missing 
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post-baseline scores at each of the scheduled visits in the study (i.e., Weeks 1, 2, 4, 8, and 
12). If the missing data does not follow a monotonic pattern, a sequential approach to 
imputing the data to produce a monotone missing data pattern will be applied, (i.e., then 
the monotone linear regression imputation methods will be applied.). 
Imputation will be performed by treatment group, with the underlying imputation 
distribution based on the reason for the missing data.  
Data will be imputed based on the placebo group distribution, irrespective of individual 
treatment assignment, under the following scenarios: 
• Discontinuation from the study due to AE(s) related to study drug  
• Received rescue therapy for MG worsening with IVIG or PLEX or eculizumab (i.e., 
treatment failure) 
Missing data will be imputed based on the subject’s assigned treatment group distribution 
under the following scenarios: 
• Discontinuation from the study for reasons unrelated to study drug 
• Any other reason for missing data  
This MI method allows for a pattern-mixture model approach assuming the data are 
missing not at random (MNAR) under the scenarios where a subject’s discontinuation 
from the study is related to study drug or the subject received rescue medications.  
For each of the 100 imputed datasets, the endpoint will be analyzed using the specified 
MMRM ANCOVA model and the results combined across the imputed datasets to 
produce an overall p-value (e.g., using SAS Proc MIANALYZE).  
Similar MI methods for handling missing data will be applied to the secondary efficacy 
analyses. 
Sensitivity analyses for the primary efficacy endpoint analysis, considering other 
methods of handling missing and censored data will be provided in the SAP.  
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be 
documented. 
12.2.6.1 Multiplicity 
The primary efficacy endpoint will be tested at the 2-sided 0.05 significance level. The 
secondary endpoints will be tested using a fixed-sequential testing procedure in the 
following order:  
• CFB to Week 12 in the QMG Score 
• CFB to Week 12 in the MGC  
• CFB to Week 12 in the MG-QOL15r Survey 
• Received rescue therapy over the 12-week Treatment Period  
• Achieving MSE, defined as an MG-ADL of 0 or 1, at Week 12 without rescue 
therapy  
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• Achieving a ≥3-point reduction in MG-ADL Score at Week 12 without rescue 
therapy 
• Achieving a ≥5-point reduction in QMG Score at Week 12 without rescue therapy 
Each secondary endpoint will be tested at the 2-sided 0.05 significance level. A 
secondary endpoint analysis will be considered statistically significant if the 2-sided p-
value is ≤ 0.05 for the endpoint analysis and the primary efficacy endpoint analysis and 
all the secondary endpoint analyses occurring earlier in the fixed-sequence are also 
statistically significant (i.e., have a 2-sided p-value ≤ 0.05).  
This method provides strong control of the family-wise error rate at the two-sided 0.05 
level. 
12.2.7 Safety Analysis 
Safety analyses will be performed on the Safety Population. 
12.2.7.1 Adverse Events 
AEs will be coded using the MedDRA. Incidence rates for TEAEs will be summarized 
overall, by maximum severity, and by relationship to study drug for each treatment 
group. SAEs will also be summarized by treatment group.  
12.2.7.2 Infection 
AEs related to infection with Neisseria meningitidis will be summarized by system organ 
class and preferred term. 
12.2.7.3 Clinical Laboratory Evaluation 
Quantitative laboratory endpoints will be summarized by treatment group at each 
scheduled assessment time point using descriptive statistics. 
12.2.7.4 Electrocardiograms 
Descriptive statistics for ECG parameters (i.e., HR, PR interval, RR interval, QRS 
interval, and QT intervals) at each assessment time point will be presented by treatment 
group.  
12.2.7.5 Vital Signs 
Descriptive statistics for vital signs (i.e., HR, body temperature, and blood pressure) will 
be presented by treatment group. 
12.2.7.6 Physical Examination 
Clinically significant physical examination abnormalities will be included and 
summarized as AEs, when appropriate.  
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12.2.8 Clinical Pharmacology Analysis 
12.2.8.1 Pharmacokinetic and Pharmacodynamic Analyses 
Pharmacokinetic and pharmacodynamic endpoints will be summarized using descriptive 
statistics by treatment and nominal time point. 
Pharmacokinetic and pharmacodynamic assessments in subjects undergoing rescue 
therapy will be analyzed separately, as appropriate. 
Plasma concentration data of zilucoplan may be subjected to population PK analysis to 
derive population estimates of PK parameters and test the effect of various covariates 
such as anti-drug antibodies, age, weight, gender. Details of the analysis will be described 
in a separate Data Analysis Plan (DAP). This analysis may be performed by combining 
the data from the current study with data from other zilucoplan studies if deemed 
appropriate. The results of the population PK analysis will not be reported in the clinical 
study report (CSR) but in a separate modelling report 
Population PD or population PK/PD analyses may be conducted for the PD variables of 
interest. Details of such PD or PK/PD analyses will be described in a separate DAP. The 
results of the analyses will not be reported in the CSR but in a separate report. 
12.2.9 Interim Analysis 
After the last subject has completed the Week 12 visit, or after the last subject has 
prematurely discontinued prior to reaching Week 12, an unblinded interim analysis will 
be performed and a corresponding interim CSR may be written. The purpose of this 
interim analysis is to perform a comprehensive evaluation of all available double-blind 
data to prepare regulatory submissions for approval of the MG target indication. If 
necessary, a final analysis and updated final CSR will be prepared once all data (through 
to the SFU visit) have been collected. If all the subjects have completed the study at the 
interim database lock (the last participants entered the extension study), then the interim 
database lock will be the final lock. 
12.3 Sample Size Determination 
For the primary efficacy endpoint, CFB to Week 12 in MG-ADL Score, assuming a 
difference in treatment group least squares means of 2.3, a SD of 3.7, and 78 subjects per 
group (156 subjects in total), the study has approximately 94% power to detect a 
difference between an active and placebo treatment group based on a 2-sided alpha of 
0.05. This assumes rates of rescue and dropout of up to 10% and 5%, respectively. 
13 ETHICAL CONSIDERATIONS 
This study shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice 
(GCP) and applicable regulatory requirement(s).  
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13.1 Institutional Review Board/Independent Ethics Committee Communications 
Prior to study initiation, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol, written ICF, consent 
form updates, subject recruitment procedures (e.g., advertisements), and any other written 
information to be provided to subjects. A current copy of the IB must be provided to the 
IRB/IEC as part of the written application. During the study, the investigator/institution 
should provide to the IRB/IEC all documents subject for review. 
13.1.1 Progress Reports 
The investigator should submit written summaries of the study status to the IRB/IEC 
annually, or more frequently, if requested by the IRB/IEC. 
13.1.2 Final Investigator Report 
Upon completion of the study, the investigator/institution should provide a summary of 
the study’s outcome to the IRB/IEC and the regulatory authorities with any required 
reports. 
13.2 Informed Consent of Study Subjects 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s) and adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised written ICF and written information should receive the 
IRB/IEC’s approval/favorable opinion in advance of use. The subject or the subject’s 
legally acceptable representative will be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. The communication of this information should be documented. 
The investigator will fully inform the subject or the subject’s legally acceptable 
representative of all pertinent aspects of the study, including the written information and 
the approval/favorable opinion by the IRB/IEC. Before informed consent may be 
obtained, the investigator should provide the subject or the subject’s legally acceptable 
representative ample time and opportunity to inquire about details of the study and to 
decide whether or not to participate in the study. All questions about the study should be 
answered to the satisfaction of the subject or the subject’s legally acceptable 
representative.  
Prior to a subject’s participation in the study, the written ICF must be signed and 
personally dated by the subject or by the subject’s legally acceptable representative and 
by the person who conducted the informed consent discussion. If a subject is unable to 
read or if a legally acceptable representative is unable to read, an impartial witness will 
be present during the entire informed consent discussion. 
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In Japan, age of adulthood is defined as 20 years or older. If a subject is 18-19 years old, 
the subject and his/her legal representative must both sign the ICF. 
Prior to participation in the study, the subject or the subject’s legally acceptable 
representative will receive a copy of the signed and dated written ICF and any other 
written information provided to the subjects. During a subject’s participation in the study, 
the subject or the subject’s legally acceptable representative will receive a copy of the 
signed and dated consent form updates and a copy of any amendments to the written 
information provided to subjects. 
Subjects will provide additional consent to participate in optional pharmacogenomic 
testing. 
13.3 Protocol Compliance 
The investigator/institution will conduct the study in compliance with the protocol agreed 
to by the Sponsor and regulatory authorities (if required) and which was given 
approval/favorable opinion by the IRB/IEC. The investigator/institution and the Sponsor 
should sign the protocol, or an alternative contract, to confirm agreement. 
The investigator should not implement any deviation from, or changes to, the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate 
immediate hazard(s) to study subjects or when the change involves only logistical or 
administrative aspects of the study (e.g., change in monitor, change of telephone 
number). When an important deviation from the protocol is deemed necessary for an 
individual subject, the investigator must contact the medical monitor for the study. 
Such contact must be made as soon as possible to permit a review by the Sponsor to 
determine the impact of the deviation on the subject’s participation and/or the assessment 
of safety or efficacy in the study. Any significant protocol deviations affecting subject 
eligibility and/or safety must be reviewed and/or approved by the IRB/IEC and regulatory 
authorities, as applicable, prior to implementation. 
The investigator should document and explain any deviation from the approved protocol.  
13.4 Protection of Confidentiality 
Prior to study participation, the investigator shall inform the subject or the subject’s 
legally acceptable representative that the monitor(s), auditor(s), IRB/IEC, and the 
regulatory authorities will be granted direct access to the subject’s original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written ICF, the subject or the subject’s legally 
acceptable representative is authorizing such access.  
In addition, prior to study participation, the subject must be informed that the records 
identifying the subject will be kept confidential and, to the extent permitted by the 
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applicable laws and/or regulations, will not be made publicly available; if the results of 
the study are published, the subject’s identity will remain confidential. 
13.5 Disclosure of Study Results 
The Sponsor will post the results of the study in a publicly accessible database in 
accordance with the applicable laws and regulations. 
14 REGULATORY AND ADMINISTRATIVE CONSIDERATIONS 
14.1 Quality Assurance 
Quality assurance and quality control systems shall be implemented and maintained with 
written standard operating procedures (SOPs) to ensure that the study is conducted, data 
are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirement(s). Quality control shall be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study related sites, source documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and of inspection by regulatory authorities. 
14.1.1 Monitoring 
On-site monitoring visits will be conducted before, at regular intervals during, and after 
the study, as appropriate, by Sponsor-approved monitors. At a minimum, the accuracy 
and completeness of the eCRF entries, source documents, and other study-related records 
will be checked against one another during these visits. After each monitoring visit, a 
report of any significant findings/facts, deviations, and deficiencies will be 
communicated to the investigator. The actions taken to address the findings and secure 
compliance should be documented.  
14.1.2 Audit 
An audit may be performed independently of, and separately from, routine monitoring to 
evaluate clinical study conduct and compliance with the protocol, SOPs, GCP, and the 
applicable regulatory requirements.  
14.2 Clinical Research Organizations  
A Clinical Research Organization (CRO) will be utilized to assist in the conduct of this 
study. Accredited central laboratories will be used for the analysis of safety laboratory 
samples and for the bioanalytical testing of PK samples.  
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14.3 Data Management 
14.3.1 Case Report Forms 
eCRFs must be completed for each subject enrolled in this study. These forms will be 
used to transmit information collected during the study to the Sponsor and regulatory 
authorities, as applicable. The eCRF data for this study is being collected with an eCRF. 
The documentation related to the validation of the eCRFs will be maintained in the Trial 
Master File (TMF). The TMF will be maintained by the CRO and the Sponsor. 
The investigator will document subject data in his/her own subject files. These subject 
files will serve as source data for the study (see Section 14.3.2). All eCRF data required 
by this protocol will be recorded by investigative site personnel.  
The investigator or an authorized member of the investigator’s staff will make any 
necessary corrections to the eCRF. All change information, including the date and person 
performing the corrections, will be available via the audit trail, which will be part of the 
electronic data capture system. For any correction, a reason for the alteration will be 
provided. The eCRFs will be reviewed periodically for completeness and acceptability by 
Sponsor personnel (or their representatives). The Sponsor (or their representatives) will 
also be allowed access to all source documents pertinent to the study in order to verify 
eCRF entries. The investigator will review the eCRFs for completeness and accuracy and 
provide his or her electronic signature and date to eCRFs as evidence thereof. 
Access to the electronic data capture system will be password-protected and will be 
removed from the study site at the end of the site’s participation in the study. Data from 
the eCRF will be archived on appropriate data media and provided to the investigator at 
that time as a durable record of the site’s eCRF data. It will be possible for the 
investigator to make paper printouts from that media. 
14.3.2 Source Documents 
Source documents are defined as original documents, data, and records. These may 
include hospital records, clinical and office charts, laboratory data/information, subjects’ 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, ECGs, X-rays, ultrasounds, angiograms, venograms, computed tomography scans, 
and/or magnetic resonance imaging scans. Data collected during this study must be 
recorded on the appropriate source documents. 
In some instances, the initial entry of data will be made by subjects and site personnel 
onto a hand-held device at the site and will be considered the source, e.g. eSource. This 
system is fully compliant with 21 Code of Federal Regulations (CFR) part 11 regulations. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s), providing direct access to source data documents. 
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14.4 Premature Termination or Suspension of the Study 
If the Sponsor terminates or suspends the study, the investigator/institution should 
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of 
the termination or suspension. If the IRB/IEC terminates or suspends its 
approval/favorable opinion of the study, the investigator/institution should promptly 
notify the Sponsor and provide the Sponsor with a detailed written explanation of the 
termination or suspension. 
14.5 Clinical Study Report 
Whether the study is completed or prematurely terminated, the clinical study report will 
be prepared and provided to the regulatory agencies as required by the applicable 
regulatory requirement(s). 
14.6 Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. The data generated in 
this clinical trial are the exclusive property of Ra Pharmaceuticals, Inc. and are 
confidential. Written approval from Ra Pharmaceuticals, Inc.is required prior to 
disclosing any information related to this clinical trial. 
 
 
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15 REFERENCES 
Barohn, R., Mcintire, D., Herbelin, L., Wolfe, G., Nations, S., & Bryan, W. (1998). Reliability 
testing of the quantitative myasthenia gravis score. Ann N Y Acad Sc, 841, 762-72. 
Benatar, M., Sanders, D., Burns, T., Cutter, G., Guptill, J., Baggi, F., & et al. (2012). Task Force 
on MG Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis 
Foundation of America. Recommendations for myasthenia gravis trials. Muscle Nerve, 45(6), 
909-917. 
Burns, T., Grouse, C., Conaway, M., & Sanders, D. (2010). Construct and concurrent validation 
of the MG-QOL15 in the practice setting. Muscle Nerve, 41(2), 2019-26. 
Burns, T., Sadjadi, R., Utsugisawa, K., & et al. (2016). International clinimetric evaluation of the 
MG‐QOL15, resulting in slight revision and subsequent validation of the MG‐QOL15r. 
Muscle Nerve, 54(6), 1015-1022. 
Chamanza, R., Marxfeld, H., Blanco, A., Naylor, S., & Bradley, A. (2010). Incidences and range 
of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity 
studies. Toxicol Pathol, 38(4), 642-57. 
Conti-Fine, B., Milani, M., & Kaminski, H. (2006). Myasthenia gravis: past, present, and future. J 
Clin Invest, 116(11), 2843-2854. 
Engel, A., Lindstrom, J., Lambert, E., & Lennon, V. (1977). Ultrastructural localization of the 
acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model. 
Neurology, 27(4), 307-15. 
EuroQOL Group. (1990). EuroQol-a new facility for the measurement of health-related quality of 
life. Health Policy(16), 199-208. 
Farmakidis, C., Pasnoor, M., Dimachkie, M., & Barohn, R. (2018). Treatment of Myasthenia 
Gravis. Neurol Clin, 36(2), 311-337. 
FDA. (2012, August). Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in 
Clinical Trials. Guidance for Industry. 
Gilhus, N. (2016). Myasthenia Gravis. N Engl J Med, 375(26), 2570-2581. 
Gilhus, N., & Verschuuren, J. (2015). Myasthenia gravis: subgroup classification and therapeutic 
strategies. Lancet Neurol, 14(10), 1023-1036. 
Howard, J. (2017). Myasthenia gravis: the role of complement at the neuromuscular junction. Ann 
N Y Acad Sci, 1412(1), 113-128. 
Howard, J., Barohn, R., Cutter, G., & al., e. (2013). A randomized, double-blind, placebo-
controlled phase II study of eculizumab in patients with refractory generalized myasthenia 
gravis. Muscle Nerve, 48(1), 76-84. 
Howard, J., Utsugisawa, K., Benatar, M., & et al. (2017). Safety and efficacy of eculizumab in 
anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis 
(REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. 
Lancet Neurol, 16(12), 976-986. 
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Jackson, M., Stephens, C., & Lecar H. (1981). Single channel currents induced by complement in 
antibody-coated cell membranes. Proc Natl Acad Sci USA, 78(10), 6421-6425. 
Katzberg, H., Barnett, C., Merkies, I., & Bril, V. (2014). Minimal clinically important difference 
in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve, 49(5), 661-665. 
Kusner, L., Sengupta, M., & Kaminski, H. (2018). Acetylcholine receptor antibody-mediated 
animal models of myasthenia gravis and the role of complement. Ann N Y Acad Sci, 1413(1), 
136-142. 
Lennon, V., Seybold, M., Lindstrom, J., Cochrane , C., & Ulevitch, R. (1978). Role of 
complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med, 
147(4), 973-83. 
Muppidi, S., Wolfe, G., Conaway, M., & Burns, T. (2011, Nov). MG-ADL: still a relevant 
outcome measure. Muscle Nerve, 44(5), 727-31. 
Nakan, S., & Engel, A. (1993). Myasthenia gravis: quantitative immunocytochemical analysis of 
inflammatory cells and detection of complement membrane attack complex at the end-plate in 
30 patients. Neurology, 43(6), 1167-72. 
Nishimura, J., Yamamoto, M., Hayashi, S., & et al. (2014). Genetic variants in C5 and poor 
response to eculizumab. N Engl J Med, 370(7), 632-9. 
Ramizuddin, M. (2014). Review on: Myasthenia gravis and telithromycin-myasthenia crisis. 
IOSR J Dent Med Sci, 13(7), 67-97. 
Reilly, M., Zbrozek, A., & Dukes, E. (1993). The Validity and Reproducibility of a Work 
Productivity and Activity Impairment Instrument. PharmacoEconomics, 4(5), 353-365. 
Riedemann, N., Guo, R., Laudes, I., & et al. (2002). C5a receptor and thymocyte apoptosis in 
sepsis. FASEB J, 16(8), 887-8. 
Sadjadi R, C. M. (2012). MG Composite and MG-QOL15 Study Group. Pyschometric evaluation 
of the myasthenia gravis composite using Rasch analysis. Muscle nerve, 45(6):820-825. 
Sanders, D., Wolfe, G., Benatar, M., & et al. (2016). International consensus guidance for 
management of myasthenia gravis: Executive summary. Neurology, 87(4), 419-25. 
Solyts, J., Kusner, L., Young, A., & et al. (2009). Novel complement inhibitor limits severity of 
experimentally myasthenia gravis. Ann Neurol, 65(1), 67-75. 
Vissing J, J. S. (2018). 'Minimal Symptom Expression' with Eculizumab in Myasthenia Gravis. 
AANEM. Washington, DC. 
Wachtman, L., & Mansfield, K. (2012). Viral Diseases of Nonhuman Primates. Nonhuman 
Primates in Biomedical Research, 2(2), 1-104. 
Wolfe, G., Herbelin, L., Nations, S., Foster, B., Bryan , W., & Barohn, R. (1999). Myasthenia 
gravis activities of daily living profile. Neurology, 52(7), 1487-9. 
Wolfe, G., Kaminski, H., Aban, I., Minisman, G., Juo, H., & Marx, A. (2016). Randomized Trial 
of Thymectomy in Myasthenia Gravis. N Engl J Med, 375(6), 511-22. 
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16 APPENDICES 
Appendix 1: MG-Activities of Daily Living Scale 
 
 
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Appendix 2: Prohibited Concomitant Medications 
Please consider the following list of prohibited medications for patients with MG 
(PNDS, 2015). Should you have any questions, please contact the Medical Monitor. 
Absolute contraindications: 
• Aminoglycosides, colomycin, polymyxin, telithromycine, injectable cyclin, 
macrolides, fluoroquinolones 
• Quinines, quinidine, hydroxychloroquine, procainamide 
• Beta-blockers (even in eye drops) 
• Diphenylhydantoin, trimethadione 
• Dantrolene 
• D-penicillamine 
• Magnesium 
Relative contraindications: 
• Curariform agents: use of non-depolarizing molecules of rapid degradation, such as 
atracurium, is possible, requires precise monitoring 
• Benzodiazepines 
• Neuroleptics (phenothiazine) 
• Carbamazepine 
• Lithium 
 
 
 
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SPONSOR SIGNATURE PAGE 
Protocol Number: 
RA101495-02.301 (RAISE) 
Protocol Title:  
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Confirm the Safety, Tolerability, and Efficacy of 
Zilucoplan in Subjects with Generalized Myasthenia Gravis 
Protocol Version:  Version 2.0/18.Dec.2020 
 
 
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Approval Signatures
Name:
mg0010-protocol-amend-v2.0
Version:
1. 0
Document Number:
CLIN-000165911
Title:
MG0010 RAISE Protocol Amendment v2.0
Approved Date:
18 Dec 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Dec-2020 08:27:09 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Dec-2020 08:31:28 GMT+0000
Approval
Verdict: Approved
Name:
Capacity: Clinical
Date of Signature: 18-Dec-2020 11:44:00 GMT+0000
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SAP_001.pdf: 
UCB 
 
6 DEC 2021 
Statistical Analysis Plan 
Zilucoplan 
MG0010 
 
 
 
Confidential 
Page 1 of 95 
 
STATISTICAL ANALYSIS PLAN 
AMENDMENT 5.0 
Study: MG0010 (RAISE)  
Product: Zilucoplan 
 
 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, 
PLACEBO-CONTROLLED STUDY TO CONFIRM THE SAFETY, 
TOLERABILITY, AND EFFICACY OF ZILUCOPLAN IN 
PARTICIPANTS WITH GENERALIZED MYASTHENIA GRAVIS  
Sponsor Name: Ra Pharmaceuticals, Inc. (now part of UCB) 
Legal Registered Address: 87 Cambridge Park Drive 
 Cambridge, MA, 02140 | USA 
                                            
Regulatory Agency Identifier Number: 
Registry 
ID 
EudraCT Number 
2019-001564-30 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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MG0010 
 
 
 
