Clinical trial NCT04025632
Conditions: Immune Mediated Necrotizing Myopathy
Sponsor: Ra Pharmaceuticals
Start date: 2019-11-07; Completion date: 2021-06-14
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of zilucoplan in patients with Immune-Mediated Necrotizing Myopathy (IMNM). Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo for 8 weeks.

Detailed description:

Arms: arm 1: Daily subcutaneous (SC) injection arm 2: Daily subcutaneous (SC) injection
Interventions: intervention 1: zilucoplan intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous (SC) inection intervention 2: Daily subcutaneous (SC) inection

Protocol documents:
Prot_000.pdf: 
Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
 
 
 
RA PHARMACEUTICALS, INC. 
 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects 
with Immune-Mediated Necrotizing Myopathy 
 
 
 
Protocol Number:  RA101495-02.202 (UCB study IMNM01) 
Protocol Version/Date: Version 2.0/16 February 2021 
Indication Studied: Immune-Mediated Necrotizing Myopathy (IMNM) 
Developmental Phase of Study: 2 
EudraCT Number: 2019-001497-29 
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 RA101495-02.202 
16 February 2021 
CONFIDENTIAL 
 
Page 2 of 72 
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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Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
CONFIDENTIAL 
 
Page 3 of 72 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Protocol Version 
Date 
Original Protocol 
1.0 
05 Apr 2019 
Protocol Amendment (United Kingdom) 
GB.1.1 
25 Jul 2019 
Protocol Amendment (France) 
FR.1.1 
20 Feb 2020 
Protocol Amendment (Global)  
2.0 
16 Feb 2021 
PROTOCOL AMENDMENT (GLOBAL) VERSION 2.0 (16 FEB 2021) 
The purpose of this protocol amendment is to make the following changes to the original 
protocol (Version 1.0 dated 05 Apr 2019): 
• Changes made in earlier United Kingdom (25 Jul 2019) and France (20 Feb 2020) 
country-specific protocol amendments 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 coronavirus disease 2019 
(COVID-19) pandemic. 
• To clarify that the snapshot will be taken after the Week 8 visit. 
• Additional administrative updates were made in the protocol. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated version number and 
date; added UCB study 
number. 
Updated. 
Section 1, Synopsis, Study 
Objectives 
Notes added that the long-term 
safety, tolerability, and 
efficacy will be evaluated 
during the open-label 
Extension Portion of the study. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 1, Synopsis, Study 
Design, paragraph 8 
Text regarding safety data 
review has been updated. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol. 
Section 1, Synopsis, Study 
Design, paragraph 9  
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
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Version 2.0 
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16 February 2021 
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Page 4 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1, Synopsis, 
Duration of Study 
Participation 
The study duration for the 
Extension Portion has been 
amended from the France 
protocol amendment from 
4 months to 18 months. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 
18 months to allow for 
enrolled patients to continue 
receiving open-label drug 
based on additional safety data 
reviewed during the updated 
Investigator's Brochure (IB). 
Section 1, Synopsis, 
Duration of Study 
Participation 
An example of zilucoplan 
access in another qualifying 
extension study has been 
added. 
To provide flexible means for 
zilucoplan access for 
participants with close medical 
supervision afforded by a 
clinical study. 
Section 1, Synopsis, 
Inclusion/Exclusion Criteria 
Added exclusion criterion 14 
(hypersensitivity to study 
drug). 
Consolidation of earlier 
country-specific (UK) protocol 
amendment 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. 
Section 1, Synopsis, Study 
Objectives and Endpoints 
“Change from Baseline to 
Week 8 in American College of 
Rheumatology/European League 
Against Rheumatism 
(ACR/EULAR) Response 
Criteria” was updated to “At 
least minimal response based 
on ACR/EULAR Response 
Criteria Scale at Week 8”.  
Updated for clarity. 
Section 1, Synopsis, Study 
Objectives and Endpoints 
“Change in physical 
examination” has been 
removed as an other safety 
endpoint. 
Clinically significant abnormal 
physical examination findings 
will be categorized as adverse 
events (AEs).  
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16 February 2021 
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Page 5 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1, Synopsis, Study 
Objectives and Endpoints 
The UK protocol amendment 
included a note that the 
primary and secondary 
efficacy endpoints evaluated in 
the Main Portion of the study 
will continue to be collected 
during in the Extension 
Portion of the study to 
determine the long-term 
safety, tolerability, and 
efficacy of zilucoplan in 
subjects with IMNM. This 
change has been incorporated 
into this global protocol 
amendment by including the 
Extension Portion objective 
and endpoints in the 
Objectives and Endpoints 
table. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 1, Statistical 
Considerations, Study 
Populations 
Per protocol population 
description has been corrected. 
Typographical error has been 
corrected. 
Section 1, Statistical 
Considerations, Study 
Populations 
General considerations 
sentence has been updated to 
clarify that subject disposition 
breakdowns will include 
reasons for discontinuation. 
Updated for clarity. 
Section 1, Statistical 
Considerations, Efficacy 
Analysis  
Efficacy analysis has been 
updated from 2-sided 
Wilcoxon rank sum test to the 
2-sided stratified Wilcoxon 
rank sum test (Van Elteren 
test).  
 
A sentence has been added to 
state that the effect of 
Zilucoplan on ACR/EULAR 
minimal response will be 
investigated using a binary 
logistic regression model with 
treatment and stratification 
included as factors. 
The Van Elteren version of the 
Wilcoxon rank sum test has 
been selected to provides a 
more specific analysis. 
 
 
 
Updated for clarity. 
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Page 6 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2, Schedule of 
assessments, Table 1: Main 
portion time and events 
table 
Footnote “a” has been updated 
to state that if a subject 
permanently discontinues 
study drug treatment prior to 
the Week 8 visit for any 
reason, he/she will not be 
eligible for the Extension 
Portion. For subjects who 
permanently discontinue 
treatment with study drug, a 
Safety Follow-up Visit will be 
performed at 40 days after the 
last dose to collect information 
on any ongoing AEs or new 
serious AEs (SAEs) since the 
last study visit. 
Clarification of study 
procedures. 
Section 2, Schedule of 
assessments, Table 1: Main 
portion time and events 
table  
Adverse event collection 
added to the screening visit, 
and footnote “k” has been 
updated to state that only 
SAEs should be collected at 
the screening visit. 
Clarification of study 
procedures. 
Section 2, Time and Events 
Table 1: Main Portion time 
and events table 
Footnote “j” after anti-drug 
antibody has been corrected to 
“h.” 
Correction of error. 
Section 2, Time and Events, 
Table 2: Extension Portion 
time and events table  
A new footnote “b” has been 
added to the “Visits after Day 
E117” to state that for France 
only, the duration of study 
participation during the 
Extension Portion will include 
an open-label, single-arm, 
18-month Treatment Period. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 
18 months to allow for 
enrolled patients to continue 
receiving open-label drug 
based on additional safety data 
reviewed during the updated 
IB. 
Section 5.4.2, Rationale for 
Blinding and Placebo 
Control, paragraph 3 
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
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Page 7 of 72 
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 6, Study Objectives 
and Endpoints 
“Change from Baseline to 
Week 8 in ACR/EULAR 
Response Criteria” was 
updated to “At least minimal 
response based on 
ACR/EULAR Response 
Criteria Scale at Week 8”.  
Updated for clarity. 
Section 6, Study Objectives 
and Endpoints 
“Change in physical 
examination” has been 
removed as an other safety 
endpoint. 
Clinically significant abnormal 
physical examination findings 
will be categorized as adverse 
events.  
Section 6, Study Objectives 
and Endpoints 
The UK protocol amendment 
included a note that the 
primary and secondary 
efficacy endpoints evaluated in 
the Main Portion of the study 
will continue to be collected 
during in the Extension 
Portion of the study to 
determine the long-term 
safety, tolerability, and 
efficacy of zilucoplan in 
subjects with IMNM. This 
change has been incorporated 
into this global protocol 
amendment by including the 
Extension Portion objective 
and endpoints in the 
Objectives and Endpoints 
table. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 7.1 Overview of 
Study Design, paragraph 9  
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 7.2 Study Periods, 
paragraph 3 
An example of zilucoplan 
access in another qualifying 
extension study has been 
added. 
To provide flexible means for 
zilucoplan access for 
participants with close medical 
supervision afforded by a 
clinical study. 
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Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
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Page 8 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 Study Periods, 
paragraph 3 
The study duration for the 
Extension Portion has been 
amended from the France 
amendment from 4 months to 
18 months. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 18 
months to allow for enrolled 
patients to continue receiving 
open-label drug based on 
additional safety data 
reviewed during the updated 
IB. 
Section 7.2.2.1 
Randomization and 
Blinding, paragraph 2  
Updated the text to specify 
Week 8 of the Main Portion of 
the study.  
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 7.4, Study Conduct 
During COVID-19 
Added new section. 
Update to include provisions 
for the COVID-19 pandemic. 
Section 8.2, Exclusion 
Criteria, Exclusion 
Criterion 14 
Added exclusion criterion 14 
(hypersensitivity to study 
drug). 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 9.2.1.1, Alternative 
Study Treatment Supply 
due to COVID-19 
Pandemic 
Added a new section. 
Update to include provisions 
for the COVID-19 pandemic. 
Section 9.1.3 
Sentence updated to clarify 
that subjects presenting with a 
body weight outside of these 
ranges will be accommodated 
on a case-by-case basis, in 
consultation with the medical 
monitor.  
Updated for clarity. 
Section 10.2.1 Physical 
Examination 
Sentence #2 has been updated 
to state that any clinically 
significant abnormalities after 
Day 1 will be recorded as AEs 
in the eCRF.  
Updated for clarity.  
Section 10.2.4.3, Pregnancy 
Testing and Contraception 
Revised information on 
contraception. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.3.2.2 Proximal 
Manual Muscle Testing  
Manual muscle testing in 8 
muscle groups has been 
corrected to 7.  
Typographical error has been 
corrected. 
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. 
Section 11.4.1.1 Adverse 
Events  
Sentence has been updated 
that AE reporting will end 
40 days following the last dose 
of study drug. 
To comply with UCB safety 
guidance. 
Section 11.4.2.1 Safety 
Monitoring Committee, 
paragraph 2 
Text regarding safety data 
review has been updated. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol. 
Section 12.1 Analysis 
population  
A sentence has been added to 
clarify that further details of 
additional analysis populations 
will be described in the SAP, 
which will be finalized prior to 
study unblinding.  
Updated for clarity. 
Section 12.2.1 General 
Methods, paragraph 3 
Updated the text to specify 
Week 8 of the Main Portion of 
the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 12.2.2 Subject 
Disposition 
Sentence has been updated to 
clarify that subject disposition 
breakdowns will include 
reasons for discontinuation 
and the disposition for the 
Main Portion as well as 
Extension Portion will be 
provided. 
Updated for clarity. 
Section 12.2.4.1 Adverse 
Events 
The last sentence has been 
updated to clarify that SAEs 
occurring before first dose of 
study drug will be listed.  
To align with the Time and 
Events Table 1. 
Section 12.2.5.1 Primary 
Efficacy Analysis 
Efficacy analysis has been 
updated from 2-sided 
Wilcoxon rank sum test to the 
2-sided stratified Wilcoxon 
rank sum test (Van Elteren 
test). 
 
Primary estimands have been 
included.  
The Van Elteren version of the 
Wilcoxon rank sum test has 
been selected to provides a 
more specific analysis. 
 
 
 
To align with the updated ICH 
E9 (R1) addendum. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.2.5.2 Secondary 
Efficacy Analysis 
Definition of the secondary 
estimands have been included. 
To align with the updated ICH 
E9 (R1) addendum. 
Section 12.2.6.1 
Pharmacokinetic and 
Pharmacodynamic Analysis 
Details of a potential 
population pharmacokinetic 
analysis and reporting have 
been added.  
To conduct, if necessary, 
additional investigation to 
support the clinical 
development of zilucoplan in 
IMNM. 
Section 12.2.7 Interim 
analysis  
Updated the text to specify 
Week 8 of the Main Portion of 
the study.  
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
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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1 
SYNOPSIS 
Protocol Title 
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, 
and Efficacy of Zilucoplan in Subjects with Immune-Mediated 
Necrotizing Myopathy 
Protocol Number 
RA101495-02.202 (UCB Study IMNM01) 
Phase of Clinical Development 
Phase 2 
Investigational Medicinal 
Product 
Zilucoplan (RA101495) administered by daily subcutaneous 
(SC) injection (0.3 mg/kg) 
Study Population 
Immune-Mediated Necrotizing Myopathy (IMNM) 
Investigative Sites 
Approximately 7 centers are planned worldwide 
Planned Number of Subjects  
Approximately 24 subjects (12 per treatment arm) 
Study Objectives 
• To evaluate the safety and tolerability of zilucoplan in subjects with IMNM 
• To evaluate the efficacy of zilucoplan in subjects with IMNM 
Please note: The long-term safety, tolerability, and efficacy will be evaluated during the open-label 
Extension Portion of the trial. 
Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and efficacy of zilucoplan in subjects with IMNM who are positive for anti-HMGCR (3-
hydroxy-3-methyl-glutaryl-coenzyme A reductase) or anti-SRP (signal recognition particle) 
autoantibodies.  
The planned enrollment is approximately 24 subjects. Subjects will be randomized in a 1:1 ratio to 
receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo. Randomization will be stratified 
based on antibody status (anti-HMGCR+ versus anti-SRP+). 
The Main Portion of the study includes a Screening Period of up to 4 weeks and an 8-week Treatment 
Period. During the Treatment Period, subjects will return to the clinic at Week 1, Week 2, Week 4, and 
Week 8 to evaluate safety, tolerability, and efficacy. Additional assessments will include biomarker 
testing, pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety assessments 
will include physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory tests, 
adverse event (AE) monitoring, and immunogenicity. 
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 8 weeks. Single-
use pre-filled syringes in injection devices will be provided for use during the study. 
All standard of care (SOC) therapy medications for IMNM should be kept at the same doses 
throughout the study, including corticosteroids, immunosuppressive drugs, and intravenous 
immunoglobulin (IVIG). 
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., ciprofloxacin, erythromycin, 
penicillin V) until at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC.   
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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 additional data 
review should become necessary to ensure subject safety, a supervisory committee [i.e., a Safety 
Monitoring Committee (SMC)] will convene and evaluate study data as appropriate.  
At the conclusion of the Treatment Period of the study, all subjects will have the option to receive 
zilucoplan in the Extension Portion of the study provided they meet the Extension Portion selection 
criteria. Visits during the first 8 weeks of the Extension Portion will be identical to the Main Portion 
of the study for all subjects to ensure appropriate monitoring of subjects transitioning from placebo 
to active treatment. The study will remain double-blinded until after the data from Week 8 of the 
Main Portion of the study have been reviewed, locked, and unblinded. 
If a subject permanently discontinues study drug treatment prior to the Week 8 visit for any reason, 
he/she will not be eligible for the Extension Portion. For subjects who permanently discontinue 
treatment with study drug, a Safety Follow-up Visit will be performed at 40 days after the last dose to 
collect information on any ongoing AEs or new SAEs since the last study visit. 
Duration of Study Participation 
Main Portion: The duration of study participation during the Main Portion will include a Screening 
Period of up to 4 weeks and an 8-week Treatment Period for a total of approximately 12 weeks. 
Extension Portion: The investigational medicinal product (IMP) will continue to be provided by the 
Sponsor until zilucoplan is approved and available in the territory (e.g. in another qualifying 
extension study begins) or until the Sponsor terminates development of zilucoplan for IMNM. 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. 
For France only: The duration of study participation during the Extension Portion of this study 
(RA101495-02.202) will include an open-label, single-arm, 18-month Treatment Period. 
Inclusion/Exclusion 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. Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy).  
4. Positive serology for anti-HMGCR or anti-SRP autoantibodies. 
5. Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at least one 
proximal limb muscle group. 
6. Creatinine kinase (CK) of >1000 U/L at Screening. 
7. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur 
during the first 8-weeks on study. 
8. No changes in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or 
anticipated to occur during the first 8-weeks on study. 
9. 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. 
10. 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 
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contraception during the study. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation.   
Subjects who meet ANY of the following exclusion criteria must be excluded from the study: 
1. History of meningococcal disease. 
2. Current or recent systemic infection within 2 weeks prior to Screening or infection requiring 
intravenous (IV) antibiotics within 4 weeks prior to Screening. 
3. Pregnant, planning to become pregnant, or nursing female subjects. 
4. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or expected to have 
surgery requiring general anesthesia during the 8-week Treatment Period. 
5. Treatment with a complement inhibitor or an experimental drug within 30 days or 5 half-lives of 
the drug (whichever is longer) prior to Baseline. 
6. Statin use within 30 days prior to Baseline or anticipated to occur during study. 
7. Rituximab use within 90 days prior to Baseline or anticipated to occur during study. 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months prior to 
Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) should be given 
upon initiation of study drug until 6 months after the last rituximab dose. 
8. Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered less than 90 
days prior to Baseline). 
9. Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-week 
Treatment Period. 
10. 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). 
11. History of any significant medical, psychiatric disorder, or laboratory abnormality that in the 
opinion of the investigator would make the subject unsuitable for participation in the study. 
12. Participation in another concurrent clinical trial involving an experimental therapeutic intervention 
(participation in observational studies and/or registry studies is permitted).  
13. Unable or unwilling to comply with the requirements of the study.  
14. Subjects who have a known hypersensitivity to zilucoplan or any of its excipients. 
Study Objectives and Endpoints 
Objectives  
Estimands / Endpoints 
Primary 
Primary Objective: to evaluate the safety and 
efficacy of zilucoplan over placebo in CK 
levels in participants with IMNM 
Primary Efficacy Estimand: 
• 
Treatment: Zilucoplan administered by 
daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• 
Target Population: is defined through the 
inclusion/exclusion criteria in Section 8.1 
and Section 8.2 of the study protocol 
reflecting the targeted IMNM population. 
• 
Endpoint: Percent change from Baseline 
to Week 8 in CK levels. 
• 
Intercurrent event (ICE) handling: 
regardless of any treatment 
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discontinuation for any reason; censoring 
after prohibited medication. 
• 
Population level summary: The 
difference in ranks of the percentage 
change from baseline between treatments 
followed by the Wilcoxon-Mann-
Whitney odds (WMWodds) and Hodges–
Lehmann estimator followed by the 
corresponding 95% Confidence Intervals 
(CI). 
Primary Safety Endpoint 
• 
Incidence of treatment-emergent adverse 
events. 
Secondary 
Secondary Objective(s): to further evaluate 
the efficacy and the safety of zilucoplan over 
placebo in participants with IMNM 
Secondary Efficacy Estimands: 
• 
Treatment: Zilucoplan administered by 
daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• 
Target Population: is defined through the 
inclusion/exclusion criteria in Section 8.1 
and Section 8.2 of the study protocol 
reflecting the targeted IMNM population. 
• 
Endpoints:  
o At least minimal response based on 
the American College of 
Rheumatology/European League 
Against Rheumatism (ACR/EULAR) 
Response Criteria Scale at Week 8;  
o Change from Baseline to Week 8 in 
Triple Timed Up and Go (3TUG) 
Test (in ambulatory patients only);  
o Change from Baseline to Week 8 in 
Proximal Manual Muscle Testing 
(MMT);  
o Change from Baseline to Week 8 in 
Physician Global Activity Visual 
Analogue Scale (VAS);  
o Change from Baseline to Week 8 in 
Patient Global Activity VAS;  
o Change from Baseline to Week 8 in 
Health Assessment Questionnaire 
(HAQ);  
o Change from Baseline to Week 8 in 
myositis disease activity assessment 
tool (MDAAT) Extramuscular 
Disease Activity VAS Score;  
o Change from Baseline to Week 8 in 
Functional Assessment of Chronic 
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Illness Therapy (FACIT)-Fatigue 
Scale;  
• 
ICE handling: regardless of any treatment 
discontinuation for any reason; censoring 
after administration of prohibited 
medication. 
• 
Population level summary: 
o Odds Ratio of ACR/EULAR ≥ 20 
response proportion between 
treatment conditions;  
o Difference in continuous endpoint 
means, between treatment conditions. 
Other 
To further evaluate the safety of zilucoplan 
over placebo in participants with IMNM 
Other safety endpoints 
• 
Change in clinical laboratory tests 
• 
Change in ECG parameters  
• 
Change vital signs parameters, and  
• 
Presence of Anti-Drug Antibodies 
Exploratory 
To assess the long term efficacy of 
zilucoplan 
• 
At least minimal response based on the 
American College of 
Rheumatology/European League Against 
Rheumatism (ACR/EULAR) Response 
Criteria Scale at each visit following 
Week 8; 
• 
Change from Baseline of Timed Up and 
Go (3TUG) Test (in ambulatory patients 
only) at each visit following Week 8; 
• 
Change from Baseline of Proximal Manual 
Muscle Testing (MMT) at each visit 
following Week 8; 
• 
Change from Baseline of Physician Global 
Activity Visual Analogue Scale (VAS) at 
each visit following Week 8; 
• 
Change from Baseline of Patient Global 
Activity Visual Analogue Scale (VAS) at 
each visit following Week 8; 
• 
Change from Baseline of Health 
Assessment Questionnaire (HAQ) at each 
visit following Week 8; 
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• 
Change from Baseline of MDAAT 
Extramuscular Disease Activity VAS 
Score at each visit following Week 8;  
• Change from Baseline of FACIT-
Fatigue Scale at each visit following 
Week 8; 
To assess the pharmacokinetics (PK) of 
zilucoplan 
• 
Plasma concentrations of zilucoplan and its 
major metabolites  
To assess the pharmacodynamics (PD) of 
zilucoplan 
 
• 
Sheep red blood cell lysis assay for 
evaluation of classical complement 
pathway activation 
• 
Complement component 5 levels 
To assess the effect of zilucoplan on 
biomarkers 
• 
Mechanistic biomarkers [e.g., complement 
fixation, complement function, 
complement pathway proteins, 
autoantibody characterization (titer and 
immunoglobulin class), myocyte markers, 
and inflammatory markers].   
To assess the effect of zilucoplan on 
pharmacogenomics 
• 
Pharmacogenomic analyses (optional): 
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. 
Statistical Considerations 
Study Populations:   
The following study populations are defined: 
• 
Intention-to-Treat (ITT) Population:  All subjects randomized. 
• 
Per Protocol Population: All subjects in the ITT Population who have completed the 8-week 
Treatment Period and have no major protocol deviations.  
• 
Safety Population:  All subjects who have 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 all consented subjects will be provided and will include a 
breakdown of subjects who were randomized, were treated, and discontinued treatment (including 
reasons for discontinuation). 
Continuous variables will be summarized using the number of observations, number of observations 
below the limit of quantification (if applicable), mean, standard deviation (SD), median, and range. 
Categorical variables will be summarized using frequency counts and percentages. 
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Stratification of Randomization:   
Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or 
matching placebo. Randomization will be stratified based on autoantibody status (anti-HMGCR+ 
versus anti-SRP+). 
Determination of Sample Size:   
A sample size of 12 subjects per group yields approximately 95% power to detect a difference in the 
percent reduction from baseline in creatine kinase between the active and placebo groups using a 
Wilcoxon rank sum test at the two-sided 0.05 type 1 error rate. The power calculations assume that the 
percent reduction in creatine kinase in the active dose group is approximately normally distributed with 
a mean of 80% and a standard deviation of 8%; that 4 of the placebo patients will have a percent 
reduction similar to the active dose group; and the remaining 8 placebo patients will have a percent 
reduction  that is normally distributed with a mean of 10% and a standard deviation of 8%. The 
estimation of the creatine kinase baseline levels and treatment effect are based on the data presented in 
Mammen et Tiniakou, 2015 (Mammen and Tiniakou 2015). 
Efficacy Analyses:   
The primary efficacy endpoint, percent reduction from baseline in creatine kinase at Week 8, will be 
compared between the two treatment groups using a 2-sided stratified Wilcoxon rank sum test (Van 
Elteren test). 
Treatment group differences for each of the continuous secondary efficacy change from baseline 
endpoints will be assessed using a mixed model analysis of covariance (ANCOVA) with treatment and 
baseline score as fixed effects and subject as a random effect. Additional subgroup analyses, including 
autoantibody serotype, will be prespecified in the SAP. 
The effect of Zilucoplan on ACR/EULAR minimal response will be investigated using a binary logistic 
regression model with treatment and stratification included as factors. 
Safety:   
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Incidence rates 
for treatment-emergent AEs 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. 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 using descriptive statistics. 
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2 
SCHEDULE OF ASSESSMENTS  
Assessments to be performed during the study are shown in Table 1 and Table 2 
Table 1: MAIN PORTION Time and Events Table 
 
 
 
Week 1 
Week 2 
Week 4 
Week 8 
 
Study Procedure 
Screening 
Days -28 to -1 
Day 1 
(‘Baseline’) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
End of Maina 
Day 57  
(± 7 days) 
Safety 
Follow-up Visita  
(last dose + 40d) 
Informed consentb 
X 
 
 
 
 
 
 
Review eligibilityb 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Medical historyc and demographics 
X 
 
 
 
 
 
 
Heightd and weight 
X 
 
 
 
X 
X 
 
Prior and concomitant medicationse 
X 
X 
X 
X 
X 
X 
X 
Safety  
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
12-Lead electrocardiogram 
X 
 
 
 
 
X 
 
Neisseria meningitidis vaccinationg 
X 
SOC 
SOC 
SOC 
SOC 
SOC 
 
Prophylactic antibioticsg (if applicable) 
 
X 
X 
X 
 
 
 
Hematology/Chemistry/CKh 
X 
X 
X 
X 
X 
X 
 
Coagulationh,i 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
X 
X 
X 
X 
X 
X 
 
Pregnancy testj 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsk 
X  
X 
X 
X 
X 
X 
Xk 
Anti-drug antibodyh 
X 
 
X 
 
X  
X 
 
Efficacy 
 
 
 
 
 
 
 
3TUGl,m 
X 
X 
 
 
X 
X 
 
Proximal MMTl 
X 
X 
 
 
X 
X 
 
Physician Global Activity VASl 
X 
X 
 
 
X 
X 
 
Patient Global Activity VASl 
X 
X 
 
 
X 
X 
 
HAQl 
X 
X 
 
 
X 
X 
 
MDAATl 
X 
X 
 
 
X 
X 
 
FACIT-Fatiguel 
X 
X 
 
 
X 
X 
 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
Zilucoplan plasma PKn 
 
X 
X 
X 
X 
X 
 
Pharmacodynamic analysisn 
 
X 
X 
X 
X 
X 
 
Exploratory 
 
 
 
 
 
 
 
Autoantibodies testingo 
X 
X 
 
 
X 
X 
 
Biomarker testingp 
 
X 
X 
X 
X 
X 
 
Pharmacogenomic analysis (optional)q 
X 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
Zilucoplan or placebo administrationr 
 
X 
X 
X 
X 
X 
 
See footnotes on following page. 
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1-a. If a subject permanently discontinues study drug prior to completion of the Day 57 visit during the Main Portion, the subject should return to clinic for an End of Main Visit. 
If a subject consents to the Extension Portion, please see Table 2 for Day 57/E1 assessments. If a subject permanently discontinues study drug treatment prior to the Week 8 
visit for any reason, he/she will not be eligible for the Extension Portion. For subjects who permanently discontinue treatment with study drug, a Safety Follow-up Visit will 
be performed at 40 days after the last dose to collect information on any ongoing AEs or new SAEs since the last study visit. 
1-b. 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.  Eligibility must be established prior to randomization on Day 1. 
1-c. Screening includes a detailed history of IMNM diagnosis information and local serology for anti-HMGCR or anti-SRP autoantibodies from a reputable laboratory. 
1-d. Height will be measured only at Screening. 
1-e. All prescriptions and over-the-counter medications taken during the 30 days prior to Baseline (i.e., Day 1) through the last study visit will be documented.  NOTE: A 
complete history of all medication taken for the treatment of IMNM will be collected. 
1-f. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
1-g. 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., ciprofloxacin, erythromycin, 
penicillin V) until at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be administered in accordance with local SOC.  
NOTE: In subjects who received rituximab more than 90 days but less than 6 months prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) should be given upon initiation of study drug until 6 months after the last rituximab dose. 
1-h. All laboratory samples should be obtained prior to administration of study drug at applicable visits.  
1-i. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
1-j. 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.  
1-k. 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. Subjects will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the 
last study visit. Only SAEs are collected during the screening period. 
1-l. The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order by the same 
well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study.  
1-m. 3TUG will only be completed in subjects who are ambulatory. 
1-n. Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
1-o. Confirmatory serology testing for anti-HMGCR or anti-SRP autoantibodies will be done at a central laboratory. 
1-p. Blood samples for biomarker testing will be obtained prior to administration of study drug (within 1 hour of dosing). 
1-q. The pharmacogenomic sample may be collected at any study visit. 
1-r. Dosing on study visit days should be held until clinical assessment and blood collection has been completed.  
 
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Table 2: EXTENSION PORTION Time and Events Table 
 
Month 2 
 
 
Month 3 
Month 4 
Month 5 
Month 6 
 
Visits after Day E117b 
 
 
 
Study Procedure 
Day E1a 
(Day 57) 
Day E8 
(± 2 days) 
Day E15 
(± 2 days) 
Day E29 
(± 2 days) 
Day E57 
(± 7 days) 
Day E87 
(± 7 days) 
Day E117 
(± 7 days) 
 
Each 
Month 
(± 7 days) 
Every 3 
Months 
(± 7 days) 
 
Final 
Extension 
Visitc 
Safety 
Follow-up 
Visit  
(last dose + 40d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility and randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
12-Lead electrocardiogram 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Neisseria meningitidis vaccinatione 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC 
 
SOC 
SOC 
 
 
 
Hematology/Chemistry/CKf 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Coagulationf, g 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Urinalysisf 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Adverse eventsi 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Xh 
Anti-drug Antibodyf 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
3TUGj,k 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Proximal MMTj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Physician Global Activity VASj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Patient Global Activity VASj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
HAQj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
MDAATj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
FACIT-Fatiguej 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zilucoplan plasma PKl 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Pharmacodynamic analysisl 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies testing 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Biomarker testingm 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zilucoplan administrationn 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
See footnotes on following page. 
 
 
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2-a. For subjects that decide and are eligible to continue in the Extension Portion of the study, the Day 57 visit from the Main Portion will serve as the Day E1 visit and will also 
include review of eligibility to continue (see Section 8.3) and signing of an informed consent for the Extension Portion. 
2-b. For France only: The duration of study participation during the Extension Portion of this study (RA101495-02-202) will include an open-label, single-arm, 18-month 
Treatment Period. 
2-c. If a subject discontinues study drug treatment at any time during the Extension Portion, the subject should return to clinic for a Final Extension Visit. 
2-d. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
2-e. During the Extension Portion of the study, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety 
card to every study visit. If the subject does not bring their card with them they will be given a new one. 
2-f. All laboratory samples should be obtained after clinical assessments and prior to administration of study drug at applicable visits.  
2-g. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
2-h. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
2-i. 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. Subjects will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the 
last study visit.  
2-j. The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order by the same 
well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study.  
2-k. 3TUG will only be completed in subjects that are ambulatory. 
2-l. Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
2-m. Blood samples for the exploratory tests will be obtained prior to administration of study drug (within 1 hour of dosing). 
2-n. Dosing on study visit days should be held until clinical assessment and blood collection has been completed. 
 
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3 
TABLE OF CONTENTS 
1 
SYNOPSIS ......................................................................................................11 
2 
SCHEDULE OF ASSESSMENTS ...............................................................18 
3 
TABLE OF CONTENTS ..............................................................................22 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................26 
5 
INTRODUCTION..........................................................................................27 
5.1 
OVERVIEW OF IMMUNE-MEDIATED NECROTIZING MYOPATHY ........................27 
5.2 
MECHANISM OF ACTION OF ZILUCOPLAN .........................................................28 
5.3 
CLINICAL TRIAL EXPERIENCE WITH ZILUCOPLAN .............................................29 
5.3.1 
ZILUCOPLAN PHASE 1 EXPERIENCE ..................................................................29 
5.3.2 
ZILUCOPLAN PHASE 2 EXPERIENCE ..................................................................30 
5.3.2.1 
COMPLETED PHASE 2 STUDY IN GMG ..............................................................30 
5.3.2.2 
COMPLETED PHASE 2 STUDIES IN PNH PATIENTS ............................................31 
5.4 
RATIONALE FOR THE CURRENT STUDY .............................................................32 
5.4.1 
RATIONALE FOR PRIMARY ENDPOINT ................................................................32 
5.4.2 
RATIONALE FOR BLINDING AND PLACEBO CONTROL ........................................33 
5.4.3 
DOSE SELECTION AND PRESENTATION ..............................................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................34 
6.1 
OBJECTIVES ......................................................................................................34 
7 
STUDY DESIGN ............................................................................................37 
7.1 
OVERVIEW OF STUDY DESIGN ..........................................................................37 
7.2 
STUDY PERIODS ................................................................................................38 
7.2.1 
SCREENING PERIOD ...........................................................................................39 
7.2.1.1 
SCREENING AND ENROLLMENT .........................................................................39 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) .................................40 
7.2.2.1 
RANDOMIZATION AND BLINDING ......................................................................40 
7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT ......................41 
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 .......................................................................................43 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION ........................................44 
8.4 
REMOVAL OF SUBJECTS IN THE STUDY .............................................................45 
8.4.1 
WITHDRAWAL OF CONSENT ..............................................................................45 
8.4.2 
PREMATURE DISCONTINUATION .......................................................................45 
8.4.3 
REPLACEMENT OF SUBJECTS .............................................................................46 
9 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................46 
9.1 
STUDY TREATMENT ADMINISTRATION .............................................................46 
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9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING 
PLACEBO ...........................................................................................................46 
9.1.2 
DOSING SCHEDULE ...........................................................................................46 
9.1.3 
DOSE PRESENTATION ........................................................................................46 
9.1.3.1 
MISSED DOSES ..................................................................................................47 
9.2 
STUDY TREATMENT MANAGEMENT ..................................................................47 
9.2.1 
PREPARATION AND DISPENSING ........................................................................47 
9.2.1.1 
ALTERNATIVE STUDY TREATMENT SUPPLY DUE TO COVID-19 
PANDEMIC.........................................................................................................47 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING ...........................................47 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ....................................47 
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 .......................................................................................48 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................48 
10.2 
SAFETY ASSESSMENTS ......................................................................................49 
10.2.1 
PHYSICAL EXAMINATION ..................................................................................49 
10.2.2 
VITAL SIGNS .....................................................................................................49 
10.2.3 
ELECTROCARDIOGRAM .....................................................................................49 
10.2.4 
LABORATORY SAFETY ASSESSMENTS ...............................................................50 
10.2.4.1 
HEMATOLOGY, CHEMISTRY, AND COAGULATION .............................................50 
10.2.4.2 
URINALYSIS ......................................................................................................51 
10.2.4.3 
PREGNANCY TESTING AND CONTRACEPTION ....................................................51 
10.2.5 
ADVERSE EVENT RECORDING ...........................................................................52 
10.2.6 
IMMUNOGENICITY .............................................................................................52 
10.3 
EFFICACY ASSESSMENTS ..................................................................................52 
10.3.1 
PRIMARY EFFICACY ASSESSMENT ....................................................................52 
10.3.2 
SECONDARY EFFICACY ASSESSMENTS ..............................................................52 
10.3.2.1 
TRIPLE TIMED UP AND GO TEST .......................................................................52 
10.3.2.2 
PROXIMAL MANUAL MUSCLE TESTING ............................................................52 
10.3.2.3 
PHYSICIAN GLOBAL ACTIVITY VISUAL ANALOGUE SCALE ..............................53 
10.3.2.4 
PATIENT GLOBAL ACTIVITY VISUAL ANALOGUE SCALE ..................................53 
10.3.2.5 
HEALTH ASSESSMENT QUESTIONNAIRE ............................................................53 
10.3.2.6 
MYOSITIS DISEASE ACTIVITY ASSESSMENT TOOL ............................................53 
10.3.2.7 
ACR/EULAR RESPONSE CRITERIA ..................................................................54 
10.3.2.8 
FACIT-FATIGUE SCALE ...................................................................................54 
10.4 
PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS ................................54 
10.5 
EXPLORATORY ASSESSMENTS ..........................................................................54 
10.5.1 
BIOMARKERS ....................................................................................................54 
10.5.2 
PHARMACOGENOMIC ASSESSMENTS .................................................................55 
11 
SAFETY REPORTING.................................................................................55 
11.1 
DEFINITIONS .....................................................................................................55 
11.1.1 
ADVERSE EVENTS .............................................................................................55 
11.1.1.1 
OCCURRENCE OF COVID-19 ............................................................................56 
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11.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................56 
11.2 
MONITORING OF INFECTION ..............................................................................56 
11.3 
EVALUATION AND CLASSIFICATIONS ................................................................57 
11.3.1 
SEVERITY ..........................................................................................................57 
11.3.2 
CAUSALITY .......................................................................................................57 
11.4 
RECORDING, REPORTING, AND MONITORING ....................................................58 
11.4.1 
RECORDING AND REPORTING ............................................................................58 
11.4.1.1 
ADVERSE EVENTS .............................................................................................58 
11.4.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................59 
11.4.1.3 
DEATH ..............................................................................................................59 
11.4.1.4 
ABNORMAL LABORATORY VALUES ..................................................................59 
11.4.2 
SAFETY MONITORING .......................................................................................59 
11.4.2.1 
SAFETY MONITORING COMMITTEE ...................................................................60 
11.4.2.2 
POST-STUDY EVENTS ........................................................................................60 
11.4.2.3 
EMERGENCY UNBLINDING ................................................................................60 
11.5 
SPECIAL CIRCUMSTANCES ................................................................................61 
11.5.1 
PREGNANCY ......................................................................................................61 
11.5.2 
OTHER ..............................................................................................................61 
12 
STATISTICAL AND ANALYTICAL PLANS ...........................................61 
12.1 
ANALYSIS POPULATIONS ..................................................................................61 
12.1.1 
INTENTION-TO TREAT (ITT) POPULATION ........................................................61 
12.1.2 
PER PROTOCOL POPULATION ............................................................................61 
12.1.3 
SAFETY POPULATION ........................................................................................61 
12.2 
ANALYSIS METHODS ........................................................................................62 
12.2.1 
GENERAL METHODS .........................................................................................62 
12.2.2 
SUBJECT DISPOSITION .......................................................................................62 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..............................62 
12.2.4 
SAFETY ANALYSIS ............................................................................................62 
12.2.4.1 
ADVERSE EVENTS .............................................................................................62 
12.2.4.2 
CLINICAL LABORATORY EVALUATION .............................................................63 
12.2.4.3 
ELECTROCARDIOGRAMS ...................................................................................63 
12.2.4.4 
VITAL SIGNS .....................................................................................................63 
12.2.4.5 
PHYSICAL EXAMINATION ..................................................................................63 
12.2.5 
EFFICACY ANALYSIS .........................................................................................63 
12.2.5.1 
PRIMARY EFFICACY ANALYSES ........................................................................63 
12.2.5.2 
SECONDARY EFFICACY ANALYSES ...................................................................64 
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS .............................................................64 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES...............................64 
12.2.7 
INTERIM ANALYSIS ...........................................................................................65 
12.3 
SAMPLE SIZE DETERMINATION .........................................................................65 
13 
ETHICAL CONSIDERATIONS ..................................................................65 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE COMMUNICATIONS .......................................................................65 
13.1.1 
PROGRESS REPORTS ..........................................................................................65 
13.1.2 
FINAL INVESTIGATOR REPORT ..........................................................................66 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS ........................................................66 
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13.3 
PROTOCOL COMPLIANCE ..................................................................................66 
13.4 
PROTECTION OF CONFIDENTIALITY ...................................................................67 
13.5 
DISCLOSURE OF STUDY RESULTS ......................................................................67 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .........67 
14.1 
QUALITY ASSURANCE .......................................................................................67 
14.1.1 
MONITORING ....................................................................................................68 
14.1.2 
AUDIT ...............................................................................................................68 
14.2 
CLINICAL RESEARCH ORGANIZATIONS .............................................................68 
14.3 
DATA MANAGEMENT ........................................................................................68 
14.3.1 
CASE REPORT FORMS .......................................................................................68 
14.3.2 
SOURCE DOCUMENTS .......................................................................................69 
14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY .............................69 
14.5 
CLINICAL STUDY REPORT .................................................................................69 
14.6 
PUBLICATION POLICY .......................................................................................69 
15 
REFERENCES ...............................................................................................70 
 
LIST OF TABLES 
Table 1: MAIN PORTION Time and Events Table ................................... 18 
Table 2: EXTENSION PORTION Time and Events Table ....................... 20 
Table 3: Clinical Efficacy Outcomes in Study RA101495-02.201 at Week 
12 (ANCOVA) .............................................................. 31 
Table 4: Zilucoplan Dose Presentations by Weight Brackets ..................... 46 
Table 5: Chemistry, Hematology, and Coagulation Analytes .................... 50 
 
LIST OF FIGURES 
Figure 1: Mechanism of Action of Zilucoplan in the Complement System 29 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
 
3TUG Triple Timed Up and Go Test 
 
ADA anti-drug antibody 
 
AChR acetylcholine receptor 
 
ACR American College of Rheumatology 
 
AE adverse event 
 
ALP alkaline phosphatase 
 
ALT alanine aminotransferase 
 ANCOVA analysis of covariance 
 
AP alternative pathway of the complement 
cascade 
 
aPTT activated partial thromboplastin time 
 
AST aspartate aminotransferase 
 
BUN blood urea nitrogen 
 
C5 complement component 5 
 
C6 complement component 6 
 
CFB change from baseline 
 
CK creatine kinase 
 
CI confidence interval 
 COVID-19 coronavirus disease 2019 
 
CP classical pathway of the complement 
cascade 
 
CRO Clinical Research Organization 
 
CRP C-reactive protein 
 
CSR clinical study report 
 
CTCAE Common Terminology Criteria for 
Adverse Events 
 
DAP data analysis plan 
 
DNA deoxyribonucleic acid 
 
ECG electrocardiogram 
 
eCRF electronic case report form 
 
ELISA enzyme-linked immunosorbent assay 
 
EMA European Medicines Agency 
 
EMG electromyography 
 
ENMC European Neuromuscular Center 
 
EULAR European League Against Rheumatism 
 
FACIT-F Functional Assessment of Chronic 
Illness Therapy-Fatigue Scale 
 
FDA United States Food and Drug 
Administration 
 
GCP Good Clinical Practice  
 
GGT gamma-glutamyl transferase 
 
gMG generalized myasthenia gravis 
 
HAQ Health Assessment Questionnaire 
 
HCG human chorionic gonadotropin 
 
HMGCR 3-hydroxy-3-methyl-glutaryl-coenzyme 
A reductase 
 
HR heart rate 
 
IB Investigator’s Brochure 
 
ICF informed consent form 
 
IEC Independent Ethics Committee 
 
IMP investigational medicinal product 
 
IMNM immune-mediated necrotizing 
myopathy 
 
INR international normalized ratio 
 
IRB Institutional Review Board 
 
ITT Intention-to-Treat Population 
 
IV intravenous 
 
IVIG intravenous immunoglobulin 
 
IXRS interactive voice/web response system 
 
LDH lactate dehydrogenase 
 
LOCF last observation carried forward 
 
LS least squares 
 
LSLV last subject last visit 
 
MAC membrane attack complex (C5b-9) 
 
MBL Mannose-binding Lectin pathway of 
the complement cascade 
 
MCH mean corpuscular hemoglobin 
 
MCHC mean corpuscular hemoglobin 
concentration 
 
MCV mean corpuscular volume 
 
MD multiple dose 
 
MDAAT myositis disease activity assessment 
tool 
 
MedDRA Medical Dictionary for Regulatory 
Activities 
 MG-ADL MG-Activities of Daily Living Scale 
 
MGC MG Composite Scale 
MG-QOL15r MG-Quality of Life 15 (revised) 
 
MITAX myositis intention to treat activity index 
 
MMRM mixed model with repeated measures 
 
MMT manual muscle testing 
 
MRI magnetic resonance imaging 
 MYOACT myositis disease activity assessment 
visual analogue scales  
 
PD pharmacodynamic(s) 
 
PK pharmacokinetic(s) 
 
PNH paroxysmal nocturnal hemoglobinuria 
 
PT prothrombin time 
 
PTT partial thromboplastin time 
 
QMG Quantitative Myasthenia Gravis Scale 
 
RBC red blood cell 
 
SAD single ascending dose 
 
SAE serious adverse event 
 
SAP statistical analysis plan 
 
SAS Statistical Analysis System 
 
SC subcutaneous 
 
SD standard deviation 
 
se standard error 
 
SMC Safety Monitoring Committee 
 
SOC standard of care 
 
SOP standard operating procedure 
 
sRBC sheep red blood cell 
 
SRP signal recognition particle 
 
TEAE treatment-emergent adverse event 
 
TMF trial master file 
 
ULN upper limit of normal 
 
VAS visual analogue scale 
 
WBC white blood cell 
 
 
 
 
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5 
INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing zilucoplan (RA101495), a SC self-administered 
15-amino acid cyclic peptide that binds to, and inhibits, the cleavage of complement 
component 5 (C5).  
Please refer to the IB for additional information on the chemistry, toxicology, 
pharmacology, and safety of zilucoplan.  
5.1 
OVERVIEW OF IMMUNE-MEDIATED NECROTIZING MYOPATHY 
Immune-mediated necrotizing myopathy (IMNM) is a rare, severe, inflammatory 
myopathy characterized by proximal limb weakness; markedly elevated serum creatine 
kinase (CK) levels; the presence of anti-SRP or anti-HMGCR auto-antibodies in serum; 
and paucicellular necrosis with prominent terminal complement deposition on muscle 
biopsy. IMNM is a relatively newly defined inflammatory myopathy, a group of diseases 
that also includes polymyositis, dermatomyositis, inclusion body myositis, and other, less 
well-defined myopathies. Previously, all patients who presented with proximal limb 
weakness and elevated CK, in the absence of skin involvement were classified as having 
polymyositis. However, many patients with the diagnostic label of ‘polymyositis’ were 
subsequently found to have distinctive findings on muscle biopsy as described above 
(Amato and Griggs 2003), leading to their separate classification as ‘necrotizing 
myopathy’. Subsequently, autoantibodies against HMGCR, a key enzyme in cholesterol 
biosynthesis, and SRP, a ubiquitous ribonucleoprotein involved in delivery of newly 
synthesized proteins to the endoplasmic reticulum, were found to be associated with this 
new entity which led to its designation as IMNM (see Pinal Fernandez 2018 for review).    
The prevalence of IMNM is estimated at approximately 16,000 patients in the US, 
Europe and Japan (Pinal-Fernandez 2018, Smoyer-Tomic 2012, Anquetil 2019). The 
disease is more common in women than in men. It does not show any clear racial 
predominance amongst Caucasians, Black or Asian populations, except for the 
association of anti-HMGCR positive IMNM with statin use, which is higher in non-Asian 
populations. The mean age at presentation is approximately 40 to 55 years old (Pinal-
Fernandez 2018). 
Clinically, IMNM presents with prominent proximal limb weakness due to the myopathy 
and can progress rapidly to disabling muscle atrophy. Although the clinicopathological 
presentation is generally similar among patients with anti-SRP and anti-HMGCR 
antibodies, there are subtle differences that have emerged since reliable and validated 
assays for these pathogenic autoantibodies have become more widely available. Patients 
with anti-SRP antibodies usually experience more severe weakness; more frequent neck 
weakness, dysphagia and respiratory insufﬁciency; and more prominent muscle atrophy. 
Moreover, clinically manifest cardiac involvement occurs in approximately 15% of 
patients with anti-SRP autoantibodies. In contrast, extra-muscular manifestations are rare 
in patients with anti-HMGCR autoantibodies (Pinal-Fernandez 2018).  
Muscle biopsy, muscle MRI and EMG are often used for narrowing of the differential 
diagnosis and further characterization of patients with IMNM. However, based on criteria 
set forth by the 224th European Neuromuscular Center (ENMC) International Workshop 
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which included experts from Europe, the US, and Japan, these additional investigations 
are not required to confirm the diagnosis of IMNM in patients with the characteristic 
clinical picture of high CK levels and positive anti-SRP or anti-HMGCR autoantibodies 
(Y. e. Allenbach 2018). If a muscle biopsy is performed, findings typically include 
myofiber necrosis and, in contrast to other inflammatory myopathies, only small numbers 
of infiltrating inflammatory cells. Moreover, with specific staining, prominent 
complement activation and diffuse deposition of the C5b-9 membrane attack complex 
(MAC) are observed, the pattern of which is distinct from other inflammatory myopathies 
(Cong 2014). MRI may demonstrate fatty replacement of muscle tissue which begins 
early after onset of IMNM (Pinal-Fernandez 2018), and EMG may confirm the presence 
of a myopathic pattern, and rules out other causes of muscle weakness. 
IMNM patients invariably exhibit the greatest elevation of serum CK levels seen among 
all forms of myositis, and serum CK levels correlate well with disease activity. Unlike in 
myopathies with less prominent tissue destruction, plasma CK levels in IMNM directly 
reflect the degree of myocyte necrosis due to ongoing release of this enzyme from injured 
skeletal muscle cells. Therefore, CK can be used for routine clinical follow-up and to 
evaluate treatment response in patients with IMNM, in addition to clinical measures such 
as standardized muscle strength testing. Specifically, CK levels may increase prior to 
manifestation or deterioration of clinical weakness, and a decline in CK levels is often the 
first sign of treatment response after treatment initiation while muscle regeneration and 
recovery of muscle strength may follow weeks to months later (Pinal-Fernandez 2018). 
Given the rapidly progressing symptoms and muscle pathology in IMNM, timely 
diagnosis and initiation of treatment are critical to help reduce long-term disability and 
improve prognosis.  While most immune mediated myopathies, to varying degrees, are 
responsive to non-specific immunosuppressive therapy, there are currently no FDA 
approved treatments for IMNM, and no randomized trials have been performed. The 
ENMC treatment recommendations identify corticosteroids as first line therapy in 
combination with, or rapidly followed by, an immunosuppressive agent such as 
methotrexate depending on disease severity. Intravenous immunoglobulin (IvIg) and 
rituximab are also increasingly used as first line therapy (Allenbach and Benveniste 
2018).  
Despite the treatments outlined above, disabling relapses and progressive muscle damage 
often continue, with particularly poor prognosis and permanent disability observed in 
younger patients and those with anti-SRP autoantibodies (Allenbach and Benveniste 
2018). Therefore, a high unmet medical need exists for additional treatment options for 
patients with IMNM.  
5.2 
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 membrane attack complex (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 
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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. 
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 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 J 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. 
5.3 
CLINICAL TRIAL EXPERIENCE WITH ZILUCOPLAN 
Zilucoplan is currently in advanced clinical development by Ra Pharmaceuticals, Inc. for 
the treatment of patients with generalized myasthenia gravis (gMG) and paroxysmal 
nocturnal hemoglobinuria (PNH).  
5.3.1 
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 
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conducted to evaluate the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) of single-ascending doses of zilucoplan at dose levels of 0.05, 
0.10, 0.20, and 0.40 mg/kg administered by SC injection, and multiple-doses of 0.20 
mg/kg 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 
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 into this 
study: 18 Japanese subjects and 18 Caucasian 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 Investigator’s Brochure (IB). 
5.3.2 
ZILUCOPLAN PHASE 2 EXPERIENCE 
5.3.2.1 
COMPLETED PHASE 2 STUDY IN gMG 
The safety and efficacy of zilucoplan was evaluated in gMG patients in 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 dreceiving 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 Quantitative Myasthenia Gravis (QMG) scale was the primary 
outcome measure, and the secondary outcome measures included the MG-ADL (MG-
Activities of Daily Living), the MGC (MG Composite), and the MG-QOL15r [MG-
Quality of Life 15 (revised)].  The study met its primary endpoint, showing a rapid, 
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 3. 
 
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Table 3: 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 
Abbreviations: ANCOVA = analysis of covariance; CFB = change from baseline; LOCF = last observation carried forward;  
 
LS = least squares; MG-ADL = MG-Activities of Daily Living; MG-QOL15r = MG-Quality of Life 15 (revised); 
MGC = MG Composite; QMG = quantitative myasthenia gravis; se=standard error 
Please refer to the zilucoplan IB for additional information regarding the results from 
studies RA101495-02.201. 
5.3.2.2 
COMPLETED PHASE 2 STUDIES IN PNH PATIENTS 
The global, dose-finding Phase 2 PNH program, consisted of studies RA101495-01.201 
and RA101495-01.203 as well as a long-term extension protocol RA101495-01.202.  A 
total of 32 subjects were screened in the zilucoplan Phase 2 PNH program, of which 29 
subjects were enrolled, 2 subjects did not meet eligibility criteria, and 1 subject declined 
to participate.  Studies RA101495-01.201 and RA101495-01.203 included an 8-week 
screening period and a 12-week Treatment Period. During the Treatment Period, subjects 
returned to the clinic weekly for the first 4 weeks followed by visits every 2 weeks. At 
the conclusion of the Treatment Period, subjects who completed the study and were 
demonstrating benefit had the option to enroll in the long-term extension protocol 
(RA101495-01.202). 
In treatment-naïve patients, zilucoplan achieved rapid, complete, and sustained inhibition 
of complement activity in the sheep red blood cell (sRBC) and MAC ELISA assays. 
Study RA101495-01.201 (Cohort A, n=10) met the pre-specified primary endpoint for 
LDH reduction from baseline (1174 U/L) to the mean of Week 6 to 12 (479 U/L) in 
treatment-naïve subjects, (p=0.002). The effects of zilucoplan on LDH, transfusion-
requirements, and quality of life measures in treatment-naïve patients were all similar to 
those observed with eculizumab in the pivotal TRIUMPH study (Hillmen P 2006). 
In patients switching from eculizumab to zilucoplan (Study RA101495-01.201 Cohort B 
and Study RA101495-01.203) near-complete, sustained, and uninterrupted inhibition of 
complement activity was observed in the sRBC and MAC ELISA assays during and after 
eculizumab washout. The level of complement inhibition achieved on zilucoplan 
exceeded the level of inhibition present at eculizumab trough. However, a divergent LDH 
response after switching from eculizumab to zilucoplan was observed. In switch patients 
with no evidence of pre-existing extravascular hemolysis on eculizumab (i.e., 
transfusion-independent and reticulocytes < 2 × ULN), switching was successful in all 
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cases with sustained LDH control after eculizumab washout. In switch patients with pre-
existing extravascular hemolysis on eculizumab (i.e., transfusion-dependent or 
reticulocytes > 2 × ULN), there was a high incidence of breakthrough intravascular 
hemolysis resulting in early withdrawal from the study. 
Please refer to the zilucoplan IB for additional information regarding the results from 
studies RA101495-01.201 and RA101495-01.203 as well as the long-term extension 
protocol (RA101495-01.202). 
5.4 
RATIONALE FOR THE CURRENT STUDY 
There is substantial pre-clinical and clinical evidence supporting a role for the terminal 
complement cascade in the pathogenesis of IMNM (Cong 2014) (Y. e. Allenbach 2018). 
80% of anti-SRP and 100% of anti-HMGCR autoantibodies are of the IgG1 
immunoglobulin subclass which efficiently activates the classical pathway of 
complement (Anquetil 2019). These autoantibodies bind to skeletal muscle and 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 MAC onto the sarcolemma, a characteristic 
finding in IMNM muscle biopsies (Y. e. Allenbach 2018).  
This uncontrolled and inappropriate activation of the classical complement cascade in 
muscle tissue is thought to lead to the characteristic histopathological findings and 
ultimately clinical weakness in patients with IMNM. Inhibition of the terminal 
complement pathway by zilucoplan is expected to prevent MAC deposition; to attenuate 
cell injury; reduce muscle cell derived creatine kinase in plasma; and potentially attenuate 
or even reverse clinical manifestations of IMNM. 
The compelling treatment effect observed with zilucoplan in patients with anti-AChR 
positive gMG (Section 5.3.2.1), a similar disease which shares with IMNM autoantibody-
driven hyperactivation of the classical complement pathway in skeletal muscle, supports 
the evaluation of zilucoplan as a potential therapy for IMNM in the present study. 
5.4.1 
RATIONALE FOR PRIMARY ENDPOINT 
IMNM patients invariably exhibit the greatest elevation of serum CK levels seen among 
all forms of myositis, and serum CK levels correlate well with disease activity. Unlike in 
myopathies with less prominent tissue destruction, plasma CK levels in IMNM directly 
reflect the degree of myocyte necrosis due to ongoing release of this enzyme from injured 
skeletal muscle cells. Therefore, CK can be used for routine clinical follow-up and to 
evaluate treatment response in patients with IMNM, in addition to clinical measures such 
as standardized muscle strength testing. Specifically, CK levels may increase prior to 
manifestation or deterioration of clinical weakness, and a decline in CK levels is often the 
first sign of treatment response after treatment initiation while muscle regeneration and 
recovery of muscle strength may follow weeks to months later (Pinal-Fernandez 2018). 
Given the reliable relationship between CK levels, disease activity and treatment 
response in IMNM, and the faster response and greater higher sensitivity of CK to 
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effective treatment interventions compared with clinical measures, CK was chosen as the 
primary endpoint for this phase 2 clinical trial. 
5.4.2 
RATIONALE FOR BLINDING AND PLACEBO CONTROL 
The secondary objective of this study is the evaluation of efficacy based on functional 
outcomes including 3TUG and components of the ACR/EULAR scale. 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 have stable disease and will be allowed to continue all of 
their pre-existing SOC therapies. 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 
(
) and are delivered in a small volume < 1 mL; therefore, 
placebo administration by daily SC injection over the 8-week study period is expected to 
be well-tolerated. Consequently, administration of a placebo in Study RA101495-02.202 
is not anticipated to cause undue burden or risk for study subjects. 
Following the completion of the 8-week Treatment Period in the Main Portion of the 
study, all subjects will have the option to receive zilucoplan in the Extension Portion of 
the study.  Therefore, subjects originally randomized to placebo will eventually have the 
opportunity to receive active study drug. The study will remain double-blinded until after 
the data from Week 8 of the Main Portion of the study have been reviewed, locked, and 
unblinded. 
5.4.3 
DOSE SELECTION AND PRESENTATION 
The dose of 0.3 mg/kg was selected for this study based on its superior efficacy, greater 
inhibition of the terminal complement pathway, and similar safety profile as compared 
with the 0.1 mg/kg and placebo arms in the completed Phase 2 studies in patients with 
myasthenia gravis and PNH. 
In the Phase 2 Study in gMG patients (RA101495-02.201), the magnitude and speed of 
improvement on the primary (QMG) and key secondary (MG-ADL) endpoints were 
greater with the 0.3 mg/kg dose than the 0.1 mg/kg dose, and both active doses were 
superior to placebo (see Investigator’s Brochure for additional details).  
The dose response seen in the clinical outcome measures is consistent with the known 
pharmacodynamic effect of zilucoplan that resulted, as expected, in rapid, sustained and 
complete (97%) inhibition of the terminal complement pathway in all gMG patients 
receiving the 0.3 mg/kg dose while the 0.1 mg/kg group achieved only submaximal 
(88%) inhibition of the terminal complement pathway. 
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There was no apparent difference with respect to the pattern and distribution of adverse 
events or tolerability between the zilucoplan treated and the placebo groups.  No dose 
response in the safety profile was seen between the 0.1 mg/kg and 0.3 mg/kg zilucoplan 
groups.   
Similarly, in the Phase 2 studies in patients with PNH (RA101495-01.201, RA101495-
01.202, and RA101495-01.203), the starting dose of 0.1 mg/kg daily tested did not 
consistently achieve complete inhibition of complement activity in the sRBC lysis assay. 
The 0.3 mg/kg daily dose, by contrast, consistently achieved complete inhibition in the 
sRBC lysis assay (≥95% inhibition at trough) and reduced LDH to levels similar to those 
observed in patients receiving eculizumab. It is expected that the same pharmacodynamic 
response to zilucoplan as seen in patients with MG and PNH, i.e. complete complement 
inhibition, will drive the therapeutic response in patients with IMNM.  Therefore, the 
well-understood and extensively-tested dosing regimen for PNH and MG, i.e. 0.3 mg/kg 
daily dosing with three weight brackets, has again been selected for use in this study. 
Study drug will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., subjects will be provided prefilled syringes containing fixed amounts of 
zilucoplan based on their weight, and each fixed amount will cover a range of subject 
weights). This weight-bracketed dosing strategy will result in the potential for a range of 
doses to be received at each dose level (see Section 9.1.3).  
6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
OBJECTIVES 
Objectives  
Estimands / Endpoints 
Primary 
Primary Objective: to evaluate the safety 
and efficacy of zilucoplan over placebo 
in CK levels in participants with IMNM 
Primary Efficacy Estimand: 
• Treatment: Zilucoplan administered 
by daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• Target Population: is defined through 
the inclusion/exclusion criteria in 
Section 8.1 and Section 8.2 reflecting 
the targeted IMNM population. 
• Endpoint: Percent change from 
Baseline to Week 8 in CK levels. 
• Intercurrent event (ICE) handling: 
regardless of any treatment 
discontinuation for any reason; 
censoring after prohibited medication. 
• Population level summary: The 
difference in ranks of the percentage 
change from baseline between 
treatments followed by the Wilcoxon-
Mann-Whitney odds (WMWodds) 
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and Hodges–Lehmann estimator 
followed by the corresponding 95% 
CIs. 
Primary Safety Endpoint 
• Incidence of treatment-emergent 
adverse events. 
Secondary 
Secondary Objective(s): to further 
evaluate the efficacy and the safety of 
zilucoplan over placebo in participants 
with IMNM 
Secondary Efficacy Estimands: 
• Treatment: Zilucoplan administered 
by daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• Target Population: is defined through 
the inclusion/exclusion criteria at 
Sections 8.1 and 8.2 of the study 
protocol reflecting the targeted IMNM 
population. 
• Endpoints:  
o At least minimal response based 
on the American College of 
Rheumatology/European League 
Against Rheumatism 
(ACR/EULAR) Response Criteria 
Scale at Week 8;  
o Change from Baseline to Week 8 
in 3TUG Test (in ambulatory 
patients only);  
o Change from Baseline to Week 8 
in Proximal Manual Muscle 
Testing (MMT);  
o Change from Baseline to Week 8 
in Physician Global Activity 
Visual Analogue Scale (VAS);  
o Change from Baseline to Week 8 
in Patient Global Activity VAS;  
o Change from Baseline to Week 8 
in Health Assessment 
Questionnaire (HAQ);  
o Change from Baseline to Week 8 
in myositis disease activity 
assessment tool (MDAAT) 
Extramuscular Disease Activity 
VAS Score;  
o Change from Baseline to Week 8 
in Functional Assessment of 
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Chronic Illness Therapy (FACIT)-
Fatigue Scale. 
• ICE handling: regardless of any 
treatment discontinuation for any 
reason; censoring after administration 
of prohibited medication. 
• Population level summary: 
o Odds Ratio of ACR/EULAR ≥ 20 
response proportion between 
treatment conditions;  
o Difference in continuous endpoint 
means, between treatment 
conditions. 
Other 
To further evaluate the safety of 
zilucoplan over placebo in participants 
with IMNM 
Other safety endpoints 
• Change in clinical laboratory tests 
• Change in ECG parameters  
• Change vital signs parameters, and 
• Presence of Anti-Drug Antibodies 
Exploratory 
To assess the long term efficacy of 
zilucoplan 
• At least minimal response based on the 
ACR/EULAR Response Criteria Scale 
at each visit following Week 8; 
• Change from Baseline of 3TUG Test 
(in ambulatory patients only) at each 
visit following Week 8; 
• Change from Baseline of Proximal 
MMT at each visit following Week 8; 
• Change from Baseline of Physician 
Global Activity VAS at each visit 
following Week 8; 
• Change from Baseline of Patient 
Global Activity VAS at each visit 
following Week 8; 
• Change from Baseline of HAQ at each 
visit following Week 8; 
• Change from Baseline of MDAAT 
Extramuscular Disease Activity VAS 
Score at each visit following Week 8;  
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• Change from Baseline of FACIT-
Fatigue Scale at each visit following 
Week 8; 
To assess the PK of zilucoplan 
• Plasma concentrations of zilucoplan 
and its major metabolites  
To assess the PD of zilucoplan 
 
• Sheep red blood cell lysis assay for 
evaluation of classical complement 
pathway activation 
• Complement component 5 levels 
To assess the effect of zilucoplan on 
biomarkers 
• Mechanistic biomarkers [e.g., 
complement fixation, complement 
function, complement pathway 
proteins, autoantibody characterization 
(titer and immunoglobulin class), 
myocyte markers, and inflammatory 
markers].   
To assess the effect of zilucoplan on 
pharmacogenomics 
• Pharmacogenomic analyses (optional): 
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. 
7 
STUDY DESIGN 
7.1 
OVERVIEW OF STUDY DESIGN  
RA101495-02.202 is a multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the safety, tolerability, and efficacy of zilucoplan in subjects with IMNM who 
are positive for anti-HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) or 
anti-SRP (signal recognition particle) autoantibodies. 
The planned enrollment is approximately 24 subjects. Subjects will be randomized in a 
1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo. 
Randomization will be stratified based on antibody status (anti-HMGCR+ versus anti-
SRP+). 
The Main Portion of the study includes a Screening Period of up to 4 weeks and an 8-
week Treatment Period. During the Treatment Period, subjects will return to the clinic at 
Week 1, Week 2, Week 4, and Week 8 to evaluate safety, tolerability, and efficacy. 
Additional assessments will include biomarker testing, pharmacokinetics, 
pharmacodynamics, and optional pharmacogenomics. Safety assessments will include 
physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory tests, 
adverse event (AE) monitoring, and immunogenicity. 
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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 8 weeks. Single use pre-filled syringes in 
injection devices will be provided for use during the study. 
All SOC therapy medications for IMNM should be kept at the same doses throughout the 
study, including corticosteroids, immunosuppressive drugs, and IVIG. 
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., ciprofloxacin, erythromycin, penicillin V) until 
at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC. (see Section 11.2). 
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, an SMC will 
convene and evaluate study data as appropriate.  
At the conclusion of the Treatment Period of the study, all subjects will have the option 
to receive zilucoplan in the Extension Portion of the study provided they meet the 
Extension Portion selection criteria. Visits during the first 8 weeks of the Extension 
Portion will be identical to the Main Portion of the study for all subjects to ensure 
appropriate monitoring of subjects transitioning from placebo to active treatment. The 
study will remain double-blinded until after the data from Week 8 of the Main Portion of 
the study have been reviewed, locked, and unblinded. 
If a subject permanently discontinues study drug treatment prior to the Week 8 visit for 
any reason, he/she will not be eligible for the Extension Portion. For subjects who 
permanently discontinue treatment with study drug, a Safety Follow-up Visit will be 
performed at 40 days after the last dose to collect information on any ongoing AEs or 
new SAEs since the last study visit. 
7.2 
STUDY PERIODS 
During the Main Portion of the study, the total duration of study participation for all 
subjects will be up to approximately 12 weeks, including a Screening Period of up to 
4 weeks and an 8-week Treatment Period. 
During the Extension Portion of the study, the investigational medicinal product (IMP) 
will continue to be provided by the sponsor until zilucoplan is approved and available in 
the territory (e.g., in another qualifying extension study) or until the sponsor terminates 
development of zilucoplan for IMNM. In countries where zilucoplan is not approved or 
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marketed, but in which sponsored clinical studies have been conducted, subjects may 
continue to receive zilucoplan through a compassionate use pathway. 
For France only: The duration of study participation during the Extension Portion of this 
study (RA101495-02.202) will include an open-label, single-arm, 18-month Treatment 
Period .  
7.2.1 
SCREENING PERIOD  
The Screening visit(s) will occur no more than 28 days (4 weeks) 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 56 days 
(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(s), subjects will be assigned a unique subject number. The 
following assessments will be performed during Screening: 
• Informed consent 
• Review of eligibility criteria 
• Review of medical history and demographics, including collection of a detailed 
history of IMNM diagnosis information, as well as local serology for anti-HMGCR or 
anti-SRP autoantibodies. 
• Review and documentation of prior and concomitant medications 
Note: A complete history of medications taken for the treatment of IMNM will be 
collected. All medications taken during 30 days prior to Screening will be recorded. 
• Completion of the following efficacy assessments: 
o 3TUG (in ambulatory subjects only) 
o Proximal MMT 
o Physician Global VAS 
o Patient Global VAS 
o HAQ 
o MDAAT 
o FACIT-Fatigue 
• Measurement of height and weight 
• Full physical examination  
• Vital signs [heart rate (HR), body temperature, blood pressure in the sitting position] 
• 12-lead ECG  
• Neisseria meningitidis vaccination and, if applicable, prophylactic antibiotics (see 
Section 11.2) 
• Collection of blood samples for laboratory testing:  hematology, chemistry, CK, 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 
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• Collection of blood samples for central testing of disease specific antibody testing 
(anti-HMGCR or anti-SRP autoantibodies) 
• 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. 
• Enrollment and randomization 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) 
Subjects will receive treatment with 0.3 mg/kg zilucoplan or placebo, according to 
randomization, from Day 1 to Day 57 during the Treatment Period of the Main Portion of 
the study. Subjects who complete the Week 8 (Day 57) visit (including those randomized 
to the placebo arm) will have the option to continue treatment with zilucoplan in the 
Extension Portion of the study. If a subject chooses not to participate in the Extension 
Portion, the subject will receive SOC treatment off-study, as recommended by the 
treating physician. 
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. Should a subject lose/misplace their safety instruction card they will be provided 
a new card. 
Please refer to the Time and Events Tables (Table 1 and Table 2) for details regarding 
assessments that must be completed at visits during the Treatment Period for both the 
Main and Extension Portions of the study.  
7.2.2.1 
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 antibody status (anti-HMGCR+ versus anti-SRP+). 
This is a double-blind study. Subjects and study staff will remain blinded to treatment 
assignments until after the data from Week 8 of the Main Portion of the study have been 
reviewed, locked, and unblinded. 
Instructions for emergency unblinding, if warranted, for safety reasons are provided in 
Section 11.4.2.3. 
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7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
During the Main Portion, if a subject permanently discontinues study drug at any time 
prior to completion of Day 57 (see Section 8.4.2), the subject should return to clinic for 
an End of Main Visit. During the Extension Portion, if a subject permanently 
discontinues study drug at any time (see Section 8.4.2), the subject should return to clinic 
for a Final Extension Visit. If a subject discontinues study drug at any time, a 40 day 
follow up visit is required. 
The following procedures will be completed at the End of Main and Final Extension 
Visits:   
• Completion of the following efficacy assessments: 
o 3TUG (in ambulatory subjects only) 
o Proximal MMT 
o Physician Global VAS 
o Patient Global VAS 
o HAQ 
o MDAAT 
o FACIT-Fatigue 
• Measurement of weight 
• Review and documentation of concomitant medications 
• 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 
• Collection of blood samples for the following assessments: 
o ADA sampling  
o PK analysis 
o PD analyses 
o Autoantibody testing 
o Biomarker analysis 
• Return of all used and unused study drug syringes to site  
All subjects who discontinue study treatment will have a Safety Follow-up Visit 40 days 
after the last dose of study drug, to collect the following information: 
• Review and documentation of concomitant medications 
• Physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• Urine pregnancy testing for females of childbearing potential only 
• Record information on ongoing AEs or new SAEs since the last study visit.  
7.3 
EARLY STUDY TERMINATION  
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 
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in the appropriate case report forms (see Section 14.3) and the study results will be 
summarized in the clinical study report (CSR) (see Section 14.5). 
The Sponsor may terminate this study early (in its entirety, in part, or at one 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. If the Sponsor terminates the study for safety reasons, the Sponsor will 
immediately notify the investigator and subsequently provide written instructions for 
study termination. 
If the Sponsor terminates or suspends the study, all applicable Competent Regulatory 
Authorities will be informed as per applicable legislation. 
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 and/or 
acceptable per local guidelines. Study sites should make efforts to inform the sponsor or 
the CRO in the event that protocol 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 will the 
subject 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 (e.g., any measures that may limit 
access to the site or may require additional actions by the subject prior to entry to the 
site). 
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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 
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. Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy). 
4. Positive serology for anti-HMGCR or anti-SRP autoantibodies. 
5. Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at 
least one proximal limb muscle group. 
6. CK (creatine kinase) of >1000 U/L at Screening. 
7. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated 
to occur during the first 8-weeks on study. 
8. No changes in immunosuppressive therapy, including dose, for at least 30 days prior 
to Baseline or anticipated to occur during the first 8-weeks on study. 
9. 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. 
10. 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. 
Postmenopausal women are, for the purposes of this protocol, defined as women who 
have gone 12 consecutive months without menstruation. 
8.2 
EXCLUSION CRITERIA 
Subjects who meet ANY of the following exclusion criteria must be excluded from the 
study:   
1. History of meningococcal disease. 
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2. Current or recent systemic infection within 2 weeks prior to Screening or infection 
requiring intravenous (IV) antibiotics within 4 weeks prior to Screening. 
3. Pregnant, planning to become pregnant, or nursing female subjects. 
4. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or 
expected to have surgery requiring general anesthesia during the 8-week Treatment 
Period. 
5. Treatment with a complement inhibitor or an experimental drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to Baseline. 
6. Statin use within 30 days prior to Baseline or anticipated to occur during study. 
7. Rituximab use within 90 days prior to Baseline or anticipated to occur during study. 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months 
prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) should be given upon initiation of study drug until 6 months after the 
last rituximab dose 
8. Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered 
less than 90 days prior to Baseline). 
9. Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-
week Treatment Period. 
10. 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). 
11. History of any significant medical, psychiatric disorder, or laboratory abnormality 
that in the opinion of the investigator would make the subject unsuitable for 
participation in the study. 
12. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is 
permitted).  
13. Unable or unwilling to comply with the requirements of the study. 
14. Subjects who have a known hypersensitivity to zilucoplan or any of its excipients. 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION 
1. Completion of the Main Portion of the study. 
2. Continues to meet inclusion criteria 2, 11, and 12 from the Main Portion of the study. 
2. Able to provide informed consent, including signing and dating the ICF. 
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. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation. 
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3. Did not start any disallowed medication per the exclusion criteria from the Main 
Portion of the study or alter the dose of any other concomitant medication, unless 
medically indicated. 
4. Is able and willing to comply with the requirements of the study. 
5. Does not have any new medical condition (since entry into the Main Portion) or any 
other reason that, in the opinion of the investigator or Sponsor, would disqualify the 
subject from participation in the Extension Portion of the study. 
8.4 
REMOVAL OF SUBJECTS IN THE STUDY 
8.4.1 
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). 
8.4.2 
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 
Subjects may be withdrawn from study treatment due to unacceptable or intolerable AEs. 
All subjects who permanently discontinue study treatment in the Main Portion of the 
study (i.e., prior to Day 57 visit) for any reason will not be eligible to participate in the 
Extension Portion of the study. 
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8.4.3 
REPLACEMENT OF SUBJECTS 
In order 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 PRODUCT 
9.1 
STUDY TREATMENT ADMINISTRATION 
9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING PLACEBO 
The IMP, zilucoplan, and the placebo will be supplied as a sterile, preservative-free, 
aqueous solution prefilled into 1 mL glass syringes with a 29-gauge, ½-inch, staked 
needle placed within a self-administration device. Subjects will be instructed to self-
administer SC doses daily. Three dosage strengths of zilucoplan will be supplied as 
shown in Table 4. 
9.1.2 
DOSING SCHEDULE 
During the Main Portion of the study, 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 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 efficacy assessments (i.e., Physician 
Global Activity VAS, Patient Global Activity VAS, Proximal MMT, HAQ, 3TUG, 
MDAAT, and FACIT-Fatigue) and PK/PD sample collection have been completed.  
Patients should be supervised while injecting to ensure adequate injection technique and 
re-instructed if and as needed. 
9.1.3 
DOSE PRESENTATION  
Investigational drug product will be provided in prefilled syringes for self-injection using 
weight bracketed dosing (i.e., subjects will be provided prefilled syringes based on their 
weight containing fixed amounts of zilucoplan, and each fixed amount will cover a range 
of subject weights). As shown in Table 4, this weight bracketed dosing strategy will 
result in the potential for a range of doses to be received, from a minimum of 0.22 mg/kg 
daily (nominal dose) to a maximum dose of 0.42 mg/kg daily. 
Matching placebo for the 0.3 mg/kg dose will be provided in 1 presentation of 0.574 mL. 
Table 4: Zilucoplan Dose Presentations by Weight Brackets 
Minimum (Nominal)  
Target Dose (mg/kg) 
Actual Dose (mg) 
Weight Range (kg) 
Dose Range (mg/kg) 
0.3 
16.6 
≥43 to <56 
0.30 to 0.39 
0.3 
23.0 
≥56 to <77 
0.30 to 0.41 
0.3 
32.4 
≥77 to 150 
0.22 to 0.42 
Subjects who present with a body weight outside of these ranges will be accommodated 
on a case-by-case basis, in consultation with the medical monitor. 
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9.1.3.1 
MISSED DOSES  
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 consecutive doses, he/she must notify the 
investigator immediately and the medical monitor should be consulted. 
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. 
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) should be retained by the subject.  
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All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the last study visit for each Treatment Period (i.e., Day 57/End of 
Main Visit or the Final Extension 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 and Table 2 for the timing of study assessments. 
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: year 
of birth, gender, ethnicity, and race.  
The screening assessment will also include disease history with documentation of the 
diagnosis of IMNM, disease course and any IMNM-specific treatments.  Muscle biopsy 
findings (including presence or absence of C5b-9 staining) and other diagnostic tests 
(e.g., MRI, serology, and electromyography) will also be recorded.  
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 and Table 2. 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Subjects are prohibited from receiving another complement inhibitor, rituximab, statins, 
or any investigational medicinal product while on study.  All other medications are 
permitted while on study. 
Subjects are expected to remain on stable doses of permitted SOC therapy for IMNM 
throughout the Main Portion of the study and through the Week 8 visit of the Extension 
Portion, including corticosteroids, immunosuppressive drugs, and IVIG. The medical 
monitor should be contacted prior to any changes throughout the duration of the study in 
IMNM specific therapy. 
All prescriptions and over-the-counter medications taken during the 30 days prior to 
Baseline (i.e., Day 1) through the last study visit will be documented. NOTE: A complete 
history of medications taken for the treatment of IMNM 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 
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necessary.  All concomitant medications necessary for the health and well-being of a 
subject will be permitted. 
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 concomitant medications eCRF.   
10.2 
SAFETY ASSESSMENTS 
10.2.1 
PHYSICAL EXAMINATION  
A physical examination will be performed on all subjects at the visits listed in the Time 
and Events tables (Table 1 and Table 2) and will include the following assessments: 
• Abdomen 
• Cardiac 
• Eyes, Ears, Nose & Throat 
• General appearance 
• Head & Neck 
• Musculoskeletal 
• Neurological 
• Respiratory 
• Skin/Mucosal 
Any clinically significant abnormalities after Day 1 found will be recorded as AEs in the 
eCRF.  
Physical examinations should also include an examination of the injection site(s). If an 
injections site reaction is observed, it should be recorded as an adverse event 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.  
10.2.3 
ELECTROCARDIOGRAM  
12-lead ECGs will be assessed as normal or abnormal by the investigator; 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. 
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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 5 and should be performed as specified in the Time and Events 
Tables (Table 1 and Table 2).  
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 5: Chemistry, Hematology, and Coagulation Analytes 
Chemistry 
Hematology 
Alanine aminotransferase (ALT)* 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST)* 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH)* 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) 
White blood cell (WBC) count and differential: 
Basophils (% and absolute) 
Eosinophils (% and absolute) 
Lymphocytes (% and absolute) 
Monocytes (% and absolute) 
Neutrophils (% and absolute) 
Coagulation (if applicable) 
International normalized ratio (INR)/prothrombin time (PT) 
Partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) 
Other 
Aldolase* 
C-reactive protein (CRP) 
Creatine Kinase (CK)* 
* The results from these labs will be blinded to site personnel in order to avoid inadvertent 
biasing of functional assessments. 
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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 (HCG) will be performed on 
female subjects of childbearing potential at Screening.  
A urine dipstick pregnancy test (HCG) will be performed on female subjects of 
childbearing potential at all other study visits as specified in the Time and Events Tables 
(Table 1 and Table 2). 
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, including the 40-
day safety follow-up visit. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation. 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. 
• 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. 
NOTE:  Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are 
not acceptable methods of contraception. 
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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 assessment will be collected as specified in the Time and Events 
Tables (Table 1 and Table 2) in all enrolled subjects. These samples will be banked and 
used to investigate and characterize any ADA response over time in the general study 
population.  
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.3 
EFFICACY ASSESSMENTS  
10.3.1 
PRIMARY EFFICACY ASSESSMENT 
The primary efficacy endpoint is percent change from Baseline to Week 8 in CK levels.    
CK levels will be measured by a central laboratory in accordance with the Time and 
Events Tables (Table 1 and Table 2). 
10.3.2 
SECONDARY EFFICACY ASSESSMENTS 
10.3.2.1 
TRIPLE TIMED UP AND GO TEST 
The 3TUG is a non-invasive and reproducible measure, which measures clinically 
important muscle weakness that impairs subject’s ability to walk, climb stairs, and stand 
up from a chair.  The test will only be performed in subjects who are ambulatory. 
The 3TUG test involves the subject getting up from a seated position in a chair, walking 
at their normal pace for 3 meters, turning around, walking back to the chair, and sitting 
down. This sequence is repeated 3 times without rest, and the 3TUG time is the average 
of the 3 lap times (Sanders, et al. 2018). 
3TUG evaluators must be adequately trained prior to conducting any 3TUG test. The 
3TUG test will be performed at Screening and at each study visit according to the Time 
and Events Tables (Table 1 and Table 2). The 3TUG test 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. 
Detailed instructions regarding the administration of the 3TUG test will be provided to 
sites. 
10.3.2.2 
PROXIMAL MANUAL MUSCLE TESTING  
The proximal MMT assesses muscle strength using manual muscle testing in 7 muscle 
groups. A zero to 10-point scale based on standard MMT grades will be used (Kendall 
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and al. 1993) of 7 proximal, distal, and axial muscles performs similarly to a total of 24 
muscle groups (Rider, Koziol, et al. 2010). 
Proximal MMT evaluators must be adequately trained prior to conducting any MMT 
grading. MMT grading will be performed at Screening and at each study visit according 
to the Time and Events Tables (Table 1 and Table 2). MMT grading 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. 
Detailed instructions regarding the administration of the proximal MMT will be provided 
to sites. 
10.3.2.3 
PHYSICIAN GLOBAL ACTIVITY VISUAL ANALOGUE SCALE 
The Physician Global Activity VAS score measures the global evaluation by the treating 
physician of the overall disease activity of the patient at the time of assessment using a 10 
cm visual analogue scale and a 5-point Likert scale (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the Physician Global Activity VAS 
will be provided to sites. 
10.3.2.4 
PATIENT GLOBAL ACTIVITY VISUAL ANALOGUE SCALE 
The Patient Global Activity VAS score measures the global evaluation by the patient of 
the patient's overall disease activity at the time of assessment using a 10 cm visual 
analogue scale (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the Patient Global Activity VAS 
will be provided to sites. 
10.3.2.5 
HEALTH ASSESSMENT QUESTIONNAIRE 
The HAQ Score is a patient related outcome measure that assesses physical function. 
There are 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and 
activities. There are 2 or 3 questions for each section. Scoring within each section is from 
0 (without any difficulty) to 3 (unable to do) (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the HAQ will be provided to sites. 
10.3.2.6 
MYOSITIS DISEASE ACTIVITY ASSESSMENT TOOL 
The MDAAT measures the degree of disease activity of extra-muscular organ systems 
and muscle. This is a combined tool that includes the myositis disease activity assessment 
visual analogue scales (MYOACT), which is a series of physician's assessments of 
disease activity of various organ systems modified from the Vasculitis Activity Index 
(Whiting-O'Keefe, Stone and Hellmann 1999), and the Myositis Intention to Treat 
Activity Index (MITAX).  The MITAX is scored on a 0 - 4 scale, based on worsening or 
improvement in specific clinical features and their correlation with the intention to treat.  
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Detailed instructions regarding the administration of the MDAAT will be provided to 
sites. 
10.3.2.7 
ACR/EULAR RESPONSE CRITERIA 
The ACR/EULAR scale was created to develop a response criterion for patients with 
myopathy. The scale utilizes a conjoint analysis-based continuous model using absolute 
percent change in core set measures (physician, patient, and MDAAT; muscle strength; 
Health Assessment Questionnaire; and muscle enzyme levels). A total improvement 
score (range 0-100) is determined by summing scores for each core set measure and 
comparing improvement in each respective core set measure. Thresholds for minimal, 
moderate, and major improvement are ≥20, ≥40, and ≥60 points in the total improvement 
score (Aggarwal, et al. 2017). The total improvement score will be calculated based on 
the core set measures as recorded in the eCRF and from central laboratory results. 
10.3.2.8 
FACIT-FATIGUE SCALE 
The FACIT-Fatigue Scale is a 13-item, easy to administer tool that measures an 
individual’s level of fatigue during their usual daily activities over the past week. The 
level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued, to 0 = 
very much fatigued) (Webster, Cella and Yost 2003). All subjects will be asked to 
complete the FACIT-Fatigue Scale in accordance with the Time and Events Tables 
(Table 1 and Table 2). 
10.4 
PHARMACOKINETIC/ 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 
Blood samples for PK and PD analysis will be obtained prior to administration of study 
drug (within 1 hour of dosing) at the study visits according to Table 1 and Table 2.  
All samples will be sent to an accredited laboratory for analysis. Detailed instructions 
regarding PK/PD sample collection, processing, and shipping will be provided to sites. 
10.5 
EXPLORATORY ASSESSMENTS  
10.5.1 
BIOMARKERS 
Blood samples for biomarker testing will be obtained prior to administration of study 
drug (within 1 hour of dosing) at study visits according to Table 1 and Table 2.  
The analysis of biomarkers pertaining to the pathophysiology of IMNM [e.g., 
complement fixation, complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class), myocyte markers, and inflammatory 
markers] may provide further insight into the clinical efficacy and safety of zilucoplan in 
subjects with IMNM. Complement protein levels and complement activity will be tested 
to evaluate response to zilucoplan and to understand subject characteristics related to 
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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 investigations may be reported separately from the 
main CSR. 
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.5.2 
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 can 
be obtained at any study visit. 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., DNA sequencing, including exploration of whether specific 
genomic features correlate with response or resistance to study drug], may be performed. 
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 CSR. 
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. 
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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 
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.  
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., ciprofloxacin, erythromycin, penicillin V) until 
at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC.  In subjects who have received rituximab 
less than 6 months prior to Day 1, prophylactic antibiotics should be given until at least 6 
months after the last rituximab dose (e.g., ciprofloxacin, erythromycin, penicillin V). 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months 
prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) 
should be given upon initiation of study drug until 6 months after the last rituximab dose. 
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 
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seek immediate medical attention if any such symptoms occur, will be provided to each 
subject. Should a subject lose/misplace their safety instruction card they will be provided 
a new card. 
11.3 
EVALUATION AND CLASSIFICATIONS 
11.3.1 
SEVERITY 
The investigator should determine the severity of the reported AE by using the CTCAE 
(Version 5.0 or higher).  
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). 
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., injection site reactions) 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.  
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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. 
When recording and/or reporting AEs or SAEs, the following elements must be included: 
• The fulfilled criteria for seriousness as presented in Section 0 
• 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 (for SAE reporting 
period, see Section 11.4.1.2) and will end 40 days following the last dose of study drug 
(i.e., the End of Main Visit, Day 57 Visit, or Final Extension 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. Subjects visit the clinic 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., 
).  
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AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA; 
Version 20.0 or higher) 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. Subjects visit the clinic 40 days after their last dose to gather information 
on ongoing AEs and report any new SAEs since the last study visit. 
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.  
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 RA101495-02.202, this 
standard safety data review will be performed while blinded to treatment assignment. 
If an additional data review should become necessary to ensure subject safety, a separate 
supervisory committee (i.e., an 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. 
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. 
11.4.2.3 
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 interactive 
voice/web response system (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. 
Following emergency unblinding, the subject’s further participation in the study should 
be discussed with the medical monitor. 
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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 whether they result in an AE/SAE or not. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
ANALYSIS POPULATIONS 
Further details of additional analysis populations will be described in the SAP, which will 
be finalized prior to study unblinding.  
12.1.1 
INTENTION-TO TREAT (ITT) 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 8-week Treatment Period and have no major protocol deviations. 
12.1.3 
SAFETY POPULATION 
The Safety Population will include all subjects who have received at least 1 dose of study 
drug, with subjects to be analyzed based on the actual treatment received. 
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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, number of 
observations above the limit of quantification (if applicable), mean, standard deviation 
(SD) median, and range. Categorical variables will be summarized using frequency 
counts and percentages. 
Once all patients have completed Week 8 of the Main Portion of the study, the study 
database will be locked, unblinded, and efficacy analyses for the Main Portion will be 
performed.  
12.2.2 
SUBJECT DISPOSITION 
A disposition of all consented subjects will be provided and will include a breakdown of 
subjects who were randomized, were treated, and discontinued treatment (including 
reasons for discontinuation) at the Main Portion. A disposition of all consented subjects 
entered the Extension Portion will be also provided. Additionally, a summary of subjects 
included in the analysis populations defined in Section 12.1 will be provided. 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS 
Demographic and baseline disease characteristics will be summarized by treatment group 
and overall. 
12.2.4 
SAFETY ANALYSIS 
Safety analyses will be performed on the Safety Population. 
12.2.4.1 
ADVERSE EVENTS 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 20.0 or higher). Incidence rates for treatment-emergent AEs 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. 
Incidence rates for TEAEs and SAEs will be summarized overall, by maximum severity, 
and by relationship to study drug. A TEAE is defined as: 
• An AE that occurs after study treatment start that was not present at the time of 
treatment start. 
• An AE that increases in severity after treatment start if the event was present at the 
time of treatment start. 
The SAEs occurring before the first dose of study drug will be listed. 
12.2.4.1.1 
INFECTION 
AEs related to infection with Neisseria meningitidis will be summarized by system organ 
class and preferred term. 
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12.2.4.2 
CLINICAL LABORATORY EVALUATION 
Quantitative laboratory endpoints will be summarized by treatment group at each 
scheduled assessment time point using descriptive statistics. 
12.2.4.3 
ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters [i.e., HR, PR interval, RR interval, QRS 
interval, QT interval, QT interval] at each assessment time point will be presented by 
treatment group. 
12.2.4.4 
VITAL SIGNS 
Descriptive statistics for vital signs (i.e., HR, body temperature, and blood pressure) will 
be presented by treatment group. 
12.2.4.5 
PHYSICAL EXAMINATION 
Clinically significant physical examination abnormalities will be included and 
summarized as AEs, when appropriate. 
12.2.5 
EFFICACY ANALYSIS 
Details of analyses beyond what is specified in this protocol will be discussed in detail in 
the SAP. 
12.2.5.1 
PRIMARY EFFICACY ANALYSES 
The primary efficacy endpoint, percent reduction from baseline in creatine kinase at 
Week 8, will be compared between the two treatment groups using a 2-sided stratified 
Wilcoxon rank sum test (Van Elteren test). Magnitude of treatment effect will be shown 
by the WMWOdds and the Hodges-Lehman estimator followed by the corresponding 
95% Confidence Intervals (CIs). 
Definition of primary estimand: 
• Treatment: zilucoplan administered by daily SC injection (0.3 mg/kg) vs matching 
placebo. 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 
and 8.2 of the study protocol reflecting the targeted IMNM population. 
• Endpoint: percentage change from Baseline to Week 8 in CK levels while on non-
prohibited medication. 
• Intercurrent event: regardless of any treatment discontinuation for any reason; 
censoring after prohibited medication 
• Population level summary: difference in ranks of the percentage change from baseline 
between treatments followed by the WMWodds and Hodges–Lehmann estimator 
followed by the corresponding 95% CIs.  
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12.2.5.2 
SECONDARY EFFICACY ANALYSES 
Secondary Estimands are defined below: 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 
mg/kg) vs matching placebo. 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 
8.1 and 8.2 of the current document, reflecting the targeted IMNM population. 
• Endpoints:  
o At least minimal response based on the ACR/EULAR minimal Response 
Criteria at Week 8 
o Change from Baseline to Week 8 in 3TUG Test (in ambulatory patients 
only);  
o from Baseline to Week 8 in Proximal MMT;  
o Change from Baseline to Week 8 in Physician Global Activity VAS;  
o Change from Baseline to Week 8 in Patient Global Activity VAS;  
o Change from Baseline to Week 8 in HAQ;  
o Change from Baseline to Week 8 in MDAAT Extramuscular Disease 
Activity VAS Score; 
o Change from Baseline to Week 8 in FACIT-Fatigue Scale; 
o  ICE handling: regardless of any treatment discontinuation for any reason; 
censoring after administration of prohibited medication; 
o Population level summary: 
▪ Odds ratio of ACR/EULAR of ACR/EULAR ≥ 20 response 
proportion between treatment conditions; 
▪ Difference in the continuous endpoint means between treatment 
conditions; 
The analysis to determine the odds ratio and the corresponding 95%CI for the 
ACR/EULAR response will be performed via logistic regression. Treatment group 
differences for each of the continuous secondary efficacy change from baseline endpoints 
will be assessed using a linear mixed effects model using the change from baseline to 
Week 8 as response variable; treatment, and baseline score (i.e., the baseline score for the 
secondary efficacy endpoint being analyzed) will be fitted as fixed effects and subject as 
a random effect. 
Secondary efficacy endpoint analyses will be performed on the ITT Population. 
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
For the PK analysis, concentrations of zilucoplan and metabolites were presented in 
listings and summarized using descriptive statistics. 
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, and gender. Details of the analysis will be 
described in a separate Data Analysis Plan (DAP). This analysis may be performed by 
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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 
CSR but in a separate modeling report. 
Pharmacodynamic endpoints will be summarized using descriptive statistics by treatment 
and time point. 
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. 
12.2.7 
INTERIM ANALYSIS 
No interim analysis is planned for the Main Portion of the study.  
Interim analyses of the Extension Portion of the study, after Week 8 of the Main Portion 
of the study has been locked and unblinded, may be performed. 
12.3 
SAMPLE SIZE DETERMINATION 
A sample size of 12 subjects per group yields approximately 95% power to detect a 
difference in the percent reduction from baseline in creatine kinase between the active 
and placebo groups using a Wilcoxon rank sum test at the two-sided 0.05 type 1 error 
rate. The power calculations assume that the percent reduction in creatine kinase in the 
active dose group is approximately normally distributed with a mean of 80% and a 
standard deviation of 8%; that 4 of the placebo patients will have a percent reduction 
similar to the active dose group; and the remaining 8 placebo patients will have a percent 
reduction  that is normally distributed with a mean of 10% and a standard deviation of 
8% (Mammen and Tiniakou 2015). 
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).  
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. 
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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. 
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. 
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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 
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 and 
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. 
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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 all clinical samples.  
14.3 
DATA MANAGEMENT 
14.3.1 
CASE REPORT FORMS 
The data for this study will be collected with an eCRF.  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 
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. All eCRF data required by this protocol will 
be recorded by investigative site personnel. All data entered into the eCRF will be 
supported by source documentation. 
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. 
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16 February 2021 
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Page 69 of 72 
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. 
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. 
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 
Aggarwal, R, LG Rider, N Ruperto, N Bayat, B Erman, BM Feldman, CV Oddis, et al. 
2017. "2016 American College of Rheumatology/European League Against 
Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in 
Adult Dermatomyositis and Polymyositis." Arthritis & Rheumatology 898-910. 
Allenbach, Y et. al. 2018. "224th ENMC International Workshop:: Clinico-sero-
pathological classification of immune-mediated necrotizing myopathies 
Zandvoort, The Netherlands, 14-16 October 2016." Neuromuscul Disord 28 (1): 
87-99. 
Allenbach, Y, and O Benveniste. 2018. "Peculiar clinicopathological features of immune-
mediated necrotizing myopathies." Curr Opin Rheumatol 30 (6): 655-663. 
Amato, AA, and RC Griggs. 2003. "Unicorns, dragons, polymyositis, and other 
mythological beasts." Neurology 288-289. 
Anquetil, C et. al. 2019. "Myositis-specific autoantibodies, a cornerstone in immune-
mediated necrotizing myopathy." Autoimmun Rev 18 (3): 223-230. 
Cong, J et. al. 2014. "Complement membrane attack complex is related with immune-
mediated necrotizing myopathy." Int J Clin Exp Pathol 7 (7): 4143-4149. 
Hay, EM, PA Bacon, C Gordon, DA Isenberg, P Maddison, ML Snaith, DP Symmons, N 
Viner, and A Zoma. 1993. "The BILAG index: a reliable and valid instrument for 
measuring clinical disease activity in systemic lupus erythematosus." Q J Med 
447-458. 
Hillmen P, Young NS, Schubert J, et al. 2006. "The complement inhibitor eculizumab in 
paroxysmal nocturnal hemoglobinuria." N Engl J Med 355 (12): 1233-43. 
Kendall, FP, and et. al. 1993. Muscles, testing and function: With Posture and pain.  
Mammen, AL, and E Tiniakou. 2015. "Intravenous Immune Globulin for Statin-
Triggered Autoimmune Myopathy." N Engl J Med 1680-1682. 
Nishimura J, Yamamoto M, Hayashi S, et al. 2014. "Genetic variants in C5 and poor 
response to eculizumab." N Engl J Med 370: 632-639. 
Pinal-Fernandez, I et. al. 2018. "Immune-Mediated Necrotizing Myopathy." Current 
Rheumatology Reports 20: 21. 
Rider, LG, D Koziol, Giannini EH, MS Jain, MR Smith, K Whitney-Mahoney, BM 
Feldman, et al. 2010. "Validation of manual muscle testing and a subset of eight 
muscles for adult and juvenile idiopathic inflammatory myopathies." Arthritis 
Care Res 465-472. 
Rider, LG, VP Werth, AM Huber, H Alexanderson, AP Rao, N Ruperto, L Herbelin, R 
Barohn, D Isenberg, and FW Miller. 2011. "Measures of adult and juvenile 
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16 February 2021 
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Page 71 of 72 
dermatomyositis, polymyositis, and inclusion body myositis: Physician and 
Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health 
Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire 
(C-HAQ), ." Arthritis Care Res 118-57. 
Sanders, DB, JT Guptill, KL Ales, LD Hobson-Webb, DP Jacobus, R Mahmood, JM 
Massey, et al. 2018. "Reliability of the triple timed-up-and-go (3TUG) test." 
Muscle Nerve 136-139. 
Smoyer-Tomic, KE et. al. 2012. "Incidence and prevalence of idiopathic inflammatory 
myopathies among commercially insured, Medicare supplemental insured, and 
Medicaid enrolled populations: an administrative claims analysis." BMC 
Musculoskeletal Disorders 13. 
Webster, K, D Cella, and K Yost. 2003. "The functional assessment of chronic illness 
therapy (FACIT) measurement system: properties, applications, and 
interpretation." Health Qual Life Outcomes (1): 79-85. 
Whiting-O'Keefe, QE, JH Stone, and DB Hellmann. 1999. "Validity of a vasculitis 
activity index for systemic necrotizing vasculitis." Arthritis Rheum 2365-71. 
 
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Page 72 of 72 
SPONSOR SIGNATURE PAGE 
Protocol Number: 
RA101495-02.202 
Protocol Title:   
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, and 
Efficacy of Zilucoplan in Subjects with Immune-Mediated 
Necrotizing Myopathy 
Protocol Version:   Version 2.0/16 February 2021 
 
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Approval Signatures
Name:
imnm01-protocol-amend-v2.0
Version:
1. 0
Document Number:
CLIN-000168746
Title:
IMNM01 (RA101495-02.202) Study Protocol v2.0
Approved Date:
17 Feb 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Feb-2021 16:05:26 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Feb-2021 18:08:29 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 17-Feb-2021 12:14:44 GMT+0000
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SAP_001.pdf: 
UCB 
 
09 June 2021 
Statistical Analysis Plan Amendment 2 
Zilucoplan 
RA101495-02.202 (UCB study IMNM01) 
 
 
 
Confidential 
Page 1 of 75 
 
STATISTICAL ANALYSIS PLAN 
AMENDMENT 2.0 
Study: RA101495-02.202 (UCB study IMNM01) 
Product: Zilucoplan 
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, AND EFFICACY OF ZILUCOPLAN IN 
SUBJECTS WITH IMMUNE-MEDIATED NECROTIZING 
MYOPATHY 
 
Ra Pharmaceuticals, Inc. (now part of UCB) 
Legal Registered Address:  
Ra Pharmaceuticals, Inc. 
87 Cambridge Park Drive 
Cambridge, MA, 02140, USA  
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
EudraCT Number 
2019-001497-29 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
Zilucoplan 
RA101495-02.202 (UCB study IMNM01) 
 
 
 
Confidential 
Page 2 of 75 
TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................ 5 
LIST OF ABBREVIATIONS .................................................................................................. 11 
1 
INTRODUCTION ........................................................................................................... 15 
1.1 
Objectives and Estimands/Endpoints ........................................................................... 15 
1.2 
Study design ................................................................................................................. 18 
2 
STATISTICAL HYPOTHESES ...................................................................................... 26 
2.1 
Primary endpoint .......................................................................................................... 26 
2.2 
Secondary endpoints .................................................................................................... 26 
3 
SAMPLE SIZE DETERMINATION .............................................................................. 27 
4 
POPULATIONS FOR ANALYSIS ................................................................................. 27 
5 
STATISTICAL ANALYSES .......................................................................................... 28 
5.1 
General Considerations ................................................................................................ 28 
5.1.1 
General study level definitions ............................................................................ 30 
5.1.1.1 
Analysis visit windows .............................................................................. 30 
5.1.1.2 
Analysis Time Points ................................................................................. 30 
5.1.1.3 
Protocol Deviations ................................................................................... 31 
5.1.1.4 
Treatment assignment and treatment groups ............................................. 31 
5.1.1.5 
Center pooling strategy ............................................................................. 32 
5.1.1.6 
Coding dictionaries .................................................................................... 32 
5.1.1.7 
Multicenter studies .................................................................................... 32 
5.1.1.8 
Handling of drop outs or missing data ...................................................... 32 
5.2 
Participant Disposition ................................................................................................. 35 
5.3 
Primary Endpoint(s) Analysis ...................................................................................... 35 
5.3.1 
Definition of endpoint(s) ..................................................................................... 36 
5.3.2 
Main analytical approach ..................................................................................... 36 
5.3.3 
Sensitivity analyses .............................................................................................. 36 
5.3.4 
Supplementary analyses ....................................................................................... 37 
5.4 
Secondary Endpoint(s) Analysis .................................................................................. 38 
5.4.1 
Key/Confirmatory secondary endpoint(s) ........................................................... 38 
5.4.2 
Definition of endpoint(s) ..................................................................................... 39 
5.4.3 
Main analytical approach ..................................................................................... 39 
5.4.4 
Sensitivity analysis .............................................................................................. 40 
5.4.5 
Supplementary analyses ....................................................................................... 40 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis.................................................................. 41 
5.5.1 
Long Term Efficacy ............................................................................................. 41 
5.5.2 
Mechanistic biomarkers ....................................................................................... 42 
5.5.3 
Pharmacogenomic analyses (optional) ................................................................ 42 
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Statistical Analysis Plan Amendment 2 
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5.6 
Safety Analyses ............................................................................................................ 43 
5.6.1 
Extent of Exposure .............................................................................................. 43 
5.6.2 
Adverse Events .................................................................................................... 43 
5.6.3 
Adverse Events of Interest ................................................................................... 46 
5.6.4 
Additional Safety Assessments ............................................................................ 47 
5.6.4.1 
Clinical laboratory evaluations .................................................................. 47 
5.6.4.2 
Vital Signs ................................................................................................. 49 
5.6.4.3 
Electrocardiograms .................................................................................... 50 
5.6.4.4 
Other safety endpoint(s) ............................................................................ 50 
5.7 
Other Analyses ............................................................................................................. 53 
5.7.1 
Other endpoints and/or parameters ...................................................................... 53 
5.7.1.1 
Pharmacokinetics ....................................................................................... 53 
5.7.1.2 
Pharmacodynamics .................................................................................... 54 
5.8 
Subgroup Analyses ...................................................................................................... 54 
5.9 
Interim Analyses .......................................................................................................... 55 
5.10 
Data Monitoring Committee (DMC) or Other Review Board ..................................... 56 
6 
SUPPORTING DOCUMENTATION ............................................................................. 56 
6.1 
Appendix 1: Non-key analysis specifications .............................................................. 56 
6.1.1 
Baseline characteristics and demographics ......................................................... 56 
6.1.2 
Protocol deviations .............................................................................................. 58 
6.1.3 
Medical history .................................................................................................... 58 
6.1.4 
Prior/concomitant Medications ............................................................................ 58 
6.1.4.1 
Prior and Concomitant Medications (non – IMNM related) ..................... 58 
6.1.4.2 
Prior and concomitant Medications (IMNM related) ................................ 59 
6.1.5 
Data derivation rules ............................................................................................ 60 
6.1.5.1 
Triple timed up and go test ........................................................................ 60 
6.1.5.2 
Proximal Manual Muscle Testing ............................................................. 60 
6.1.5.3 
Physician Global Activity Visual Analogue Scale .................................... 61 
6.1.5.4 
Patient Global Activity Visual Analogue Scale ........................................ 61 
6.1.5.5 
Health Assessment Questionnaire (HAQ) ................................................. 61 
6.1.5.6 
Myositis Disease Activity Assessment Tool (MDAAT) ........................... 62 
6.1.5.7 
ACR/EULAR Response Criteria ............................................................... 64 
6.1.5.8 
FACIT-Fatigue Scale ................................................................................ 66 
6.1.6 
AEs of Special Interest ........................................................................................ 67 
6.1.7 
Markedly Abnormal (MA) Criteria for Safety Endpoints ................................... 67 
6.1.8 
Compliance .......................................................................................................... 70 
6.2 
Appendix 2: MedDRA Algorithmic Approach to Anaphylaxis .................................. 70 
6.3 
Appendix 2: Changes to Protocol-Planned Analyses .................................................. 73 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
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RA101495-02.202 (UCB study IMNM01) 
 
 
 
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Page 4 of 75 
7 
REFERENCES ................................................................................................................ 74 
 
LIST OF TABLES 
Table 1‒1: 
Objectives and Estimands/Endpoints ............................................................... 15 
Table 1‒2: 
Schedule of Assessments During the Main Portion of the Study .................... 20 
Table 1‒3: 
Schedule of Assessments During the Extension Portion of the Study............. 23 
Table 5‒1: 
Laboratory Assessments .................................................................................. 47 
Table 5‒2: 
ADA Classification .......................................................................................... 51 
Table 6‒1: 
ACR/EULAR Response Criteria ..................................................................... 65 
Table 6‒2: 
FACIT-Fatigue Scale Items ............................................................................. 66 
Table 6‒3: 
CTCAE v5.0 grades for laboratory assessments to be analyzed ..................... 67 
Table 6‒4: 
Markedly Abnormal Criteria for Liver Function Tests.................................... 69 
Table 6‒5: 
Abnormality Criteria in Vital Signs ................................................................. 69 
Table 6‒6: 
Abnormality Criteria in ECG ........................................................................... 69 
 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
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RA101495-02.202 (UCB study IMNM01) 
 
 
 
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Page 5 of 75 
 
VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study RA101495-02.202 (UCB study IMNM01) is based 
on the protocol amendment dated 16 February 2021.  
SAP Version 
Approval  
Date 
Change 
Rationale 
1.0 
11 February 
2020 
Not Applicable 
First Creation 
Amendment 1 
18 February 
2021 
Sections / Paragraphs numbers are 
renumbered / reorganized 
Update to meet UCB 
Standards / Template 
Data description and precision rules 
Update to meet UCB 
Standards / Template 
Text is added to describe analyses 
for all efficacy endpoints and list 
the estimand attributes 
To align with the protocol 
amendment 2, dated 16 
February 2021 
Abbreviation List is updated 
Ensure abbreviations are 
used in the appropriate way 
Addition of populations: 
ITT No COVID-19 
Safety Set No Covid-19 
Additional summaries based on 
COVID-19 subgroups, pre or 
during the COVID-19 pandemic  
Update analysis to include 
COVID-19 strategy 
The following populations are 
defined: 
Enrolled Set 
Intention to Treat Extension  
Pharmacodynamic Per-Protocol Set 
Pharmacokinetic Per-Protocol Set 
To capture all the analysis 
populations 
RA101495 Safety Population is 
deleted 
Information is redundant  
Disposition on all participants 
enrolled and screen failures is 
defined 
To display the disposition 
of screen failures as per 
UCB guidance 
Definition of treatment exposure is 
added 
Information was missing 
Categories of prior and concomitant 
medications are defined 
Further clarification 
Age and BMI cutoffs are 
introduced in the summary statistics 
To describe the parameters 
summarized in more details 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
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RA101495-02.202 (UCB study IMNM01) 
 
 
 
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SAP Version 
Approval  
Date 
Change 
Rationale 
Demographics and baseline 
characteristics will not be compared 
between IMPs 
To map the UCB policy 
Summaries on Related of IMNM 
and non-IMNM related medications 
are added 
To describe the parameters 
summarized in more details 
Analysis based the Van Elteren test 
is upgrade to primary analysis  
To align with protocol 
amendment 2, dated 16 
February 2021 
Wilcoxon Mann Whitney Odds 
estimation Hodges–Lehmann 
estimator are added. 
To align with the protocol 
amendment 2, dated 16 
February 2021 
Main analysis of the primary and 
secondary efficacy endpoints is 
changed from the Last Observation 
Carried Forward approach (LOCF) 
to observed case analysis. LOCF 
was downgraded to supplementary 
analysis.  
To follow the treatment 
policy of the study 
estimands based on the 
protocol amendment 2, 
dated 16 February 2021 
Separate Wilcoxon signed rank 
tests for each IPM will not be 
implemented 
Information is not relevant 
The following text has been 
deleted: “No control for multiplicity 
will be applied for the secondary 
endpoint analyses in this Phase 2 
study” 
Team’s decision 
Secondary endpoints are re-ordered 
to define the hierarchy and setting 
the multiplicity controls  
To control multiplicity  
Analysis using trimmed mean 
approach was added as supportive 
analysis 
To present sensitivity 
analysis for robustness of 
the results if necessary  
Further analysis based on CK is 
added:  
a. responder analysis of percentage 
change from baseline based on 
80%, 50% and normalization 
b. analysis based on logCK is added 
To provide additional 
information on the CK 
response  
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Statistical Analysis Plan Amendment 2 
Zilucoplan 
RA101495-02.202 (UCB study IMNM01) 
 
 
 
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SAP Version 
Approval  
Date 
Change 
Rationale 
MMRM modeling for the CK 
percentage change from baseline to 
Week 8 was deleted 
Team’s decision 
Linear Mixed Effects Models 
instead of Mixed Models for 
Repeated Measures to be employed 
for main analysis of Secondary 
Endpoints; model covariates are re-
defined 
To reduce the degrees of 
freedom in the model for 
better convergence due to 
limited number of 
participants analyzed 
Any inferential statistics related to 
the Primary and Secondary 
Endpoints will be performed only at 
Week 8 and complementary at 
Week 4. 
To reduce multiple testing 
Individual items within each 
performance outcomes, clinician-
reported outcome and patient-
reported outcomes will not be 
tested between Investigational 
Medicinal Products (IMPs). 
Team’s decision 
Definition of baseline derivation 
during the Main Portion was 
updated 
To provide more clarity 
Definition of study relative day and 
study periods is added 
To provide more clarity 
Imputation of any missing dates 
and time was redefined 
To map the UCB guidance 
Calculation rules for the AE 
duration are added 
To align across UCB 
programs 
Adverse Events of interest were 
introduced 
To align with UCB safety 
guidance 
Update the AE summaries during 
the Extension with Exposure 
Adjusted Incidence Rate 
To provide additional 
exposure information for 
the AEs 
TEAEs occurring in the first 8 
Weeks of the Extension Period in 
the subjects who received placebo 
in the Main portion and 
subsequently received 0.3 mg/kg in 
the Extension Portion will not be 
summarized separately.” 
Information will be 
captured in listings 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
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RA101495-02.202 (UCB study IMNM01) 
 
 
 
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Page 8 of 75 
SAP Version 
Approval  
Date 
Change 
Rationale 
Markedly Abnormal (MA) values 
for the lab parameters, ECG and 
Vital signs are defined  
To align with UCB safety 
policy 
Inferential analysis of lab 
parameters during the main and/or 
extension portion is removed 
Team’s decision 
The analysis of immunogenicity 
related to anti-drug antibodies 
(ADA) is clarified 
To provide more clarity and 
better understanding of the 
data 
Amendment 2 
09 June 2021 
Table 6.3 CTCAE v5.0 grades for 
laboratory assessments to be 
analyzed, is updated as follows:  
 
1.Total Bilirubin (TBL) (standard) 
changed from Umol/L to μmol/L  
To provide clarity on units 
employed 
2. Creatinine units (standard) 
changed from Umol/L to μmol/L 
To provide clarity on units 
employed 
3. CRP units (conventional) 
changed from “mg/L” to “mg/dL”; 
CRP units (standard) changed from 
To correctly display the 
conventional and standard 
CRP units used in study 
4.CRP Markedly Abnormal criteria 
changed from “>10mg/L; >100 
g/L” to “>10mg/dL >100 mg/L” 
To align the CRP Markedly 
Abnormal criteria with 
published literature 
5.Potassium units (conventional) 
were updated from “mmol/L” to 
“mEq/L” 
To correctly display the 
conventional Potassium 
units used in study datasets 
6.Potassium Marked Abnormality 
criterion (low) was changed from 
“<2.5mmol/L” to “<3.0mmol/L” 
To align with CTCAE v5, 
November 17th, 2017 
7.Sodium conventional units were 
updated from mmol/L to mEq/L 
To correctly display the 
conventional Sodium units 
used in study datasets 
9.Marked Abnormality Criterion 
for WBC high abnormal values 
was added: High: >100 x 109/L 
To align with CTCAE v5, 
November 17, 2017 
10.Marked Abnormality Criterion 
for AST changed from >5.0xULN 
to >5.0xULN if Baseline value is 
normal; > 5.0x Baseline value if 
Baseline is abnormal 
To align with CTCAE v5, 
November 17, 2017 
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09 June 2021 
Statistical Analysis Plan Amendment 2 
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SAP Version 
Approval  
Date 
Change 
Rationale 
11.Marked Abnormality 
Criterion for ALT changed from 
>5.0xULN to >5.0xULN if 
Baseline value is normal; > 5.0x 
Baseline value if Baseline is 
abnormal 
To align with CTCAE v5, 
November 17, 2017 
12.Marked Abnormality 
Criterion for ALP changed from 
>5.0xULN to >5.0xULN if 
Baseline value is normal; > 5.0x 
Baseline value if Baseline is 
abnormal 
To align with CTCAE v5, 
November 17, 2017 
13.Marked Abnormality 
Criterion for γ-GT changed from 
>5.0xULN to >5.0xULN if 
Baseline value is normal; > 5.0x 
Baseline value if Baseline is 
abnormal 
To align with CTCAE v5, 
November 17, 2017 
14.Marked Abnormality 
Criterion for low corrected 
calcium abnormal values was 
changed to: Low: Corrected 
serum calcium of <7.0 mg/dL; 
<1.75 mmol/L 
To align with CTCAE v5, 
November 17, 2017 
15. Table row indicating 
“Triglycerides” assessment is 
deleted 
Triglycerides lab values are 
not part of the study 
assessments 
 
 
Adverse of Interest regarding 
“Hepatic events and drug-
induced liver injuries, Drug 
related hepatic disorders” 
To capture the specific 
Adverse of Interest 
accurately 
 
 
Abbreviation of PCSA is added  
To provide more clarity 
 
 
“Markedly Abnormal Criteria” 
terminology for ECG and vital 
sings is replaced with 
Abnormality Criteria. 
Corresponding text within the 
body of the SAP is amended 
accordingly. 
Team’s decision 
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Statistical Analysis Plan Amendment 2 
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SAP Version 
Approval  
Date 
Change 
Rationale 
 
 
Reference is added: Karbhari, 
DS, Karbhari, NS, Patel, S 
(2017). Significance of 
measurement of corrected 
calcium in patients with 
normoalbuminemia. 
International Journal of Medical 
Science and Public Health 1069-
1071. 
To support the derivation of 
Corrected Calcium 
 
 
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LIST OF ABBREVIATIONS 
aPTT 
activated Partial Thromboplastin Time 
ALQ 
Above Limit of Quantification 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AEIR 
Adverse Event Incidence Rate 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANCOVA 
Analysis of Covariance 
anti-HMGCR 
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase 
anti-SRP 
Signal Recognition Particle  
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BSL 
Baseline 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
C5 
Complement component 5 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CPStat 
Clinical Program Biostatistician 
CRP 
C-Reactive Protein 
CS 
Completer Set 
CSR 
Clinical Study Report 
CTStat 
Clinical Trial Biostatistician 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAP 
Data Analysis Plan 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid  
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LIST OF ABBREVIATIONS 
DRM 
Data Review Meeting 
eCRF 
electronic Care Report Form 
EDV 
Early Discontinuation Visit 
EMA 
European Medicines Agency 
EULAR 
European League Against Rheumatism 
ES 
Enrolled Set 
EAER 
Exposure Adjusted Event Rate  
EAIR 
Exposure Adjusted Incidence Rate 
eGFR 
estimate Glomerular Filtrate Rate 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
US Food and Drug Administration 
γ-GT 
gamma-Glutamyl Transferase 
geoCV 
geometric Coefficient of Variation 
HAQ 
Health Assessment Questionnaire 
ICH 
International Council for Harmonisation  
ICE 
Intercurrent Event 
IMNM 
Immune-Mediated Necrotizing Myopathy 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IPD 
Important Protocol Deviations  
ITT 
Intention to Treat  
ITTEXT 
Intention to Treat - Extension  
ITTNoCOVID-19 
Intention to Treat No Covid-19 
IVIG 
Intravenous Immunoglobulin G 
kg 
Kilograms 
LDH 
Lactate dehydrogenase 
LLoQ 
Lower Limit of Quantification 
LOCF 
Last Observation Carried Forward 
LPFV 
Last Participant First Visit 
LPLV 
Last Participant Last Visit 
LSM 
Least Squares Mean  
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LIST OF ABBREVIATIONS 
LSMD 
Least Squares Mean Difference 
MA 
Markedly Abnormal 
MCH 
Mean corpuscular hemoglobin  
MCHC 
Mean corpuscular hemoglobin concentration  
MCV 
Mean corpuscular volume  
MDAAT 
Myositis Disease Activity Assessment Tool   
MedDRA 
Medical Dictionary for Regulatory Activities 
MMT 
Manual Muscle Testing 
ms 
millisecond 
OR 
Odds Ratio 
PDILI 
Potential Drug Induced Liver Injury 
PBO 
Placebo 
PCSA 
Potentially Clinically Significant Abnormalities 
PD 
Pharmacodynamic 
PD-PPS 
Pharmacodynamic Per Protocol Set 
PK 
Pharmacokinetic 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PPS 
Per Protocol Set 
PRO 
Patient Reported Outcome 
PSOC 
Primary System Organ Class 
PT 
Preferred Term 
PTT 
Partial prothrombin time 
PEY 
Participant-years exposure 
QoL 
Quality of Life 
QTc(F) 
Fridericia corrected QT interval 
RS 
Randomized Set 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
scIg 
Subcutaneous Immunoglobulin  
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LIST OF ABBREVIATIONS 
SD 
Standard Deviation 
SE 
Standard Error 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
sRBC 
Sheep red blood cell 
SS 
Safety Set 
SSNOCOVID-19 
Safety Set No Covid-19 
TBL 
Total bilirubin (blood) 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables Figures and Listings 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WMWodds 
Wilcoxon-Mann-Whitney odds 
3TUG 
Triple Timed Up and Go Test  
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all the necessary information of 
the full statistical methodology to be performed for the statistical analysis of the IMNM01 study 
(legacy Ra Pharma study RA101495-02.202) which is sponsored by UCB S.A.  
The content of this SAP and the statistical methodology described, is compatible with the 
International Council for Harmonisation guidance documents (ICH E9, ICH E9(R1) addendum).  
Data will be analyzed by eClinical Solutions Contract Research Organization (CRO) based on 
the methodology described at the study protocol amendment 2 (dated 16 February 2021) and the 
current SAP amendment 2. Any changes and/or deviations from the study protocol are 
documented in Section 6.3. 
This SAP includes efficacy, safety, immunogenicity, pharmacokinetics [PK], pharmacodynamics 
[PD] data, that covers the entire study duration.  
Summary tables figures and listings (TFLs) to be included in the Clinical Study Report(s) (CSR) 
are defined in the current document. TFLs specifications are stated in a separate document. If 
deemed appropriate, Statistical Analysis System (SAS) outputs and details for critical statistical 
analysis will be made available and placed in the corresponding CSR appendix. 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, this SAP may be amended accordingly.  
 
1.1 
Objectives and Estimands/Endpoints 
The estimands corresponding to the analysis of the primary and secondary objectives are 
described below:  
Table 1‒1: 
Objectives and Estimands/Endpoints 
Objectives 
Estimands / Endpoints 
Primary Efficacy Objective 
To evaluate the 
efficacy of Zilucoplan 
over placebo in 
creatinine kinase (CK) 
levels in participants 
with IMNM 
Primary Estimand: 
• 
Treatment: Zilucoplan administered by daily subcutaneous (SC) injection 
(0.3 mg/kg) vs matching placebo 
• 
Target Population: is defined through the inclusion/exclusion criteria at 
Sections 8.1 and 8.2 of the study protocol reflecting the targeted IMNM 
population 
• 
Endpoint: Percent change from Baseline to Week 8 in CK levels;  
• 
Intercurrent event (ICE) handling: regardless of any treatment 
discontinuation for any reason; censoring after prohibited medication;  
• 
Population level summary: difference in ranks of the percentage change 
from Baseline between treatment conditions followed by the Wilcoxon-
Mann-Whitney odds (WMWodds) and Hodges–Lehmann estimator. 
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Table 1‒1: 
Objectives and Estimands/Endpoints 
Objectives 
Estimands / Endpoints 
Primary Safety Objective 
To evaluate the safety 
Zilucoplan over 
placebo in creatinine 
kinase (CK) levels in 
participants with 
IMNM 
Primary Safety Endpoint: 
• 
Incidence of Treatment-emergent Adverse Events 
Secondary Efficacy Objective 
To further evaluate the 
efficacy of Zilucoplan 
over placebo in 
participants with 
IMNM 
 
Secondary Estimands: 
• 
Treatment: Zilucoplan administered by daily subcutaneous (SC) injection 
(0.3 mg/kg) vs matching placebo 
• 
Target Population: is defined through the inclusion/exclusion criteria at 
Sections 8.1 and 8.2 of the study protocol, reflecting the targeted IMNM 
population 
• 
Endpoints:  
− 
At least minimal response based on the American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) 
Response Criteria Scale at Week 8;  
− 
Change from Baseline to Week 8 in Triple Timed Up and Go (3TUG) 
Test (in ambulatory patients only);  
− 
Change from Baseline to Week 8 in Proximal Manual Muscle Testing 
(MMT);  
− 
Change from Baseline to Week 8 in Physician Global Activity Visual 
Analogue Scale (VAS);  
− 
Change from Baseline to Week 8 in Patient Global Activity Visual 
Analogue Scale (VAS);  
− 
Change from Baseline to Week 8 in Health Assessment Questionnaire 
(HAQ);  
− 
Change from Baseline to Week 8 in MDAAT Extramuscular Disease 
Activity VAS Score;  
− 
Change from Baseline to Week 8 in FACIT-Fatigue Scale.  
• 
Intercurrent event (ICE) handling: regardless of any treatment 
discontinuation for any reason; censoring after administration of prohibited 
medication 
• 
Population level summary:  
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Table 1‒1: 
Objectives and Estimands/Endpoints 
Objectives 
Estimands / Endpoints 
− 
Odds Ratio (OR) of ACR/EULAR ≥ 20 response proportion between 
treatment conditions;  
− Difference in continuous endpoint means, between treatment 
conditions. 
Other Safety Objective 
To further evaluate the 
safety of Zilucoplan 
over placebo in 
participants with 
IMNM 
 
Other Safety Endpoints 
• 
Change in clinical laboratory tests 
• 
Change in ECG parameters  
• 
Change in vital signs parameters 
• 
Presence of Anti-Drug Antibodies 
Exploratory Objectives 
To assess the long-
term efficacy of 
Zilucoplan 
• 
At least minimal response based on the American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) 
Response Criteria Scale at each visit following Week 8; 
• 
Change from Baseline of Timed Up and Go (3TUG) Test (in ambulatory 
patients only) at each visit following Week 8; 
• 
Change from Baseline of Proximal Manual Muscle Testing (MMT) at each 
visit following Week 8; 
• 
Change from Baseline of Physician Global Activity Visual Analogue Scale 
(VAS) at each visit following Week 8; 
• 
Change from Baseline of Patient Global Activity Visual Analogue Scale 
(VAS) at each visit following Week 8; 
• 
Change from Baseline of Health Assessment Questionnaire (HAQ) at each 
visit following Week 8; 
• Change from Baseline of MDAAT Extramuscular Disease Activity 
VAS Score at each visit following Week 8;  
• Change from Baseline of FACIT-Fatigue Scale at each visit 
following Week 8;  
To assess the PK 
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 
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Table 1‒1: 
Objectives and Estimands/Endpoints 
Objectives 
Estimands / Endpoints 
• 
Complement component 5 (C5) levels 
To assess the effect of 
Zilucoplan on 
biomarkers 
Mechanistic biomarkers [e.g., complement fixation, complement function, 
complement pathway proteins, autoantibody characterization (titer and 
immunoglobulin class), myocyte markers, and inflammatory markers].   
To assess the effect of 
Zilucoplan on 
pharmacogenomics 
Pharmacogenomic analyses (optional): 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. 
 
1.2 
Study design 
IMNM01 is a multicenter, randomized, double-blind, placebo-controlled parallel study to evaluate 
the safety, tolerability and efficacy of Zilucoplan in IMNM cases who are positive for anti-
HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) or anti-SRP (signal recognition 
particle) autoantibodies.  
The planned enrollment is approximately 24 participants.  
Participants are randomized at Day 1 to 1:1 ratio in order to receive: 
• daily SC doses of 0.3 mg/kg Zilucoplan (12 participants), or 
• matching placebo administered SC (12 participants).  
Randomization is stratified based on the antibody status (anti-HMGCR+ versus antiSRP+).  
Following in-clinic education and training all participants will self-inject daily SC doses of 
blinded study drug, according to randomized treatment allocation, for the subsequent 8 weeks. 
Single use pre-filled syringes in injection devices are provided for use during the study.  
All standard of care therapy medications for IMNM should be kept at the same doses throughout 
the study, including corticosteroids, immunosuppressive drugs, and IVIG. 
The study is comprised of the Main Portion and the Extension Portion. The Main Portion of the 
study includes a Screening Period of up to 4 Weeks and an 8 Week Treatment Period.  
During the Treatment Period, participants will return to the clinic at Week 1, Week 2, Week 4 
and Week 8 for safety, tolerability and efficacy evaluations.  
Efficacy assessments include Creatine Kinase (CK) levels, as well as performance outcomes, 
clinician-reported outcomes and patient-reported outcomes (PRO).  
Safety assessments include physical examination, vital signs, electrocardiogram (ECG), clinical 
laboratory tests, adverse event (AE) monitoring and immunogenicity.  
Additional assessments include biomarker testing, pharmacokinetics, pharmacodynamics, and 
optional pharmacogenomics.  
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At the end the study Treatment Period, participants have the option to receive Zilucoplan in the 
Extension Portion of the study provided they meet the Extension Portion selection criteria. Visits 
during the first 8 Weeks of the Extension Portion are identical to the Main Portion of the study 
for all participants to ensure appropriate monitoring of participants transitioning from placebo to 
active treatment.  
The study remains double-blinded until after the data from the Week 8 Main Portion have been 
reviewed, locked and unblinded. If a participant permanently discontinues study treatment prior 
to Week 8 visit for any reason, he/she will not be eligible for the Extension Portion. For 
participants who permanently discontinue treatment with study drug, a Safety Follow-up Visit is 
performed 40 days after the last dose to collect information on any ongoing AEs or new SAEs 
since last visit. 
Schedule of Assessments at Table 1‒2 and Table 1‒3 illustrate the time and events schedule for 
the Main Portion and the Extension Portion of the study. 
 
 
 
 
 
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Table 1‒2: 
Schedule of Assessments During the Main Portion of the Study 
 
Week 1 
Week 2 
Week 4 
Week 8 
 
Study Procedure 
Screening  
Days  
–28 to –1 
Day 1 
(Baseline) 
Day 8  
(±2 days) 
Day 15  
(±2 days) 
Day 29  
(±2 days) 
End of Maina 
Study Day 57  
(±7 days) 
Safety Follow-
up Visit (last 
dose + 40d) 
Informed consentb 
X 
 
 
 
 
 
 
Review eligibilityb 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Medical historyc and demographics 
X 
 
 
 
 
 
 
Heightd and weight 
X 
 
 
 
X 
X 
 
Prior and concomitant medicationse 
X 
X 
X 
X 
X 
X 
X 
Safety 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
Neisseria meningitidis vaccinationg 
X 
 
 
 
 
 
 
Prophyfactic antibioticsg (if applicable) 
 
X 
X 
X 
 
 
 
Hematology / Chemistry / CKh 
X 
X 
X 
X 
X 
X 
 
Coagulationh, i 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
X 
X 
X 
X 
X 
X 
 
Pregnancy testj 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsk 
X 
X 
X 
X 
X 
X 
Xk 
Anti-Drug Antibodyh 
X 
 
X 
 
X 
X 
 
Efficacy 
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Table 1‒2: 
Schedule of Assessments During the Main Portion of the Study 
 
Week 1 
Week 2 
Week 4 
Week 8 
 
Study Procedure 
Screening  
Days  
–28 to –1 
Day 1 
(Baseline) 
Day 8  
(±2 days) 
Day 15  
(±2 days) 
Day 29  
(±2 days) 
End of Maina 
Study Day 57  
(±7 days) 
Safety Follow-
up Visit (last 
dose + 40d) 
3TUGl, m 
X 
X 
 
 
X 
X 
 
Proximal MMTl 
X 
X 
 
 
X 
X 
 
Physician Global Activity VASl 
X 
X 
 
 
X 
X 
 
Patient Global Activity VASl 
X 
X 
 
 
X 
X 
 
HAQl 
X 
X 
 
 
X 
X 
 
MDAATl 
X 
X 
 
 
X 
X 
 
FACIT-Fatiguel 
X 
X 
 
 
X 
X 
 
Pharmacokinetic / Pharmacodynamic 
Zilucoplan plasma PKn 
 
X 
X 
X 
X 
X 
 
Pharmacodynamic analysisn 
 
X 
X 
X 
X 
X 
 
Exploratory 
Autoantibodies testingo 
X 
X 
 
 
X 
X 
 
Biomarker testingp 
 
X 
X 
X 
X 
X 
 
Pharmacogenomic analysis (optional)q   
X 
X 
 
 
 
 
 
Study Drug 
Zilucoplan or placebo administrationr 
 
X 
X 
X 
X 
X 
 
a If a subject permanently discontinues study drug prior to completion of the Day 57 visit during the Main Portion, the subject should return to clinic for an End 
of Main Visit. If a participant consents to the Extension Portion, please see Table 1‒3 for Day 57/E1 assessments.  If a subject permanently discontinues study 
drug treatment prior to the Week 8 visit for any reason, he/she will not be eligible for the Extension Portion. For subjects who permanently discontinue 
treatment with study drug, a Safety Follow-up Visit will be performed at 40 days after the last dose to collect information on any ongoing AEs or new SAEs 
since the last study visit. 
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b Procedures performed as standard of care 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 standard of care. Eligibility must be established prior to randomization on Day 1. 
c Screening includes a detailed history of IMNM diagnosis information and local serology for anti-HMGCR or anti-SRP autoantibodies from a reputable 
laboratory. 
d Height will be measured only at Screening 
e All prescriptions and over-the-counter medications taken during the 30 days prior to Baseline (i.e., Day 1) through the last study visit will be documented. 
NOTE: A complete history of all medication taken for the treatment of IMNM will be collected.  
f The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position. 
g 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 standard of care, 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., ciprofloxacin, erythromycin, penicillin V) until at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be administered in 
accordance with local standard of care. NOTE: In participants who received rituximab more than 90 days but less than 6 months prior to Baseline, prophylactic 
antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) should be given upon initiation of study drug until 6 months after the last rituximab dose. 
h All laboratory samples should be obtained prior to administration of study drug at applicable visits. 
i Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy. 
j 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. 
k 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. Participants will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report 
any new SAEs since the last study visit. Only SAEs are collected during the screening period. 
l The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order 
by the same well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study. 
m 3TUG will only be completed in subjects who are ambulatory. 
n Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
o Confirmatory serology testing for anti-HMGCR or anti-SRP autoantibodies will be done at a central laboratory. 
p Blood samples for biomarker testing will be obtained prior to administration of study drug (within 1 hour of dosing). 
q The pharmacogenomic sample may be collected at any study visit.  
r Dosing on study visit days should be held until clinical assessment and blood collection has been completed. 
 
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Table 1‒3: 
Schedule of Assessments During the Extension Portion of the Study 
 
Month 2 
 
Month 3 
Month 4 
Month 5 
Month 6 
Visits after Day E117 
 
Study Procedure 
Day E1a 
(Day 57) 
Day E8 
(±2 days) 
Day E15 
(±2 days) 
Day E29 
(±2 days) 
Day E57 
(±2 days) 
Day E87 
(±7 days) 
Day 
E117 
(±7 days) 
Each 
Month 
(±7 days) 
Every 3 
Months 
(±7 days) 
Final 
Exten-
sion 
Visitb 
Safety 
Follow-up 
Visit (last 
dose + 
40d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility and 
randomization 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Physical examination 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
 
 
X 
 
 
Neisseria meningitidis 
vaccinationd 
X 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
Standard 
of Care 
 
 
Hematoloy / 
Chemistry / CKe 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Coagulatione,f 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Urinalysise 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Pregnancy testg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Anti-Drug Antibodye 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Efficacy 
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Table 1‒3: 
Schedule of Assessments During the Extension Portion of the Study 
 
Month 2 
 
Month 3 
Month 4 
Month 5 
Month 6 
Visits after Day E117 
 
Study Procedure 
Day E1a 
(Day 57) 
Day E8 
(±2 days) 
Day E15 
(±2 days) 
Day E29 
(±2 days) 
Day E57 
(±2 days) 
Day E87 
(±7 days) 
Day 
E117 
(±7 days) 
Each 
Month 
(±7 days) 
Every 3 
Months 
(±7 days) 
Final 
Exten-
sion 
Visitb 
Safety 
Follow-up 
Visit (last 
dose + 
40d) 
3TUGi, j 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Proximal MMTi 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Physician Global 
Activity VASi 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Patient Global Activity 
VASi 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
HAQi 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
MDAATi 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
FACIT-Fatiguei 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Pharmacokinetic / Pharmacodynamic 
Zilucoplan plasma PKk 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Pharmacodynamic 
analysisk 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Exploratory 
Autoantibodies testing 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
Biomarker testingl 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Study Drug 
Zilucoplan or placebo 
administrationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a For participants that decide and are eligible to continue in the Extension Portion of the study, the Day 57 visit from the Main Portion will serve as the Day E1 
visit and will also include review of eligibility to continue and signing of an informed consent for the Extension Portion. 
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administered in the same order by the same well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study. 
b If a participant discontinues study drug treatment at any time during the Extension Portion, the participant should return to clinic for a Final Extension Visit.  
c The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position. 
d During the Extension Portion of the study, all participants should have Neisseria meningitidis booster vaccinations as indicated by standard of care. Participants 
should bring their patient safety card to every study visit. If a participant does not bring the card, then a new one will be given to him/her.  
e All laboratory samples should be obtained after clinical assessments and prior to administration of study drug at applicable visits. 
f Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy. 
g Urine pregnancy tests will be conducted in female subjects of childbearing potential.   
h 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. Participants will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report 
any new SAEs since the last study visit.   
i The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order 
by the same well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study.    
j 3TUG will only be completed in subjects that are ambulatory.  
k Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
l Blood samples for the exploratory tests will be obtained prior to administration of study drug (within 1 hour of dosing). 
m Dosing on study visit days should be held until clinical assessment and blood collection has been completed. 
 
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2 
STATISTICAL HYPOTHESES 
The hypotheses to be included in the testing strategy are listed at the next sections; type 1 error 
will be set such that a family wise type 1 error of 5% is maintained.  
The primary hypothesis H01 will be tested at 2-sided α=5%. Should H01 is rejected then the whole 
α will be passed to the next hypothesis until all hypotheses are rejected. Of note, the level of a 
rejected hypothesis should only pass on the next testing only if the treatment effect is in favour 
of Zilucoplan. 
 
2.1 
Primary endpoint 
The Null Hypothesis for the primary endpoint is that there is no treatment difference in Week 8 
between Zilucoplan and placebo treatment conditions in the percentage change from baseline of 
CK levels.  
The Null Hypothesis (H01) asserts that it is equally likely to one treatment group to be less than 
or greater than the other splitting ties evenly:  
Let Y1 and Y2 be observations drawn independently from the two IMP (Investigational 
Medicinal Products) distributions.  
Then: 
• H01: π= 0.5 for both strata, where π = Prob(Y1 < Y2) + 1/2 Prob(Y1 = Y2) and 
• HA1: πi ≠ 0.5 for at least one stratum (Alternative Hypothesis) 
Converting π to an odds measure: WMWodds = π / (1 – π) the H01 and HA1 can be re-written as:  
• H01: WMWodds = 1 
• HA1: WMWodds ≠ 1 
 
2.2 
Secondary endpoints 
H02.1: Zilucoplan is not different to placebo regimen with respect to the proportion of patients 
achieving at least minimal response based on the ACR/EULAR Response Criteria Scale 
H02.2: Zilucoplan is not different to placebo regimen with respect to change from baseline in 
Triple Timed Up and Go (3TUG) Test to Week 8 among ambulatory patients 
H02.3: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in Proximal Manual Muscle Testing (MMT) 
H02.4: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in Physician Global Activity Visual Analogue Scale (VAS) 
H02.5: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in Patient Global Activity VAS 
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H02.6: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in Health Assessment Questionnaire (HAQ) 
H02.7: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in MDAAT VAS Score in the Extramuscular Disease Activity item 
H02.8: Zilucoplan is not different to placebo regimen with respect to change from baseline to 
Week 8 in FACIT-Fatigue Scale 
 
3 
SAMPLE SIZE DETERMINATION 
A sample size of 12 study participants per group yields approximately 95% power to detect a 
difference in the percent reduction from baseline in creatine kinase between the active and 
placebo groups using a Wilcoxon rank sum test at the two-sided 0.05 type 1 error rate.  
The power calculations assume that the percent reduction in creatine kinase in the active dose 
group is approximately normally distributed with a mean of 80% and a standard deviation of 8%; 
that 4 of the placebo patients will have a percent reduction similar to the active dose group; and 
the remaining 8 placebo patients will have a percent reduction that is normally distributed with a 
mean of 10% and a standard deviation of 8% (Mammen and Tiniakou 2015). 
 
4 
POPULATIONS FOR ANALYSIS 
• Enrolled Set (ES): will include in all screened participants including screen failures. 
• Intention-to-Treat Population (ITT): will include all randomized participants.  
• ITTNoCOVID-19: will include all ITT participants excluding those with confirmed COVID-19 
as observed during any visit of the Main Portion of the study and reported in the AE eCRF 
form. 
Of note, ITTNOCOVID-19 will be considered in any analysis specified in the current document 
during the Main Portion only, provided it differs by at least 15% from the ITT in terms of 
number of participants. 
• Per Protocol Set (PPS): will include all participants in the ITT Population who have 
completed the 8 Week Treatment Period and have no important protocol deviations. 
Important protocol deviations will be evaluated during ongoing data cleaning meetings prior 
to unblinding of the data. 
If a participant received multiple doses of different study drug (i.e., placebo and 0.3 mg/kg), 
the patient will be assigned to the dose group which they received at the highest frequency 
within the Main Portion of the study. 
• Intention to Treat - Extension (ITTEXT): will include all participants who entered the 
Extension Portion of the study.  
• Safety Set (SS): will include all participants who received at least 1 dose of study drug 
during the Main Portion of the study irrespective if they continued to the Extension Portion. 
Participants will be analyzed based on the actual treatment received. 
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If a study participant received multiple doses of different study drug (i.e., placebo and 0.3 
mg/kg), the participant will be assigned to the dose group which he/she received at the 
highest frequency within the Main Portion of the study.  
Of note, participants who were on placebo during the Main Portion of the study and 
continued to the Extension Portion will be included in both groups depending on the study 
period assessed. Safety results on 0.3 mg/kg across the Main and Extension Portions will be 
combined. 
• Safety Set No Covid-19 (SSNOCOVID-19): will include all participants in the SS except 
those with confirmed COVID-19 (as reported in AE eCRF form) during any time of the 
study (Main or Extension Portion). 
Of note, SSNOCOVID-19 will be considered in any analysis specified in the current document, 
provided it differs by at least 15% from the ITT in terms of number of participants. 
• Pharmacokinetic Per-Protocol Set (PK-PPS): will include those study participants in 
the SS who received 1 dose, had at least 1 valid PK measurement post first dose of study 
treatment, and no important protocol deviations affecting the PK variable, as confirmed 
during a pre-analysis review of the data prior to database lock. 
• Pharmacodynamic Per-Protocol Set (PD-PPS): will include those study participants 
in the SS who received 1 dose, had at least 1 valid PD measurement post first dose of study 
treatment, and no important protocol deviations affecting the PD variable, as confirmed 
during a pre-analysis review of the data prior to database lock. 
 
5 
STATISTICAL ANALYSES 
5.1 
General Considerations 
• Descriptive statistics for continuous endpoints will include number of participants with 
available measurements (n), mean, standard deviation (SD), median, 25% and 75% 
percentiles, minimum and maximum. Confidence Intervals (CIs) will be provided where 
appropriate. In general, all study endpoints will be summarized descriptively by IMP and 
overall (if applicable). 
• Frequencies and percentages will be presented by IMP for categorical and ordinal variables. 
Unless otherwise noted, the denominator for percentages will be based on the number of 
participants included in the respective analysis set.  
Participants with missing data can generally be accounted for using the following approaches: 
• For summaries of demographics and baseline characteristics: summarize percentages based 
on all participants in the analysis set and include a “Missing” category (corresponding to 
participants with missing data for the variable being summarized) as the last row in the list of 
categories being summarized. Percentages are associated with the missing row so that 
percentages sum to 100. 
• For summaries of efficacy and safety variables, unless otherwise specified: summarize 
percentages based only on those participants with observed data for the variable being 
summarized. As the denominator may be different from the number of participants in the 
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analysis set being considered, the denominator should be displayed in the table. The general 
format for displaying this will be “n/Nsub (%).” 
All percentages will be displayed with one decimal place. No percentage will be displayed for 
zero counts and no decimals will be presented when the percentage is 100%. If there are no 
missing data for a variable, then the missing row can be removed for that variable in the shell. If 
there are no observations in any specific eCRF-specified category, then retain that row and 
present 0’s across the table. E.g., if there are no ‘American Indian/Alaskan native’ participants in 
the study but this was one of the Racial Group categories in the eCRF, then retain the row and 
populate it with 0 values.  
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer; 
• Mean, SD, and percentiles will use one additional decimal place compared to the original 
data reported; 
• CV [%] will be presented with one decimal place; 
• Minimum and maximum will have the same number of decimal places as the original value 
reported. 
Derived variables in general will be displayed to 1 more decimal place than the variables used in 
the derivation. If the number of decimal places reported in the raw data is varied, then either the 
maximum raw number of reported decimal places or 3 will be used, whichever is the lowest. 
If no participants have data at a given time point, for example, then only n=0 will be presented. 
However, if n<3, present the n, minimum and maximum only. If n=3, n, mean, median, 
minimum and maximum will be presented only. The other descriptive statistics will be left blank.  
If for a particular output there are no valid cases to summarize for any variable, then report “No 
data observed”. 
Demographics and baseline characteristics will be analyzed in ITT. Separate tables based on the 
enrollment date relative to 11 Mar 2020 will be created. 
Efficacy analyses will be performed primarily in the ITT population. Prior and Concomitant 
medications summaries will be performed in the SS. Medical History will be analyzed in the 
ITT. Safety, PK and PD analyses will be performed primarily in the SS, PK-PPS and PD-PPS.  
Comparative efficacy analysis (inferential statistics) will focus on the Main Portion of the study 
only where both active and placebo treatments are given in blinded manner.  
Baseline is defined in Section 5.1.1.2.4.  
Change from Baseline is defined as: post baseline value - baseline value.  
Percentage Change from Baseline is defined as: 100 x (Change from Baseline/Baseline), if 
baseline is greater than zero. 
IEs are defined as these events that may preclude an observation from the study or affect the 
interpretation of the results; in the current setting the following is considered as IE: 
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• Intake of medication which is prohibited by the protocol (complement inhibitor, rituximab, 
statins, or any investigational medicinal product while on study) 
Since the primary analysis of the primary and secondary endpoints will be based on treatment 
policy estimand (that is, observed case analysis) the only data manipulation to be considered is the 
censoring of efficacy values following to the administration of any prohibited medication. 
 
5.1.1 
General study level definitions 
5.1.1.1 
Analysis visit windows 
All data will be analyzed based on the visits identified per the schedule of activities in protocol. 
Mapping to analysis visit windows will not be applied, except for end of treatment (EDV) visits 
(specified in Section 5.1.1.2.3). 
 
5.1.1.2 
Analysis Time Points 
5.1.1.2.1 
Relative day 
• For days on or after the day of first dose of study drug and prior to or on the day of last study 
drug dose (e.g., the day of 1st dose will be Day 1.) the relative day will be calculated as: 
• For days after the last dose of study drug, the relative day will be calculated as: 
• For days prior to the 1st dose of study drug, the relative day will be calculated as: 
• Relative day will not be calculated for partial dates and it must be left blank in these 
instances. 
There is no relative Day 0. Relative day is not calculated for partial dates in cases where relative 
day is shown in a participant data listing. In such cases, relative day should be presented as ‘- -’ 
in the participant data listings. 
 
5.1.1.2.2 
Study periods 
• Screening Period is defined as any time prior to the date/time of first dose of study drug and 
after the date/time of the ICF signature. Screening period starts at maximum 28 days prior to 
the randomization day. 
• Treatment Period is defined as the period on or after the date/time of the first dose of study 
drug and ends at the date/time of Week 8 visit or at the date/time the participant has performed 
the End of Study Visit prior to Week 8. If a participant does not have a Week 8 visit or End of 
Study Visit, then either the date of the last scheduled or unscheduled visit during the Main 
Portion or the date of the last known dose of study drug during the Main Portion, whichever is 
later, will define the end date of Blinded Period. 
• Follow-up Period starts one day after the Week 8 visit and ends after the final assessments on 
the safety Follow-up visit (40 days later). For participants who permanently discontinue the 
study during the treatment period, the follow-up period starts the next day and ends 40 days 
later after the final safety assessments. Participants with assessments after the blinded period 
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are considered to have started the Follow-up Period provided, they have not entered the 
Extension Portion of the study. 
• Extension Period starts one day after the end of Treatment Period and lasts until the day of 
the final extension visit. 
• Extension Follow-up Period starts one day after the end of the final extension visit and ends 
at the day when final assessments are performed on the safety Follow-up visit (40 days later). 
 
5.1.1.2.3 
Mapping of assessments performed at Early Discontinuation Visit 
If a participant prematurely discontinues treatment at any time during the Main Portion, then 
he/she should return to the clinic for a stand-alone End of Main Visit. Corresponding 
assessments will be mapped to the next visit scheduled where each assessment is done as per 
protocol. 
 
5.1.1.2.4 
Definition of Baseline values 
Unless otherwise specified, the Baseline value for the Treatment Period is defined as the most 
recent (date/time considered) non-missing value obtained prior to the administration of the first 
study dose. If there are multiple assessments on that day then the time will be considered for the 
selection of the appropriate measurement. For parameters with no Baseline value as per schedule 
of assessments the screening value will be set as Baseline value. If a Baseline measurement is 
not available but an unscheduled measurement occurs after the planned Baseline measurement 
time point but before dosing, then the unscheduled measurement will be used.  
For participants who received placebo in the Treatment Period, the value obtained prior to the 
first administration of Zilucoplan will occur on the Day E1 (Day 57) visit during the Extension 
Portion of the study and this will be the Baseline value for them for any summary tables during 
the Extension Portion of the study. If Day 57 dose is missing the last non-missing dose on 
placebo during the Main Portion will define the baseline date for the placebo patients who 
change to active in Extension Portion. 
 
5.1.1.3 
Protocol Deviations 
Important protocol deviations (IPDs) are deviations from the protocol which potentially could 
have a meaningful impact on the study conduct or on the primary efficacy, key safety, or PK/PD 
outcomes (if applicable) for an individual participant. IPDs will be reviewed as part of the 
ongoing data cleaning process and data evaluation. IPDs will be identified and documented prior 
to unblinding and will be utilized to decide which data will exclude study participants from the 
PPS and PK-PPS.  
Analysis related to protocol deviations is described in Section 6.1.2. 
 
5.1.1.4 
Treatment assignment and treatment groups 
SS and SSNOCOVID-19 analyses will be based on the actual treatment received.  
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• If after unblinding it is determined that participants at any time received incorrect treatment 
as compared to the one they were randomized to, then these participants will be reallocated to 
the appropriate IMP. For example, if participants randomized to placebo received Zilucoplan, 
then for the safety and PK/PD analyses, these participants will be reallocated to Zilucoplan. 
Participants randomized to Zilucoplan will only be reallocated to the placebo IMP if they 
never received Zilucoplan. Placebo  
• 0.3 mg/kg Zilucoplan 
• All participants (if appropriate) 
For specific safety analysis, data from the Main and the Extension Portion will be combined and 
summarized. Specifically, safety data of participants who received Zilucoplan 0.3 mg/kg during 
the Main Portion of the study will be combined with the Extension Portion safety data. 
Efficacy data during the Extension Portion will be shown based on the combination of the 
randomized and treatment switch:  
• Placebo - 0.3 mg/kg Zilucoplan 
• 0.3 mg/kg Zilucoplan - 0.3 mg/kg Zilucoplan. 
Following to the analysis of Week 8 Main Portion of the study, re-alignment based on duration 
of medication exposure might be considered if deemed necessary.  
 
5.1.1.5 
Center pooling strategy 
All centers will be pooled together for the efficacy analysis of this study. Coding dictionaries 
Adverse events (AEs) and medical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®) using the existing version at the date of the database lock. 
The MedDRA version will be stated at each relevant table.  
Medical procedures will not be coded. 
Medications will be coded according to the Anatomical Therapeutic Chemical Classification 
system (ATC) / World Health Organization Drug Dictionary and (WHODD), using the existing 
version at the date of database lock. The version will be stated at each corresponding table. 
 
5.1.1.7 
Multicenter studies 
This is a study targeting 24 participants and conducted at 18 sites. No efficacy results will be 
displayed by study site. 
 
5.1.1.8 
Handling of drop outs or missing data 
5.1.1.8.1 
Missing efficacy data 
The rules for handling missing data of individual items in the calculation of the PROs and 
performance outcomes are described in Section 6.1.5. 
Main Analysis  
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• No multiple imputation methodology will be considered with respect to the main analysis of 
the primary and secondary efficacy objectives.  
• If a participant receives prohibited medication, then efficacy data will be censored at the 
date/time that he/she received the medication.  
Sensitivity Analysis  
• Trimmed means methodology with imputation at extreme unfavorable value for the primary 
objective of CK levels (if applicable based on SAP criterion, see Section 5.3.3). 
 
5.1.1.8.2 
Missing data due to Covid-19 
Missing data is expected to be one of the implications of the COVID-19 pandemic. The 
following approaches/strategies will be applied to assess the impact of COVID-19 in this study.  
• Added an eCRF page “COVID-19 Impact”, including impacted visits, and reasons. 
• Additional fields were added in protocol deviation specification documents to record 
protocol deviations relationship to COVID-19. 
• Included additional summary analyses based on the timing of COVID-19 impact (pre or 
during the COVID-19 pandemic period). 
• An overall summary of number of visits impacted by COVID-19 by IMP.  
• Summary on numbers of actual visits performed for each nominal visit (along with the 
summary on the primary reason the assessments were impacted (COVID-19 Precaution 
Measures / Participant was Diagnosed with COVID-19). 
 
5.1.1.8.3 
Missing dates and times 
Partially or completely missing dates may be imputed for the following reasons: 
• 
Classification of AEs as TEAEs; 
• 
Classification of medications as past, prior, or concomitant medications;  
Imputed dates will not be shown in listings (dates will be displayed as reported in the database). 
The following rules will be applied for partially or completely missing start dates: 
• 
If year, month and day are all missing then assign the date of first dose of study intervention. 
If an imputed start date is after the specified end date, then assign January 01 of the year of 
the end date, or the date of screening if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then use January 01). 
• 
If month and day are missing, and year is: 
− the same as the year of the first dose of IMP then assign the month-day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign January 01, or 
the month-day of screening date if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then assign January 01); 
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− not the same as the year of the first dose of IMP then assign January 01. 
• 
If only day is missing and month-year is: 
− the same as the month-year of the first dose of IMP then assign the day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign first day of the 
month, or the day of screening date if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then assign first day of the month); 
− not the same as the month-year of the first dose of IMP then assign the first day of the 
month. 
The following rules will be applied for partial stop dates: 
• 
If only the month and year are specified, then use the last day of the month; 
• 
If only the year is specified, then use December 31 of the known year; 
• 
If the stop date is completely unknown, then use discharge date or data cut-off date. 
Date of discontinuation, the date of last contact will be used as the discharge date. For 
participants still ongoing at the time of the data cut-off, and for whom no discharge date is 
available, the date of the data cut-off will be used instead of the discharge date.  
In the event of ambiguity or incomplete data that makes it impossible to determine whether a 
medication was concomitant, the medication will be considered as concomitant. Similarly, in the 
event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication is to be assigned to the Main Portion or to the Extension Portion of the study or both, 
then the medication will be assigned to both study portions. 
The following rules are applied to impute partial onset and resolution dates for AEs. AEs with 
partial onset date are classified as either non-treatment- or treatment-emergent based on the 
imputed onset date. The imputed onset date is also used to classify TEAEs by study portion or 
into time intervals. Each TEAE should be classified into exactly one study portion for the 
classification of TEAEs into study periods.  
Imputation of Partial Onset Dates  
• If only the month and year are specified and the month and year of first dose is not the same 
as the month and year of onset, then use the 1st of the month  
• If only the month and year are specified and the month and year of first dose is the same as 
the month and year of onset, then use the date/time of first dose  
• If only the year is specified, and the year of first dose is not the same as the year of onset, 
then use January 1 of the year of onset  
• If only the year is specified, and the year of first dose is the same as the year of onset, then 
use the date/time of first dose  
• If the AE onset date is completely unknown, then use the date of first dose  
Imputation of Partial Resolution Dates (if needed)  
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• If only the month and year are specified, then use the last day of the month  
• If only the year is specified, then use December 31 of that year  
• If the stop date is completely unknown, then use discharge date or data cut-off date. 
Note: Discharge date refers to the date of the end of study visit for completed participants or the 
date of discontinuation for participants that were withdrawn. For any AEs with known start date 
after the date of discontinuation, the date of last contact will be used as the discharge date. For 
participants still ongoing in the study at the time of the data cut-off, and for whom no discharge 
date is available, the date of the data cut-off will be used instead of the discharge date. 
Consequently, AE duration will be calculated as stop date – start date + 1. 
In the event of ambiguity or incomplete data that makes it impossible to determine whether an 
AE was treatment emergent, the AE will be considered treatment emergent. Similarly, in the 
event of ambiguity or incomplete data which makes it impossible to determine whether an AE is 
to be assigned to the Main Portion of the study or to the Extension study portion, then the AE 
will be assigned to the Main Portion. 
 
5.2 
Participant Disposition 
To assess the impact of COVID-19, a table based on the ITT (overall and by IMP) for each 
country (and overall) will indicate the number of participants at each visit performed, number of 
participants with missed visits, number of participants with telephone calls or video calls 
performed. Corresponding listing will be created in ES. 
A separate table by IMP for the Main and Extension Portion will provide details on subjects 
discontinued due to AEs. More precisely, the number and percentage of participants who 
discontinued the study due to AE (AEs leading to discontinuation of only the following type: 
serious fatal, non-fatal, non-serious fatal) will be presented. 
 
5.3 
Primary Endpoint(s) Analysis 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg) vs 
matching placebo 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol reflecting the targeted IMNM population 
• Endpoint: percentage change from baseline to Week 8 in CK levels  
• Intercurrent event handling: regardless of any treatment discontinuation for any reason; 
censoring after prohibited medication 
• Population level summary: difference in ranks of the percentage change from baseline 
between treatments followed by the Wilcoxon-Mann-Whitney odds (WMWodds) and 
Hodges–Lehmann estimator. 
The statistical hypothesis being tested at Week 8 is that there is no difference in the percentage 
change from baseline in CK levels between Zilucoplan and placebo as described at Section 2.1. 
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5.3.1 
Definition of endpoint(s) 
The primary endpoint is the percentage change from baseline of CK levels at Week 8, defined as: 
%CHG= 100 x (ValueWEEK8 – ValueBSL) / ValueBSL 
 
5.3.2 
Main analytical approach 
The statistical hypothesis is stated at Section 2.1. The analysis will be conducted in the ITT using 
a 2-sided Van Elteren test (Van Elteren, 1960) which stands for an extension of the Wilcoxon rank 
sum test for comparing two treatments in a stratified experiment using within-stratum ranks 
assigning greater weight to rank sums from smaller strata.  
The magnitude of association between groups will be expressed as in WMWodds followed by the 
95% CI and by the Hodges–Lehmann estimator which quantifies the location shift.  
WMWodds will be estimated based on the weighted average WMWodds for the strata. The 
methodology is described below: 
• For each stratum the WMWOdds will be calculated via ROC analysis for the CK levels.  
• The derived AUC and SE values will be used for the calculation of the stratified WMWOdds: 
WMWoddsi = AUCi/(1-AUCi), i=1,2  
The WMWoddsi and the Standard Error (SE) will be transformed to the logarithmic scale to 
ensure positive values of the corresponding 95%CIs: 
LnWMWoddsi = Ln(AUC/(1-AUCi)), i=1,2   
LnSEi = SEi/(AUCi*(1-AUCi)), i=1,2  
• Inverse variance weights will be assigned at each strata: Wi= 1/(LnSEi * LnSEi), i=1,2 :  
• The weighted average WMWodds (WMWodds
̅̅̅̅̅̅̅̅̅̅̅̅̅̅) and the corresponding 95%CI can be then 
calculated as shown below:  
(WMWodds
̅̅̅̅̅̅̅̅̅̅̅̅̅̅) =  exp ( 
∑
Wi ∗ LnWMWoddsi
𝑖=2
𝑖=1
   
∑
Wi 
𝑖=2
𝑖=1
   
) 
95%𝐶𝐼=  exp (( 
∑
Wi ∗ LnWMWoddsi
𝑖=2
𝑖=1
   
∑
Wi 
𝑖=2
𝑖=1
   
) ± 𝑍0.025 ∗ 1/√∑
𝑊𝑖
𝑖=2
𝑖=1
) 
Additionally, for the unweighted WMWodds and Hodges–Lehmann estimator followed by the 
corresponding 95%CI, will also be calculated.  
 
5.3.3 
Sensitivity analyses 
Analysis based on Van Elteren test and on trimmed means methodology (Permutt 2017) in ITT if 
at Week 8 at least 15% of participants do not have evaluable CK results. All missing data will be 
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imputed at an extreme unfavorable value. A permutation-based test will be carried out, with the 
trimming fraction applied adaptively at 1000 treatment permutations. The fraction trimmed will 
be chosen adaptively as that greatest of the proportion of missings in the group.  
First, data should be ordered and trimmed by equal fractions, always trimming all drop outs. 
Then, the summary measure will be computed based on the trimmed data. Previous steps to be 
repeated on permuted data to construct a reference distribution for testing and interval 
estimation. 
Estimand: 
− Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg) vs 
matching placebo 
− Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 
8.2 of the study protocol reflecting the targeted IMNM population 
− Endpoint: percentage change from baseline to Week 8 in CK levels 
− Intercurrent event: regardless of any treatment discontinuation for any reason; censoring 
after prohibited medication 
− Population level summary: difference in ranks of the percentage change from baseline 
between treatments followed by trimmed means 
 
5.3.4 
Supplementary analyses 
• Analysis methodology mentioned in Section 5.3.2 will be repeated in ITT using the LOCF 
approach; that is any Week 8 missing data for any reason will be imputed by the closest non-
missing value of the parameter. 
• Analysis methodology mentioned in Section 5.3.2 will be repeated in PPS. 
• Analysis methodology mentioned in Section 5.3.2 will be repeated in ITTNOCOVID-19. 
 
Further analysis within the ITT population, based on the percentage change of CK levels from 
baseline to Week 4 and Week 8 will be considered as indicated below: 
Definition of Estimand(s): 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg) vs 
matching placebo 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol reflecting the targeted IMNM population 
• Endpoints:  
− (A): percentage change from baseline to Week 4 in CK levels  
− (B): change from baseline to Week 4 and to Week 8 in Log10CK levels  
− (C): Week 4 and Week 8 response defined as at least 80% reduction in CK levels  
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− (D): Week 4 and Week 8 response defined as at least 50% reduction in CK levels 
− (E) Week 4 and Week 8 CK levels within normal range 
• Intercurrent events: regardless of treatment discontinuation due to lack of efficacy, or any 
AE, death; censoring after prohibited medication 
• Population level summary:  
− (A): difference in ranks of the percentage change from baseline between treatment 
conditions followed by the Wilcoxon-Mann-Whitney odds (WMWodds) and Hodges–
Lehmann estimator;  
− (B): difference in mean change from baseline to Week 4 and Week 8 of Log10CK 
between treatment conditions; 
− (C), (D), (E): OR of response proportion categories between treatment conditions;  
 
For the population level summary (A): analysis will be performed as described in Section 5.3.2. 
For the population level summary (B): analysis will be based on linear mixed effects model. As 
response variable will be the change from baseline to Week 4 and to Week 8 respectively. 
Treatment and strata will be fitted as fixed factors whereas baseline levels of the parameter as 
covariate; participants will be fitted at random. The Kenward-Roger approximation will be used 
to estimate the denominator’s degrees of freedom. The antilogs of the least squares means 
(LSMs) of each IMP and the least squares mean differences (LSMDs) between the Zilucoplan 
and placebo will be reported for the Week 8 and Week 4 change from baseline, along with the 
corresponding 2-sided 95% CIs and p-values. 
For the population level summary (C, D, E): Analysis will be performed via logistic regression 
model with treatment and stratification factors included for each response parameter; the OR of 
Zilucoplan over placebo will be given followed by the 95% CI. 
Corresponding summary statistics will be presented in each IMP.  
 
5.4 
Secondary Endpoint(s) Analysis 
5.4.1 
Key/Confirmatory secondary endpoint(s) 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg) vs 
matching placebo 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol, reflecting the targeted IMNM population 
• Endpoints:  
− At least minimal response based on the American College of Rheumatology/European 
League Against Rheumatism (ACR/EULAR) Response Criteria Scale at Week 8;  
− Change from Baseline to Week 8 in Triple Timed Up and Go (3TUG) Test (in 
ambulatory patients only);  
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− Change from Baseline to Week 8 in Proximal Manual Muscle Testing (MMT);  
− Change from Baseline to Week 8 in Physician Global Activity Visual Analogue Scale 
(VAS);  
− Change from Baseline to Week 8 in Patient Global Activity Visual Analogue Scale 
(VAS);  
− Change from Baseline to Week 8 in Health Assessment Questionnaire (HAQ);  
− Change from Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS 
Score;  
− Change from Baseline to Week 8 in FACIT-Fatigue Scale;  
• Intercurrent event (ICE) handling: regardless of any treatment discontinuation for any reason; 
censoring after administration of prohibited medication 
• Population level summary:  
− Odds Ratio (OR) and ACR/EULAR ≥ 20 response proportion between treatment 
conditions;  
− Difference in continuous endpoint means between treatment conditions 
 
5.4.2 
Definition of endpoint(s) 
• ACR/EULAR response is defined based on the total improvement score, see Section 6.1.5.7 
for the response criteria. The endpoint of minimal response is defined as achievement of 
ACR/EULAR ≥ 20 at Week 8.  
• Absolute change from baseline to Week 8 of:  
− 3TUG,  
− Proximal MMT,  
− Physician Global Activity VAS,  
− Patient Global Activity VAS,  
− HAQ,  
− Extramuscular Disease Activity VAS Score of MDAAT Score and 
− FACIT-Fatigue Scale. 
Change from baseline to Week 8 (CHGWeek8) of each secondary continuous endpoint is 
defined as: CHGWeek8 = (ValueWeek8-ValueBSL). 
 
5.4.3 
Main analytical approach 
Analysis to determine the OR and the 95%CI of ACR/EULAR ≥ 20 (minimal treatment 
response) between IMPs will be performed via binary logistic regression with IMP and strata as 
fixed factors. Bar charts by treatment will be created to illustrate the treatment effect. 
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In order to assess secondary efficacy for any continuous parameter, a separate linear mixed effect 
model will be employed for each secondary continuous efficacy parameter. At each linear mixed 
effect model, the response variable will be the change from baseline to Week 8. Treatment and 
strata will be fitted as fixed factors whereas baseline levels of the parameter as covariate; 
participants will be fitted at random. The Kenward-Roger approximation will be used to estimate 
the denominator’s degrees of freedom. The least squares means (LSMs) of each IMP and the least 
squares mean differences (LSMDs) between the Zilucoplan and placebo will be reported for the 
Week 8 change from baseline along with the corresponding 2-sided 95% CIs and p-values. 
Statistical estimators based on Least Square Means (LSMs) and Standard Errors (SE) or 95%CIs 
will be plotted for each treatment.  
 
5.4.4 
Sensitivity analysis 
No sensitivity analysis to be performed. 
 
5.4.5 
Supplementary analyses 
Analysis mentioned at Section 5.4.3 will be repeated in ITT with missing values imputed based 
on the LOCF approach from the previous non missing visit of Week 8. Based on this approach, 
the elements of ACR/EULAR will also be imputed with the last non missing parameter in order 
the score to be calculated at Week 8. 
Analysis mentioned at Section 5.4.3 will be repeated in the ITTNOCOVID-19. In case of non-
convergence, only the summary statistics will be reported. 
Analysis mentioned at Section 5.4.3 will be repeated in the PPS. 
Estimand: 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg) vs 
matching placebo 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol reflecting the targeted IMNM population 
• Endpoints:  
− ACR/EULAR of at least minimal response at Week 4; 
− ACR/EULAR ordinal treatment esponse at Week 4 and Week 8; 
− ACR/EULAR Total Improvement Score at Week 4 and Week 8; 
− Change from Baseline to Week 4 in Triple Timed Up and Go (3TUG) Test (in 
ambulatory patients only);  
− Change from Baseline to Week 4 in Proximal Manual Muscle Testing (MMT);  
− Change from Baseline to Week 4 in Physician Global Activity Visual Analogue Scale 
(VAS);  
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− Change from Baseline to Week 4 in Patient Global Activity Visual Analogue Scale 
(VAS);  
− Change from Baseline to Week 4 in Health Assessment Questionnaire (HAQ);  
− Change from Baseline to Week 4 in MDAAT Extra muscular Disease Activity VAS 
Score;  
− Change from Baseline to Week 8 in FACIT-Fatigue Scale;  
• Intercurrent event: regardless of treatment discontinuation for any reason; censoring after 
administration of prohibited medication;  
− Population level summary: Odds Ratio (OR) of ACR/EULAR ≥ 20 response proportion 
between treatment conditions (analysis will be performed as mention Section 5.4.3).  
− Population level summary: ACR/EULAR ordinal treatment response proportion in 
treatment conditions;  
− Difference in continuous endpoint means between treatment conditions (analysis will be 
performed as mention Section 5.4.3).  
For the determination of ACR/EULAR response categories, see Section 6.1.5.7. Ordinal 
ACR/EULAR treatment response (no improvement, minimal improvement, moderate 
improvement, major improvement) at Week4 and Week 8 will be only be summarized by IMP. 
 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
5.5.1 
Long Term Efficacy 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 mg/kg)  
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol, reflecting the targeted IMNM population 
• Endpoints:  
− At least minimal response based on the American College of Rheumatology/European 
League Against Rheumatism (ACR/EULAR) Response Criteria Scale at each study visit 
following Week 8;  
− Change from Baseline in Triple Timed Up and Go (3TUG) Test (in ambulatory patients 
only) at each study visit following Week 8;  
− Change from Baseline in Proximal Manual Muscle Testing (MMT) at each study visit 
following Week 8;  
− Change from Baseline in Physician Global Activity Visual Analogue Scale (VAS) at each 
study visit following Week 8;  
− Change from Baseline in Patient Global Activity Visual Analogue Scale (VAS) at each 
study visit following Week 8 at each study visit following Week 8;  
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− Change from Baseline in Health Assessment Questionnaire (HAQ) at each study visit 
following Week 8;  
− Change from Baseline in MDAAT Extramuscular Disease Activity VAS Score at each 
study visit following Week 8;  
− Change from Baseline in FACIT-Fatigue Scale at each study visit following Week 8;  
• Intercurrent event (ICE) handling: regardless of any treatment discontinuation for any reason; 
censoring after administration of prohibited medication 
• Population level summary:  
− ACR/EULAR ≥ 20 response proportion;  
− Mean change from Baseline to each extension portion visit 
Further summaries by IMP to be provided for each ACR/EULAR response category (no 
response, minimal response, moderate response and major response) and for the ACR/EULAR 
TIS. 
Analysis will be performed in descriptive manner without any statistical comparisons to be 
considered. 
 
5.5.2 
Mechanistic 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) as indicated at Table 1‒2 and Table 1‒3. 
The analysis of biomarkers pertaining to the pathophysiology of IMNM [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 IMNM participants. Complement protein levels 
and complement activity will be tested to evaluate response to Zilucoplan and to understand 
participant 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 will be reported separately from the main clinical study 
report analyses and therefore analysis will not be stated in this document. 
 
5.5.3 
Pharmacogenomic analyses (optional) 
Participation in the pharmacogenomic assessment is optional, and participants must provide 
additional consent for the pharmacogenomic analysis. For cases who choose to participate in 
pharmacogenomic studies, a blood sample is obtained. All genomic analyses will be performed 
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at an accredited laboratory. 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. 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 will be reported separately from the main clinical study 
report analyses and therefore analysis will not be stated in this document. 
 
5.6 
Safety Analyses 
5.6.1 
Extent of Exposure 
Any analysis related to the exposure will be based the SS. 
The number and percentage of participants with cumulative IMP duration (e.g. any duration, ≥1 
week, ≥2 weeks, ≥3 weeks,…., etc.) will be presented by IMP. 
IMP duration = Date of Last Dose – Date of First Dose +1 
The duration of exposure to each treatment will be summarized by IMP: 
Duration of exposure in years (or Participant Exposure Years (PEY)) = [(min(Date of Last Dose 
+ 40 days, Last Visit) - Date of First Dose+1)] /365.25 
Thus, exposure will be adjusted for the 5 half-lives of active treatment which is 40 days. 
Duration of exposure (100 participant years) = PEY / 100.  
Summaries on the treatment exposure and time at risk in subject years will be given. 
Participants which are exposed to both treatments will be presented in either study treatments using 
the corresponding start and stop treatment date. 
The number of doses missed (from the eCRF Study drug administration page after Day 1) will be 
summarized overall and by IMP. 
 
5.6.2 
Adverse Events 
Adverse events will be captured from the time of informed consent signature (only the SAEs) or 
from the time of first administration (Treatment Emergent Adverse Events) and will be reported 
if occurred during scheduled on unscheduled visits. As Treatment Emergent AE (TEAE) is 
defined as an AE starting on or after the time of first administration of study drug or an AE that 
increases in severity after treatment start, if the event was present at the time of the treatment 
initiation. Reporting of TEAEs refer to the period until the administration of the last study dose 
plus 40 days (or last visit depending which occurs first).  
AEs will be classified according to the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 for severity. For any AE where it is not possible to provide a CTCAE 
grading, the event will be assessed using a standard intensity classification (mild, moderate and 
severe). For the purpose of the tabulations all CTCAE severity classifications will be mapped to 
a mild/moderate/severe grade as described below: 
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• 
Grade 1 - Mild 
• 
Grade 2 - Moderate 
• 
Grade 3, 4, 5 - Severe  
These will be tabulated together with the AEs that were not classified according to CTCAE 
criteria i.e., all Grade 1 AEs as per CTCAE criteria will be included in the ‘mild’ category 
together with those AEs classified as mild as per the ‘standard’ intensity classification. 
If a particular AE severity is missing, then this will be listed as missing and treated as missing in 
summaries. If a participant has experienced more than one TEAE within the same PT, then the 
AE with the greatest severity will be presented. If a participant reported more than on AE within 
the same (System Organ Class) SOC then the participant will be counted only once with the 
greatest severity at the SOC where applicable. 
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent 
unless evidence exists that does not allow the AE to be treatment-emergent. Handling of missing 
dates for classification of AEs as TEAEs is described in Section 5.1.1.8. 
TEAE summaries will be performed in SS and repeated in SSNOCOVID-19 if at least 15% of the 
participants have at least one AE as ‘Confirmed COVID-19’.  
Summaries may also be repeated in SS among participants with at least one TEAT based on the 
COVID-19 period defined as: 
• Before the pandemic: a TEAE will be assigned to this period if the start date of the event is 
on or after the date of the first administration of study drug on Day 1 but before the cut-off 
date of 11th MAR 2020. 
• During/after the pandemic: a TEAE will be assigned to the during/after the pandemic Period 
if the start date of the event is on or after the date of the first administration of study drug on 
Day 1 but after the cut-off date of 11th MAR 2020.  
A TEAE will be counted as related to study drug if the response to the question “Relationship to 
Study Medication” is “Related”. Severe TEAEs are those with CTCAE Grade 3 or above, or 
those without a CTCAE grading classified as ‘severe’ by the Investigator. If a participant reports 
the same event with different relationship assessments, then participant will be counted under 
both related and not related categories. 
Adverse events will be presented as “number of participants (percentage of participants) [number 
of events]”. In this style of output, “[number of events]” will include all cases of an AE including 
repeat occurrences in individual participants, while “number of participants” will count each 
participant only once. 
TEAE Summaries will be reported separately within the Main Portion and within the Main and 
Extension Portion of the study and presented by primary system organ class (PSOC) and 
preferred term (PT) within each IMP. PSOCs will be sorted alphabetically. PTs will be sorted by 
decreasing frequency of Zilucoplan within each PSOC; ties will be sorted alphabetically within 
Zilucoplan. TEAEs will be mapped to a study portion based on the onset date. 
The following summaries will be produced: 
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• TEAE overview table in SS and SSNOCOVID-19, displaying participants with at least one 
TEAE, with at least one TEAE before/after 11th March 2020, with at least one serious TEAE, 
with at least one TEAE resulting to permanent withdrawal from study medication, with at 
least one drug-related TEAE and with at least one TEAE leading to death 
• TEAEs by PSOC and PT, in SS 
• TEAEs by PSOC and PT by COVID-19 period, in SS  
• Serious TEAEs by PSOC and PT in SS  
• Serious TEAEs by PSOC and PT for each COVID-19 period, in SS  
• TEAEs by PSOC, PT and maximum CTCAE V5.0 Grade, in SS 
• TEAEs by PSOC, PT and maximum relationship, in SS 
• Serious TEAEs by PSOC, PT and maximum relationship, in SS 
• Fatal TEAEs by PSOC, PT and maximum relationship, in SS 
• Non-Serious TEAEs by PSOC and PT of at least 5% within any IMP (Main Portion) or 
active treatment (Extension Portion), in SS  
• TEAEs by PSOC and PT leading to drug discontinuation, in SS  
• TEAEs by PSOC and PT leading to death, in SS  
Of note, 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 treatments  
− Elective procedures that were scheduled prior to study participation (i.e., signing of the 
ICF) 
Safety tables for the combined Main and Extension Portion of the study, will display the 
Treatment Emergent Adverse Event Incidence Rate (AEIR) per 100 patient-years of Zilucoplan 
treatment (thus no placebo arm to be summarized due to limited exposure time as compared to 
active). Tables will include the PEY per 100 patient years (as defined in Section 5.6.1), number 
and percentage of participants with a particular TEAE, the exposure adjusted incidence rate 
EAIR) followed by 95%CI  and the exposure adjusted event rate (EAER): 
• EAIR for TEAEs by PSOC and PT, in SS 
• EAIR for serious TEAEs by PSOC and PT, in SS  
The EAIR is defined as the number of study participants with a specific new TEAE divided by 
the duration of exposure of all participants (scaled to100 participant years). The time at risk for a 
study participant is censored at the date of this event. If a study participant has no events, the 
total time at risk (i.e. exposure) is used.  
Exact Poisson 95% CIs for EAIR are calculated using the relationship between the Poisson and 
the Chi-square distribution (Ulm, 1990; Fay and Feuer, 1997):  
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𝐿𝑜𝑤𝑒𝑟 𝐶𝑜𝑛𝑓𝑖𝑑𝑒𝑛𝑐𝑒 𝐿𝑖𝑚𝑖𝑡= 𝑥2𝑛,𝛼/2
2
/2 
𝑈𝑝𝑝𝑒𝑟 𝐶𝑜𝑛𝑓𝑖𝑑𝑒𝑛𝑐𝑒 𝐿𝑖𝑚𝑖𝑡= 𝑥2𝑛(𝑛+1),1−𝛼/2
2
/2 
where n stands for the number of participants with a specific TEAE for the incidence rate of 
interest and is the basis for the number of the degrees of freedom for the chi-square quantile for 
the upper tail probability χ2. 
The EAER is defined as the total number of TEAEs including repeat occurrences in individual 
study participants divided by the total time at risk scaled to 100 patient-years. No confidence 
interval will be computed for the EAER. 
Individual data listing of all AEs (TEAEs and non TEAEs) will be created and displayed by IMP 
based on the ES. Also, by participant listings for all the TEAEs leading to permanent withdrawal 
of study drug, for all the TEAEs related to study drug and for all the TEAEs leading to death will 
be presented by IMP. In each listing, a COVID-19 flag will be present indicating the time frame 
of the event relevant to the COVID-19 period. A separate data listing for participants with 
confirmed COVID-19 will be produced. 
 
5.6.3 
Adverse Events of Interest 
The following bullets define the TEAEs of interest for Zilucoplan: 
• Infections 
− Serious infections: Serious TEAEs in MedDRA SOC “Infections and infestations”  
− Infections: TEAEs in MedDRA SOC “Infections and infestations” 
− Neisseria infections: TEAEs in MedDRA HLT “Neisseria infections” 
− Serious Neisseria infections: Serious TEAEs in MedDRA HLT “Neisseria infections” 
• Adverse events potentially related to hypersensitivity (including anaphylaxis) 
Potential anaphylactic reactions are defined via a MedDRA algorithmic approach (see 
Section 6.2), which combines a number of different TEAEs/anaphylactic reaction symptoms. 
Some cases are dependent on the presence of multiple symptoms/TEAEs (i.e. TEAEs with the 
same AE onset day or one day later) in order to be classified as an anaphylactic reaction; at least 
one of the symptoms/TEAEs needs to be serious for the reaction to be classified as a serious 
anaphylactic reaction.   
− Anaphylactic reactions are defined as follows: 
Serious Anaphylactic reactions: MedDRA algorithmic approach to anaphylaxis where at 
least one of the TEAEs needs to be serious 
Anaphylactic reactions: MedDRA algorithmic approach to anaphylaxis among TEAES 
− Hypersensitivity reactions are defined as follows: 
Serious hypersensitivity reactions: Serious TEAEs in MedDRA Standardized MedDRA 
Query (SMQ) “Hypersensitivity (narrow scope)”  
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Hypersensitivity reactions: TEAEs in MedDRA SMQ “Hypersensitivity (narrow scope)” 
• Injection site reactions 
− TEAEs in MedDRA HLT “Injection site reactions” or HLT “Administration site 
reactions NEC”.  
• Hepatic events and drug-induced liver injuries, Drug related hepatic disorders   
− TEAEs in MedDRA SMQ narrow scope of “Drug related hepatic disorders - 
comprehensive search (SMQ)” excluding the 2 sub-SMQs of “Liver neoplasms, benign 
(incl cysts and polyps) (SMQ)” and “Liver neoplasms, malignant and unspecified 
(SMQ)”. 
• Malignancies 
− Malignant or unspecified tumours: TEAEs in MedDRA SMQ “Malignant or unspecified 
tumours (SMQ)” 
− Malignant tumours: TEAEs in MedDRA SMQ “Malignant tumours (SMQ)” 
Note: the events included in the “Malignant tumours” table will be a subset of the events 
included in the “Malignant or unspecified tumours” table. While the “Malignant tumours 
(SMQ)” is most relevant, “Malignant or unspecified tumours (SMQ)” will be reviewed for 
potential malignancies. 
Should an Adverse Event of Interest has not occurred during the study, the corresponding line 
should be included with zero occurrences. 
The following tables will be created: 
• TEAEs of interest by PT, in SS, 
• EAIR for TEAEs of interest by PT, in SS (combined Main and Extension Portion among 
participant received at least one dose Zilucoplan). 
 
5.6.4 
Additional Safety Assessments  
Further safety assessments include laboratory data, vital signs and 12 Lead ECG. Details of 
analysis are written further below. All analysis will be based on the SS. 
 
5.6.4.1 
Clinical laboratory evaluations 
The following table lists all hematology, chemistry, urinalysis and coagulation analytes collected 
throughout the study, using a central laboratory according to the schedule of the study protocol. 
Table 5‒1: 
Laboratory Assessments 
Chemistry 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Hematocrit 
Hemoglobin 
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Table 5‒1: 
Laboratory Assessments 
Chemistry 
Hematology 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Aldolase 
Blood urea nitrogen (BUN) 
C-reactive protein (CRP) 
Calcium 
Chloride 
Creatinine 
Creatine Kinase (CK) 
Gamma-glutamyl transferase (γ-GT) 
Glucose 
Lactate dehydrogenase (LDH) 
Lipase 
Potassium 
Sodium 
Total bilirubin (TBL) 
Total protein 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) 
White blood cell (WBC) count and differential: 
    Basophils (% and absolute) 
    Eosinophils (% and absolute) 
    Lymphocytes (% and absolute) 
    Monocytes (% and absolute) 
    Neutrophils (% and absolute) 
Coagulation (among participants receiving anticoagulant 
treatment) 
International normalized ratio (INR)/prothrombin time (PT) 
Partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) 
Urinalysis 
pH, specific gravity, protein (qualitative), glucose (qualitative), 
ketones (qualitative), bilirubin (qualitative), urobilinogen, 
occult blood, hemoglobin, cells and microscopic examination 
(if necessary). 
 
5.6.4.1.1 
Laboratory values over time 
All laboratory values listed at Table 5‒1 of Section 5.6.4.1 will include on treatment data for 
analysis defined as the values after the first dose of the study drug until on or before the last dose 
plus 40 days (or last visit depending which occurs first). At all tables, laboratory assessments 
will be sorted by panel (chemistry, hematology, coagulation, urinalysis). Within each panel the 
assessments will be sorted alphabetically. 
Summaries on Markedly Abnormal (MA) values will also be provided for the Main portion by 
scheduled visit and overall (including unscheduled visits) and for the Extension portion by 
scheduled visit and overall (including unscheduled visits), for each IMP. MA criteria are listed at 
Section 6.1.7, Table 6‒3 MA criteria are defined by Grade 3 or higher events according to the 
Common Terminology for Adverse Events (CTCAE), Version 5.0, November 17, 2017 unless 
otherwise noted.  
All laboratory test results will be listed, including baseline, scheduled and unscheduled visits 
with results in standard units. Values outside the reference range for the continuous variables 
will be flagged in the listings. The reference ranges will also be displayed. In addition, the 
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listings will include a flag for values identified as MA. Additional lab test for pregnancy testing, 
will also be listed.  
 
5.6.4.1.2 
Individual Subject Changes of Laboratory Values 
The laboratory variables that are categorized as normal, high or low based on the reference range 
as supplied by the analytical laboratory will be presented in shift tables from baseline to each 
scheduled post-baseline visit by IMP and any post-baseline visit (including unscheduled visits) 
by IMP.  
The number and percentage of participants who meet the criteria with respect to elevated liver 
function tests and drug-induced liver injuries (PDILI) will be summarized by IMP at each 
scheduled visit and at any visit (including unscheduled visits), Table 6‒4 in Section 6.1.7. A 
listing will also be provided for participants who meet at least one of the criteria.  
 
5.6.4.2 
Vital Signs 
The vital signs assessed are the Heart Rate, the Body Temperature and the Systolic and Diastolic 
Blood Pressure, all in sitting position. 
 
5.6.4.2.1 
Vital Sign Values Over Time 
Vital signs summaries will only include on treatment data defined as those measurements after 
the first study treatment dose until the day of the last dose plus 40 days (or last visit depending 
which occurs first). 
Analysis will be performed descriptively for the change from baseline to each post baseline visit 
by IMP. Change from baseline of each vital sign parameter will be summarized only among 
participants with both baseline and post baseline values:  
Change from Baseline = post Baseline – Baseline value 
Summaries of vital sign abnormalities will be created for the Main and Extension portion by 
scheduled visit and overall (including unscheduled visits) for each IMP. Criteria for vital sign 
abnormal values are shown in Table 6‒5,Section 6.1.7. 
A by-participant listing of all vital sign measurements at each visit and change from baseline will 
be presented by IMP and visit. The listing will include a flag for values identified as abnormal.  
 
5.6.4.2.2 
Individual Subject Changes of Vital Sign Values 
A by patient listing will be provided (assessing scheduled and unscheduled visits), capturing for 
each vital sign parameter of the participants with at least one abnormality in the value post-
baseline. Results obtained for the vital sign parameters will be displayed. 
 
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5.6.4.3 
Electrocardiograms 
The following assessments will be summarized and reported: PR interval, RR interval, QRS 
duration, QT interval, QT corrected for heart rate using Fridericia’s formula (QTcF = QT/RR1/3). 
 
5.6.4.3.1 
Electrocardiogram Values Over Time 
ECG summaries will only include on treatment data defined as those measurements after the first 
study treatment dose and on or before the last dose plus 40 days (or last visit, depending which 
occurs first). 
Analysis will be performed descriptively for the change from baseline to each post baseline visit 
by IMP. Change from baseline of each ECG parameter, will be summarized only among 
participants with both baseline and post baseline values:  
Change from baseline = post baseline – baseline value 
Summaries of ECG abnormalities will be created for the Main and Extension portion by scheduled 
visit and overall (including unscheduled visits) for each IMP. Criteria for ECG abnormalities 
values are listed in Table 6‒6 in Section 6.1.7. 
A by-participant listing of all ECG measurements when performed and change from baseline 
will be presented by IMP and visit. The listing will include a flag for values identified as based 
on the abnormality criteria. 
 
5.6.4.3.2 
Individual Subject Changes of Electrocardiograms Values 
The ECG that are categorized as normal, high or low based on the reference range in shift tables 
from baseline to each scheduled post-baseline visit by IMP and any post-baseline visit (including 
unscheduled visits) by IMP.  
A by patient listing will be provided (assessing scheduled and unscheduled visits), capturing 
each or the 12 Lead ECG parameters of the participants with at least one abnormalvalue post-
baseline based on the abnormality criteria. Results obtained for the ECG parameters will be 
displayed. 
 
5.6.4.4 
Other safety endpoint(s) 
5.6.4.4.1 
Physical examination 
Any clinically significant abnormalities in physical examination will be reported as AEs when 
appropriate with reference the period after the first administration of study dose until the last day 
of study dose administration plus 40 days (or last visit, depending which occurs first).  
 
5.6.4.4.2 
Immunogenicity 
Blood samples for ADA assessment will be collected prior to dose administration at baseline 
(screening data will be considered as baseline data for ADA assessments), Day 8, Day 29 and 
Day 57 as well as Day E8, Day E28, Day E57, Day E117 and every 3 months after, including 
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final Extension visit in all participants prior to drug administration. These samples will be used 
to investigate and characterize any ADA response over time in SS. 
− Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
− Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
− Samples that could not be tested for ADA status due to inadequate sample volume, 
mishandling, or errors in sample collection, processing, storage, etc, will be defined as 
Missing 
Sample neutralizing antibody (NAb) status (positive/negative/missing) will be determined for 
ADA positive samples. 
The following ADA classifications will be derived from the sample ADA status: 
Table 5‒2: 
ADA Classification 
Classification 
Classification Label 
Definition 
1 
Pre-ADA negative – 
treatment induced ADA 
negative 
Participants who are ADA negative at baseline and ADA 
negative at all sampling points post-baseline. 
2 
Pre-ADA negative – 
treatment induced ADA 
positive 
Participants who are ADA negative at baseline and ADA 
positive at any sampling point post-baseline. It also 
includes participants who have a missing pre-treatment 
sample (either missing or insufficient volume) at 
baseline with one or more ADA positive post-baseline 
samples. 
3 
Pre-ADA positive – 
treatment reduced ADA 
Participants who are ADA positive at baseline, and ADA 
negative at all sampling points post-baseline (including 
the Extension Portion of the study). 
4  
Pre-ADA positive – 
treatment unaffected 
ADA  
Includes participants who are ADA positive at Baseline 
and ADA positive at any sampling point post-Baseline 
(including Extension Portion) with titer values of the 
same magnitude as baseline (less than a predefined fold 
difference from the baseline value which will be defined 
within the validation of the assay, i.e. minimum 
significant ratio of the assay).  
5  
Pre-ADA positive – 
treatment boosted ADA 
positive  
Includes participants who are ADA positive at Baseline 
and ADA positive at any sampling point post-Baseline 
(including Extension Portion) with increased titer values 
compared to baseline (greater than a predefined fold 
difference increase from Baseline value which will be 
defined within the validation of the assay i.e. minimum 
significant ratio of the assay).  
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Classification 
Classification Label 
Definition 
6 
Inconclusive 
Participants who have an ADA positive Baseline sample 
and some post-Baseline samples are missing, while other 
post-Baseline samples are ADA negative.  
7  
Treatment emergent 
ADA positive 
Combination of 2 and 5. 
8  
Pre-ADA positive  
Combination of 3, 4, and 5.  
 
In addition to the ADA classifications above, for the purpose of evaluations of the impact of 
ADA on plasma concentrations and efficacy and safety endpoints, the following definitions will 
be used: 
 
• Cumulative ADA status (positive/negative). If a participant had at least one positive sample 
at any time point up to and including the given time point, that participant will be counted as 
positive at that time point, regardless of any subsequent negative measurements. Thus, the 
number of participants included in the summary of positive and negative samples will vary 
by time point for each IMP.  
• Overall ADA status. A participant will be classified as overall ADA Positive if at least one 
post-baseline measurement is positive. A participant will be classified as overall ADA 
negative if at all post-Baseline visits the ADA status is Negative. 
The ADA of Zilucoplan will be measured using a three-tiered assay approach: screening assay, 
confirmatory assay and titration assay. Any sample confirmed positive for ADA will be assayed 
to determine whether there is neutralizing potential. 
The following tables will be presented on the SS. 
• Number and percentage of participants with positive, negative or missing sample ADA status 
at the time of each visit and all visits by IMP. 
• Number and percentage of participants in each of the ADA classifications presented in 
Table 5‒2 by IMP. 
• Number and percentage of participants in each of the NAb classifications presented in 
Table 5‒2 by IMP. 
• The prevalence of immunogenicity (Classification 2, 3, 4 and 5), defined as the (cumulative) 
proportion of participants having ADA positive samples (including pre-ADA positive) at any 
point up to and including that time point will be summarized by IMP and total. Missing 
samples will not be included in the denominator.  
• The same table will be repeated for Nab (cumulative and overall Nab status will be defined 
as described above for ADA).  
• The first occurrence of treatment-emergent ADA positive will be summarized using 
frequency and percentage at each post-baseline visit by IMP group. Participants will be 
counted only once in the numerator based on the earliest visit at which treatment-emergent 
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ADA positivity is observed. At other visits, participants will be counted in the denominator 
(assuming a measurement is available). Missing measurements will not be included in the 
denominator. 
• A summary table of all immune related TEAEs by ADA status will be presented by IMP 
group. For this summary, participants will be presented for TEAEs occurring prior to 
becoming treatment emergent ADA positive, TEAEs occurring after becoming TE ADA 
positive and TEAEs for participants who remained TE ADA negative (classifications 1,3,4).  
− Notes: Study physician/safety physician/safety lead will mark the Preferred Term of 
immune related AEs based on an excel output of all TEAEs (blinded) after database lock. 
The marked AEs will be used for the summary.  
The results for the ADA assessments will be listed by IMP group and timepoint, including the 
screening assay, confirmatory assay, ADA titer, NAb titer, PK concentration, change from 
Baseline, treatment-emergent ADA status and ADA classifications. In addition, time since 
administration of IMP will be reported (in days). 
A TEAE overview table will be presented for active treatment by ADA status. Additionally, the 
number and percentage of participants who experience some AEIs (Hypersensitivity reactions, 
injection sites reactions as defined in Section 5.6.3 and autoimmune disorders) will be presented 
by SOC and PT and by ADA Status. Autoimmune disorders will be defined if HLT is in 
“Autoimmune disorders”. For these summaries, participants will be presented for TEAEs 
occurring prior to becoming treatment emergent ADA positive, TEAEs occurring after becoming 
treatment emergent ADA positive, and TEAEs for participants who remained TE ADA negative 
(classifications 1,3,4,6).   
 
5.7 
Other Analyses 
5.7.1 
Other endpoints and/or parameters 
5.7.1.1 
Pharmacokinetics 
The plasma concentrations of Zilucoplan and its two major metabolites (
) 
will be summarized by IMP and by scheduled sampling day for the PK-PPS using n, arithmetic 
mean, median, SD, minimum, maximum, geometric mean, geometric coefficient of variation 
(geoCV) and 95% CI (assuming log-normally distributed data). 
A spaghetti plot of combined individual concentration versus time profiles will be presented by 
analyte in linear and semi-logarithmic scale with all participants overlaid on the same plot.  
Additionally, Mean (+SD) plasma concentration versus time overlaid for both analytes will also 
be presented for all scheduled timepoints on a linear and semi-logarithmic scale. The SD will not 
be provided on the semi-logarithmic scale.  
All figures will include the lower limit of quantification (LLOQ) on the semi-logarithmic plots. 
The following rules will apply for PK data listings and summaries: 
• Values below the LLOQ will be reported as below the limit of quantification (BLQ) 
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• Descriptive statistics of concentrations will be calculated if at most 1/3 of the individual data 
points at a timepoint are missing or are not quantifiable (<LLOQ). Values that are BLQ will 
be replaced by the numerical value of the LLOQ/2 in this instance.  
• The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geoCV) is 0 
• The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data 
 geoCV(%) = √exp(SD2) −1 × 100. 
Individual concentrations will be listed by IMP for the PK-PPS and will include the actual 
sampling time in days relative to the previous dose the ADA titer observed for the binding assay 
and the NAb titer for the same visit and CK change from baseline for the corresponding visit.   
Summary statistics (mean, SD, median, minimum, maximum, geometric mean and geometric 
CV%) will be produced for each PK parameter for each analyte. 
The results of the PK will be reported separately from the main clinical study report analyses and 
therefore analysis will not be stated at the current document. 
Plasma concentration data of Zilucoplan may be subject to population pharmacokinetic analysis 
to derive population estimates of PK parameters and test the effect of various covariates such as 
anti-drug antibodies, age, weight, gender. Details of the analysis will be described separately. 
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 study CSR but in a separate modeling report. 
 
5.7.1.2 
Pharmacodynamics 
Pharmacodynamic analyses will be performed on the PD-PPS. The pharmacodynamic endpoints 
include sRBC lysis assay and C5 levels. 
Summary statistics based on observed data will be provided for the values, change from baseline, 
and percent change from baseline at each of the scheduled assessment time point.  
The change from baseline for each of these endpoints will be assessed by an ANCOVA model 
with treatment as a factor and the corresponding baseline value as covariate. The active dose will 
be compared to the placebo group based on the ANCOVA model; corresponding 90%CIs will be 
produced. 
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 separately. The results of the analyses 
will not be reported in the study CSR but in a separate modeling report. 
 
5.8 
Subgroup Analyses 
The primary and continuous secondary efficacy endpoints will be summarized in ITT for the 
Main Portion of the study, based on the following subgroups:  
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• Sex (male, female) 
• Age:<55 years, ≥55 years 
• Stratification factor:  anti-HMGCR / anti-SRP groups (positive / negative, negative / 
positive) 
Note: The stratification factor in the subgroup analysis will be based on the values entered 
into the IWRS at randomization. 
The associated estimand for the subgroup analysis is defined as:  
• Treatment: Zilucoplan administered by daily SC injection (0.3 mg/kg) vs matching placebo 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 and 8.2 
of the study protocol reflecting the targeted IMNM population in the specific subgroup 
• Endpoints:  
− Percentage change from baseline to Week 4 and Week 8 in CK levels;  
− At least minimal response based on (ACR/EULAR) Response Criteria Scale at Week 4 
and Week 8;  
− Change from baseline to Week 4 and Week 8 in Triple Timed Up and Go (3TUG) Test 
(in ambulatory patients only);  
− Change from baseline to Week 4 and Week 8 in Proximal Manual Muscle Testing 
(MMT);  
− Change from Baseline to Week 4 and Week 8 in Physician Global Activity Visual 
Analogue Scale (VAS);  
− Change from baseline to Week 4 and Week 8 in Health Assessment Questionnaire 
(HAQ);  
− Change from baseline to Week 4 and Week 8 in MDAAT Extramuscular Disease 
Activity VAS Score;  
− Change from Baseline to Week 4 and Week 8 in FACIT-Fatigue Scale;  
• Intercurrent event (ICE) handling: regardless of any treatment discontinuation for any 
reason; censoring after prohibited medication;  
• Population level summary:  
− Continuous endpoints: mean change from baseline 
− Proportion of patients achieving at least minimal ACR/EULAR response 
Analysis will be based only on descriptive statistics (no hypothesis testing). 
 
5.9 
Interim Analyses 
No interim analysis is planned for the Main Portion of the study.  
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Interim analyses of the Extension Portion of the study, after Week 8 of the Main Portion of the 
study has been locked and unblinded, may be performed. 
 
5.10 
Data Monitoring Committee (DMC) or Other Review Board 
The safety of study participants is monitored throughout the study on an ongoing basis. Given 
the double blind, placebo-controlled design of the study, this standard safety data review is 
performed while blinded to treatment assignment. If an unblinded data review should become 
necessary to ensure subject safety, a separate DMC will convene and evaluate study data as 
appropriate. To ensure the scientific integrity of the study, members of the DMC are not be 
directly involved in management of the study. 
 
6 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1: Non-key analysis specifications 
6.1.1 
Baseline characteristics and demographics 
A separate table on demographics and baseline characteristics based on the ITTEXT will be 
created. 
• Age (years), calculated as (informed consent date – date of birth + 1)/365.25.  
If day and month are missing from the date of birth, impute January 1st; if only the day is 
missing then impute the 1st.  
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) (kg/m2) calculated as: BMI= "Weight (kg)" / ("Height (m)")^2 using 
the weight and height measurements obtained at screening.  
• Sex (Male/Female) 
• Racial Group (American Indian /Alaska native, Asian, Black, Native Hawaiian or Other 
Pacific Islander, White, Other/Mixed) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
• Years of Age (≤18, >18 - < 55, ≥55 - < 65, ≥ 65). 
• Weight in Kg (<56, 56-<77, ≥ 77 - <150, ≥ 150) 
• BMI in kg/m2 (<18.5, 18.5 - <25, ≥25 - <30, ≥30 - >40, ≥ 40) 
• Ambulatory participant (yes, no) 
• Geographic region (North America, