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
Phase: PHASE3
Conditions: Myasthenia Gravis, Generalized
Sponsor: Ra Pharmaceuticals, Inc.

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 
CONFIDENTIAL 
 
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 
CONFIDENTIAL 
 
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  
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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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Protocol RA101495-02.301 
18.Dec.2020 
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Page 12 of 79 
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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18.Dec.2020 
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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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