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TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................ 6 
Amendment 1.0 ...................................................................................................................... 6 
Amendment 2.0 .................................................................................................................... 12 
Amendment 3.0 .................................................................................................................... 14 
Amendment 4.0 .................................................................................................................... 15 
Amendment 5.0 .................................................................................................................... 18 
LIST OF ABBREVIATIONS .................................................................................................. 21 
1 
INTRODUCTION ........................................................................................................... 25 
1.1 Objectives and Estimands/Endpoints ............................................................................... 25 
1.2 Study design ..................................................................................................................... 29 
2 
STATISTICAL HYPOTHESES ...................................................................................... 31 
2.1 Primary Endpoint ............................................................................................................. 31 
2.2 Secondary Endpoints and multiplicity ............................................................................. 31 
3 
SAMPLE SIZE DETERMINATION .............................................................................. 32 
4 
POPULATIONS FOR ANALYSIS ................................................................................. 32 
5 
STATISTICAL ANALYSES .......................................................................................... 33 
5.1 General Considerations .................................................................................................... 33 
5.1.1 
General study level definitions ............................................................................ 34 
5.1.1.1 
Analysis Time Points ................................................................................. 34 
5.1.1.2 
Protocol Deviations ................................................................................... 36 
5.1.1.3 
Treatment assignment and treatment groups ............................................. 36 
5.1.1.4 
Center pooling strategy ............................................................................. 37 
5.1.1.5 
Coding dictionaries .................................................................................... 37 
5.1.1.6 
Multicenter studies .................................................................................... 37 
5.1.1.7 
Missing data .............................................................................................. 37 
5.1.1.8 
Handling of repeated and unscheduled measurements .............................. 40 
5.1.1.9 
Handling of rescue therapy visits .............................................................. 40 
5.1.1.10 
Handling of missing dates and times ......................................................... 40 
5.2 Participant Dispositions ................................................................................................... 41 
5.3 Primary Endpoint Analysis .............................................................................................. 42 
5.3.1 
Definition of endpoint .......................................................................................... 42 
5.3.2 
Main analytical approach ..................................................................................... 43 
5.3.2.1 
Primary Analysis ....................................................................................... 43 
5.3.2.2 
Handling of missing data ........................................................................... 43 
5.3.3 
Sensitivity analysis .............................................................................................. 44 
5.3.3.1 
Sensitivity #1: MMRM using J2R approach ............................................. 44 
5.3.3.2 
Sensitivity #2: Tipping point analysis ....................................................... 44 
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5.3.3.3 
Sensitivity #3: MMRM on CFS ................................................................ 46 
5.3.4 
Supplementary analyses ....................................................................................... 46 
5.3.4.1 
Supplementary #1: MMRM under treatment policy approach ................. 46 
5.3.4.2 
Supplementary #2: MMRM on the PPS .................................................... 46 
5.3.4.3 
Supplementary #3: MMRM using Pattern-Mixture Model (PMM) .......... 46 
5.3.4.4 
Exploratory: Worst-Rank analysis of covariance at Week 12................... 47 
5.4 Secondary Endpoint Analysis .......................................................................................... 47 
5.4.1 
Week 12 CFB in the QMG score, in MGC score, in MG-QoL15r Survey ......... 48 
5.4.1.1 
Definition of endpoints .............................................................................. 48 
5.4.1.2 
Main analytical approach .......................................................................... 48 
5.4.1.3 
Sensitivity analysis .................................................................................... 49 
5.4.1.4 
Supplementary analyses ............................................................................ 49 
5.4.2 
Time first administration of rescue therapy over the 12-week Treatment period 49 
5.4.2.1 
Definition of endpoint ............................................................................... 49 
5.4.2.2 
Main analytical approach .......................................................................... 49 
5.4.2.3 
Sensitivity analysis .................................................................................... 49 
5.4.2.4 
Supplementary analyses ............................................................................ 49 
5.4.3 
Achieving MSE, MG-ADL score responder rate, QMG score responder rate 
without rescue therapy at Week 12 ...................................................................... 50 
5.4.3.1 
Definition of endpoints .............................................................................. 50 
5.4.3.2 
Main analytical approach .......................................................................... 50 
5.4.3.3 
Sensitivity analysis .................................................................................... 51 
5.4.3.4 
Supplementary analyses ............................................................................ 52 
5.5 Exploratory Endpoints Analysis ...................................................................................... 52 
5.5.1 
Achievement of Minimal Manifestation Status per MGFA-PIS at Week 12 
Without Rescue Therapy ..................................................................................... 52 
5.5.2 
CFB to Week 12 in Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem (WPAI:SHP) ................................................................ 52 
5.5.3 
CFB to Week 12 in EQ-5D-5L ............................................................................ 52 
5.5.4 
CFB to Week 12 in Neuro-QOL Short Form Fatigue Scale ................................ 53 
5.5.5 
Responder analysis for changes in QMG, MG-ADL, MG-QOL15r, and MG 
Composite Scores from baseline without rescue therapy .................................... 53 
5.5.6 
Sub-scores of the QMG, MG-ADL, MG-QOL15r, and MG-Composite scores . 54 
5.6 Safety Analyses ................................................................................................................ 55 
5.6.1 
Extent of Exposure .............................................................................................. 55 
5.6.2 
Adverse Events .................................................................................................... 55 
5.6.2.1 
Data considerations ................................................................................... 55 
5.6.2.2 
AE summaries ........................................................................................... 56 
5.6.3 
Other Safety Assessments .................................................................................... 59 
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5.6.3.1 
AE of Interest (AEIs) ................................................................................ 59 
5.6.3.2 
Clinical laboratory evaluations .................................................................. 60 
5.6.3.3 
Vital Signs ................................................................................................. 63 
5.6.3.4 
Electrocardiograms .................................................................................... 63 
5.6.3.5 
Physical examination ................................................................................. 64 
5.6.3.6 
Total serum IgG and IgG subclasses ......................................................... 64 
5.6.3.7 
Immunogenicity ......................................................................................... 64 
5.6.3.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................. 67 
5.7 Other Analyses ................................................................................................................. 68 
5.7.1 
Other Exploratory endpoints ................................................................................ 68 
5.7.1.1 
Pharmacokinetics ....................................................................................... 68 
5.7.1.2 
Pharmacodynamics .................................................................................... 69 
5.7.1.3 
Biomarkers and Autoantibodies ................................................................ 69 
5.7.1.4 
Pharmacogenomic ..................................................................................... 69 
5.7.1.5 
Additional Rescue Therapy analyses ........................................................ 69 
5.7.2 
Specific analyses for Japanese Participants ......................................................... 70 
5.8 Subgroup analyses ........................................................................................................... 72 
5.9 Interim Analyses .............................................................................................................. 73 
5.10 Data Monitoring Committee (DMC) or Other Review Board ......................................... 73 
6 
SUPPORTING DOCUMENTATION ............................................................................. 73 
6.1 Appendix 1 Non-key analysis specifications ................................................................... 73 
6.1.1 
Baseline characteristics and demographics ......................................................... 73 
6.1.2 
Protocol deviations .............................................................................................. 74 
6.1.3 
Medical history .................................................................................................... 75 
6.1.3.1 
Medical history (other than MG disease history) ...................................... 75 
6.1.3.2 
gMG disease history .................................................................................. 75 
6.1.4 
Prior/concomitant medications ............................................................................ 76 
6.1.4.1 
Prior/concomitant medications classification ............................................ 76 
6.1.4.2 
Prior and concomitant medications (non-MG therapy) ............................. 76 
6.1.4.3 
MG Specific Prior and Concomitant Medications .................................... 77 
6.1.4.4 
Refractory criteria ...................................................................................... 78 
6.1.5 
Data derivation rules ............................................................................................ 78 
6.1.5.1 
MG Activities of Daily Life score (MG-ADL score) ................................ 78 
6.1.5.2 
Quantitative Myasthenia Gravis (QMG) Score ......................................... 79 
6.1.5.3 
MG Composite (MGC) score .................................................................... 81 
6.1.5.4 
Myasthenia Gravis Quality of Life (MG-QoL 15r) ................................... 82 
6.1.5.5 
Minimal Symptom Expression (MSE) ...................................................... 83 
6.1.5.6 
MGFA Post-Intervention Status ................................................................ 83 
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MG0010 
 
 
 
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6.1.5.7 
Work Productivity and Activity Impairment Questionnaire ..................... 83 
6.1.5.8 
EQ-5D-5L .................................................................................................. 84 
6.1.5.9 
Neuro-QOL Fatigue Short Form ............................................................... 85 
6.1.6 
AEs of Interest (AEIs) ......................................................................................... 85 
6.1.7 
Compliance .......................................................................................................... 89 
6.1.8 
COVID-19 terms ................................................................................................. 89 
6.2 Appendix 2: Abnormality criteria for Laboratory, Vital Sign and Electrocardiogram 
Parameters .................................................................................................................... 90 
6.2.1 
Laboratory Assessments Marked Abnormality Criteria ...................................... 90 
6.2.2 
Marked Abnormalities Vital Signs ...................................................................... 92 
6.2.3 
Marked Abnormalities Electrocardiogram (ECG) ............................................... 93 
6.3 Appendix 3: Changes to Protocol-Planned Analyses ...................................................... 93 
7 
REFERENCES ................................................................................................................ 95 
 
LIST OF TABLES 
Table 1‒1: 
Estimands ......................................................................................................... 26 
Table 5-1: 
Primary and Secondary Estimands .................................................................. 37 
Table 5‒2: 
Functional Sub-scores ...................................................................................... 54 
Table 5‒3: 
Laboratory ........................................................................................................ 60 
Table 5‒4: 
ADA Classification .......................................................................................... 64 
Table 6‒1: 
Prior and Concomitant Medications ................................................................ 76 
Table 6‒2: 
Concomitant Class ........................................................................................... 77 
Table 6‒3: 
MG-ADL Score ............................................................................................... 79 
Table 6‒4: 
QMG Score ...................................................................................................... 80 
Table 6‒5: 
MG-C score items and scoring algorithm ........................................................ 81 
Table 6‒6: 
WPAI:SHP ....................................................................................................... 84 
Table 6‒7: 
AEs of Interest selection criteria ...................................................................... 85 
Table 6‒8: 
Anaphylactic Reactions Categories ................................................................. 86 
Table 6.9: 
Preferred Terms to define COVID-19 infection .............................................. 89 
Table 6‒10: 
Laboratory Marked Abnormalities .................................................................. 91 
Table 6‒11: 
Marked Abnormalities Vital Signs .................................................................. 92 
Table 6‒12: 
Marked Abnormalities ECG ............................................................................ 93 
 
 
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VERSION HISTORY 
 
This Statistical Analysis Plan (SAP) for study MG0010 is based on the protocol amendment 2.0 
dated 18 Dec 2020.  
SAP Version 
Approval Date 
Change 
Rationale 
1.0 
06 Nov 2019 
Not Applicable 
Original version 
amendment 1.0 
01 Feb 2021 
Described Below 
Update to UCB 
standards 
amendment 2.0 
13 May 2021 
Described Below 
Anti-PEG antibodies 
analyses added 
Refractory definition 
updated 
amendment 3.0 
17 June 2021 
Described Below 
Multiplicity strategy 
for secondary 
endpoints modified 
amendment 4.0 
13 Oct 2021 
Described Below 
Update following 
FDA’s feed-back 
amendment 5.0 
06 Dec 2021 
Described Below 
Clarification added 
and typos corrected. 
 
Amendment 1.0 
The purpose of the SAP amendment 1.0 was to make the following changes based on the SAP 
Version 1.0 dated 6 Nov 2019:  
− The SAP was updated considering the protocol amendment version 2.0 (18 Dec 2020) 
− Additional analyses were added to consider the impact of the COVID-19 pandemic on 
the reliability of the results of the study 
− Specific analyses were added for the Japanese population 
− Additional analyses were requested by sponsor 
− SAP was written according to UCB SAP template 
 
Modifications and changes 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Re-organized the paragraphs and added some 
clarifications. 
To comply with UCB 
format 
Global 
“subject” has been changed to “participant” 
To keep consistent 
terminology  
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Section # and Name 
Description of Change 
Brief Rationale 
Global 
Updated abbreviations 
Updates 
Title page 
Updated version number and date; added 
UCB study number 
Updates 
1 Introduction 
Change Protocol to protocol amendment 2.0 
Updates 
1.1 Objectives and 
Estimands/Endpoints 
Added safety objectives and exploratory 
objectives 
As per protocol 
amendment 2.0 
2 Statistical Hypotheses 
Added Statistical Hypotheses for primary and 
secondary endpoints 
To comply with UCB 
SAP format 
3 Sample Size 
Increased total sample size to 156 participants 
(78 participants per treatment group) 
As per protocol 
amendment 2.0 
4. Population for analysis 
Per protocol set: changed ‘major’ to 
‘important’ protocol deviations. The 
definition: ‘If a participant receives both 
doses of study drug (i.e., placebo and 0.3 
mg/kg), the participant will be assigned to the 
dose group which they received at the highest 
frequency within the study’ has been removed 
A switch of treatment 
should be reported as an 
important PD and 
therefore such a 
participant would be 
excluded from the PPS. 
4. Population for analysis 
Added population ITTNOCOVID and SS NOCOVID  
 
To comply with FDA’s 
guidance on conduct of 
clinical trials of medical 
products during COVID-
19 Public Health 
Emergency. 
4. Population for analysis 
Added PK Set 
Need for PK analysis 
4. Population for analysis 
Added PD Set 
Need for PD analysis 
5.1. General 
Considerations 
Some baseline characteristics, efficacy and 
safety data will be summarized by pre-, 
during COVID-19 relative to the pandemic 
cut-off date, using WHO defined date of 
11Mar2020. 
ITTNOCOVID and SS NOCOVID analyses will be 
done if respectively ITT and SS includes at 
least 15% of participants infected with 
COVID-19. 
To comply with FDA’s 
guidance on conduct of 
clinical trials of medical 
products during COVID-
19 Public Health 
Emergency. 
5.1. General 
Considerations 
Added interim database lock after last 
recruited participant has completed Week 12 
or has withdrawn before Week 12 
As per protocol 
amendment 2.0 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1.1 General study level 
definitions 
Some sections have been added: 
Analysis Time points  
Relative Day 
Mapping of End date of the treatment period 
in case of IMP withdrawal 
Study Periods 
Missing data due to COVID-19 
Handling of repeated and unscheduled 
measurements 
Handling of missing dates and times for AEs 
and concomitant medications. 
More details for 
programming on how to 
handle missing dates, 
missing data, mapping 
of visits, etc… 
5.1.1.3 Treatment 
assignment and treatment 
groups 
Added that for PK/PD analyses, participants 
will be analyzed per actual treatment group 
PK/PD analyses are also 
based on actual 
treatment group. 
5.1.1.5 Coding dictionaries 
Updated MedDRA version to 23.0 
Latest coding version 
will be used in the study. 
5.2 Participant disposition 
Summaries of impact of Covid-19 by visit 
added 
To consider the COVID-
19 pandemic 
5.2 Participant disposition 
Added additional summaries of screen failure 
and disposition by pre-, during the COVID-
19 pandemic 
To analyze the amount 
of data pre-, during 
COVID-19 pandemic. 
5.3.2.1 Primary Analysis 
Some interaction terms in the main model 
removed  
As per protocol 
amendment 2.0 
5.3.2.1 Primary Analysis 
Change to AR (1) autocorrelation structure if 
an unstructured correlation structure does not 
converge. 
More likely to converge 
in case there are some 
issues in terms of 
convergence 
5.3.2.1 Primary Analysis 
Added figures for LSMs (idem for secondary 
endpoints) 
To improve the 
presentation of results 
5.3.3 Sensitivity analysis 
Removed MMRM with LOCF 
LOCF would not be 
acceptable. 
5.3.3 Sensitivity analysis 
Removed MMRM with Treatment interaction 
terms for primary endpoint and all secondary 
endpoints 
Model is very unlikely 
to converge due to the 
number of parameters 
and number of 
participants. Moreover, 
the model can become 
very difficult to interpret 
5.3.3 Sensitivity analysis 
Removed MMRM with Additional Covariates Subgroup analyses are 
sufficient 
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Section # and Name 
Description of Change 
Brief Rationale 
5.3.3 Sensitivity analysis 
Added Tipping point analysis for primary 
endpoint 
Added as sensitivity 
analyses 
5.3.4 Supplementary 
analysis 
Move MMRM on PPS from sensitivity 
analysis to supplementary analysis 
To comply with ICH E9 
Addendum 
5.3.4 Supplementary 
analysis 
Added MMRM under treatment policy 
approach and removed MMRM using 
Observed Case. 
 
Recommended during 
EMA scientific Advice 
5.3.4 Supplementary 
analysis 
MMRM using ITTNOCOVID added 
To take into account the 
COVID-19 pandemic 
5.4.2 Time to receive 
rescue therapy over the 12-
week Treatment period 
Added table for statistical analyses with 
median time to receive rescue therapy, 
95%CI  
Statistical analysis for 
time-to-event data 
5.4.2 Time to receive 
rescue therapy over the 12-
week Treatment period 
Removed Time-to-event analysis using 
Observed Case 
Analysis where 
discontinued subjects 
were excluded from the 
model would not reflect 
the treatment effect. 
5.4.3 Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Removed sensitivity analysis using Observed 
Case 
Analysis where missing 
and censored 
observations are 
missing. Since a non-
responder imputation is 
done for these endpoints, 
this analysis is not 
needed. 
5.4.3. Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Changed Logistic Regression at each visit by 
GEE model 
Better to use a repeated 
measure model 
5.4.3. Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Forest Plots added 
To improve the 
presentation of the 
results 
5.4.3. Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Removed Logistic regression with treatment 
interaction term and Logistic Regression with 
additional covariates 
Too many covariates in 
the model, unlikely to 
converge 
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Section # and Name 
Description of Change 
Brief Rationale 
5.4.3. Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Removed Chi-square test on the ITT 
population.  
Main model with 95%CI 
and p-value are a better 
estimate 
5.4.3 Achieving MSE, 
MG-ADL score responder 
rate, QMG score responder 
rate without rescue therapy 
at Week 12 
Changed Logistic Regression using LOCF by 
Logistic Regression using NRI 
LOCF will not be used  
5.5 Tertiary/Exploratory 
Endpoints analysis 
On additional endpoints (EQ-5D-5L, MGFA 
status and sub scores of QMG, MGC, MG-
ADL, Mg-Qol15r) only summary statistics 
are provided (no statistical analysis) 
No statistical analyses 
on minor endpoints.  
5.5 Tertiary/Exploratory 
Endpoints analysis 
Neuro-QOL and WPAI: change LOCF 
approach by using MMRM with multiple 
imputation (same as main analysis for the 
primary endpoint) 
Time to Response (defined as CFB MG-ADL 
≥2, CFB MG-ADL ≥3, CFB QMG ≥3, CFB 
QMG ≥5) analyzed as time to event data 
using KM curves and log rank test. 
Additional graphs added. 
LOCF will not be used 
5.6.1 Extent of exposure 
IMP duration added 
As per UCB standards 
5.6.2 Adverse Events 
New section was added to specify additional 
summary on TEAE before/during COVID-19 
pandemic 
To analyze the amount 
of data pre-, during the 
COVID-19 pandemic. 
5.6.2.2 AE summaries 
AEs summaries may be done on the 
SSNOCOVID if there is at least 15% of 
participants in the SS are infected by COVID-
19 
To analyze the safety on 
participants not 
impacted by COVID 
5.6.2.2 AE summaries 
Added summary of any TEAEs above 
threshold of 5% of participants in any 
treatment group 
To comply with study 
reporting requirements 
5.6.2.2 AE summaries 
Added summary of treatment related TEAEs 
above threshold of 5% of participants in any 
treatment group 
To comply with study 
reporting requirements 
5.6.2.2 AE summaries 
Added Non-serious TEAEs above threshold 
of 5% of participants in any treatment group 
To comply with study 
reporting requirements 
5.6.3.1 AE of Interest 
(AEIs) 
Added 
To better understand the 
safety profile of 
Zilucoplan 
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Section # and Name 
Description of Change 
Brief Rationale 
5.6.3.2 Clinical laboratory 
evaluations 
Added Shift tables from baseline to each 
post-baseline visit 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.2 Clinical laboratory 
evaluations 
Added marked abnormalities 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.2 Clinical laboratory 
evaluations 
Added Potential drug-induced liver injury 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.3 Vital Signs 
Added Shift tables from baseline to each 
post-baseline visit 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.3 Vital Signs 
Added marked abnormalities 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.4 ECGs 
Added marked abnormalities 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.4 ECGs 
Added Shift tables from baseline to each 
post-baseline visit 
To better understand the 
safety profile of 
Zilucoplan 
5.6.3.6 Total serum IgG 
and IgG subclasses  
Added 
As per protocol 
5.6.3.7 Immunogenicity 
New section was created for ADAs and 
neutralizing antibodies  
To better understand the 
immunogenicity profile 
of Zilucoplan 
5.7.1.1 Pharmacokinetics 
More details given in this section 
 To better understand the 
PK profile of Zilucoplan 
5.7.2 Specific analyses for 
Japanese population 
All set of analyses asked for PMDA 
submission 
Specific analyses were 
requested for patients in 
Japan only 
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Section # and Name 
Description of Change 
Brief Rationale 
5.8 Subgroup analyses 
Following subgroups have been added: 
Ethnicity (Hispanic or Latino, Not Hispanic 
or Latino)  
Race (Asian, Black, White, Other/Mixed) 
Weight in Kg (<56, 56-<77, 77-<150≥ 150) 
Duration of disease at Baseline (<median, ≥ 
median) 
MGFA disease class at Baseline (Class II (IIa, 
IIb), III (IIIa, IIIb), or IV (IVa or IVb)) 
CKD Stage 
Only summary statistics will be provided. 
Some safety analyses on TEAE will be 
provided on some subgroups. 
 
As suggested in FDA’s 
guidance  
6.1.1 Demographics 
Added additional summaries by pre-, during 
the COVID-19 pandemic 
To analyze the amount 
of data pre and during 
the COVID-19 
pandemic. 
6.1.1 Demographics 
Removed p-value to compare similarity of the 
distribution of demographics and baseline 
characteristics 
As per UCB standards 
6.1.2 Protocol deviations 
Added PD relationship to COVID-19 in 
summary table  
To analyze PD due to 
the COVID-19 
pandemic. 
6.1.3 Medical history  
Added additional summaries by pre-, during 
the COVID-19 pandemic 
To analyze the amount 
of data pre and during 
the COVID-19 
pandemic. 
6.1.4 Prior/Concomitant 
medications 
Updated categories of 
past/Prior/Baseline/Concomitant/Concomitant 
only categories 
Further clarification 
6.1.4.4 Refractory criteria 
Updates to reflect what is collected in eCRF 
Further clarification 
6.1.5.9 Neuro-QoL SF 
Total score will be calculated 
Further clarification 
6.3 Changes to Protocol-
Planned Analyses 
Updated after protocol amendment 2.0 
Protocol amendment 2.0 
 
Amendment 2.0 
The purpose of the SAP amendment 2.0 was to make the following changes based on the SAP 
Amendment 1.0 dated 01 February 2021:  
− Anti-PEG antibodies analyses added in Immunogenicity section  
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MG0010 
 
 
 
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− Refractory definition updated 
− Minor changes to add clarity 
Modifications and changes 
Section # and Name 
Description of Change 
Brief Rationale 
Abbreviations 
Updated Abbreviations  
To add clarity 
5.1.1.5 Coding 
dictionaries 
Updated MedDRA version 24.0 
Update WHODD version March 2021 
Latest coding version 
will be used in the 
study. 
5.2 Participant 
Dispositions 
Pre- and during the COVID-19 period will be 
based on the enrollment date relative to the 
pandemic cut-off. 
Rewording for the differentiation of visits 
between those done on video call and those 
on site  
To add clarity for 
programming 
 
5.5.5 
Responder 
analysis for changes in 
QMG, MG-ADL, MG-
QOL15r, and MG 
Composite Scores from 
baseline without rescue 
therapy   
The improvement values will start at the 
maximum level of worsening and will 
continue to the maximum level of 
improvement seen in the study 
To add clarity for 
programming 
5.5.6 
Sub-scores of the 
QMG, MG-ADL, MG-
QOL15r, and MG-
Composite scores 
Exploratory analysis added: The individual 
items for each total score (i.e. QMG, MG-
ADL, MG-QOL15r, MGC) will also be 
summarized by treatment group in a shift 
table from Baseline to Week 12 visit. 
To add insight  
5.6.2.2 AE summaries 
“leading to study discontinuation” reworded 
to “leading to permanent withdrawal from 
IMP” 
To add clarity for 
programming 
5.6.2.2 AE summaries 
Number, percentage of participants and 
frequency of fatal TEAEs summarized by 
relationship, SOC, PT added 
To comply with 
regulatory 
requirements 
5.6.2.2 AE summaries 
Summaries of TEAE during COVID 
infection was added 
To better describe 
TEAEs during 
COVID-19 infection 
5.6.3.1 AE of Interest 
(AEIs) 
Each summary of TEAE of interest will be 
provided for each AE of interest separately 
To add clarity 
5.6.3.7 Immunogenicity 
Immunogenicity will be provided for both 
active and placebo treatment group. Anti-
PEG antibodies summaries were added 
To better describe 
analyses done for 
immunogenicity 
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Section # and Name 
Description of Change 
Brief Rationale 
5.7.2 Specific analyses 
for Japanese Participants 
Treatment-related TEAEs and Treatment-
related TEAEs resulting in permanent 
withdrawal of IMP due to TEAEs were 
added. 
To support submission 
in Japan 
5.7.2 Specific analyses 
for Japanese Participants 
Chemistry, Vital Signs and ECG summaries 
were removed 
Removed since not 
necessary for PMDA 
submission  
5.8 Subgroup analyses 
Age group changed to: Age (<65 years / ≥ 65 
years) 
Typo error in previous 
version. 
5.8 Subgroup analyses 
‘Japan’ region changed to ‘East Asia’ 
Stratification factor 
was re-labelled from 
‘Japan’ to ‘East Asia’ 
as additional 
participants from East 
Asia were included in 
the stratum. 
5.8 Subgroup analyses 
Chronic Kidney Disease Stages subgroup 
added 
To comply with 
guidelines  
6.1.1 
Baseline 
characteristics and 
demographics 
Age definition updated  
To account for data 
collected in the eCRF 
6.1.3.1 Medical history 
(other than MG disease 
history) 
Sorting within HLT added 
More details for 
programming 
6.1.4.3 MG Specific 
Prior and Concomitant 
Medications 
MG Specific Concomitant only summaries 
added 
To give more insight 
6.1.4.4 Refractory 
criteria 
Refractory definition was updated to account 
for other corticosteroids that were taken for 
at least one year and any other 
immunosuppressive therapy.  
Refractory definition 
updated after eCRF 
was updated. 
Table 6‒8 
Updated PT list for anaphylactic reactions 
categories 
Two PT missed from 
the previous list 
6.2.1 
Laboratory 
Assessments Marked 
Abnormality Criteria 
Conventional units updated 
Triglycerides removed  
Typos corrected  
To reflect data transfer 
specifications 
 
Amendment 3.0 
The purpose of the SAP amendment 3.0 was to make the following changes based on the SAP 
amendment 2.0 dated 13 May 2021:  
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Section # and Name 
Description of Change 
Brief Rationale 
2.2 Secondary endpoints 
and multiplicity 
The fixed sequential testing procedure using 
a pre-defined order of the secondary 
endpoints was modified using a Holm 
procedure for the last 4 secondary endpoints 
in the hierarchy within a gatekeeping 
framework.  
  
To account for the low 
number of events of 
the lowest secondary 
endpoints in the 
hierarchy. 
6.3 Appendix 3 Changes 
to Protocol-Planned 
Analyses 
Explanation given for the change in the 
multiplicity procedure 
To describe additional 
changes between SAP 
Amendment 3.0 and 
the protocol. 
 
Amendment 4.0 
The purpose of this SAP amendment 4.0 is to make the following changes based on FDA’s 
feedback on the SAP Amendment 3.0 dated 17 June 2021:  
Section # and Name 
Description of Change 
Brief Rationale 
Abbreviations 
NRI, LOCF, J2R, PD-PPS, PK-
PPS, TEMA were added. 
Missing in previous version. 
1.1 Objectives and 
Estimands/Endpoints 
Intercurrent event handling was 
updated in the primary 
estimand where use of rescue 
therapy (ICE1), adverse event 
of death or myasthenic crisis 
(ICE2) were assumed to be 
treatment failure whereas any 
other missing data is assumed 
to be missing at random in the 
primary analysis. Other 
secondary Estimands were 
updated accordingly. 
FDA suggested this change for 
the primary estimand 
1.1 Objectives and 
Estimands/Endpoints 
Difference for time to first 
administration of rescue will be 
assessed using Kaplan-Meier 
plots 
Update due to the low number 
of expected events 
4 Population for analysis 
ITT population was removed.  
RS and mITT were added. 
FDA suggested this change in 
population from ITT to mITT 
due to the change in the 
primary estimand. 
4 Population for analysis 
ITT no COVID and SS No 
Covid used only if 15% of the 
population is infected by 
COVID was removed. 
FDA suggested that the 
efficacy and safety analyses 
should be done on the total 
study populations followed by 
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Section # and Name 
Description of Change 
Brief Rationale 
To analyze the impact of 
COVID-19 infection on the 
primary estimand, a COVID-19 
Free Set was added defined as 
study participants having 
neither a COVID-19 related 
IPD, nor impacted visits on the 
COVID-19 eCRF page, nor a 
COVID-19 related AE. 
sensitivity analyses to assess 
the effects of COVID-19 
infections on the study results. 
4 Population for analysis 
Population PKS updated to PK-
PPS and PDS updated to PD-
PPS. 
This change is to remove 
subjects with important 
protocol deviations affecting 
the PD or the PK of the drug. 
5.1 General Considerations 
Changed ITT to mITT. 
Population CFS added. 
Population ITTnoCovid et SS 
noCovid removed.  
Changes needed due to the 
changes in population 
5.1.1.1.3.2 Coronavirus 
Disease 2019 pandemic periods 
COVID-19 pandemic periods 
(prior/during/post) added 
More details provided 
compared to previous version 
5.1.1.1.4 Mapping of 
assessment 
Clarification added on early 
termination visit 
Clarified for programming 
5.1.1.3 
Updated populations 
as per FDA's recommendation  
5.1.1.7.2 Efficacy endpoints 
Summary of Primary, 
Sensitivity and supplementary 
for primary and secondary 
efficacy endpoint added, with 
handling of missing data. 
Based on FDA’s proposal 
5.1.1.7.4 Missing data due to 
COVID-19 
Missing data due to COVID 
updated with additional 
sensitivity and subgroup 
analysis on the CFS. 
Based on FDA’s comments 
5.1.1.9 Handling of rescue 
therapy visits 
Paragraph added to clarify 
handling of rescue therapy visit 
Clarification in the SAP 
5.2 Participant dispositions 
Populations updated 
Due to changes in populations 
suggested by the FDA 
5.3.2.2 Handling of missing 
data 
Imputation rules for 
intercurrent events updated 
Based on FDA’s proposal 
5.3.3.1 Sensitivity 1 
Clarification added for the 
jump to reference approach 
To add clarity 
5.3.3.2 Sensitivity 2 
Tipping point analysis slightly 
modified due to the change in 
the primary estimand 
Due to the change in primary 
estimand 
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Section # and Name 
Description of Change 
Brief Rationale 
5.3.3 Sensitivity 3 
MMRM on CFS 
Added as per FDA’s comment 
5.3.4.3 Supplementary 3 
MMRM using PMM changed 
from primary analysis to 
supplementary analysis 
Based on FDA’s proposal 
5.3.4.4 Exploratory 
Worst-rank analysis added 
Based on FDA’s proposal 
5.4.1.2 Main analytical 
approach 
Imputation method updated 
Based on FDA’s proposal 
5.4.1.3 Sensitivity 
Part updated to reflect the 
change in the primary estimand 
Based on FDA’s proposal 
5.4.2.2 Main analytical 
approach 
Median time to rescue removed 
Difficult to interpret due to the 
low number of events expected 
5.4.2.3.2 Sensitivity 
Additional sensitivity analysis 
on the CFS/ Analysis on ITT 
no COVID removed. 
Added as per FDA’s comment 
5.4.3.1 Definition of endpoint 
Algorithm updated to reflect 
the change in imputation rules 
Change of imputation rules 
suggested by the FDA 
5.4.3.3.3 Sensitivity 3 
GEE changed to weighted GEE 
GEE could produce invalid 
estimates 
5.4.3.3.4 Sensitivity 4 
Analysis on CFS added 
Added as per FDA’s comment 
5.5.5 Responder analysis 
MMRM added as exploratory 
for MG-ADL responder 
(defined as improvement ≥2) 
and QMG responder (defined 
as improvement ≥3) 
To add defined threshold in the 
literature used for MG-ADL 
and QMG. 
5.6.1 Extent of exposure 
Exposure duration added 
To be consistent across the 
gMG Zilucoplan studies. 
5.6.2 Adverse Events 
Analyses to assess the impact 
of COVID-19 on the safety as 
well as the impact of COVID-
19 vaccination 
COVID 19 related analysis 
added based on feedback from 
FDA 
5.6.2 Adverse Events 
Definition of treatment-
emergence updated 
To include the 5 half-lives of 
Zilucoplan after the last dose 
when defining treatment 
emergent adverse events. 
5.6.3.2 Clinical Laboratory 
evaluations 
 
Treatment-emergence defined 
To add clarity and consistency 
across the gMG Zilucoplan 
studies 
5.7.2 Specific analyses for 
Japanese Participants  
Summary on prior and 
concomitant medications (other 
To comply with PMDA’s 
requirements 
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Section # and Name 
Description of Change 
Brief Rationale 
than MG therapy) on Japanese 
removed 
Added plot on observed and 
standard errors for MG-ADL 
and QMG added 
5.8 Subgroup analyses 
Safety analyses on the 
subgroup MG Refractory was 
added 
To comply with PMDA’s 
requirements 
5.8 Subgroup analyses 
Subgroup based on the 
pandemic period was added 
Based on FDA’s guidance 
6.1.2 Protocol Deviations 
Clarification added on how the 
relationship to COVID will be 
assessed 
Added clarification for 
programming 
6.1.5.4 MG-QOL-15r 
Clarification added 
To add clarity 
6.1.8 COVID-19 terms 
COVID-19 terms added 
To identify study participants 
infected by COVID-19 
Table 6-10 
Table updated 
To add clarity and consistency 
across the gMG Zilucoplan 
studies. 
6.3 
Changes to protocol-Planned 
analysis updated to reflect 
these changes 
To reflect additional changes in 
SAP Amendment 4.0 compared 
to the protocol. 
 
Amendment 5.0 
The purpose of the SAP amendment 5.0 was to make the following changes based on the SAP 
Amendment 4.0 dated 13 Oct 2021:  
− Typos were corrected 
− Rationales for changes for SAP Amendment 4.0 were clarified 
 
Section # and Name 
Description of Change 
Brief Rationale 
Version History 
Rationale for change was 
updated 
To document with more clarity 
changes in various SAP 
Amendments. 
Table 1-1 
Any other monotone missing 
data was renamed as ICE3 
Clarification was added on 
ICE2 
To add clarity for programming 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 
MMRM on PPS done as a 
supplementary analysis 
To be consistent with the rest 
of the SAP. 
5.1.1.1.2 
End of Study Visit (defined in 
the protocol) defined as well as 
Early Termination Visit 
To clarify for programming 
purposes 
Table 5-1 
Any other monotone missing 
data was renamed as ICE3 
Added clarification on how to 
program intercurrent events 
To add clarity for programming 
5.1.1.7.2 Efficacy Endpoints 
Handling on how to identify 
ICE1, ICE2 and ICE3 was 
added 
To add clarity for programming 
5.2 Participant Disposition 
Spaghetti plot was replaced by 
a linear plot for each study 
participants 
To improve the presentation of 
results 
5.3.2.1 Primary Analysis 
Standard errors were added for 
LSMs 
To add clarity for programming 
5.3.2.2 Handling of missing 
data 
Definition of intercurrent event 
was homogenized  
To be consistent throughout the 
document 
5.3.3.1 Sensitivity 1 
Plot added 
To improve the presentation of 
results 
5.3.3.2.2 Algorithm 
5.3.4.3 Supplementary 3 
5.3.4.4 Exploratory 
5.4.1.2 Main Analytical 
Approach 
5.4.3.1 Definition of endpoints 
Typos corrected  
To be consistent with the rest 
of the document 
5.5.5 Responder analysis 
The wording of waterfall plot 
replaced by a cumulative 
frequency plot 
To add clarity for programming 
5.6.2.2 AE summaries 
COVID-19 tables not repeated 
for each period 
Not needed as only one 
treatment period in MG0010 
5.7.2 Specific Analyses for 
Japanese Participants 
All summaries presented for all 
visits 
To add clarity for programming 
5.8 Subgroups 
MMRM used separately for 
Refractory/non-Refractory 
participants 
To assess treatment effect in 
both strata of these populations 
separately. 
Table 6-10 
Amylase and lipase added in 
the Laboratory marked 
abnormalities 
Missing in the previous version 
and to be consistent across the 
Zilucoplan’s program. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2 Appendix 2: Abnormality 
criteria for Laboratory, Vital 
Sign and Electrocardiogram 
Parameters 
Typos corrected 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
ADA 
anti-drug antibody 
AE 
Adverse Event 
AEIs 
Adverse Events of Interest 
ALP 
alkaline phosphatase 
ALQ 
above the limit of quantification 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AR 
Autoregressive 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
below the limit of quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
blood urea nitrogen 
C5 
Complement component 5 
CFB 
Change from Baseline 
CI 
confidence interval 
CKD 
Chronic Kidney Disease 
COVID-19 
Coronavirus Disease 2019 
CPStat 
Clinical Program Biostatistician 
CRF 
Case Report Form 
CS 
Completer Set 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTStat 
Clinical Trial Biostatistician 
CV 
coefficient of variation 
DAP 
Data Analysis Plan 
DEM 
data evaluation meeting 
DRM 
Data Review Meeting 
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ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ VAS 
EQ visual analogue scale 
EQ-5D-5L 
Euro-Quality of Life 5-Dimensions, 5 levels 
ES 
Enrolled Set 
ESV 
End of Study Visit 
FDA 
US Food and Drug Administration 
geoCV 
geometric coefficient of variation 
geoMean 
geometric mean 
GGT 
gamma glutamyltransferase 
HbA1c 
glycosylated hemoglobin 
hCG 
human chorionic gonadotropin 
HLGT 
High Level Group Term 
HLT 
high level term 
ICH 
The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICE 
intercurrent event 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IPD 
important protocol deviation 
IST 
Immunosuppressive therapy 
J2R 
Jump to reference 
LFT 
Liver Function Test 
LLoQ 
Lower Limit of Quantification 
LLT 
Lower Level Term 
LOCF 
Last Observation Carried Forward 
LSM 
Least Squares Mean 
LSMD 
Least Squares Mean Difference 
MA 
Markedly Abnormal 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MG 
myasthenia gravis 
MG-ADL 
Myasthenia Gravis -Activities of Daily Living 
MG-C 
Myasthenia Gravis- Composite 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL15r 
Myasthenia Gravis MG Quality of Life 15 Item scale revised 
MI 
Multiple Imputation 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
MSE 
minimal symptom expression 
n 
number of participants 
NAb 
neutralizing antibody 
NRI 
non-responder imputation 
PEG 
Polyethylene glycol 
PBO 
Placebo 
PD 
Pharmacodynamic 
PD-PPS 
Pharmacodynamic Per Protocol Set 
PDILI 
Potential Drug Induced Liver Injury 
PK 
Pharmacokinetic 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PPS 
Per Protocol Set 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred term 
PTT 
partial thromboplastin time 
QMG 
Quantitative Myasthenia Gravis 
RBC 
red blood cell  
sRBC 
Sheep red blood cell 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Query 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
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TEMA 
treatment-emergent marked abnormalities  
TFLs 
tables, figures and listings 
WBC 
white blood cell 
WHODD 
World Health Organization Drug Dictionary 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the statistical analyses of study MG0010 (Ra-Pharma reference number RA101495-
02.301). It also defines the summary tables, figures and listings (TFLs) to be included in the 
Clinical Study Report (CSR) according to the protocol. 
This SAP includes efficacy, safety, immunogenicity, pharmacokinetics [PK], pharmacodynamics 
[PD] analyses. Changes to protocol-planned analysis are documented in Section 6.3. Table, 
Figure and Listing (TFL) specifications are contained in a separate document. 
This SAP is based upon and assumes familiarity with protocol amendment 2.0 dated 18 
December 2020. 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, this SAP may be amended accordingly. The content of this SAP is compatible with 
the International Council for Harmonization (ICH)/Food and Drug Administration (FDA) E9 
Guidance documents.  
The statistical analyses and production of the outputs described in the SAP will be conducted by 
eClinical Solutions using SAS software version 9.3. The final analyses and outputs will be 
approved by UCB. 
1.1 
Objectives and Estimands/Endpoints 
The estimand corresponding to the primary objective and primary efficacy analyses are described 
below. The estimands corresponding to the secondary objectives and secondary efficacy analyses 
are also described below.  
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Table 1‒1: 
Estimands 
Objectives 
Estimands/Endpoints 
Primary Efficacy Objective 
To confirm the 
efficacy of zilucoplan 
in participants with 
gMG 
Primary Estimand: 
Treatment: Zilucoplan administered by daily subcutaneous (SC) 
injection (0.3 mg/kg) vs Placebo 
Target Population: Adults with generalized myasthenia gravis 
(gMG) with inclusion/exclusion criteria provided in section 8.1 and 
8.2 of the protocol. 
Endpoint: Change from Baseline (CFB) in Week 12 in Myasthenia 
Gravis-Activities of Daily Living (MG-ADL) Score 
Intercurrent event handling: 
Administration of rescue therapy (ICE1): will be assumed to be a 
treatment failure from the time of the intercurrent event. 
Any death or myasthenic crisis (ICE2) will be assumed to be a 
treatment failure from the time of the intercurrent event. 
Any other monotone missing data (ICE3) will be assumed to be 
missing at random: it is assumed that the participant had remained 
on their treatment throughout the study (i.e., a "Hypothetical-
strategy" assuming participants did not discontinue the study and 
remained on treatment).  
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the mean CFB in the Week 12 MG-
ADL. 
Secondary Efficacy Objective 
To confirm the 
efficacy of zilucoplan 
in participants with 
gMG 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint: CFB to Week 12 in the Quantitative Myasthenia Gravis 
(QMG) Score 
Intercurrent event handling: Same as primary estimand. 
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the mean CFB in the Week 12 
QMG 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
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Endpoint: CFB to Week 12 in the Myasthenia Gravis Composite 
(MGC) Score 
Intercurrent event handling: Same as primary estimand. 
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the mean CFB in the Week 12 
MGC. 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint: CFB to Week 12 in the Myasthenia Gravis – Quality of 
Life revised (MG-QOL15r) Score  
Intercurrent event handling: Same as primary estimand. 
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the mean CFB in the Week 12 MG-
QOL15r. 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint: Time to first administration of rescue therapy over the 
12-week Treatment Period 
Intercurrent event handling: For participants that discontinue from 
the study without having previously received rescue therapy, the 
"while on treatment approach" will be assumed, such that a 
participant will be censored at the time of discontinuation.  
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the Kaplan-Meier curves. 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint: Achieving Minimal Symptom Expression (MSE), 
defined as an MG-ADL of 0 or 1 at Week 12 without rescue therapy 
Intercurrent event handling:  Any participant using rescue therapy 
(ICE1) and any death or myasthenic crisis (ICE2) will be assumed to 
be non-responder from the time of the intercurrent event. Any other 
monotone missing data (ICE3) will be assumed to be missing at 
random before the endpoint is dichotomized.  
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Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the proportion of participants 
achieving MSE. 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint:  Achieving a ≥ 3-point reduction in MG-ADL Score at 
Week 12 without rescue therapy 
Intercurrent event handling:   Any participant using rescue 
therapy (ICE1) and any death or myasthenic crisis (ICE2) will be 
assumed to be non-responder from the time of the intercurrent event. 
Any other monotone missing data (ICE3) will be assumed to be 
missing at random before the endpoint is dichotomized.  
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the proportion of participants 
achieving a ≥3-point reduction in MG-ADL Score at Week 12 
without rescue therapy. 
 
Secondary Estimand: 
Treatment: Same as primary estimand. 
Target Population: Same as primary estimand. 
Endpoint: Achieving a ≥5-point reduction in QMG Score at Week 
12 without rescue therapy  
Intercurrent event handling:   Any participant using rescue 
therapy (ICE1) and any death or myasthenic crisis (ICE2) will be 
assumed to be non-responder from the time of the intercurrent event. 
Any other monotone missing data will be assumed to be missing at 
random before the endpoint is dichotomized. 
Population level summary: The difference between the zilucoplan 
and placebo treatment groups in the proportion of participants 
achieving a ≥5-point reduction in QMG Score at Week 12 without 
rescue therapy. 
 
 
Secondary Safety Objective 
To confirm the safety 
and tolerability of 
zilucoplan in 
participants with 
gMG 
Secondary Safety Endpoint 
Incidence of Treatment Emergent Adverse Events (TEAEs) 
 
Other Safety Endpoints 
Adverse events of interest (AEIs) 
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1.2 
Study design 
Study MG0010 is a phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
confirm the efficacy, safety, and tolerability of zilucoplan in participants with gMG. The planned 
enrollment is approximately 156 participants. 
Participants will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan 
or placebo. Randomization will be stratified based on the baseline MG-ADL Score (≤9 versus 
≥10), QMG Score (≤17 versus ≥18), and geographical region. 
Physical Examination 
Vital Signs 
ECG 
Clinical Laboratory Tests 
Immunogenicity (i.e. ADAs and neutralizing antibodies, anti-PEG 
antibodies) 
C-SSRS 
Exploratory Objectives 
To assess the PK of 
zilucoplan 
 
Plasma concentrations of zilucoplan and its major metabolites  
To assess the PD of 
zilucoplan 
 
Sheep red blood cell (sRBC) lysis assay for evaluation of classical 
complement pathway activation 
Complement component 5 (C5) levels 
To explore the 
efficacy on additional 
efficacy endpoints 
 
Achievement of Minimal Manifestation Status per MGFA Post-
Intervention Status (MGFA-PIS) at Week 12 without rescue therapy 
CFB to Week 12 in Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem (WPAI:SHP)  
CFB to Week 12 in EQ-5D-5L [5-item questionnaire and visual 
analog scale (VAS)]  
CFB to Week 12 in QMG sub-scores: ocular, bulbar, respiratory, 
limb  
CFB to Week 12 in Neuro-QOL Short Form Fatigue Scale 
Responder analysis for changes in QMG, MG-ADL, MG-QOL15r, 
and MG Composite Scores from baseline without rescue therapy 
Sub-scores of the QMG, MG-ADL, MG-QOL15r, and MG-
Composite scores 
To assess the effect 
on biomarkers 
Mechanistic biomarkers pertinent to MG pathophysiology [e.g., 
complement fixation, complement function, complement pathway 
proteins, autoantibody characterization (titer and immunoglobulin 
class) and inflammatory markers] 
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In order to ensure a gradual initiation of the study in Japan, each Japanese site will be capped to 
an enrollment rate of no more than one participant per week (i.e., one participant per site per 
week). 
The study includes a Screening Period of up to 4 weeks and a 12-week Treatment Period. During 
the Treatment Period, participants will return to the clinic at Week 1, Week 2, and monthly visits 
at Week 4, Week 8, and Week 12 to evaluate efficacy, safety, and tolerability. Additional 
assessments will include questionnaires, biomarker samples, pharmacokinetics, 
pharmacodynamics, and optional pharmacogenomics. Safety assessments will include physical 
examinations, vital signs, ECG, clinical laboratory tests, AE monitoring, immunogenicity, and 
C-SSRS. 
Randomized participants will receive 0.3 mg/kg zilucoplan or placebo administered SC at the 
Day 1 visit. Following in-clinic education and training, all participants will self-inject daily SC 
doses of blinded study drug, according to randomized treatment allocation, for the subsequent 12 
weeks. Single use pre-filled syringes in injection devices will be provided for use during the 
study. 
In Japan, following their Day 1 dose, participants will be hospitalized overnight for observation 
to ensure safety of study drug administration. Prior to discharge, participants will be asked to 
self-administer their Day 2 dose under supervision to ensure that their technique for self-
injection is adequate and appropriate, and to answer any additional questions. These pre-
scheduled overnight observational hospitalizations will not be considered SAEs in this study 
(even if hospital stay is extended, provided that the sole purpose of the extension is improvement 
of the injection technique). Participants will continue to self-inject daily SC doses of blinded 
study drug, according to randomized treatment allocation, for the subsequent 12 weeks. 
Participants are expected to remain on stable doses of all medications unless medically indicated 
changes become necessary. All SOC therapy medications for gMG should be kept at the same 
dose throughout the study, including corticosteroids and IST drugs. If escalation of gMG therapy 
(i.e., ‘rescue therapy’) becomes necessary due to major deterioration of a participant’s clinical 
status, or risk of MG crisis as per the investigator’s judgment, the participant may receive IVIG 
or PLEX treatment or eculizumab as ‘rescue therapy’. In Germany, the choice of eculizumab as 
‘rescue therapy’ will not be withheld, if the investigator considers this to be the best course of 
action. 
The safety of participants will be monitored in a blinded manner on an ongoing basis. If an 
unblinded data review should become necessary to ensure participant safety, a SMC will 
convene and evaluate study data as appropriate.  
At the conclusion of the Treatment Period, all participants will have the option to receive 
zilucoplan in a separate Extension Study (Study MG0011), provided they meet the Extension 
Study inclusion criteria.  
If a participant discontinues study drug treatment prior to the Week 12 visit for any reason, 
he/she will not be eligible for the MG0011 Extension Study. For participants who permanently 
discontinue study drug, a Safety Follow-up Visit will be performed at 40 days after the last dose 
of study drug, to collect information on any ongoing AEs or new SAEs since the last study visit. 
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2 
STATISTICAL HYPOTHESES 
2.1 
Primary Endpoint 
The null statistical hypothesis for the primary endpoint is that the treatment difference between 
zilucoplan and placebo in CFB in Week 12 MG-ADL score is zero. The alternative statistical 
hypothesis is that the treatment difference between zilucoplan and placebo in CFB in Week 12 
MG-ADL score is different from zero.  
The primary efficacy endpoint will be tested at the 2-sided 0.05 significance level. 
2.2 
Secondary Endpoints and multiplicity 
The statistical analysis of the secondary efficacy endpoints will account for multiplicity and 
control the familywise type I error rate at a 2-sided alpha level of 0.05 by using a parallel 
gatekeeping testing framework with different testing procedure for each of the 2 type I error 
families. This will only be done if the primary endpoint is significant at 2-sided type 1 error of 
0.05. 
Family 1: 
Family 1 will include the key secondary endpoints. Testing will be done using a fixed-sequential 
testing procedure in the following order: 
1. CFB to Week 12 in the QMG score  
2. CFB to Week 12 in the MGC score 
3. CFB to Week 12 in the MG-QOL15r Survey 
A secondary endpoint analysis in Family 1 will be considered statistically significant if the 2-
sided p-value is ≤ 0.05 for  the endpoint analysis, providing that the primary efficacy endpoint 
analysis, and all the secondary endpoint  analyses occurring earlier in the fixed-sequence are also 
statistically significant (i.e., have a 2- sided p-value ≤ 0.05). This method provides strong control 
of the family-wise error rate at the two-sided 0.05 level. At the first endpoint that is not 
significant, no further testing will be done. 
Family 2: 
If all secondary endpoints in the Family 1 are significant at 2-sided type 1 error of 5%, family 2 
will be tested using a Holm procedure at 2-sided type 1 error. Family 2 includes the following 
secondary endpoints: 
- 
Time to receive rescue therapy over the 12-week Treatment Period  
- 
Achieving MSE, defined as an MG-ADL of 0 or 1, at Week 12 without rescue 
therapy  
- 
Achieving a ≥3-point reduction in MG-ADL Score at Week 12 without rescue 
therapy 
- 
Achieving a ≥5-point reduction in QMG Score at Week 12 without rescue therapy 
The Holm procedure is a multi-step, step-down procedure. The procedure starts with the smallest 
p-value that will be compared to 0.0125. If the first test shows statistical significance, treatment 
effect for the respective endpoint is considered significant. Then, testing will proceed comparing 
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the next-smallest p-value to 0.017. If the second test shows statistical significance, testing will 
proceed comparing the third smallest p-value to 0.025. If the third test shows statistical 
significance, testing will proceed comparing the largest p-value to 0.05.  The procedure stops 
whenever a step yields a non-significant result. Once an ordered p-value is not significant, the 
remaining larger p-values are not evaluated. In this case, treatment effect cannot be concluded 
for the remaining secondary endpoints.  
3 
SAMPLE SIZE DETERMINATION 
For the primary efficacy endpoint, CFB to Week 12 in MG-ADL Score, assuming a difference in 
treatment group least squares means of 2.3, a SD of 3.7, and 78 participants per group (156 in 
total), the study has approximately 94% power to detect a difference between an active and 
placebo treatment group based on a 2-sided alpha of 0.05. This assumes rates of rescue and 
dropout of up to 10% and 5%, respectively. 
4 
POPULATIONS FOR ANALYSIS 
• Enrolled Set: The Enrolled Set (ES) will consist in all screened participants including 
screen failures 
• Randomized Set: The Randomized Set (RS) will include all randomized participants.  
• Modified Intention-to-Treat Population: The modified Intention-to-Treat (mITT) 
Population will include all randomized participants who received at least 1 dose of study 
drug and have at least 1 post-dosing MG-ADL score. 
• Per Protocol Set: The Per Protocol Set (PPS) will include all participants in the mITT 
Population who have completed the 12-week Treatment Period and have no important 
protocol deviations affecting the primary efficacy endpoint. Important protocol deviations 
will be evaluated during ongoing data cleaning meetings prior to unblinding of the data. 
• Safety Set: The Safety Set (SS) will include all participants who received at least 1 dose of 
study drug with participants to be analyzed based on the actual study treatment received. 
• COVID-19 Free Set: The Covid-19 Free Set (CFS) will include all participants in the mITT 
who have neither:  
− a COVID-19 IPD 
− Nor impacted visits on the COVID-19 impact eCRF page 
− Nor a COVID-19 AE  reported in the Adverse Event eCRF form using Appendix 6.1.8.  
• Pharmacokinetic Per-Protocol Set: The Pharmacokinetic Per-Protocol Set (PK-PPS) 
will consist of all participants in the safety population who received at least 1 dose of study 
drug and had at least 1 quantifiable PK measurement post-dose of study treatment without 
important protocol deviations that would affect the PK. 
• Pharmacodynamic Per-Protocol Set: The Pharmacodynamic Per-Protocol Set (PD-
PPS) will consist of all participants in the safety population who received at least 1 dose of 
study drug and had at least 1 quantifiable PD measurement post-dose of study treatment 
without important protocol deviations that would affect the PD . 
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5 
STATISTICAL ANALYSES 
5.1 
General Considerations 
Statistical analysis and generation of tables, figures, participant data listings, and statistical 
output will be performed using SAS® Version 9.3 or higher. All tables and listings will use 
Courier New font size 9. 
All clinical study data will be presented in participant data listings. 
Descriptive statistics will be displayed to provide an overview of the study results. For 
continuous variables, descriptive statistics will include number of participants with available 
measurements (n), mean, SD, median, minimum, and maximum. For categorical variables, the 
number and percentage of participants in each category will be presented. Unless otherwise 
noted, the denominator for percentages will be based on the number of participants included in 
the respective analysis set. 
 Participants with missing data can generally be accounted for using the following approaches: 
− For summaries of demographics and Baseline characteristics: summarize percentages 
based on all participants in the analysis set and include a “Missing” category 
(corresponding to participants with missing data for the variable being summarized) as 
the last row in the list of categories being summarized.  
− For summaries of efficacy and safety variables, unless otherwise specified: summarize 
percentages based only on those participants with observed data for the variable being 
summarized. As the denominator may be different from the number of participants in the 
analysis set being considered, the denominator should be displayed in the table. The 
general format for displaying this will be “n/Nsub (%).” 
Unless otherwise noted, all percentages will be displayed to one decimal place. No percentage 
will be displayed for zero counts, and no decimal will be presented when the percentage is 100%.  
For the purpose of the tabulations the lower and upper confidence limits for the percentages will 
be truncated at 0 and 100% respectively. 
For PK concentrations, summary statistics will include geometric mean, geometric coefficient of 
variation (CV), 95% confidence intervals (CIs) for geometric mean, arithmetic mean, SD, 
median, minimum, and maximum. All summaries of PK variables will be based on the observed 
values. No imputation will be used. 
Decimal places for descriptive statistics will always apply the following rules: 
• 
“n” will be an integer; 
• 
Mean, SD, and median will use one additional decimal place compared to the original data; 
• 
CV [%] will be presented with one decimal place; 
• 
Minimum and maximum will have the same number of decimal places as the original value. 
Derived variables in general will display the mean, SD and median to 1 more decimal place than 
the variables used in the derivation. If the number of decimal places reported in the raw data is 
varied, then use either the maximum raw number of reported decimal places or 3, whichever is 
the lowest, as a guide for the descriptive statistics. 
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Statistical tests of efficacy variables will be presented as p-values rounded to four decimal 
places. P-values less than 0.001 will be presented as “<0.001” and p-values greater than 0.999 
will be presented as “>0.999.” Statistical comparisons will be two-sided and will be performed at 
the 0.05 level of significance unless specified otherwise. The significance levels used as part of 
the multiple testing procedure are detailed in Section 2.2 .  
If no participants have data at a given time point, for example, then only n=0 will be presented. 
However, if n<3, present the n, minimum and maximum only. If n=3, n, mean, median, 
minimum and maximum will be presented only. The other descriptive statistics will be left blank.  
Demographics and baseline characteristics will be analyzed in the mITT population. Prior and 
Concomitant medications will be done in the SS. Efficacy analyses will be done in the mITT 
population, in the CFS as sensitivity analyses and in PPS as supplementary analysis. Safety, PK 
and PD analyses will be done respectively in the SS, PK-PPS and PD-PPS.  
Once the last study participant has completed the Week 12 visit, or the last study participant has 
prematurely discontinued prior to reaching Week 12, the study database will be locked (interim 
database lock). The study will be unblinded and all the TFLs will be produced. The purpose of 
this unblinded interim analysis is to perform a comprehensive evaluation of all available double-
blind data to prepare regulatory submissions for approval of the MG indication. All TFLs will be 
produced again once all data (through to the SFU visit) have been collected. If all the participants 
have completed the study at the interim database lock (the last participants entered the extension 
study), then the interim database lock will be the final lock. 
5.1.1 
General study level definitions 
5.1.1.1 
Analysis Time Points 
All data will be analyzed based on the visits identified per the Schedule of Activities in the 
protocol. Mapping to analysis visit windows is not applied, except for early termination visits 
(specified in Section 5.1.1.1.4). 
5.1.1.1.1 
Relative day 
Relative day will be provided in different listings and will be calculated as follows:  
− If the start (stop) date occurred on or after the first dose, but prior to the double-blind 
drug stop date, relative day is calculated as start (stop) date minus first dose date + 1 (the 
day of first dose will be Day 1).  
− If the start (stop) date occurred before the first dose, the relative day is calculated as date 
of first dose of IMP minus the start (stop) date (the day prior to first dose will be Day -1)  
− If the start (stop) date occurred after the last dose of IMP, the relative day to the most 
recent dose is calculated as start (stop) date minus last dose of IMP including a ‘+’to 
denote posttreatment days (e.g. the day after last dose will be Day +1).   
Relative day will only be computed for fully completed dates and will be missing for partial 
dates. In such cases, relative day should be presented as ‘- -’ in the participant data listings. 
Relative day will be calculated from first dose of IMP for all treatment groups. 
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5.1.1.1.2 
End date of the Treatment Period 
The end date of the Treatment period will be either the date of the Week 12 visit for participants 
completing the Treatment Period or the date of the End of Study Visit (ESV) (i.e., Early 
Termination Visit) for participants who discontinued during the Treatment Period. If a 
participant does not have a Week 12 visit or ESV, then either the date of the last scheduled or 
unscheduled visit during Treatment Period or the date of the last known dose of study drug 
during the Treatment Period, whichever is later, will define the end date of the Treatment Period. 
5.1.1.1.3 
Study periods 
Based on the specific requirements of safety and efficacy analyses, two concepts of the definition 
of periods need to be considered for the study, which will be defined in detail in the sections 
below. 
5.1.1.1.3.1 
Study periods for safety and efficacy data 
The total duration of study participation for all participants will be up to approximately 16 
weeks, including a Screening Period of up to 4 weeks and a 12-week Treatment Period. The 
participants who choose not to enter the Extension Study or who terminate the study prior to 
Week 12 will return to the clinic for a Follow-up Visit 40 days +/- 7 days after their last dose. 
• 
Screening Period: 1 to 28 days 
• 
Treatment Period: 12 weeks  
• 
Follow-up Period: up to 7 weeks 
The end of the study is defined as the date of the last visit of the last participant in the study. 
The following definitions for starting and entering the study periods will be applied: 
• 
Treatment Period starts with the first day of IMP and at the end date of treatment period 
defined in Section 5.1.1.1.2 .  All participants in the Safety Set will be considered to have started 
the Treatment Period. A participant is considered to have completed the Treatment Period if 
assessments from Treatment Period Week 12 Visit are completed.  
• 
Follow-up Period starts one day after the end of the Treatment Period and ends after the final 
assessments on the Safety Follow-up visit. Participants with assessment after the Treatment 
period are considered to have started the Follow-up Period. Participants who entered the 
Extension Study will not do the Follow-up period. 
5.1.1.1.3.2 
Coronavirus Disease 2019 (COVID-19) pandemic periods 
The following COVID-19 pandemic periods will be defined:  
• Prior to COVID-19 pandemic period: Period prior to COVID-19 pandemic start date, which 
is defined as 11-Mar-2020 by the World Health organization (WHO), not including the 
pandemic start date.  
• COVID-19 pandemic period: Period from 11-Mar-2020 through the COVID-19 pandemic 
end date (which is currently not defined), including the dates of pandemic start and end.  
• Post COVID-19 pandemic period: Period after the WHO declaration of the end of the 
pandemic, beginning on the day after the pandemic end date. The end of the pandemic had 
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not yet been declared at the time of SAP finalization. As a result, this period will only be 
included in analyses if the WHO declares an end to the pandemic prior to the end of the 
study. 
These periods will be used to classify the timing of the following relative to COVID-19 
pandemic:  
• study participant enrolment in the study,  
• study participant Week 12 Visit,  
• AE onset date. 
5.1.1.1.4 
Mapping of assessments performed at Early Termination Visit 
If a participant prematurely discontinues study drug at any time prior to Week 12, the participant 
should return to clinic for a stand-alone Early Termination Visit. These assessments will be 
mapped to the next scheduled visit, where each assessment is done as per protocol. 
5.1.1.1.5 
Definition of Baseline values 
Unless otherwise specified, Baseline will be the last available pre-dose value prior to the first 
injection of IMP in the Treatment Period, or if missing, the Screening value. Scheduled or 
unscheduled measurements can be used as the Baseline value. If a Baseline measurement is not 
available but an unscheduled measurement occurs after the planned baseline measurement time 
point but before dosing, then the unscheduled measurement will be used. 
Change from Baseline (CFB) is defined as the value minus baseline value. Percent Change from 
Baseline is defined as 100 x (Change from Baseline/Baseline). 
5.1.1.2 
Protocol Deviations 
Analyses related to protocol deviations are given in Appendix 6.1.2 . 
5.1.1.3 
Treatment assignment and treatment groups 
RS, mITT and CFS analyses will be based on the randomized treatment.  
PPS analyses will be based on the actual treatment received.  
SS, PK-PPS and PD-PPS analyses will be based on the actual treatment received. If after 
unblinding it is determined that participants at any time receive incorrect treatment from their 
randomized assignment, these participants will be reallocated to the appropriate treatment group. 
For example, if participants randomized to placebo received zilucoplan, then for the safety and 
PK/PD analyses, these participants will be reallocated to zilucoplan. Participants randomized to 
zilucoplan will only be reallocated to the placebo treatment group if they never received 
zilucoplan.  
Treatment groups will be shown as below:  
• 
Placebo  
• 
Zilucoplan 0.3mg/kg 
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5.1.1.4 
Center pooling strategy 
It is planned to recruit participants in North America, Europe, and Japan in this study, with 
possible extension to other regions and countries. The data from all sites will be pooled for 
analyses. 
5.1.1.5 
Coding dictionaries 
Adverse events (AEs) and medical histories will be coded using version 24.0 or later of the 
Medical Dictionary for Regulatory Activities (MedDRA®).  
Medications will be coded according to version March 2021 or later of the World Health 
Organization Drug Dictionary (WHODD). 
5.1.1.6 
Multicenter studies 
Individual center results will not be displayed. 
5.1.1.7 
Missing data  
5.1.1.7.1 
Censoring values due to Rescue therapy 
If a participant receives rescue therapy, efficacy endpoints occurring after rescue therapy will be 
censored.   
5.1.1.7.2 
Efficacy endpoints 
Rules for calculating total scores (i.e. MG-ADL, QMG, MG-C, MG-QOL15r) when an 
individual item is missing from an instrument are provided in Section 6.1.5. Imputation methods 
for overall missing scores for the analyses of the primary and secondary endpoints are listed 
below. The estimands corresponding to these analyses are described in Section 1.1. 
Table 5-1: 
Primary and Secondary Estimands 
Efficacy 
Endpoints 
Statistical 
Analysis Type 
Statistical Analysis 
Methods 
Imputation Methods 
Population 
Primary 
Primary 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
mITT 
 
Sensitivity 1 
MMRM 
Imputation: J2R 
mITT 
 
Sensitivity 2 
MMRM 
Imputation: Tipping point 
mITT 
 
Sensitivity 3 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
CFS 
 
Supplemental 1 
MMRM 
Imputation: maximum 
likelihood estimation 
mITT 
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Efficacy 
Endpoints 
Statistical 
Analysis Type 
Statistical Analysis 
Methods 
Imputation Methods 
Population 
 
Supplemental 2 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
PPS 
 
Supplemental 3 
MMRM 
Imputation: Pattern-
mixture approach 
mITT 
 
Exploratory 
ANCOVA 
Imputation: worst rank  
mITT 
Secondary 
(continuous) 
Main 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
mITT 
 
Sensitivity 1 
MMRM 
Imputation: J2R 
mITT 
 
Sensitivity 2 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
CFS 
 
Supplemental 1 
MMRM 
Imputation: maximum 
likelihood estimation 
mITT 
 
Supplemental 2 
MMRM 
Imputation: Baseline or 
last score whichever is 
worse from time of ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
PPS 
 
Supplemental 3 
MMRM 
Imputation: Pattern-
mixture  
mITT 
Secondary 
(binary) 
Main 
Logistic 
Imputation: NRI for ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
mITT 
 
Sensitivity 1 
Logistic model 
Imputation: J2R 
mITT 
 
Sensitivity 2 
Logistic model 
Imputation: NRI 
mITT 
 
Sensitivity 3 
Weighted GEE model 
Imputation: NRI 
mITT 
 
Sensitivity 4 
Logistic 
Imputation: NRI for ICE1 
and ICE2 and maximum 
CFS 
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Efficacy 
Endpoints 
Statistical 
Analysis Type 
Statistical Analysis 
Methods 
Imputation Methods 
Population 
likelihood estimation for 
ICE3. 
 
Supplementary  
Logistic 
Imputation: NRI for ICE1 
and ICE2 and maximum 
likelihood estimation for 
ICE3. 
PPS 
Secondary 
(Time to Event) 
Main 
Kaplan-Meier plots 
No imputation 
mITT 
 
Sensitivity 1 
Kaplan-Meier plots 
Imputation: Discontinued 
participants assumed to 
have taken rescue therapy 
mITT 
 
Sensitivity 2 
Kaplan-Meier plots 
No imputation 
CFS 
 
Supplementary 
Kaplan-Meier Plots 
No imputation 
PPS 
MMRM=mixed model for repeated measures; ANCOVA= analysis of covariance; J2R=Jump to reference; NRI= non-
responder imputation 
If a study participant is administered a rescue therapy (ICE1), any data strictly after the start date 
of the first rescue therapy administration (in the Rescue Therapy Cycle Administration eCRF 
page) will be flagged as intercurrent event 1 (ICE1). 
If a study participant experiences a death (ICE2), then data after the death date on the Early 
Termination eCRF page will be flagged as intercurrent event 2 (ICE2). 
If a study participant experiences a myasthenic crisis (i.e., MedDRA PT = ‘myasthenia gravis 
crisis’), then any data after the start date of the adverse event on the AE eCRF page will be 
flagged as intercurrent event 2 (ICE2).  
Any other monotone missing data will be flagged as intercurrent event 3 (ICE3) in each relevant 
dataset (depending on the efficacy endpoint). ICE3 is defined as any missing value where all 
values at subsequent visits are missing.  
For other binary efficacy endpoints (e.g. QMG responder, MG-ADL responder), missing data 
will be imputed using nonresponse imputation (NRI). That is, study participants with missing 
data at the timepoint of interest will be treated as non-responders. 
For ordinal endpoints (EQ-5D-5L), the observed case method will be applied. No further 
imputation is used. 
 
5.1.1.7.3 
Safety, PK and PD endpoints 
Missing data for Safety, PK and PD endpoints will not be imputed; observed cases will be used. 
This will include observations occurring after a participant receives rescue-medication. 
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5.1.1.7.4 
Missing data due to COVID-19 
Missing data is expected to be one of the major implications of the COVID-19 pandemic. The 
following approaches/strategies will be applied to assess the impact of COVID-19 in this study.  
• Added an eCRF page “COVID-19 Impact”, including impacted visits, impacted assessments 
and reason why these assessments were impacted  
• Protocol deviations related to COVID-19 will be documented 
• Included additional summary analyses based on the COVID-19 pandemic period 
(prior/during). A post COVID-19 time period may be added if relevant. 
• Sensitivity analyses on the primary efficacy endpoint using the same method as the primary 
analysis on the Covid-19 Free Set and by timing of the Week 12 Visit relative to the start and 
end date (if applicable) of the COVID-19 pandemic period. 
• Subgroups analyses will be performed on the primary efficacy endpoint based on the timing 
of participant enrollment and timing of the Week 12 visit relative to the COVID-19 pandemic 
period as exploratory. 
5.1.1.8 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the listings, where applicable. 
The following general rules will apply to all repeated and unscheduled measurements: 
• For repeated or unscheduled measurements obtained prior to the first dose of IMP the latest 
reliable value (scheduled or unscheduled) will be used in the calculation of descriptive 
statistics (i.e. Screening and/or Baseline) as defined in Section 5.1.1.1.5.  
• For repeated or unscheduled measurements obtained at Day 1 and prior to the first dose of 
IMP, the latest reliable value (scheduled or unscheduled) will be defined as the Baseline; 
• For repeated or unscheduled measurements obtained at any time point after the first dose of 
IMP, the original values (if non-missing) will be used in the calculation of changes from 
Baseline and for the descriptive statistics (i.e. in summaries by time point).  
5.1.1.9 
Handling of rescue therapy visits 
All rescue therapy visits will be presented in the listings, where applicable. However, the rescue 
therapy visits will not be presented for descriptive statistics (i.e. summaries by time point). The 
statistical analyses will present summaries at each scheduled visit as well as outputs of the 
statistical modelling using the imputation rules defined in Section 5.1.1.7.2.  
5.1.1.10 
Handling of missing dates and times 
Partially or completely missing dates may be imputed for the following reasons: 
• Classification of AEs as TEAEs; 
• Classification of medications as past, prior, baseline or concomitant medications; 
• Duration of AEs  
Imputed dates will not be shown in listings.  All dates will be displayed as reported in the 
database. 
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The following rules will be applied for partially or completely missing start dates: 
• 
If year, month and day are all missing then assign the date of first dose of IMP. If an imputed 
start date is after the specified end date, then assign January 01 of the year of the end date, or the 
date of screening if this is later (if the latter imputation results in an end date that is earlier than 
the start date, then use January 01). 
• 
If month and day are missing, and year is: 
− the same as the year of the first dose of IMP then assign the month-day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign January 01, or 
the month-day of screening date if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then assign January 01); 
− not the same as the year of the first dose of IMP then assign January 01. 
• 
If only day is missing, and month-year is: 
− the same as the month-year of the first dose of IMP then assign the day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign first day of the 
month, or the day of screening date if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then assign first day of the month); 
− not the same as the month-year of the first dose of IMP then assign the first day of the 
month. 
The following rules will be applied for partial stop dates: 
• 
If only the month and year are specified, then use the last day of the month; 
• 
If only the year is specified, then use December 31 of the known year; 
• 
If the stop date is completely unknown, then use discharge date or data cut-off date. 
Note: Discharge date refers to the date of the end of study visit for completed participants or the 
date of discontinuation for participants that were withdrawn. For any AEs with known start date 
after the date of discontinuation, the date of last contact will be used as the discharge date. For 
participants still ongoing in the study at the time of the data cut-off, and for whom no discharge 
date is available, the date of the data cut-off will be used instead of the discharge date. 
In the event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication was concomitant or not, the medication will be considered as concomitant. Any 
medication with a start date on the first dosing date and time unknown, will be assumed to be 
concomitant. In the event of ambiguity or incomplete data which makes it impossible to 
determine whether an adverse event was treatment-emergent or not, the adverse event will be 
considered as treatment-emergent. 
Imputed AE dates will be used for the calculation of duration of AEs, defined as: 
Duration of AE = stop date – start date + 1 
5.2 
Participant Dispositions 
The following summaries will be created. 
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− Reasons for screen failures will be summarized using the ES for overall. Additionally, 
the reasons for screen failures will be summarized by pre- and during the COVID-19 
pandemic based on the enrollment date relative to the pandemic cut-off date. 
− Disposition of analysis sets will be summarized by treatments groups and overall, by 
analysis sets (RS, mITT, CFS, SS, PPS, PK-PPS, PD-PPS). Percentages will be based on 
the number of participants in the RS in the respective treatment groups and overall. 
Disposition of analysis sets will also be summarized in the ES by region, with number of 
sites, principal investigator name, dates of first participant in and last participant out as 
well as the number of participants screened/screen failures 
− Disposition and discontinuation reasons using the RS and mITT population will 
contain the number and percentage of study participants who started, completed, 
permanently discontinued Treatment Period with primary reason of discontinuation and 
entered into the extension study RAISE-XT overall. Percentages will be based on the 
number of participants in the RS and mITT population in the respective treatment group 
and overall.   
− Discontinuation due to AEs using the RS and mITT population will summarize the total 
number of study participants who discontinued the study due to AEs by treatment group 
and the categories: AE, serious fatal, AE non-fatal and other (AE non-serious fatal). 
− Impact of COVID-19 using the mITT population will summarize number and 
percentage of participants in each impact category by visit. This table will be done 
overall and by country. Visits and assessments done via video calls will be listed.  For 
both the listing and the summary table, only visits at which efficacy or safety assessments 
are scheduled will be included. 
Listings of study participant disposition and study discontinuation, analysis set and study 
participants who did not meet study eligibility criteria will be provided. Listing of all participants 
impacted by COVID-19 will also be provided.  
Additionally, a linear plot of MG-ADL score versus scheduled visit will be presented by 
treatment group for each participant having performed at least one video call. Visits will be 
differentiated between those performed by video call and visits performed on site. 
Finally, the number of study participants enrolled during each COVID-19 pandemic period as 
well as the number of study participants still in the study during each COVID-19 pandemic 
period will be summarized in one table on the randomized set. The table will be done overall and 
by region (North America, Europe and East Asia). 
5.3 
Primary Endpoint Analysis 
The primary efficacy analysis will be the comparison of zilucoplan 0.3 mg/kg dose group versus 
placebo in CFB to Week 12 in MG-ADL Score at a 2-sided 0.05 significance level based on the 
mITT population using least squares means.  
5.3.1 
Definition of endpoint 
The primary endpoint is the CFB in Week 12 MG-ADL Score. The complete list of MG-ADL 
items and scores and calculation of total score are provided in Appendix 6.1.5.1 . The total score 
calculated after single item imputation will be used to calculate change from Baseline, in 
summaries and for efficacy analyses. 
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5.3.2 
Main analytical approach 
5.3.2.1 
Primary Analysis 
For the primary efficacy endpoint, CFB to Week 12 in MG-ADL Score, treatment group 
differences will be assessed using a mixed model repeated measures (MMRM) analysis of 
covariance (ANCOVA) with treatment, baseline MG-ADL Score, baseline QMG Score, 
geographical region, treatment-by-visit (interaction term), baseline MG-ADL Score-by-visit 
(interaction term) as fixed effects and participant as a random effect. The MMRM ANCOVA 
will include Weeks 1, 2, 4, 8, and 12.  
The treatment and geographical region (North America, Europe and East Asia) terms in the 
MMRM model will be treated as categorical, visit as an ordinal (categorial) variable, and 
baseline MG-ADL and QMG Scores will be treated as continuous.   
The MMRM will use an “unstructured” covariance structure for the repeated measures. In the 
event the “unstructured” covariance structure model fails to converge, an AR (1) covariance 
structure will be used.  The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. The least square means (LSMs) and standard errors (SE) of 
each treatment group, and the least squares mean differences (LSMDs) between zilucoplan and 
placebo will be reported for the Week 12 Visit along with the corresponding 2-sided 95% CIs 
and p-values. Statistical outputs such as LSM and 95% Confidence Intervals (95% CI) will be 
plotted from Week 1 to Week 12. The least squares mean (LSMs) of each treatment group, and 
the least squares mean differences (LSMDs) between zilucoplan and placebo at Weeks 1, 2, 4, 
and 8 will also be reported with the corresponding 2-sided 95% CIs. 
Model assumptions (Independence, Normality, Homoscedasticity) will be checked by using 
normal probability plots of studentized residuals by actual residuals and a random variation plot 
of studentized residuals by predicted values. Results of the diagnostics procedures may be 
included in the CSR appendix “Documentation of statistical methods” if deemed relevant. 
CFB in MG-ADL score will be summarized by treatment group and by visit using descriptive 
statistics in the mITT. The same summary will be done by subgroup as defined in Section 5.8. 
CFB MG-ADL will be listed for all participants of the RS with visit flagged if the visit was done 
prior to the COVID-19 pandemic cut-off date. For participants infected with COVID-19 as per 
the AE page, CFB in MG-ADL will be listed by visit separately. 
5.3.2.2 
Handling of missing data 
The number of missing values by visit for primary and secondary endpoints will be provided by 
treatment group and overall using descriptive statistics on the mITT. Additionally, the number of 
missing values by visit due to COVID-19 will be summarized by treatment group for the primary 
and secondary endpoints (using the “COVID-19 Impact” e-CRF page) as explained in 
Section 5.2.  
For the primary efficacy analysis, missing or censored data will be imputed the baseline or the 
last available MG-ADL score (including unscheduled visit), whichever is worse from the time of 
the following intercurrent events:  
− ICE1: Data occurring after a participant received rescue therapy  
− ICE2: Data occurring after a participant had any death or myasthenic crisis  
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Any other monotone missing data (ICE3) will be assumed to be missing at random. 
Note: if a MG-ADL assessment is done on the rescue therapy visit, then this will be considered 
as the last score available prior to rescue therapy. The number and percentage of participants 
with each intercurrent event (ICE1, ICE2 and ICE3) will be summarized by treatment group. 
5.3.3 
Sensitivity analysis 
5.3.3.1 
Sensitivity #1: MMRM using J2R approach 
Deviations from the missing at random pattern will be evaluated using a J2R approach using 
Multiple Imputation (MI method) under the missing not at random assumption (MNAR) to 
handle any missing scores. Intermittent missing data will be imputed using the Markov-Chain 
Monte Carlo method, using the MCMC impute=monotone option in PROC MI (SAS System).  
Monotone missing/censored data will be imputed using the placebo distribution irrespective of 
individual treatment assignment.  The MNAR option in PROC MI (SAS system) will be used to 
impute the placebo distribution.   
The following variables will be included in the imputation model:   
− Baseline MG-ADL Score (continuous variable) 
− The participant’s MG-ADL scores at previous visits (e.g. Week 12 CFB MG-ADL 
imputed score will use scores at Week 1, 2, 4 and 8). If a participant starts rescue therapy, 
then the most recent MG-ADL score will be used which may occur at an unscheduled 
visit 
The seed used for these imputations will be 2021 (note that all other multiple imputation 
procedures described in this SAP related to MCMC/Monotone regression analyses will use this 
same seed as well). If the MI model does not converge or produce estimates (e.g., due to over-
specification) the set of imputation variables may be modified.   
Each of the imputed datasets will be analyzed via the specified MMRM model (see 
Section 5.3.2.1). The treatment effects and standard errors from the least squares means 
(LSMeans) treatment difference will be combined across the 100 imputed datasets using Rubin’s 
rule to produce an overall p-value using SAS PROC MIANALYZE. LSMs and 95% Confidence 
Intervals (95% CI) will be plotted from Week 1 to Week 12. 
 
5.3.3.2 
Sensitivity #2: Tipping point analysis 
5.3.3.2.1 
Methodology 
An additional sensitivity analysis using the tipping-point approach will be conducted to assess 
the robustness of the MAR assumptions in the primary analysis. These tipping point analyses 
will only be performed if the primary efficacy analysis results in a statistically significant 
treatment effect (p<0.05). Various delta adjustments will be made to the assumed responses on 
the monotone missing data (ICE3) in each treatment group independently with various degrees 
of plausibility. It will include scenarios where study participants who have missing data and are 
randomized to zilucoplan are less likely to respond than compared to study participants who have 
missing data and were randomized to placebo. 
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Tipping point analysis is a means of exploring the influence of missingness on the overall 
conclusion from statistical inference by positing a wide spectrum of assumptions regarding the 
missingness mechanism (from less conservative to more conservative). The analysis finds a 
(tipping) point in this spectrum of assumptions, at which conclusions change from being 
favorable to the experimental treatment to being unfavorable. After such a tipping point is 
determined, clinical judgment can be applied as to the plausibility of the assumptions underlying 
this tipping point. The tipping point can be identified while the result is no longer statistically 
significant.  
Participants that receive rescue therapy (ICE1) or participants with a death or myasthenic crisis 
(ICE2) will be imputed as baseline or the last available MG-ADL score (including unscheduled 
visit), whichever is worse from the time of the intercurrent events as in the primary analysis. The 
tipping point analysis will be used for ICE3 assumed to be missing at random in the primary 
analysis. 
5.3.3.2.2 
Algorithm 
Delta adjustments will be made to the imputed values for observations in each treatment group 
(for ICE3 only) with various degrees of plausibility with the goal to find for each treatment 
group the “tipping point” that will significantly reverse the primary result that yielded a p-value 
less than 0.05.  
These delta adjustments (by adding a positive or a negative shift) will be done on the MG-ADL 
score and will be implemented as follows:  
• Step 1: Intermittent missing data will be imputed using the Markov-Chain Monte Carlo 
method, using the MCMC impute=monotone option in PROC MI (SAS System).   
• Step 2: A set of 100 sets of imputations will be produced: 
A monotone regression model will be applied while adjusting the imputed values by various shift 
parameters. These shift parameters will be defined within the pre-defined range of values. A 
positive shift will be applied to the imputed value for study participants randomized to zilucoplan 
to decrease the imputed value, whereas a negative shift will be applied to the placebo group to 
increase the imputed value. Assumptions will be varied independently in each treatment group 
(i.e. whenever a shift will be applied to the Zilucoplan treatment group, then the placebo group 
will be fixed). Shift parameters will be chosen according to the range of values observed at 
baseline. Once defined, the same shift parameter value will be applied on the imputed endpoint 
value for all visits.  
• Step 3: Each of the 100 imputed datasets will then be analyzed using the same MMRM 
model used for the main analytical approach as the primary endpoint. 
• Step 4: The 100 LSMDs will then be combined for overall inference using Rubin’s rules, and 
the results obtained for each shift parameter will be presented in a single table.  
• Step 5: Step 2 to 4 will be repeated using a bisection algorithm. The tipping point will be 
found, if it exists, when the difference between the p-value obtained for the LSMD between 
zilucoplan and placebo and the target p-value (0.05) is very small (<0.0000001). 
The LSMD and 95%CI and p-values obtained for each shift parameter will be combined in one 
single table. Results will be displayed graphically in a contour plot where y-axis display the 
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Zilucoplan shift and x-axis is the placebo shift, with contours at selected p-value levels: 0.01, 
0.025, 0.05 and 0.1.  
5.3.3.3 
Sensitivity #3: MMRM on CFS 
To assess the impact of the COVID-19 pandemic on the primary efficacy endpoint, the same 
analysis method as the primary analysis described in Section 5.3.2 will be done on the COVID-
19 Free Set. 
5.3.4 
Supplementary analyses 
5.3.4.1 
Supplementary #1: MMRM under treatment policy approach 
The primary efficacy endpoint analyses will be performed on the mITT population using a 
treatment policy approach, where all the data will be used regardless of any intercurrent events 
(i.e. no data will be censored) using the treatment initially assigned at randomisation. Any 
missing MG-ADL score will be handled based on the maximum likelihood estimation method 
under the MAR assumption. The same model as the main analytical approach will be 
implemented. 
5.3.4.2 
Supplementary #2: MMRM on the PPS 
The primary efficacy endpoint analysis will be performed on the PPS. 
5.3.4.3 
Supplementary #3: MMRM using Pattern-Mixture Model (PMM) 
Multiple imputation (MI) methods will be used to handle missing data and data after rescue 
therapy use (i.e., data collected after a participant has used rescue therapy will be censored and 
treated as missing data for the primary efficacy analysis).  
For this supplementary analysis, 100 imputed datasets will be created using monotone linear 
regression imputation methods which will impute the participants’ missing post-baseline scores 
at each of the scheduled visits in the study (i.e., Weeks 1, 2, 4, 8, and 12). If the missing data 
does not follow a monotonic pattern, a sequential approach to imputing the data to produce a 
monotone missing data pattern will be applied using the MCMC impute=monotone option in 
PROC MI (SAS System).  
Then the monotone linear regression imputation methods will be applied. Imputation will be 
performed by treatment group, with the underlying imputation distribution based on the reason 
for the missing data.   
Missing and censored data will be imputed based on the placebo group distribution, irrespective 
of individual treatment assignment, under the following intercurrent events:  
− ICE1: Data occurring after a participant received rescue therapy  
− ICE2: Data occurring after a participant had a death or myasthenic crisis.  
Missing data will be imputed based on the participant’s assigned treatment group distribution 
under the following scenarios:  
− ICE3: Monotone missing data for any other reason.  
This MI method allows for a pattern-mixture model approach assuming the data are missing not 
at random (MNAR) under ICE1 and ICE2 (i.e., treatment failure). The MNAR option in PROC 
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MI (SAS system) will be used to impute the placebo distribution as described in Yuan (2014).  
Each of the imputed datasets will be analyzed via the specified MMRM model (see 
Section 5.3.2.1). The treatment effects and standard errors from the least squares means 
(LSMeans) treatment difference will be combined across the 100 imputed datasets to produce an 
overall p-value using SAS PROC MIANALYZE.  
The following variables will be included in the imputation model:   
− Baseline MG-ADL Score (continuous variable) 
− The participant’s CFB MG-ADL scores at previous visits (e.g. Week12 CFB MG-ADL 
imputed score will use scores at Week 1, 2, 4 and 8). If a participant starts rescue therapy, 
then the most recent CFB MG-ADL score will be used which may occur at an 
unscheduled visit 
Note that the imputations will be such that they will either be performed by treatment or only the 
placebo distribution will be used for the imputation (i.e., for MNAR).   
Note: if the MI model does not converge or produce estimates (e.g., due to over-specification) 
the set of imputation variables may be modified.   
5.3.4.4 
Exploratory: Worst-Rank analysis of covariance at Week 12   
A worst-rank analysis of covariance will be used on the mITT population at Week 12, where 
participants with poor outcomes will be assigned the highest rank in the following order:  
(a) participants who died by Week 12  
(b) participants who experienced myasthenic crisis  
(c) participants who received rescue therapy, or those who discontinued the study having 
deteriorated. Deterioration will be defined as a positive change from baseline MG-ADL.  
(d) all other participants (ranked in ascending order of the improvement from baseline in MG-
ADL total score at Week 12 [LOCF]) 
Participants with the same outcome will be assigned ranks depending on the timing of the event, 
where an event occurring earlier will have a higher rank. Participants with the best outcome (i.e. 
largest improvement) will be assigned the lowest rank. Any missing data (other than due to 
death, myasthenic crisis, rescue therapy or discontinuation due to deterioration) will be imputed 
with a last observation carried forward (LOCF) approach. Therefore, each participant will be 
ranked from 1 (best outcome) to the number of participants in the mITT population (poorest 
outcome).  
Ranks will then be analyzed using an analysis of covariance (ANCOVA) with treatment as fixed 
effect and baseline MG-ADL score.  LS Means rank and 95% confidence intervals will be 
provided as well as LS means difference and 95% confidence intervals. The p-value will be 
provided as exploratory. 
5.4 
Secondary Endpoint Analysis 
All secondary endpoints will be listed for all participants of the RS with visit flagged if the visit 
was done prior to the COVID-19 pandemic cut-off date. For participants infected with COVID-
19 as per the AE page, secondary endpoints will be listed by visit separately. 
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5.4.1 
Week 12 CFB in the QMG score, in MGC score, in MG-QoL15r Survey 
5.4.1.1 
Definition of endpoints 
The change from Baseline to Week 12 in the QMG score, in the MGC score and in the MG-
QoL15r Survey will be analyzed on the mITT population. More details on how these scores are 
calculated can be found respectively in Appendix 6.1.5.2 , Appendix  6.1.5.3  and 
Appendix 6.1.5.4.  
5.4.1.2 
Main analytical approach 
Each of the continuous secondary endpoints (i.e. Week 12 CFB in QMG Score, MGC Score, and 
MG-QOL15r Survey) will be analyzed using a mixed model repeated measures (MMRM) 
analysis of covariance (ANCOVA). As for the primary endpoint, data after use of rescue therapy 
(ICE1) and death or myasthenic crisis (ICE2) will be imputed baseline or the last available 
corresponding score (including unscheduled visit), whichever is worse from the time of the 
following intercurrent events.  Any other monotone missing data (ICE3) will be assumed to be 
missing at random.  
For Week 12 CFB QMG Score, MMRM ANCOVA will include treatment, baseline MG-ADL 
Score, baseline QMG Score, geographical region (North America, Europe and East Asia), 
treatment-by-visit (interaction term), baseline QMG Score-by-visit (interaction term) as fixed 
effects and participant as a random effect. The MMRM ANCOVA will include Weeks 1, 2, 4, 8, 
and 12.  
Similarly, for Week 12 CFB MGC Score, MMRM ANCOVA will include treatment, baseline 
MG-ADL Score, baseline QMG Score, geographical region (North America, Europe and East 
Asia), baseline MGC, treatment-by-visit (interaction term), baseline MGC Score-by-visit 
(interaction term) as fixed effects and participant as a random effect.  
Similarly, for Week 12 CFB in MG-QOL15r, MMRM ANCOVA will be include treatment, 
baseline MG-ADL Score, baseline QMG Score, geographical region (North America, Europe 
and East Asia), baseline MG-QOL15r, treatment-by-visit (interaction term), baseline MG-
QOL15r Score-by-visit (interaction term) as fixed effects and participant as a random effect. 
For each secondary endpoint, the MMRM will use an “unstructured” covariance structure for the 
repeated measures. In the event that the “unstructured” covariance structure model fails to 
converge, an AR (1) covariance structure will be used. The Kenward-Roger approximation will 
be used to estimate the denominator degrees of freedom. The least square means (LSMs) of each 
treatment group, and the least squares mean differences (LSMDs) between zilucoplan and 
placebo will be reported for the Week 12 Visit along with the corresponding 2-sided 95% CIs 
and p-values. The least squares mean (LSMs) of each treatment group with standard errors (SE), 
and the least squares mean differences (LSMDs) between zilucoplan and placebo at Weeks 1, 2, 
4, and 8 will also be reported with the corresponding 2-sided 95% CIs. Statistical outputs such as 
LSMs and 95% CIs will be plotted from Week 1 to Week 12. 
These secondary endpoints will be summarized by treatment group and by visit using descriptive 
statistics on the mITT. The same summaries will be done by subgroup as defined in Section 5.8. 
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5.4.1.3 
Sensitivity analysis  
5.4.1.3.1 
Sensitivity #1: MMRM using J2R approach 
The same approach as Section 5.3.3.1 will be done on these secondary endpoints in the mITT. 
5.4.1.3.2 
Sensitivity #2: MMRM in CFS 
The same approach as Section 5.3.3.3 will be done on these secondary endpoints in the CFS. 
5.4.1.4 
Supplementary analyses 
5.4.1.4.1 
Supplementary #1: MMRM under treatment policy approach 
The same approach as Section 5.3.4.1 will be done on these secondary endpoints in the mITT.  
5.4.1.4.2 
Supplementary #2: MMRM on the PPS 
The same approach as Section 5.3.4.2 will be done on these secondary endpoints in the PPS.  
5.4.1.4.3 
Supplementary #3: MMRM using Pattern-Mixture Model (PMM) 
The same approach as Section 5.3.4.3 will be done on these secondary endpoints in the mITT. 
5.4.2 
Time first administration of rescue therapy over the 12-week 
Treatment period 
5.4.2.1 
Definition of endpoint 
Time to receive rescue therapy over the 12-week treatment period (in days) is defined as: Date of 
first rescue therapy use – date of first IMP + 1.  
Participants who do not take rescue therapy will be censored at the date of withdrawal/study 
completion.  
5.4.2.2 
Main analytical approach 
Time to receive rescue therapy over the 12-week treatment period will be analyzed as time-to-
event on the mITT, using Kaplan-Meier plots. KM estimated survival up to Week 12 will be 
calculated. Treatment difference will be evaluated using a Log Rank test. 
5.4.2.3 
Sensitivity analysis 
5.4.2.3.1 
Sensitivity #1: Assuming Discontinued Participants took Rescue 
Medication 
The time-to-event analyses will be repeated assuming the participants who discontinued took 
rescue medication at the time they discontinued.   
5.4.2.3.2 
Sensitivity #2: CFS 
The time-to-event analyses as described in Section 5.4.2.2  will be performed on the CFS. 
5.4.2.4 
Supplementary analyses 
5.4.2.4.1 
Supplementary #1: Time-to-event on PPS 
The time-to-event analyses as described in Section 5.4.2.2 will be performed on the PPS. 
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5.4.3 
Achieving MSE, MG-ADL score responder rate, QMG score 
responder rate without rescue therapy at Week 12 
5.4.3.1 
Definition of endpoints 
These dichotomous secondary endpoints are defined as below: 
• Achieving MSE is defined as achieving a MG-ADL value of a 0 or 1 at Week 12 and not 
having taken rescue therapy 
• MG-ADL score responder rate is defined as achieving ≥ 3-point improvement from Baseline 
(decrease) at Week 12 and not having taken rescue therapy 
• QMG score responder rate is defined as achieving ≥ 5-point improvement from Baseline 
(decrease) at Week 12 and not having taken rescue therapy 
Intermittent missing data will be imputed using Markov Chain Monte Carlo (MCMC) to obtain 
monotone missing pattern. Any monotone missing data will be imputed using MAR assumption. 
Participants who received rescue therapy or who had an event of death or myasthenic crisis will 
be considered as non-responders. The endpoints above will then be dichotomized at Week 12 
from the imputed continuous endpoint. 
Achieving MSE is defined as achieving a MG-ADL value of a 0 or 1 at Week 12 (after multiple 
imputation where appropriate), calculated as:   
Week 12 MG-ADL value = Baseline MG-ADL + Week 12 CFB in MG-ADL.  
The criteria for success will be a value ≤ 1.0 to account to imputed Week 12 MG-ADL value that 
may not be integers. 
5.4.3.2 
Main analytical approach 
Achieving MSE without rescue therapy will be analyzed in the mITT in each imputed dataset 
using a logistic regression with treatment as factor and baseline MG-ADL score as covariate. 
Odd Ratios, 95% Confidence interval and associated p-value will be provided. The treatment 
effects and standard errors will then be combined across the 100 imputed datasets to produce an 
overall p-value using the SAS proc MIANALYZE. 
A ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy and a ≥ 5-point 
reduction in QMG Score at Week 12 without rescue therapy will be analyzed in the mITT in 
each imputed datasets with treatment as a factor, baseline MG-ADL Score, baseline QMG score, 
and geographical regions (North America, Europe and East Asia) as covariates.  The treatment 
effects and standard errors will then be combined across the 100 imputed datasets to produce an 
overall p-value using the SAS proc MIANALYZE. 
Note: the logistic regression model for Achieving MSE, defined as an MG-ADL of 0 or 1, at 
Week 12 without rescue therapy endpoint has a reduced number of covariates as the anticipated 
number of events for this endpoint will be lower. 
Odds Ratios and 95% confidence intervals of these 3 endpoints will be plotted on a forest plot. 
The number and percentages of participants achieving MSE without rescue therapy will be 
summarized by treatment group for each scheduled visit. Similarly, descriptive statistics for each 
scheduled visit will be provided for MG-ADL responder rate and QMG responder rate without 
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rescue therapy. The same summary will be done by subgroup as defined in Section 5.8.  
Proportion of responder rates will be plotted on a bar chart with all scheduled visits on the same 
graph. Chi-square p-value will be added on the graph for Week 12 visit only, as exploratory.  
5.4.3.3 
Sensitivity analysis 
5.4.3.3.1 
Sensitivity #1: J2R 
Deviations from the missing at random pattern for any other missing data will be evaluated using 
a J2R approach using Multiple Imputation (MI method) under the missing not at random 
assumption (MNAR) to handle any missing scores as explained in Section 5.3.3.1. Endpoints 
will then be dichotomized. Participants who received rescue therapy or who had any death or 
myasthenic crisis will be considered as non-responders. Each imputed dataset will be analyzed 
using a logistic regression as described in Section 5.4.3.2 for each of these secondary endpoints 
to provide Odd Ratios, 95% confidence intervals and p-values. The treatment effects and 
standard errors will then be combined across the 100 imputed datasets to produce an overall p-
value using the SAS proc MIANALYZE. 
5.4.3.3.2 
Sensitivity #2: Logistic Regression using NRI at Week 12 
Logistic regression analysis will be performed on the mITT population using non responder 
imputation (NRI). If a participant is missing a value, or a value is censored due to rescue therapy 
use or an adverse event of myasthenic crisis, missing data at Week 12 will be treated as non-
responders. A logistic regression will then be used with the same covariates as defined in 
Section 5.4.3.2 for each of these dichotomous secondary endpoints to provide Odd Ratios with 
95% confidence intervals and p-values. 
5.4.3.3.3 
Sensitivity #3: weighted GEE model at Weeks 1, 2, 4, 8 and 12:  
Participants who received rescue therapy or who had an adverse event of death or myasthenic 
crisis will be considered as non-responders from the time of the intercurrent event. Other missing 
data will be assumed to be missing at random (i.e. no further imputation will be done).  Each 
dichotomous secondary endpoint at Week 1, 2, 4, 8 and 12 will be analyzed as repeated measures 
using weighted Generalized Estimating Equations (GEE) on the mITT population. A binomial 
distribution with logit link will be used.  
For achieving MSE, the model will include baseline MG-ADL score as covariate, treatment and 
visit as fixed effects, baseline-by-visit and treatment-by-visit interactions.  
For MG-ADL and QMG responder rates, the model will include baseline MG-ADL score, 
baseline QMG score and geographical region (North America, Europe and East Asia) as 
covariates, treatment and visit as fixed effects, baseline-by-visit and treatment-by-visit 
interactions. The GEE procedure in SAS will be used. 
An unstructured covariance matrix will be used to model the within-participant variance-
covariance errors. In case of non-convergence, covariance structures with fewer parameters will 
be considered. The estimated odds will be reported for each treatment group at each scheduled 
visit. For the comparisons of zilucoplan versus placebo, Odd Ratios (OR) with 95% CI and p-
values will be reported at each scheduled visit.  
5.4.3.3.4 
Sensitivity #4: Logistic Regression on CFS 
The logistic regression as described in Section 5.4.3.2 will be performed on the CFS. 
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5.4.3.4 
Supplementary analyses 
5.4.3.4.1 
Supplementary #1: Logistic Regression on PPS 
The logistic regression analysis as defined in Section 5.4.3.2 will be performed on the PPS.  
5.5 
Exploratory Endpoints Analysis 
5.5.1 
Achievement of Minimal Manifestation Status per MGFA-PIS at Week 
12 Without Rescue Therapy  
Minimal manifestation status is a dichotomous endpoint. This is defined by the participant 
having a response of “Minimal Manifestations” on the MGFA-PIS eCRF page at Week 12 
without having taken rescue therapy during the 12-week treatment period.  Minimal 
manifestation status will be summarized using descriptive statistics in the mITT by treatment 
group and at each scheduled visit. Change in Status will also be summarized by treatment group 
at each scheduled visit. 
5.5.2 
CFB to Week 12 in Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem (WPAI:SHP)   
The WPAI:SHP endpoints will be summarized using descriptive statistics by treatment group at 
each scheduled visit. These endpoints are described in Section 6.1.5.7.  
Each CFB to Week 12 WPAI endpoint will be analyzed in the mITT using a mixed model 
repeated measures (MMRM) analysis of covariance (ANCOVA). The same imputation approach 
will be used as for the main analysis of the primary endpoint for ICE1 and ICE2 
(Section 5.3.2.2).  
For each WPAI endpoint, MMRM ANCOVA will include treatment, baseline WPAI score, 
baseline MG-ADL Score, baseline QMG Score, geographical region (North America, Europe 
and East Asia), treatment-by-visit (interaction term), baseline WPAI score-by-visit (interaction 
term) as fixed effects and participant as a random effect. The MMRM ANCOVA will include 
Weeks 1, 2, 4, 8, and 12. An “unstructured” covariance structure will be used. In the event the 
“unstructured” covariance structure model fails to converge, an AR (1) covariance structure will 
be used.  The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. The least square means (LSMs) of each treatment group, and the least squares mean 
differences (LSMDs) between zilucoplan and placebo will be reported for the Week 12 Visit 
along with the corresponding 2-sided 95% CIs and p-values. The least squares mean (LSMs) of 
each treatment group, and the least squares mean differences (LSMDs) between zilucoplan and 
placebo at Weeks 1, 2, 4, and 8 will also be reported with the corresponding 2-sided 95% CIs. 
Statistical outputs such as LSMs and 95% CIs will be plotted from Week 1 to Week 12. 
5.5.3 
CFB to Week 12 in EQ-5D-5L  
The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS). These endpoints are described in Section 6.1.5.8. 
A frequency table will be produced to summarize answers provided to each of the 5 dimensions 
of the EQ-5D descriptive system at each scheduled visit by treatment group in the mITT. The 
observed values of EQ VAS scores and change from Baseline will be summarized by treatment 
group at each scheduled visit. No imputation will be applied on missing item in EQ-5D 
descriptive system and EQ VAS.  
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A by-participant listings of EQ-5D-5L will be provided. 
5.5.4 
CFB to Week 12 in Neuro-QOL Short Form Fatigue Scale   
CFB to Week 12 in total score in Neuro-QOL Short Form Fatigue Scale will be analyzed in the 
mITT using a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA). 
The same imputation approach will be used as for the main analysis of the primary endpoint for 
ICE1 and ICE2 (Section 5.3.2.2).  
MMRM ANCOVA will include treatment, baseline total score in Neuro-QOL, baseline MG-
ADL Score, baseline QMG Score, geographical region (North America, Europe and East Asia), 
treatment-by-visit (interaction term), baseline Neuro-QOL score-by-visit (interaction term) as 
fixed effects and participant as a random effect. The MMRM ANCOVA will include Weeks 1, 2, 
4, 8, and 12. An “unstructured” covariance structure will be used. In the event the “unstructured” 
covariance structure model fails to converge, an AR (1) covariance structure will be used.  The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
The least square means (LSMs) of each treatment group, and the least squares mean differences 
(LSMDs) between zilucoplan and placebo will be reported for the Week 12 Visit along with the 
corresponding 2-sided 95% CIs and p-values. The least square means (LSMs) of each treatment 
group, and the least squares mean differences (LSMDs) between zilucoplan and placebo at 
Weeks 1, 2, 4, and 8 will also be reported with the corresponding 2-sided 95% CIs. Statistical 
outputs such as LSMs and 95% CIs will be plotted from Week 1 to Week 12. 
The CFB to Week 12 in Neuro-QOL Short Form Fatigue Scale will also be summarized in the 
mITT using descriptive statistics at each scheduled visit and by treatment group. A by-participant 
listing will be provided. Derivation rules for this endpoint are described in Section 6.1.5.9. 
5.5.5 
Responder analysis for changes in QMG, MG-ADL, MG-QOL15r, and 
MG Composite Scores from baseline without rescue therapy   
For each assessment, at each post-baseline assessment week (Weeks 1, 2, 4, 8, and 12) the 
number and percentage of participants who have a reduction (i.e., improvement) of ≥ X will be 
summarized by treatment group in the mITT. The improvement values will start at the maximum 
level of worsening and will continue to the maximum level of improvement seen in the study. 
Note this is an extension of the “Achieving a ≥3-point reduction in MG-ADL Score at Week 12 
without rescue therapy” and “Achieving a ≥5-point reduction in QMG Score at Week 12 without 
rescue therapy” secondary endpoints. Additionally, the number and percentage of participants 
who have an increase (i.e., worsening) of ≤ X will be summarized. The worsening values will 
start at ≤ 1 and will continue to the maximum level of worsening seen in the study.   
For each assessment, these results from maximum level of worsening to maximum level of 
improvement will be plotted on a cumulative frequency plot: right part of the bar plot will 
represent cumulative proportion of participants with the improvement/worsening for zilucoplan 
and left part will be for placebo. A reference line of 2 points improvements for MG-ADL, 3 
points for QMG and 5 points for MGC will be provided. Maximum level of worsening and 
improvement may be redefined to increase the clarity of the graph. 
MG-ADL response ( defined as ≥ 2 points improvement from baseline) will be analyzed using 
the logistic Regression defined in Section 5.4.3.2. Similarly, QMG response (defined as ≥ 3 
points improvement from baseline) will be analyzed using the logistic Regression defined in 
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Section 5.4.3.2. Odd Ratios, 95% Confidence interval and associated p-value will be provided as 
exploratory. Additionally, time to first MG-ADL response (≥ 2 points improvement from 
baseline) will be analyzed as exploratory over the 12-week treatment period. It will be defined 
(in days) as: Date of first MG-ADL response – date of first IMP + 1.  
Participants who used rescue therapy prior to Week 12 or who are withdrawn from the 
treatment/study before achieving first MG-ADL response will be censored at time of event, 
whichever occurs first.  Participants who never achieved a response at Week 12 will be censored 
at the date of their last MG-ADL assessment.  
Time to first MG-ADL response over the 12-week treatment period will be analyzed as time-to-
event, using Kaplan-Meier plots. Median time to MG-ADL response over the treatment period 
will also be calculated with 95% CIs. Treatment difference will be evaluated using a Log Rank 
test. 
The same analysis will be done on: 
− MG-ADL response, defined as ≥ 3 points improvement from baseline; 
− QMG response, defined as ≥ 3 points improvement from baseline; 
− QMG response, defined as ≥ 5 points improvement from baseline. 
5.5.6 
Sub-scores of the QMG, MG-ADL, MG-QOL15r, and MG-Composite 
scores 
Items for the functional scales are defined in Table 5‒2. The functional sub-score for a 
participant is defined as the total score of the corresponding items (or the value of the item if it is 
a single score).   
Table 5‒2: 
Functional Sub-scores  
Function 
Scales 
QMG 
MG ADL 
MG-QOL15r 
MGC 
Ocular 
1-3 
7-8 
2 
1-3 
Bulbar 
4-5 
1-3 
3,9 
4-6 
Respiratory 
8 
4 
- 
7 
Limb/Axial 
6-7, 9-13 
5-6 
12,15 
8-10 
If an item response has a missing value, the methods defined in Section 6.1.5.1, Section 6.1.5.2, 
Section 6.1.5.3, Section 6.1.5.3 for imputing missing values will be used.  
The 4 sub-scores on QMG, MG-ADL, MG-QOL15r, MGC will be summarized using descriptive 
statistics by treatment group and by scheduled visit in the mITT. A by-participant listing will be 
provided. 
The individual items for each total score (i.e. QMG, MG-ADL, MG-QOL15r, MGC) will also be 
summarized by treatment group in a shift table from Baseline to Week 12 visit. 
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5.6 
Safety Analyses 
Safety analyses will be presented on the Safety Set (SS) by dose group and overall. Listings for 
all safety analyses will be presented.   
5.6.1 
Extent of Exposure 
IMP duration will be summarized by treatment group. The number of days on IMP will be 
calculated as follows: 
IMP duration = [(Date of Last Dose Received) -(Date of First Dose Received)] +1 
 
The exposure duration (i.e. total time at risk that incorporates 5 half-lives of zilucoplan) is 
defined as: 
 
Exposure duration (in days) = [min (Last dose + 40 days, Last Visit/Contact) - (Date of First 
Dose Received)] +1 
 
Patient-years exposure (PEY) for a treatment group will be calculated as the as the sum of the 
exposure durations of all study participants in the group divided by 365.25. 
The number of study participants in each treatment group and overall extent of exposure in the 
SS will be summarized. 
 
Note that temporary drug discontinuations and missed doses will not be incorporated into the 
calculations of the extent of study drug exposure analyses. 
 
The number of doses missed (from the eCRF Study drug administration page after Day 1) will be 
summarized cumulatively treatment group. 
 
In addition to the assessment of study medication duration as a continuous variable, the number 
and percent of study participants with treatment duration meeting the following criteria will also 
be summarized: 
≥ 1 day  
≥ 8 day  
≥ 15 day  
≥ 29 day  
≥ 57 days 
≥ 84 days 
All drug administration details will be listed. 
5.6.2 
Adverse Events 
5.6.2.1 
Data considerations 
Pre-existing conditions that are detected prior to administration of the first dose of study drug 
will be recorded as part of the medical history. For all subjects, the AE reporting period will start 
with the first administration of study drug on Day 1 and will end with the last study visit (i.e., 
End of Study Visit, Week 12 Visit), after which no new non-serious AEs are to be reported. 
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During the screening period and the safety follow-up period for the subjects who did not roll 
over into MG0011, only serious adverse events will be reported. 
In addition, AEs will be classified for severity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5 or later. For any AEs where it is not possible to provide 
a CTCAE grading, the events will be assessed using a standard intensity classification (mild, 
moderate and severe). For the purpose of the tabulations all CTCAE severity classifications will 
be mapped to a mild/moderate/severe grade as described below: 
• Grade 1 - Mild 
• Grade 2 - Moderate 
• Grade 3, 4, 5 - Severe  
These will be tabulated together with the AEs that were not classified according to CTCAE 
criteria i.e., all Grade 1 AEs as per CTCAE criteria will be included in the ‘mild’ category 
together with those AEs classified as mild as per the ‘standard’ intensity classification. 
A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to 
and including 40 days after the final dose (or last contact depending on which occurs first).  
Adverse events starting before the date of the first administration of IMP will not be considered 
TEAEs. 
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent 
unless evidence exists that does not allow the AE to be treatment-emergent. Handling of missing 
dates for classification of AEs as TEAEs is described in Section 5.1.1.10.  
All TEAE summaries will be performed during the overall study and by study period of the 
COVID-19 pandemic period as defined in Section 5.1.1.1.3.2 . A TEAE will be counted as a 
TEAE related to IMP if the response to the question “Relationship to Study Medication” is 
“Related”. Severe TEAEs are those with CTCAE Grade 3 or above, or those without a CTCAE 
grading classified as ‘severe’ by the Investigator. 
AEs will be presented as “number of participants (percentage of participants) [number of 
events]”.  In this style of output, “[number of events]” will include all cases of an AE including 
repeat occurrences in individual participants, while “number of participants” will count each 
participant only once. 
5.6.2.2 
AE summaries 
1. A TEAE overview table will be provided by treatment group, including the number, 
percentage of participants and frequency of the following TEAEs: 
− Any TEAEs 
− Serious TEAEs  
− TEAEs leading to permanent withdrawal from IMP 
− Treatment-related TEAEs  
− Severe TEAEs  
− TEAEs leading to death 
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− All deaths (AEs leading to death) 
2. The number, percentage of participants and frequency of the following TEAEs will be 
summarized by SOC, HLT, PT, and by treatment group:  
− Any TEAEs  
− Serious TEAEs 
− Severe TEAEs 
− Treatment-related TEAEs 
− TEAEs leading to permanent withdrawal from IMP 
− Treatment-related TEAEs leading to permanent withdrawal from IMP 
− TEAEs leading to death 
3. The number, percentage of participants and frequency of the following TEAEs will be 
summarized by SOC, PT, and by treatment group: 
− Any TEAEs above threshold of 5% of participants (in any treatment group) 
− Non-serious TEAEs above reporting threshold of 5% of participants (in any treatment 
group) 
− Treatment-related TEAEs above reporting threshold > 5% of participants (in any 
treatment group) 
4. The number, percentage of participants with TEAEs will be summarized by maximum 
intensity (mild, moderate and severe), SOC, PT, and by treatment group. 
5. The number, percentage of participants and frequency of the following TEAEs will be 
summarized by relationship, SOC, PT, and by treatment group: 
− Any TEAEs 
− Serious TEAEs 
− Fatal TEAEs 
− Non-serious TEAEs above threshold of 5% of participants 
For these summaries, the number and percentage of participants who experienced at least one 
TEAE as well as the number and percentage of participants who experienced each specific SOC 
and PT will be presented by treatment group. The corresponding number of TEAEs will also be 
presented for the Overall Summary of TEAEs table. For the presentation of TEAE incidences, 
the SOCs will be sorted alphabetically, and HLT within SOC – (if HLT is presented), and within 
HLT, the PT will be used and presented by decreasing total frequency based on the Zilucoplan 
treatment group. 
The TEAE overview table and the number of percentage of participants of any TEAEs by SOC, 
HLT and PT will also be produced on the SS by treatment group on the subgroups defined in 
Section 5.8. Listings of all AEs, permanent withdrawal of IMP due to AEs, participant 
discontinuation from study due to AEs, AEs leading to death will be presented by treatment 
group and participants. 
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To assess the impact of the COVID-19 pandemic on safety, additional summaries and listings 
will be presented. For reporting purposes, AEs will be assigned to either pre-COVID-19, 
COVID-19 or post COVID-19 pandemic period by comparing the AE start date (based on 
imputed date) to the COVID-19 pandemic period start and end dates (Section 5.1.1.1.3.2). AE 
will be allocated to a period if it starts during the period. The following categories of TEAE will 
be summarized by MedDRA SOC, HLT and PT:  
− All TEAEs by time of onset relative to COVID-19 pandemic period (prior/during/post) 
by region and overall  
− All serious TEAEs by time of onset relative to COVID-19 pandemic period 
(prior/during/post) by region and overall  
− All TEAEs leading to study discontinuation by time of onset relative to COVID-19 
pandemic period (prior/during/post) by region and overall  
− All TEAEs leading to permanent withdrawal of study medication by time of onset 
relative to COVID-19 pandemic period (prior/during/post) by region and overall  
− All COVID-19 related TEAEs by treatment group, region and overall  
COVID-19 related TEAEs will be identified by searching for selected MedDRA terms as defined 
in Section 6.1.8 .  
A separate listing of all COVID-19 related AEs will be presented. 
In addition, all listing of AEs will include a column for COVID-19 relatedness (as defined 
above) and the time of onset of each AE relative to the COVID-19 pandemic. 
A listing of all TEAE during the COVID-19 infection will be provided for participants infected 
by COVID-19. A TEAE during the COVID-19 infection is a TEAE that started from 5 days prior 
to the start date/ onset of a COVID-19 infection until the end date of the infection. If the 
COVID-19 infection is ongoing or the end date is missing at the time of database lock, TEAEs 
will be included up to 3 months (91 days) after the start of the infection or until the end of study 
date, which occurs first.  
 
COVID-19 vaccination follows a specific mass vaccination program in a short time frame and 
the novelty of a vaccine is likely to increase the reporting of AEs. Vaccination might have an 
impact on the safety reporting in the non-COVID-19 vaccine clinical trials. Due to this, the 
potential impact of concomitant COVID-19 vaccination on the current trial may be different 
from other types of concomitant drugs and established vaccination, due to the frequency of 
potential events related to the COVID-19 vaccination and the evolving safety profile of these 
new vaccines. To control the potential bias arising when an important proportion of the 
vaccinated participants reported AEs to vaccination in the active group (which inappropriately 
may be captured as adverse reactions in the product information) additional safety outputs within 
the frame of sensitivity analysis will be created. 
 
Additional sensitivity safety analysis with outputs presenting the TEAEs occurred when 
participants were considered as not at risk of TEAEs related to COVID-19 vaccination is 
proposed. The approach of interval censoring will be employed:  interval censoring between 
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COVID-19 vaccination date and a pre-specified period in which participants are considered as at 
risk for COVID-19 vaccination related AEs. A 7-day period may allow the removal of the 
potentially most frequently reported AEs related to COVID-19 vaccines.  
In such outputs, all TEAE data will be included, with the exception of the events occurred within 
for the defined window of 7 days post COVID-19 vaccination(s) for those participants 
vaccinated during the study and all TEAE data for those participants not vaccinated during the 
study. 
 
The number, percentage of participants and frequency of the following TEAEs will be 
summarized by SOC, HLT, PT, and by treatment group:  
− Any TEAE during the study but excluding TEAEs occurred within the 7-day period post 
each covid-19 vaccination (period including the day of vaccination)  
− Any TEAE during the study occurring within the 7-day period post each COVID-19 
vaccination (period including the day of vaccination) 
− Any non-serious TEAE above threshold of 5% of participants (in any treatment group) 
censoring for AEs within the 7-day period post each COVID-19 vaccination (period 
including the day of vaccination).  
− Any non- serious TEAE above reporting threshold of 5% of participants (in any treatment 
group), by relationship to study drug. 
 
All AEs after the first COVID-19 vaccination will be listed for all vaccinated participants.     
Two separate listings will display the AEs after adjustment of the interval censoring (within the 
ES) and the concomitant COVID-19 vaccination (within the RS). 
 
At all the outputs referring to the interval vaccination censoring, the following footnote will be 
incorporated: “COVID-19 Vaccination Interval Censored (TE)AEs exclude those (TE)AEs 
occurred within the pre-specified time period of 7 days post COVID-19 vaccination(s) for each 
participant, if applicable.” 
 
5.6.3 
Other Safety Assessments  
Other safety assessments (AE of interest, Laboratory data, Vital Signs, ECG and 
Immunogenicity) will also be performed.  
5.6.3.1 
AE of Interest (AEIs) 
The following are AEIs (as defined in Section 6.1.6) that require special statistical analyses: 
− Infections 
− Neisseria infections 
− Hypersensitivity reactions  
− Anaphylactic reactions 
− Injection site reactions 
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− Drug related hepatic disorders 
− Malignancies 
− Malignancies or unspecified tumors 
The number and percentage of participants who experience each AE of Interest will be 
summarized by treatment group separately for each AE of interest. The following summaries will 
be presented: 
− Incidence of AEIs and serious AEIs by SOC and PT (serious and non-serious will appear 
in the same table) 
− Incidence of AEIs by relationship, SOC and PT 
− Incidence of AEIs by maximum intensity (mild, moderate and severe), SOC and PT 
Duration of TEAE (as defined in Section 5.1.1.10)  for Injection site reactions (as defined in 
Section 6.1.6) will be summarized by treatment group and overall. 
5.6.3.2 
Clinical laboratory evaluations 
The following table (Table 5‒3) lists hematology, chemistry and coagulation analytes that are 
collected throughout the study, using a central laboratory and following the schedule of 
assessments according to the protocol. 
Table 5‒3: 
Laboratory 
Chemistry 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Bilirubin (total) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lipase 
Potassium 
Sodium 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count and differential (%) 
Basophils (% and absolute) 
Eosinophils (% and absolute) 
Lymphocytes (% and absolute) 
Monocytes (% and absolute) 
Neutrophils (% and absolute) 
Coagulation 
International normalized ratio (INR)/prothrombin time (PT) 
Partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) 
Urinalysis 
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Table 5‒3: 
Laboratory 
Chemistry 
Hematology 
pH, Specific gravity, protein (qualitative), glucose 
(qualitative), ketones (qualitative), urobilinogen, occult blood, 
hemoglobin and cells, microscopic examination 
Other 
C-reactive protein (CRP) 
Thyroid Stimulating Hormone (TSH) – screening only 
All laboratory samples are collected prior to IMP administration at applicable visits. Coagulation 
test should only be performed in participants receiving anticoagulant therapy. 
5.6.3.2.1 
Laboratory values over time 
Chemistry, hematology, coagulation and quantitative urinalysis (observed value, absolute change 
from Baseline) will be summarized in standard unit using descriptive statistics by treatment 
group at each scheduled visit. Qualitative urinalysis results will be summarized in frequency 
tables for each visit by treatment group. 
The central data will be used for the summary tables. If multiple central lab data were captured at 
scheduled visits, the average would be used for continuous values, or the worst will be used for 
categorical values. 
Measurements BLQ will be imputed with half of the lower limit of quantification LLOQ, and 
measurements ALQ will be imputed to the upper quantification limit for the purpose of 
quantitative summaries. 
All laboratory test results will be listed, including Baseline, scheduled and unscheduled visits 
with results in standard unit. Values outside the reference range for the continuous variables will 
be flagged in the listings. The reference ranges will also be reported in the listings. Additional 
lab test, including pregnancy testing, will also be listed. 
5.6.3.2.2 
Individual Participant Changes of Laboratory Values 
The laboratory variables that are categorized as normal, high or low based on the reference range 
supplied by the analytical laboratory will be presented in shift tables from Baseline to each 
scheduled post-Baseline visit and any post-Baseline visit (including unscheduled visit) by 
treatment group. 
5.6.3.2.3 
Laboratory Marked abnormalities 
Treatment-emergent marked abnormalities (TEMAs) in laboratory parameters will be 
summarized by treatment group at each scheduled visit and at any visit (including unscheduled 
visit).  Thresholds for defining marked abnormalities for relevant laboratory parameters are 
available in Appendix 6.2.1. Treatment-emergent is defined as meeting the criteria at any post-
Baseline visit. 
Listings will include a flag for values identified as Treatment-emergent Marked abnormalities 
(TEMA). 
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5.6.3.2.4 
Assessment of potential liver toxicity 
To assess the potential for liver toxicities, the following criteria will be used to define levels of 
liver function tests (LFT) elevation: 
−  Aspartate aminotransferase (AST) : >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 
x ULN 
− Alanine aminotransferase (ALT) : >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x 
ULN 
− AST or ALT: >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN 
− Total bilirubin (TBL): >1.5 x ULN, >2 x ULN 
− Alkaline phosphatase (ALP) >1.5 x ULN 
Drug Hepatic disorders TEAEs will be defined as: 
− TEAEs with narrow SMQ of “Drug related hepatic disorders - comprehensive search 
(SMQ)”. However, these 2 sub-SMQs are to be excluded: “Liver neoplasms, benign (incl 
cysts and polyps) (SMQ)” and “Liver neoplasms, malignant and unspecified (SMQ)”. 
The following laboratory criteria for potential drug induced liver injuries are defined as follows: 
− AST or ALT >3xULN with TBL >1.5xULN 
− AST or ALT >3xULN with TBL >2xULN 
In addition, post-baseline potential Hy’s Law cases will be identified using the following 
definition: 
– either AST or ALT > 3×ULN with concurrent ALP < 2 × ULN and concurrent total 
bilirubin > 2×ULN  
In order to meet the above criteria, a study participant must experience the elevation in Bilirubin 
and ALT and AST (and the absence of the ALP elevation) at the same date. For example, a study 
participant who experiences a > 2xULN elevation of bilirubin at one date and a > 3xULN 
elevation in ALT (or AST) at a subsequent visit date has not fulfilled the Hy’s law criteria. 
The number and percentage of study participants with elevated liver function tests will be 
presented by treatment group at any visit (including unscheduled visits) in the Safety Set. The 
number and percentage of study participants with potential drug induced liver injuries including 
those who potentially meet the Hy’s law criteria and Drug related hepatic disorders TEAEs will 
be summarized by treatment group. The liver function results for study participants with elevated 
liver function results will be listed. Scatterplots for each liver function test will be presented to 
show the shifts from Baseline to the maximum post-Baseline result. The upper limit of normal 
(ULN) of concern (i.e. 3xULN for ALT or AST, and 2xULN for TBL or ALP) will also be 
presented as lines on the plots. In addition, a scatterplot of the maximum post-Baseline TBL 
(/ULN) versus the maximum post-Baseline ALT (/ULN) will be provided on a logscale. 
Reference lines of 3ULN for ALT and 2ULN for TBL will be presented on the graph. If any 
study participant meets the potential Hy’s law criteria, a graph displaying each liver function test 
(expressed as X ULN on a logscale) by time will be presented for each identified case. 
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5.6.3.3 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressure, and temperature) will be collected 
throughout the study. 
5.6.3.3.1 
Vital Sign Values Over Time 
Observed values and changes from Baseline will be summarized by vital sign variables and by 
scheduled visit by treatment group.   
The number and percentage of participants who meet each of the marked abnormality criteria 
outlined in Appendix 6.2.2  will be summarized by treatment group at each scheduled visit and at 
any visit (including unscheduled visit). 
Repeated and unscheduled measurements will be handled as described in Section 5.1.1.8 . 
5.6.3.3.2 
Individual Participant Changes of Vital Sign Values 
The Vital Signs that are categorized as normal, high or low based on the reference will be 
presented in shift tables from Baseline to each scheduled post-Baseline visit and any post-
Baseline visit (including unscheduled visit) by treatment group. 
A by-participant listing of all vital sign measurements and change from Baseline will be 
presented. The listing will include a flag for values identified as MA. 
5.6.3.4 
Electrocardiograms 
The following variables will be reported: 
• 
Heart rate 
• 
PR interval 
• 
RR interval 
• 
QRS duration 
• 
QT interval 
• 
QT corrected for heart rate using Fridericia’s formula (QTcF = QT/RR1/3) 
5.6.3.4.1 
Electrocardiogram Values Over Time 
Observed values and changes from Baseline will be summarized by treatment group at scheduled 
visit and by ECG variable. Baseline value will be based on the screening visit as ECG is not 
performed on Day 1. 
The number and percentage of participants who meet each of the marked abnormality criteria 
outlined Section 6.2.3 will be summarized by treatment group at each scheduled visit and at any 
visit (including unscheduled visit). 
5.6.3.4.2 
Individual Participant Changes of Electrocardiograms Values 
The number and percentage of participants with normal, abnormal not clinically significant and 
abnormal clinically significant, not evaluable and not done ECG results will be provided in a 
shift table from Baseline to worst post-Baseline interpretation during the study. 
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A listing of electrocardiogram data will be presented, including repeated and unscheduled 
measurements. 
5.6.3.5 
Physical examination 
Results of clinically significant physical examination abnormalities were reported as adverse 
events. No additional listing will be provided. 
5.6.3.6 
Total serum IgG and IgG subclasses 
Total serum IgG concentrations and IgG subclasses will be summarized by treatment group and 
time point for observed values, change from Baseline, and percentage change from Baseline.  
The maximum decrease from Baseline in total serum IgG (absolute and percentage decrease) 
will be reported in the listing and summarized for each treatment. In the event that a decrease 
from Baseline in total serum IgG is not observed in a given participant, the maximum decrease 
will be reported as the smallest increase from Baseline.  
Mean and mean percentage change from Baseline values in total serum IgG will be plotted over 
time by treatment with all treatments overlaid on the same plot.  
5.6.3.7 
Immunogenicity 
The ADA status for both active and placebo will be determined for each pre-treatment (Baseline) 
and post-treatment (post-Baseline) visit where samples are taken for ADA analysis. 
− Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
− Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
− Samples that could not be tested for ADA status due to inadequate sample volume, 
mishandling, or errors in sample collection, processing, storage, etc, will be defined as 
missing. 
Sample neutralizing antibody (NAb) status (positive/negative/missing) will be determined for 
ADA positive samples only. 
The same definitions will be used for anti-PEG antibodies except for the determination of the 
Nab status. 
5.6.3.7.1 
ADA and anti-PEG Classification 
Day 1 will be the baseline value for ADA status. The following ADA classifications will be 
derived from the sample ADA status: 
Table 5‒4: 
ADA Classification 
Classification 
Classification Label 
Definition 
1 
Pre-ADA negative – treatment 
induced ADA negative 
Participants who are ADA negative at Baseline 
and ADA negative at all sampling points post-
Baseline 
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Table 5‒4: 
ADA Classification 
Classification 
Classification Label 
Definition 
2 
Pre-ADA negative – treatment 
induced ADA positive 
Participants who are ADA negative at Baseline 
and ADA positive at any sampling point post-
Baseline. It also includes participants who have 
a missing pre-treatment sample (either missing 
or insufficient volume) at Baseline with one or 
more ADA positive post-Baseline samples. 
3 
Pre-ADA positive – treatment 
reduced ADA 
Participants who are ADA positive at Baseline, 
and ADA negative at all sampling points post-
Baseline 
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who are ADA positive at 
Baseline and ADA positive at any sampling 
point post-Baseline (including Observation 
Period) with titer values of the same magnitude 
as Baseline (less than a predefined fold 
difference from the Baseline value which will be 
defined within the validation of the assay, i.e. 
MSR of the assay). 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who are ADA positive at 
Baseline and ADA positive at any sampling 
point post-Baseline (including Observation 
Period) with increased titer values compared to 
Baseline (greater than a predefined fold 
difference increase from Baseline value which 
will be defined within the validation of the assay 
i.e. MSR of the assay). 
6 
Inconclusive 
Participants who have an ADA positive Baseline 
sample and some post-Baseline samples are 
missing, while other post-Baseline samples are 
ADA negative.  
7 
Treatment emergent ADA 
positive  
Combination of 2 and 5 
8 
Pre-ADA positive 
Combination of 3, 4, and 5 
MSR = minimum significant ratio 
In addition to the ADA classifications above, for the purpose of evaluations of the impact of 
ADA on plasma concentrations, IgG, and efficacy and safety endpoints, the following definitions 
will be used: 
• 
Cumulative ADA status (positive/negative): if a participant has had at least one positive 
sample at any time point up (including unscheduled visits) to and including the given time point, 
that participant will be counted as positive at that time point, regardless of any subsequent 
negative measurements. Thus, the number of participants included in the summary of positive 
and negative samples will vary by time point for each treatment group.  
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• 
Overall ADA status: a participant will be classified as overall ADA Positive if at least one 
post-Baseline measurement (including unscheduled visits) is Positive. A participant will be 
classified as overall ADA Negative if at all post-Baseline visits the ADA status is Negative. 
The ADA classification in Table 5‒4 will be repeated for NAb for classifications 2, 3, 4, 5, 7 and 
8. In addition, cumulative and overall Nab status will be defined as described above for ADA. 
Classification in Table 5‒4 will be repeated only for anti-PEG antibodies, and no Nab status will 
be determined for the anti-PEG antibodies. 
5.6.3.7.2 
ADA summaries 
The following outputs will be presented on the SS. 
Tables:  
• Number and percentage of participants with positive, negative or missing sample ADA status 
at the time of each visit will be summarized by treatment group. 
• Number and percentage of participants in each of the ADA classifications presented will be 
summarized by treatment group. 
• The prevalence of immunogenicity (Classification 2, 3, 4 and 5), defined as the (cumulative) 
proportion of participants having ADA positive samples (including pre-ADA positive) at any 
point up to and including that time point will be summarized by treatment group.  Missing 
samples will not be included in the denominator. The same table will be repeated for NAb.  
• The first occurrence of treatment-emergent ADA positive (Classification 2 and 5) will be 
summarized using frequency and percentage at each post-Baseline visit by treatment group. 
Participants will be counted only once in the numerator based on the earliest visit at which 
treatment-emergent ADA positivity is observed. At other visits, participants will be counted 
in the denominator (assuming a measurement is available). Missing measurements will not 
be included in the denominator. 
• The time to achieving treatment-emergent ADA positivity, separated by treatment group, will 
be summarized and analyzed based on Kaplan-Meier methods. Participants will be 
considered to have an event at the time point at which treatment-emergent ADA positive is 
first achieved. Participants who never had a treatment-emergent ADA positivity will be 
censored at the date of their last visit. This will also be plotted graphically. 
• The TEAE overview table will be presented by treatment group and by ADA 
status. Additionally, the number and percentage of participants who experience some AEIs 
(Hypersensitivity reactions, injection sites reactions as defined in Section 6.1.6 and 
autoimmune disorders) will be presented by SOC and PT, by treatment group and by ADA 
Status. Autoimmune disorders will be defined if HLT is in ‘Autoimmune disorders. For these 
summaries, participants will be presented for TEAEs occurring prior to becoming treatment 
emergent ADA positive, TEAEs occurring after becoming treatment emergent ADA positive, 
and TEAEs for participants who remained TE ADA negative (classifications 1,3,4,6).    
Figures: 
• Individual plots per participant will be plotted representing total IgG, MG-specific 
autoantibodies, neutralizing antibody (NAb) titer, MG-ADL total score. The sub-title of the 
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graph will include the participant number, bodyweight, treatment group, treatment-emergent 
ADA status, and ADA classifications. The dosing will be represented in the x axis with 
bars/arrows at the time of dose.  
• The mean change from Baseline with 95% CI in MG-ADL total score versus time, by 
cumulative ADA status (positive/negative) at each individual timepoint will be plotted for 
each treatment group. The cumulative ADA positive and negative will be overlaid for 
comparison. The same plot will be repeated with cumulative NAb status. 
• A plot of geometric mean with 95% CI of plasma concentrations of zilucoplan data by 
cumulative ADA status (positive/negative) at each scheduled visit will be presented. 
• A plot of geometric mean with 95% CI of total IgG (absolute) and arithmetic mean of 
percentage change from Baseline by cumulative ADA status will be presented by treatment 
group. 
5.6.3.7.3 
Anti-PEG antibody summaries 
The same tables will be provided for anti-PEG antibodies only (no Nab status, results or 
classification) by treatment group. 
All individual study participant-level ADA results will be listed including the results from the 
screening assay, confirmatory assay with anti-PEG antibodies results, the status (of both ADA 
and anti-PEG antibodies), classification (of both ADA and anti-PEG antibodies) with the NAb 
results, status and classification for ADA. 
5.6.3.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Results of the C-SSRS will be summarized in SS by treatment group and scheduled timepoint 
using the number of participants and percentage with (i) suicidal ideation, (iii) suicidal behavior, 
(iii) suicidal ideation or behavior, and (iv) self-injurious behavior without suicidal intent. 
Suicidal ideation is defined as an event in any of the following 5 categories: 
• 
Wish to be dead  
• 
Non-specific active suicidal thoughts  
• 
Active suicidal ideation with any methods (not plan), without intent to act  
• 
Active suicidal ideation with some intent to act, without specific plan  
• 
Active suicidal ideation with specific plan and intent  
Suicidal behavior is defined as an event in any of the following 5 categories: 
• 
Actual attempt 
• 
Interrupted attempt 
• 
Aborted attempt 
• 
Preparatory acts or behavior 
• 
Completed suicide 
Suicidal behavior or ideation is defined as an event in any of the above 10 categories. 
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Self-injurious behavior without suicidal intent is corresponding to the response to “Has 
participant engaged in Non-Suicidal Self-Injurious Behavior?” in questionnaire. 
A separate summary on frequency of C-SSRS number of episodes will be provided by treatment 
group. 
A by-participant listing of the C-SSRS questionnaire data will be provided by treatment group. 
5.7 
Other Analyses 
5.7.1 
Other Exploratory endpoints 
5.7.1.1 
Pharmacokinetics 
The plasma concentrations of zilucoplan and its two major metabolites (
) 
will be summarized by scheduled sampling day for the PK-PPS using n, arithmetic mean, 
median, SD, minimum, maximum, geometric mean, geometric coefficient of variation (geoCV) 
and 95% CI (assuming log-normally distributed data). 
A spaghetti plot of combined individual concentration versus time profiles will be presented by 
analyte in linear and semi-logarithmic scale with all participants overlaid on the same plot.  
Additionally, mean (+SD) plasma concentration versus time overlaid for both analytes will also 
be presented for all scheduled timepoints on a linear and semi-logarithmic scale. The SD will not 
be provided on the semi-logarithmic scale.  
All figures will include the lower limit of quantification (LLOQ) on the semi-logarithmic plots. 
PK summaries will be based on observed value. No imputation will be done. The following rules 
will apply for PK data listings and summaries: 
• Values below the LLOQ will be reported as below the limit of quantification (BLQ) 
• Descriptive statistics of concentrations will be calculated if at least 2/3 of the individual data 
points at a timepoint are above the LLOQ. Values that are BLQ will be replaced by the 
numerical value of the LLOQ/2 in this instance.  
• The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geoCV) is 0 
• The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data 
 geoCV(%) = √exp(SD2) −1 × 100. 
Individual concentrations will be listed for the PK-PPS and will include the actual sampling time 
in days relative to the previous dose.   
PK assessments in participants undergoing rescue therapy will be analyzed separately. 
Plasma concentration data of Zilucoplan may be subjected to population pharmacokinetic 
analysis to derive population estimates of PK parameters and test the effect of various covariates 
such as anti-drug antibodies, age, weight, gender. Details of the analysis will be described in a 
separate Data Analysis Plan (DAP). This analysis may be performed by combining the data from 
the current study with data from other Zilucoplan studies if deemed appropriate. The results of 
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the population PK analysis will not be reported in the clinical study report (CSR) but in a 
separate modelling report. 
5.7.1.2 
Pharmacodynamics 
Pharmacodynamic analyses will be performed on the PDS.  
 The pharmacodynamic endpoints include: 
−  sRBC lysis assay  
− C5 levels  
Summary statistics will be provided for the values, change from baseline, and percent change 
from baseline at each of the scheduled assessment time points.  The change from baseline for 
each of these endpoints will be assessed by an ANCOVA model with treatment as a factor and 
the corresponding baseline value as a covariate. The active dose will be compared to the placebo 
group based on the ANCOVA model. 
PD assessments in participants undergoing rescue therapy will be analyzed separately. 
Population PD or population PK/PD analyses may be conducted for the PD variables of interest. 
Details of such PD or PK/PD analyses will be described in a separate DAP. The results of the 
analyses will not be reported in the CSR but in a separate report. 
5.7.1.3 
Biomarkers and Autoantibodies 
Blood samples for mechanistic biomarker testing [e.g., complement fixation, complement 
function, complement pathway proteins, autoantibody characterization (titer and 
immunoglobulin class), and inflammatory markers] will be obtained prior to administration of 
study drug (within 1 hour of dosing). The results of the biomarker analysis and autoantibodies 
will be summarized by treatment group on the SS. This data will be listed on the RS. Other 
biomarker testing may be done and will be reported separately. 
5.7.1.4 
Pharmacogenomic  
Participation in the pharmacogenomic assessment is optional, and participants must provide 
additional consent for the pharmacogenomic analysis. For participants who choose to participate 
in pharmacogenomic studies, a blood sample will be obtained. All genomic analyses will be 
performed at an accredited laboratory.  
Pharmacogenomic assessment may be analyzed in a separate report. 
5.7.1.5 
Additional Rescue Therapy analyses 
Participants are expected to remain on stable doses of all medications unless medically indicated 
changes become necessary.  
Participants requiring rescue therapy during Treatment Period are analyzed as time-to event in 
Section 5.4.2 as secondary efficacy endpoint. In addition, the frequency and type of rescue 
medication (Immunoglobulin or Plasma Exchange) a participant receives will be summarized. 
These summaries will be provided by treatment group for the mITT Population. The frequency 
of use of rescue therapy will be compared between both treatment groups using a Pearson’s chi-
square test. Rescue therapy use will also be summarized by subgroup as defined in Section 5.8. 
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5.7.2 
Specific analyses for Japanese Participants 
Study participant characteristics   
Study participant characteristics will be summarized for participants in the mITT population 
from Japan only (as specified in Section 6.1 ): 
• Analysis Population and Patient Disposition (Section 5.2) 
• Demographics and other baseline characteristics (as specified in Section 6.1) 
• Protocol deviations (as specified in Section 6.1) 
• MG specific Prior and Concomitant Medications (as specified in Section 6.1) 
• Study Treatment Duration (as specified in Section 5.6.1)  
• Rescue medication (as specified in Section 5.7.1.5).  
Efficacy endpoints 
The following endpoints will be summarized using descriptive statistics for participants in the 
mITT population in Japan only by treatment: 
• Primary efficacy endpoint  
− Change from Baseline (CFB) in Week 12 MG-ADL score. It will also be presented by 
visit. 
• Secondary efficacy endpoints  
− CFB to Week 12 in the Quantitative Myasthenia Gravis (QMG) Score. It will also be 
presented by visit.  
− CFB to Week 12 in the Myasthenia Gravis Composite (MGC) Score. It will also be 
presented by visit. 
− CFB to Week 12 in the Myasthenia Gravis – Quality of Life revised (MG-QOL15r) 
Score. It will also be presented by visit.  
− Time to first administration of rescue therapy over the 12-week Treatment Period  
− Achieving Minimal Symptom Expression (MSE), defined as an MG-ADL of 0 or 1 at 
Week 12 without rescue therapy. It will also be presented by visit. 
− Achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy. It 
will also be presented by visit.  
− Achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12. It will 
also be presented by visit. 
The observed change from baseline with standard errors will be plotted by visit for MG-ADL 
and for QMG. In addition to the overall summary, the primary endpoint CFB in Week 12 MG-
ADL scores will be analyzed in the mITT population using a mixed model repeated measures 
(MMRM) analysis of covariance (ANCOVA) with treatment, baseline MG-ADL Score, baseline 
QMG Score, treatment-by-visit (interaction term), baseline MG-ADL Score-by-visit (interaction 
term), as fixed effects and participant as a random effect. The MMRM ANCOVA will include 
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Weeks 1, 2, 4, 8, and 12. An AR (1) correlation structure will be used to model the within 
participant covariance errors. The Kenward-Roger approximation will be used to estimate the 
degrees of freedom. Least squares mean (LSM) and standard errors (SE) will be provided by 
treatment group for each visit. LSM treatment difference and 95% confidence intervals will also 
be provided for all visits.  The same imputation as the main analysis of the primary endpoint for 
ICE1 and ICE2 will be used. More details can be provided in Section 5.3.2.2. 
• Pharmacokinetics 
The plasma concentrations of zilucoplan and its two major metabolites (
) 
will be summarized by treatment group and by scheduled sampling day for the PK-PPS for 
Japanese participants (as specified in Section 5.7.1.1)  
• Pharmacodynamics 
Pharmacodynamic parameters (as specified in Section 5.7.1.2) will be summarized on the PD-
PPS in Japanese participants. 
• ADA summaries (as mentioned in Section 5.6.3.7): 
− Number and percentage of participants with positive, negative or missing ADA status at 
the time of each visit and overall will be summarized by treatment group. 
− Number and percentage of participants in each of the ADA classifications will be 
summarized by treatment group. 
− Number and percentage of participants with first occurrence of treatment-emergent ADA 
positive at each visit will be summarized by treatment group. 
− The cumulative number of participants with treatment-emergent ADA positive will also 
be presented.  
− The time to achieving treatment-emergent ADA positive, separated by treatment group 
and ADA category, will be analyzed based on Kaplan-Meier methods.  
Safety endpoints 
• An TEAE overview table will be provided. 
• The number, percentage of participants and frequency of the following TEAEs will be 
summarized by SOC, HLT, PT, and by treatment group:  
− Any TEAEs 
− Serious TEAEs 
− Severe TEAEs 
− Treatment-related TEAEs 
− Permanent withdrawal of IMP due to TEAEs 
− Treatment-related TEAEs resulting in permanent withdrawal of IMP due to TEAEs  
− TEAEs leading to death 
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• The number, percentage of participants and frequency of any TEAEs will be summarized by 
maximum intensity (mild, moderate and severe), SOC, PT, and by treatment group. 
• The number, percentage of participants and frequency of the following TEAEs will be 
summarized by relationship, SOC, PT, and by treatment group: 
− Any TEAEs 
− Serious TEAEs 
• Incidence of AEIs by SOC and PT by treatment group (as defined in Section 5.6.3.1) 
5.8 
Subgroup analyses 
Safety analyses on TEAEs and the primary and secondary efficacy endpoints will be analyzed on 
the following subgroups:   
− Race (Asian, Black or African American, White, Other/Mixed) 
− Age (<65 years / ≥ 65 years)  
− Gender (Male / Female)  
− Duration of disease at Baseline (<median, ≥ median) 
− MGFA disease class at Baseline (Class II (IIa, IIb), III (IIIa, IIIb), or IV (IVa or IVb)) 
− Chronic Kidney Disease Stages: normal renal function (eGFR ≥ 90 mL/min/1.73m2) , 
mild (eGFR 60–89 mL/min/1.73m2 [CKD stage 2]), moderate (eGFR 30–59 
mL/min/1.73m2 [CKD stage 3]), severe (eGFR 15–29 mL/min/1.73m2 [CKD stage 4]) 
renal insufficiency end stage renal disease : eGFR < 15 mL/min/1.73m² 
− MG Refractory (yes/no; defined in Section 6.1.4.4)  
Additionally, the primary and secondary efficacy endpoints will also be analyzed on the 
following subgroups: 
− Baseline MG-ADL (≤9 / ≥10)  
− Baseline QMG (≤17 / ≥18)  
− Region (North America, Europe, and East Asia) 
− Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
− Weight in Kg (<43, 43-56, 56-<77, 56-<150, ≥ 150) 
− BMI:  <18.5, 18.5 - <25, ≥25 - <30, ≥30 - <40, ≥ 40 (kg/m2) 
− Ever had a crisis (dichotomous yes/no class variable)  
− Prior thymectomy (dichotomous yes/no class variable)  
− Prior steroid therapy (i.e., Group A from Table 6‒2 dichotomous yes/no class variable) 
− Steroid therapy taken at baseline (i.e., Group A from Table 6‒2; dichotomous yes/no 
class variable)  
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− Prior immunosuppressive therapy (nonsteroidal) (i.e., Group E from Table 6‒
2;dichotomous yes/no class variable)  
− Immunosuppressive therapy (nonsteroidal) at baseline (i.e., Group E from Table 6‒2; 
dichotomous yes/no class variable)  
− Prior history of IVIG or SC immunoglobulin or PLEX (i.e., Group D from Table 6‒2; 
dichotomous yes/no class variable)  
− Diagnosed with Thymoma  
− By timing of study participants enrollment relative to COVID-19 pandemic periods 
(prior/during/after) as defined in Section 5.1.1.1.3.2  
− By timing of Week 12 visit relative to COVID-19 pandemic periods (prior/during/after) 
as defined in Section 5.1.1.1.3.2  
All subgroup analyses will be descriptive; no statistical testing of treatment-by-subgroup 
interactions nor statistical testing of treatment effects within subgroups will be carried out.   
 
For refractory and non-refractory participants, the CFB at Week 12 in MG-ADL will be assessed 
in each stratum separately using a MMRM with treatment and visit (categorial) as fixed effects, 
baseline MG-ADL, baseline QMG, region as covariates and baseline-by-time, treatment-by-time 
interactions. An “unstructured” covariance structure will be used. In the event the “unstructured” 
covariance structure model fails to converge, an AR (1) covariance structure will be used. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
The least square means (LSMs) and standard errors (SE) of each treatment group, and the least 
squares mean differences (LSMDs) between zilucoplan and placebo will be reported for the 
Week 12 Visit along with the corresponding 2-sided 95% CIs for each subgroup stratum. 
 
Subgroup analyses will only be performed for subgroups where there are at least 5 participants in 
each subgroup level, otherwise it will not be performed. 
 
5.9 
Interim Analyses 
Not Applicable 
5.10 
Data Monitoring Committee (DMC) or Other Review Board 
Not Applicable 
6 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1 Non-key analysis specifications 
6.1.1 
Baseline characteristics and demographics 
Participant demographics and baseline characteristics will be summarized by treatment group 
and overall, for the mITT, PPS and Safety Populations, using descriptive statistics.  Additional 
subgroup summary will be presented based on the enrolled date relative to the cut-off date by 
prior and during/post COVID-19 pandemic period based on the mITT. 
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Descriptive statistics for continuous variables (including n, mean, SD, Median, Min and Max) 
will be provided for: 
−  Age (years), calculated as (year of informed consent date – year of birth  
− Height (cm) 
− Weight (kg) 
− Body mass index (BMI) (kg/m2) calculated as: 𝐵𝑀𝐼= 
Weight (kg)
(Height (m))2 using the weight and 
height measurements obtained at screening.  
− Baseline MG-ADL and QMG scores  
Descriptive statistics for categorial variables (including counts and percentages) will be provided 
for: 
− Gender (Male/Female) 
− Race (American Indian or Alaska native, Asian, Black, Native Hawaiian or other Pacific 
Islander, White, Other/Mixed) 
− Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
− Age (<18, 19- <65 and ≥65 years). 
− Geographic region (North America, Europe, and East Asia)  
− Country 
− BMI in kg/m2 (<18.5, 18.5 - <25, ≥25 - <30, ≥30 - >40, ≥ 40) 
− Weight in Kg (<56, 56-<77, ≥ 77 - <150, ≥ 150) 
− MD-ADL scores (≤9/≥10) 
− QMG scores (≤17 / ≥18) 
− Chronic Kidney Disease Stages: normal renal function (eGFR ≥ 90 mL/min/1.73m2) , 
mild (eGFR 60–89 mL/min/1.73m2 [CKD stage 2]), moderate (eGFR 30–59 
mL/min/1.73m2 [CKD stage 3]), severe (eGFR 15–29 mL/min/1.73m2 [CKD stage 4]) 
renal insufficiency end stage renal disease : eGFR < 15 mL/min/1.73m²A by-participant 
listing of Baseline characteristics will be provided. 
 
6.1.2 
Protocol deviations 
Important protocol deviations (IPDs) are deviations from the protocol which could potentially 
have a meaningful impact on the study conduct, on the primary analysis, key safety or PK/PD 
outcomes for an individual participant. IPDs will be identified and documented prior to 
unblinding to confirm exclusion from analysis sets. 
A summary of number and percentage of participants having important protocol deviation by 
relationship to COVID-19 will be provided for the RS population by treatment group 
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Relationship to COVID-19 will be programmed from the COVID-19 Impact eCRF page or when 
available, it will be assessed by the sites. 
6.1.3 
Medical history 
6.1.3.1 
Medical history (other than MG disease history) 
Medical History will be summarized by treatment group and overall, by system organ class 
(SOC), high level term (HLT) and preferred term (PT) for the mITT population. A participant 
will be counted only once for each preferred term. The summary will present the results 
alphabetically by System Organ Class (SOC), HLT within SOC, and within HLT, by decreasing 
frequency for the PT in active treatment group. Additionally, the summary will be repeated by 
pre-, during the COVID-19 pandemic based on the medical history start date relative to the 
pandemic cut-off date. 
Medical History will be listed on the RS population.  
6.1.3.2 
gMG disease history  
The following gMG disease history data will be summarized by treatment group and overall, for 
the mITT Population. 
− Age at onset (years) 
− Duration of disease (years) = (Date of Study Day 1 – Date of Diagnosis)/365.25 
Note: If the Date of Diagnosis day and month are missing impute July 2nd, if only the day is 
missing impute the 15th. If the imputed Date of Diagnosis date is later than the date of Study 
Day 1, impute Study Day 1. 
− Symptoms at onset (Ocular/Generalized) 
− MGFA Disease Class at Screening (Class II (IIa, IIb), III (IIIa, IIIb), or IV (IVa or IVb)) 
− Ever had a Crisis (Yes/No) 
− Time since most recent crisis (months) 
◦ 
Time since most recent crisis will be calculated as (Date of Study Day 1– Date of 
crisis)/ (365.25/12) 
Note: If the Date of Crisis day and month are missing impute July 2nd, if only the day is 
missing impute the 15th. If the imputed Date of Crisis date is later than the date of Study Day 
1, impute the date of Study Day 1. 
− Crisis History (Number of crises: 1, 2, 3, more than 3) 
− Family members have MG (Yes, No) 
− Diagnosed with Thymoma (Yes, No) 
− Prior Thymectomy (No: Yes [Total Thymectomy, Subtotal Thymectomy]) 
− Time since Thymectomy (months), calculated as (Date of Study Day 1 – Date of 
Thymectomy)/ (365.25/12) 
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Note: If the Date of Thymectomy day and month are missing impute July 2nd, if only the day 
is missing impute the 15th. If the imputed Date of Thymectomy date is later than the date of 
Study Day 1, impute the date of Study Day 1. 
Baseline characteristics will be listed overall and by COVID-19 pandemic period. 
6.1.4 
Prior/concomitant medications 
6.1.4.1 
Prior/concomitant medications classification 
Medications will be classified as follow based on imputed start and stop dates & times as 
outlined in Section 5.1.1.10.  
• Past medications will include any medications that started and stopped before the first 
administration of IMP.  
• Prior medications will include any medications that started before the first administration of 
IMP. 
• Baseline medications will include any medications that started prior to dosing and continued 
after (classified as prior and concomitant medications). 
• Concomitant medications will include any medications that have been taken at least once 
after the first administration of IMP during the Treatment Period.  
• Concomitant Only medications will include any medication that started after the first 
administration of IMP and continues during the Treatment Period. 
Table 6‒1: 
Prior and Concomitant Medications 
Medication Started 
Medication finished 
Classification 
Before 1st Dose IMP 
Before 1st Dose IMP 
Past 
Before 1st Dose IMP 
Any time 
Prior 
Before 1st Dose IMP 
After 1st Dose IMP 
Baseline (= prior and 
concomitant) 
Any time 
After 1st Dose IMP 
Concomitant 
After 1st Dose IMP 
After 1st Dose IMP 
Concomitant Only 
Where a medication start date is partially or fully missing, and it is unclear as to whether the 
medication is prior or taken at baseline, it will be assumed that it is taken at baseline. 
6.1.4.2 
Prior and concomitant medications (non-MG therapy) 
A non – MG related medication is defined by the “indication” value on the Prior and 
Concomitant Medication eCRF form not equal to “Therapy for MG”. 
Past, Prior, Baseline, Concomitant or Concomitant Only medications will be summarized by 
treatment group and overall, on the SS. Medications will be presented in alphabetical order by 
Anatomical Main Group (ATC Level 1), then by Pharmacological Subgroup (ATC level 3) and 
finally by decreasing frequency of PT within Zilucoplan group. In the case of ties, sort these 
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alphabetically within the Zilucoplan treatment group. Summaries will include the overall number 
and percentage of participants receiving at least one treatment of a PT. 
A by-participant listing will be provided. 
Medications classified as past, prior, baseline, concomitant or concomitant only will be listed 
using the SS. A by-participant listing of concomitant procedures will also be listed using the SS. 
Originally reported dates will be used for listings.  
6.1.4.3 
MG Specific Prior and Concomitant Medications 
MG specific medication will be presented separately from the other prior and concomitant 
medications (for both tables and listings). A MG specific medication is defined by the 
“indication” value on the Prior and Concomitant Medication eCRF form = “Therapy for MG”.   
MG specific Past, Prior, Baseline, Concomitant and Concomitant only medications will be 
summarized by treatment group and overall on the SS as defined in Section 6.1.4.2.  
A by-participant listing will be provided. 
Additionally, the number and percentage of participants who are taking one or more of the sets 
of MG specific medications presented in Table 6‒2 (i.e., Groups A-E) will be summarized using 
the same 2 sets of tables: MG specific prior medications and MG specific medications taken at 
baseline.  
Table 6‒2: 
Concomitant Class 
Group 
Concomitant 
Preferred Term 
A 
Prednisone for MG 
PREDNISONE 
Other corticosteroids for MG 
DEXAMETHASONE 
METHYLPREDNISONE 
METHYLPREDNISONE SODIUM 
SUCCINATE 
TBD* 
B 
azathioprine 
AZATHIOPRINE 
mycophenolate 
MYCOPHENOLATE MOFETIL 
C 
IV Ig 
IMMUNOGLOBULINS NOS 
SC Ig 
IMMUNOGLOBULINS NOS 
D 
IVIg, SCIg, or plasma exchange* 
IMMUNOGLOBULINS NOS PLEX 
E 
cyclosporine 
CICLOSPORIN 
cyclophosphamide 
CYCLOPHOSPHAMIDE 
methotrexate 
METHOTREXATE 
tacrolimus 
TACROLIMUS 
rituximab 
RITUXIMAB 
Other third line immunosupressants 
TBD** 
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*plasma exchange will be on the Procedures eCRF 
**TBD: To be defined: a complete list of corresponding medications and preferred terms will be provided by UCB 
prior to DBL 
6.1.4.4 
Refractory criteria 
A participant will be considered “MG Refractory” if they meet the following criteria (based on 
eCRF MG Treatment History page):  
Treatment for at least one year with two or more of the following therapies:  
• Prednisone  
• Azathioprine  
• Mycophenolate  
• Cyclosporine  
• Cyclophosphamide  
• Methotrexate  
• Tacrolimus  
• Rituximab  
• Eculizumab  
• Other Corticosteroids for MG 
• Other Immunosuppressive therapies (IST) 
OR History of treatment with at least one of the above therapies for 1 year or more and required 
chronic plasma exchange or IVIG or Subcutaneous IG at least every 3 months for the 12 months 
prior to enrolment.  
The MG Refractory status at baseline will be summarized by treatment group and overall, on the 
SS population. Additionally, the number and percentage of participants who have ever received 
one or more of the MG specific medications presented above will be summarized accordingly in 
the same table (eCRF form = “MG Treatment History”) 
6.1.5 
Data derivation rules 
6.1.5.1 
MG Activities of Daily Life score (MG-ADL score) 
The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. Higher 
scores are associated with more severe symptoms of MG. A 2-point change in MG-ADL Score is 
considered clinically meaningful [Wolfe et al. 1999; Muppidi et al. 2011].  
Table 6‒3 presents the 8 items with corresponding response scale, each scored on a 0 to 3-point 
scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 8 
individual scores; range 0 to 24.   
If a participant is missing a response for one of the 8 individual MG-ADL items, the participant’s 
corresponding item score from the previous MG-ADL assessment will be imputed for the 
missing item score (and the total score calculated using this imputed value and the non-missing 
item scores). If the item response is also missing from the previously scheduled MG-ADL, the 
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MG-ADL total score will be set to missing for that visit. If the participant is missing responses to 
more than one of the 8 items, the MG-ADL total score will be set to missing for that visit. 
Table 6‒3: 
MG-ADL Score 
Grade 
0 
1 
2 
3 
Talking 
Normal 
Intermittent slurring 
or nasal speech 
Constant slurring or 
nasal, but can be 
understood 
Difficult to 
understand speech 
Chewing 
Normal 
Fatigue with solid 
food 
Fatigue with soft food 
Gastric tube 
Swallowing 
Normal 
Rare episode of 
choking 
Frequent choking 
necessitating changes in 
diet 
Gastric tube 
Breathing 
Normal 
Shortness of breath 
with exertion 
Shortness of breath at 
rest 
Ventilator 
dependence 
Impairment of 
ability to brush 
teeth or comb hair 
None 
Extra effort but no 
rest periods needed 
Rest periods needed 
Cannot do one of 
these functions 
Impairment of 
ability to arise from 
a chair 
None 
Mild, sometimes uses 
arms 
Moderate, always uses 
arms 
Severe, requires 
assistance 
Double vision 
None 
Occurs but not daily 
Daily, but not constant 
Constant 
Eyelid droop 
None 
Occurs but not daily 
Daily but not constant 
Constant 
6.1.5.2 
Quantitative Myasthenia Gravis (QMG) Score 
The QMG is a standardized and validated quantitative strength scoring system that was 
developed specifically for MG. Higher scores are representative of more severe impairment. A 
change in the QMG Score of 3 points or more may be considered clinically meaningful, in a 
typical clinical trial population of MG patients [Barohn, 1998; Katzberg, 2014].   
Table 6‒4 presents the scoring scale for the 13 individual assessments, each scored on a 0 to 3-
point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 
individual scores; range 0 to 39.   
If a participant is missing a response for one of the 13 individual QMG items, the participant's 
corresponding item score from the previous QMG assessment will be imputed for the missing 
item score (and the total score calculated using this imputed value and the non-missing item 
scores). If the item response is also missing from the previously scheduled QMG, the QMG total 
score will be set to missing for that visit. If the participant is missing responses to more than one 
of the 13 items, the QMG total score will be set to missing for that visit. 
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Table 6‒4: 
QMG Score 
Item 
None 
Mild 
Moderate 
Severe 
Grade 
0 
1 
2 
3 
Double vision (lateral 
gaze) (seconds) Measured 
both to the right and to 
the left (take worst score 
between both eyes) 
61 
11-60 
1-10 
Spontaneous 
Ptosis (upward gaze) 
(seconds) 
61 
11-60 
1-10 
Spontaneous 
Facial muscle 
Normal lid 
closure 
Complete, weak, 
some resistance 
Complete, 
without 
resistance 
Incomplete 
Swallowing (4 oz water, 
½ cup) 
Normal 
Minimal 
coughing or 
throat clearing 
Sever coughing. 
Choking or nasal 
regurgitation 
Cannot 
swallow (test 
not attempted) 
Speech following 
counting aloud from 1 to 
50 (onset of dysarthria) 
None at 50 
Dysarthria at 30-
49 
Dysarthria at 10-
29 
Dysarthria at 9 
Right arm outstretched 
(90° sitting) (seconds) 
240 
90-239 
10-89 
0-9 
Left arm outstretched 
(90° sitting) (seconds) 
240 
90-239 
10-89 
0-9 
Forced vital capacity 
≥80% 
65-79% 
50-64% 
<50% 
Right hand grip (kg) 
≥45 (M) 
≥30 (F) 
15-44 (M) 
10-29 (F) 
5-14 (M) 
5-9 (F) 
0-4 (M) 
0-4 (F) 
Left hand grip (kg) 
≥35 (M) 
≥25 (F) 
15-34 (M) 
10-24 (F) 
5-14 (M) 
5-9 (F) 
0-4 (M) 
0-4 (F) 
Head, lifted (45% supine) 
(seconds) 
120 
30-119 
1-29 
0 
Right leg outstretched 
(45-50%, supine) 
(seconds) 
100 
31-99 
1-30 
0 
Left leg outstretched (45-
50%, supine) (seconds) 
100 
31-99 
1-30 
0 
F=female; M=male. 
 
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6.1.5.3 
MG Composite (MGC) score 
The MG Composite (MGC) is a 10-item scale that has been used to measure the clinical status of 
patients with MG, both in the practice setting and in clinical trials, in order to evaluate treatment 
response. Higher scores in the MGC indicate more severe impairment due to the disease. A 3-
point change in this assessment is considered clinically meaningful [Benatar et al. 2012; Sadjadi 
2012].   
Table 6‒5 presents the 10 items with corresponding response scale scores. The total score is the 
sum of the 10 individual scores; range 0 to 50.   
If a participant is missing a response for one of the 10 individual MG Composite items, the 
participant's corresponding item score from the previous MG Composite assessment will be 
imputed for the missing item score (and the total score calculated using this imputed value and 
the non-missing item scores). If the item response is also missing from the previously scheduled 
MG Composite assessment, the MG Composite total score will be set to missing for that visit. If 
the participant is missing responses to more than one of the 10 items, the MG Composite total 
score will be set to missing for that visit. 
Table 6‒5: 
MG-C score items and scoring algorithm 
 
Item 
Result/Grade Result/Grade 
Result/Grade 
Result/Grade 
Imputed from QMG 
Ptosis, upward gaze 
(physician examination) 
>45 
seconds/0 
11-45 
seconds/1 
1-10 seconds/2 
Immediate/3 
Double vision on lateral 
gaze, left or right 
(physician examination) 
>45 
seconds/0 
11-45 
seconds/1 
1-10 seconds/3 
Immediate/4 
Eye closure (physician 
examination) 
Normal/0 
Mild weakness 
(can be forced 
open with 
effort)/0 
Moderate 
weakness (can 
be forced open 
easily)/1 
Severe 
weakness 
(unable to keep 
eyes closed)/2 
Imputed from MG-ADL 
Talking (patient history) 
Normal/0 
Intermittent 
slurring or 
nasal speech/2 
Constant 
slurring or nasal 
but can be 
understood/4 
Difficult to 
understand 
speech/6 
Chewing (patient history) 
Normal/0 
Fatigue with 
solid food/2 
Fatigue with 
soft food/4 
Gastric tube/6 
Swallowing (patient 
history) 
Normal/0 
Rare episode 
of choking or 
trouble 
swallowing/2 
Frequent 
trouble 
swallowing eg, 
necessitating 
changes in 
diet/5 
Gastric tube/6 
Breathing (thought to be 
caused by MG) 
Normal/0 
Shortness of 
breath with 
exertion/2 
Shortness of 
breath at rest/4 
Ventilator 
dependence/9 
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Table 6‒5: 
MG-C score items and scoring algorithm 
 
Item 
Result/Grade Result/Grade 
Result/Grade 
Result/Grade 
 
Neck flexion or extension 
(weakest) (physician 
examination) 1 
Normal/0 
Mild 
weakness/1 
Moderate 
weakness (ie, 
50% weak, +/-
15%)/3 
Severe 
weakness/4 
 
Shoulder abduction 
(physician examination) 1 
Normal/0 
Mild 
weakness/2 
Moderate 
weakness (ie, 
50% weak, +/-
15%)/4 
Severe 
weakness/5 
 
Hip flexion (physician 
examination) 1 
Normal/0 
Mild 
weakness/2 
Moderate 
weakness (ie, 
50% weak, +/-
15%)/4 
Severe 
weakness/5 
1 Moderate weakness for head and neck items should be construed as weakness that equals roughly 50%+/-15% of 
expected normal strength. Any weakness milder than that would be mild and any weakness more severe than that 
would be classified as severe 
6.1.5.4 
Myasthenia Gravis Quality of Life (MG-QoL 15r) 
The Myasthenia Gravis-Quality of Life Revised (MG-QOL15r) is a 15-item survey that was 
designed to assess quality of life in patients with MG. Higher scores indicate more severe impact 
of the disease on aspects of the patient’s life [Burns, 2010; Burns, 2016]. The following are the 
15 questions and the corresponding response scales, each scored on a 0-2 point scale (0=Not 
much at all, 1=Somewhat, 2=Very Much).  
1. I’m frustrated by my myasthenia gravis.  
2. I have trouble using my eyes because of my MG (e.g. double vision).  
3. I have trouble eating because of my myasthenia gravis.  
4. I have limited my social activity because of my myasthenia gravis.  
5. My myasthenia gravis limits my ability to enjoy hobbies and fun activities.  
6. I have trouble meeting the needs of my family because of my myasthenia gravis.  
7. I have to make plans around my myasthenia gravis.  
8. I am bothered by limitations in performing my work (include work at home) because of my  
9. I have difficulty speaking due to my myasthenia gravis.  
10. I have lost some personal independence because of my myasthenia gravis (e.g. driving, 
shopping, running errands) 11. I am depressed about my myasthenia gravis  
12. I have trouble walking due to my myasthenia gravis  
13. I have trouble getting around public places because of my myasthenia gravis.  
14. I feel overwhelmed by my myasthenia gravis.  
15. I have trouble performing my personal grooming needs due to my myasthenia gravis.  
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The MG-QOL15r total score is the sum of the 15 individual item scores with a range of 0 to 30.   
If a participant is missing a response for one of the 15 individual MG-QOL15r items, the 
participant's corresponding item score from the previous MG-QOL15r assessment will be 
imputed for the missing item score (and the total score calculated using this imputed value and 
the non-missing item scores). If the item response is also missing from the previously scheduled 
MG-QOL15r, the MG-QOL15r total score will be set to missing for that visit. If the participant is 
missing responses to more than one of the 15 items, the MG-QOL15r total score will be set to 
missing for that visit. 
6.1.5.5 
Minimal Symptom Expression (MSE) 
Minimal Symptom Expression (MSE) is designed to assess how many participants become free 
or virtually free of MG symptoms as measured by achieving an MG-ADL total score of 0 or 1 on 
therapy [Vissing et al. 2018]. 
6.1.5.6 
MGFA Post-Intervention Status 
The MGFA Post-Intervention Status (MGFA-PIS) is a physician-determined assessment of 
clinical symptoms of MG after initiation of MG specific therapy.  
 Pharmacologic Remission (PR) is defined as follows: The participant has no symptoms or signs 
of MG since baseline and continues to take therapy for MG. Participants taking cholinesterase 
inhibitors are excluded from this category because their use suggests the presence of weakness.  
Minimal manifestation is defined as follows: ‘The patient has no symptoms of functional 
limitations from MG but has some weakness on examination of some muscles. This class 
recognizes that some patients who otherwise meet the definition of Complete Stable Remission 
(CSR) or Pharmacologic Remission (PR) do have weakness that is only detectable by careful 
examination.’ For the purpose of the current study, minimal manifestation will be determined at 
each timepoint after treatment initiation (rather than after 1 year).  
Change in status since baseline (improved, unchanged, worse, exacerbation, or died of MG) will 
also be determined.   
 
6.1.5.7 
Work Productivity and Activity Impairment Questionnaire 
The Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP) is a standardized 6-item questionnaire for assessing the amount of both 
absenteeism (work time missed) and presenteeism (reduced on-the-job effectiveness) due to 
health problems [Reilly et al. 1993]. All participants will be asked to complete the WPAI:SHP 
questionnaire at Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12. The questions and 
response scales are provided in Table 6‒6.  
WPAI:SHP endpoints are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity (i.e., worse outcomes).   
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Table 6‒6: 
WPAI:SHP 
 
The WPAI:SHP endpoints and endpoint algorithms are provided below. If a question’s response 
is missing the endpoint which uses that response will be set to missing.  Endpoint scores will be 
multiplied by 100 to express results as percentages.  
6.1.5.8 
EQ-5D-5L 
The 5-level EuroQol-5D (EQ-5D-5L) version is a standardized instrument for measuring generic 
health status. The EQ-5D-5L is comprised of the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression; each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, extreme problems [EuroQOL 
Group 1990]. Participants answer questions based on symptoms and health status on the day the 
questionnaire is completed. There is also an overall good or bad health question on a 0-100-point 
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VAS (visual analog scale). All participants will be asked to complete the EQ-5D-5L at Day 1, 
Week 1, Week 2, Week 4, Week 8 and Week 12. 
6.1.5.9 
Neuro-QOL Fatigue Short Form 
The Neuro-QOL Fatigue Short Form is part of the Neuro-QOL battery of measures that quantify 
the physical, mental, and social effects experienced by patients with neurological conditions. The 
instrument consists of 8 questions each answered on a 1-5 integer ordinal scale (1: Never; 2: 
Rarely; 3: Sometimes; 4: Often; and 5: Always) with higher scores indicating greater level of 
fatigue. The total raw score will be calculated as the sum of the values of the response to each 
question. The total score ranges from 8 to 40. The total score can be approximated (i.e. prorated)  
if at least 4 of the questions are non-missing by summing the response scores from the items that 
were answered, multiply by 8 and divide by the number of items that were answered (if the 
prorated score is a fraction it will be rounded up to the nearest whole number). The raw score 
will not be transformed to a standardized T-score as this is only accurate when all questions on 
the short form have been answered.  
All participants will be asked to complete the Neuro-QOL Fatigue Short Form at Day 1, Week 1, 
Week 2, Week 4, Week 8 and Week 12. 
6.1.6 
AEs of Interest (AEIs) 
Table 6‒7: 
AEs of Interest selection criteria 
No Event (also included in 
Title of TFL output) 
Selection criteria 
1 
Infections 
TEAE with SOC “Infections and infestations” 
2 
Neisseria infections 
TEAE with HLT “Neisseria infections” 
3 
Hypersensitivity reactions  
SMQ=’Hypersensitivity’ (narrow scope) 
4 
Anaphylactic reactions 
SMQ= ‘Anaphylactic reaction’ and  
TEAEs meeting at least one of the following criteria where 
the different terms (within each sub-category) occur on the 
same date or on 2 consecutive days, under the condition 
that the zilucoplan treatment is still ongoing at the first of 
these 2 days. 
 
1. If a participant reports any TEAE which codes to a PT 
included in Category A, then the event will be flagged 
as an anaphylactic reaction. 
 
2. If a participant reports any TEAE which codes to a PT 
included in Category B AND reports any TEAE which 
codes to a PT included in Category C, and both 
TEAEs have the same start date or on 2 consecutive 
days, then both events will be flagged as anaphylactic 
reactions.  
If a participant reports any TEAE which codes to a PT 
included in Category D AND reports (either a TEAE 
which codes to a PT included in Category B OR a TEAE 
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which codes to a PT included in Category C), and both 
TEAEs have the same start date or on 2 consecutive 
days, then both events will be flagged as anaphylactic 
reactions. 
5 
Injection site reactions 
TEAE with 
HLT=’Injection site reactions’ or 
HLT=’Administration site reactions NEC’ 
6 
Drug related hepatic 
disorders  
TEAEs in  
SMQ narrow scope=’Drug related hepatic disorders - 
comprehensive search’ but excluding these 2 sub-SMQs: 
“Liver neoplasms, benign (incl cysts and polyps) (SMQ)” 
and “Liver neoplasms, malignant and unspecified (SMQ)”.  
7 
Malignancies  
TEAEs in  
SMQ= “Malignant tumours (SMQ)” 
8 
Malignancies or 
unspecified tumours 
TEAEs in  
SMQ= “Malignant or unspecified tumours (SMQ)” or 
“Malignant tumours (SMQ)” 
Note: the events included in the “Malignant tumours” table 
will be a subset of the events included in the “Malignant or 
unspecified tumours” table. While the “Malignant tumours 
(SMQ)” is most relevant, “Malignant or unspecified 
tumours (SMQ)” must be reviewed for potential 
malignancies.Table  
Table 6‒8: 
Anaphylactic Reactions Categories 
Category 
Preferred Term 
A 
ANAPHYLACTIC REACTION 
ANAPHYLACTIC SHOCK 
ANAPHYLACTIC TRANSFUSION REACTION 
ANAPHYLACTOID REACTION 
ANAPHYLACTOID SHOCK 
CIRCULATORY COLLAPSE 
DIALYSIS MEMBRANE REACTION 
KOUNIS SYNDROME 
SHOCK 
SHOCK SYMPTOM 
TYPE 1 HYPERSENSITIVITY 
B 
ACUTE RESPIRATORY FAILURE 
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Table 6‒8: 
Anaphylactic Reactions Categories 
Category 
Preferred Term 
ASTHMA 
BRONCHIAL OEDEMA 
BRONCHOSPASM 
CARDIO-RESPIRATORY DISTRESS 
CHEST DISCOMFORT 
CHOKING 
CHOKING SENSATION 
CIRCUMORAL OEDEMIA 
COUGH 
CYANOSIS 
DYSPNOEA 
HYPERVENTILATION 
IRREGULAR BREATHING 
LARYNGEAL DYSPNOEA 
LARYNGEAL OEDEMA 
LARYNGOSPASM 
LARYNGOTRACHEAL OEDEMA 
MOUTH SWELLING 
NASAL OBSTRUCTION 
OEDEMA MOUTH 
OROPHARYNGEAL SPASM 
OROPHARYNGEAL SWELLING 
RESPIRATORY ARREST 
RESPIRATORY DISTRESS 
RESPIRATORY DYSKINESIA 
RESPIRATORY FAILURE 
REVERSIBLE AIRWAYS OBSTRUCTION 
SENSATION OF FOREIGN BODY 
SNEEZING 
STRIDOR 
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Table 6‒8: 
Anaphylactic Reactions Categories 
Category 
Preferred Term 
SWOLLEN TONGUE 
TACHYPNOEA 
THROAT TIGHTNESS 
TONGUE OEDEMA 
TRACHEAL OBSTRUCTION 
TRACHEAL OEDEMA 
UPPER AIRWAY OBSTRUCTION 
WHEEZING 
C 
ALLERGIC OEDEMA 
ANGIOEDEMA 
ERYTHEMA 
EYE OEDEMA 
EYE PRURITUS 
EYE SWELLING 
EYELID OEDEMA 
FACE OEDEMA 
FLUSHING 
GENERALISED ERYTHEMA 
INJECTION SITE URTICARIA 
LIP OEDEMA 
LIP SWELLING 
NODULAR RASH 
OCULAR HYPERAEMIA 
OEDEMA 
PERIORBITAL OEDEMA 
PRURITUS 
PRURITUS ALLERGIC 
PRURITUS GENERALIZED 
RASH 
RASH ERYTHEMATOUS 
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Table 6‒8: 
Anaphylactic Reactions Categories 
Category 
Preferred Term 
RASH GENERALIZED 
RASH PRURITIC 
SKIN SWELLING 
SWELLING FACE 
URTICARIA 
URTICARIA PAPULAR 
D 
BLOOD PRESSURE DECREASED 
BLOOD PRESSURE DIASTOLIC DECREASED 
BLOOD PRESSURE SYSTOLIC DECREASED 
CARDIAC ARREST 
CARDIO-RESPIRATORY ARREST 
CARDIOVASCULAR INSUFFICIENCY 
DIASTOLIC HYPOTENSION 
HYPOTENSION 
6.1.7 
Compliance 
Not Applicable.  
6.1.8 
COVID-19 terms 
Table 6.9: 
Preferred Terms to define COVID-19 infection 
Name 
Scope 
Asymptomatic COVID-19 
Narrow 
COVID-19 
Narrow 
COVID-19 pneumonia 
Narrow 
COVID-19 treatment 
Narrow 
Post-acute COVID-19 syndrome 
Narrow 
SARS-CoV-2 antibody test positive 
Narrow 
SARS-CoV-2 RNA increased 
Narrow 
SARS-CoV-2 sepsis 
Narrow 
SARS-CoV-2 test false negative 
Narrow 
SARS-CoV-2 test positive 
Narrow 
SARS-CoV-2 viraemia 
Narrow 
Suspected COVID-19 
Narrow 
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6.2 
Appendix 2: Abnormality criteria for Laboratory, Vital Sign and 
Electrocardiogram Parameters 
6.2.1 
Laboratory Assessments Marked Abnormality Criteria 
The following criteria will be applied in the determination of marked abnormalities for 
laboratory parameters. They are based on Version 5 of the Common Terminology Criteria for 
Adverse Events (CTCAE) grade 3 or higher criteria unless otherwise noted. If both high and low 
criteria are shown for a parameter, the criteria should be summarized separately in tabular or 
graphical summaries. 
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Table 6‒10: Laboratory Marked Abnormalities  
Parameter 
Unit 
(conventional) 
Unit  
(Standard) 
Marked Abnormality Criteria 
Hematology 
 
 
 
Hemoglobin 
g/dL 
g/L 
<8.0 g/dL; <80 g/L 
WBC (Leukocytes)  
109/L 
109/L  
Low: <2.0 x 109/L 
High: >100 x 109/L 
Lymphocytes Absolute 
109/L 
109/L 
Low: <0.5 x 109/L 
High: >20 x 109/L 
Neutrophils Absolute 
109/L 
109/L 
<1.0 x 109/L 
Platelets 
109/L 
109/L 
<50.0 x 109/L 
 
 
 
 
Other 
 
 
 
CRPa 
mg/dL 
mg/L 
>10 mg/dL; >100 mg/L 
 
 
 
 
Biochemistry 
 
 
 
AST 
U/L 
U/L 
>5.0 x ULN if Baseline value is 
normal; >5.0 x Baseline value if 
Baseline is abnormal 
ALT 
U/L 
U/L 
>5.0 x ULN if Baseline value is 
normal; >5.0 x Baseline value if 
Baseline is abnormal 
ALP 
U/L 
U/L 
>5.0 x ULN if Baseline value is 
normal; >5.0 x Baseline value if 
Baseline is abnormal 
Albumin 
g/dL 
g/L 
< 2g/dL; < 20g/L 
Bilirubin (total) 
 
mg/dL 
umol/L 
>3.0 x ULN if Baseline value is 
normal 
> 3.0 x Baseline value if Baseline 
is abnormal 
Calcium 
mg/dL 
mmol/L 
Low: Corrected serum calcium of 
<7.0 mg/dL; <1.75 mmol/L 
High: Corrected serum calcium of 
>12.5 mg/dL; >3.1 mmol/L 
Creatinine 
mg/dL 
umol/L 
>3.0 x ULN 
GGT 
U/L 
U/L 
>5.0 x ULN if Baseline value is 
normal; > 5.0 x Baseline value if 
Baseline is abnormal 
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Estimate glomerular 
filtrate rate (eGFR)b 
mL/min/1.73 m2 
mL/min/1.73 m2 
<29 mL/min/1.73m2 
Glucosec 
mg/dL 
mmol/L 
Low: <40 mg/dL;  
< 2.2 mmol/L 
High: >250 mg/dL; >13.9 
mmol/L 
Potassium 
mEq/L 
mmol/L 
Low: <3.0 mmol/L 
High: >6.0 mmol/L 
Sodium 
mEq/L 
mmol/L 
Low: <125 mmol/L 
High: >155 mmol/L 
Amylase 
U/L 
U/L 
>2.0 x ULN  
Lipase 
U/L 
U/L 
>2.0 x ULN 
a Includes CRP and High Sensitivity (HS) CRP. Reference for marked abnormality criteria: Nehring, S.M.; Goyal, 
A.; Patel, B.C. (2020). StatPearls Publishing, web link: https://www.ncbi.nlm.nih.gov/books/NBK441843/ 
   ALT= alanine aminotransferase; AST = aspartate aminotransferase; CRP = C-reactive protein;  dL = deciliter;  
GGT: gamma-glutamyltransferase; L = liter; mg = milligram; mmol = millimoles; μg = microgram; U = unit;  
ULN = upper limit of normal 
b eGFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration or CKD-EPI formula 
(https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi) which is eGFR = 141 * min(Scr/κ,1)α * 
max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black];  where Scr is serum creatinine (mg/dL), κ is 
0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of 
Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. For derivation from values in standard units (umol/L) 
the κ values are 61.9 for females and 79.6 for males. Subjects with missing race was considered as non-black for 
eGFR calculation.  
c Glucose high criterion defined by Grade 3 and higher events according to CTCAE, Version 4.03, June 14, 2010 
Note: Marked abnormality criteria are defined by Grade 3 or higher events according to the Common Terminology 
for Adverse Events (CTCAE), Version 5.0, November 17, 2017 unless otherwise noted. 
 
6.2.2 
Marked Abnormalities Vital Signs 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below: 
Table 6‒11: Marked Abnormalities Vital Signs 
Parameter 
Abnormality Criteria 
Pulse rate (beats/min) 
≤50 and a decrease from Baseline≥15 
≥120 and an increase from Baseline≥15 
Systolic Blood Pressure (mmHg) 
≤90 and a decrease from Baseline≥20 
≥160 and an increase from Baseline≥20 
Diastolic Blood Pressure (mmHg) 
≤50 and a decrease from Baseline≥15 
≥105 and an increase from Baseline≥15 
Temperature 
>1010F (38.3 0C) 
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Table 6‒11: Marked Abnormalities Vital Signs 
Parameter 
Abnormality Criteria 
Body Weight 
≥ 10% decrease from Baseline 
≥ 10% increase from Baseline 
6.2.3 
Marked Abnormalities Electrocardiogram (ECG) 
Abnormality criteria to be applied in the assessment of ECG parameter values are given below: 
Table 6‒12: Marked Abnormalities ECG 
Parameter 
Abnormality Criteria 
QT interval (ms) 
≥500ms 
≥60ms increase from Baseline 
QTcF (ms) 
≥500ms 
≥60ms increase from Baseline 
PR interval (ms) 
Treatment-emergent value >200ms 
QRS interval (ms) 
Treatment-emergent value >100ms 
Heart Rate (bpm) 
<50bpm 
>120bpm 
Abbreviations: bpm = beats per minute; ms = milliseconds; QTc(F) = Fridericia corrected QT interval;  
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit after the first dose of IMP. 
6.3 
Appendix 3: Changes to Protocol-Planned Analyses 
A modified ITT population (mITT) was added. PK-PPS and PD-PPS were added in Section 4 to 
analyze PK and PD data. Additionally, a COVID-19 Free Set (CFS) was added. 
Following FDA review, the primary estimand was revised so that data after rescue therapy, after 
any death or myasthenic gravis are assumed to be treatment failure whereas any other missing 
data are assumed to be missing at random. Multiple imputation described in the protocol was 
updated accordingly where data after rescue therapy or any death or myasthenic crisis will be 
imputed baseline or the last efficacy score (including unscheduled visit), whichever is worst, 
based on FDA’s feedback. The main analysis population was revised from ITT to mITT, 
including all randomized participants with at least 1 study drug and at least 1 post baseline 
efficacy assessment. The pattern-mixture model approach was proposed as a supplementary 
analysis. 
Moreover, more extensive analysis on efficacy were added on the COVID-19 Free Set as 
sensitivity analysis to support the efficacy on the overall population. Some safety analyses were 
added to assess the impact of the COVID-19 pandemic. 
The analysis of the secondary endpoint, received rescue therapy over the 12-week Treatment 
Period, was modified from a logistic regression (i.e., as specified in the protocol) to a time-to-
event, log-rank test (Section 5.4.2).  
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Additionally, the set of covariates in the logistic regression model for the endpoint: Achieving 
MSE, defined as an MG-ADL of 0 or 1, at Week 12 without rescue therapy; was reduced (i.e., 
removing baseline QMG Score, and geographical region as covariates as described in 
Section 5.4.3). This change was made to ensure the number of covariates was appropriate for the 
number of events anticipated for this endpoint. 
Moreover, the protocol initially planned to use a fixed-sequential testing procedure using a pre-
defined order of all the seven secondary endpoints. However, considering the small number of 
events expected for the secondary endpoints in the lowest part of the hierarchy (last 4 secondary 
endpoints) and the fact that the study is not powered to detect a statistically significant effect on 
these endpoints, it was changed to test these 4 secondary endpoints using a Holm procedure 
within a gatekeeping framework. Therefore, the order of the key secondary endpoints in the first 
family based on clinical expertise is not changed. 
 
 
 
 
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7 
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Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of 
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Burns, TM, Grouse CK, Conway MR, Sanders DB, and MG Composite and MG-QOL 15 study 
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Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et al. International 
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Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in 
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Muppidi S, Wolfe GI, Conaway M, Burns TM; MG Composite and MG-QOL15 study group. 
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Sadjadi R, Conaway M, Cutter G, Sanders DB, Burns TM; MG Composite MG-QOL15 Study 
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Muscle Nerve. 2012;45(6):820-825. 
United States Department of Health and Human Services, National Cancer Institute. Common 
Terminology for Adverse Events (CTCAE), Version 5.0, November 17, 2017. 
Vissing J, J. S. (2018). 'Minimal Symptom Expression' with Eculizumab in Myasthenia Gravis. 
AANEM. Washington, DC. 
Yuan, Y. Sensitivity Analysis in Multiple Imputation for Missing Data. Paper SAS270-2014. 
SAS Institute (2014).  
 
 
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Approval Signatures
Name:
mg0010-sap-amendment 5.0
Version:
2. 0
Document Number:
CLIN-000181834
Title:
MG0010 SAP Amendment 5.0
Approved Date:
29 Apr 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Apr-2022 10:29:54 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 29-Apr-2022 01:51:37 GMT+0000
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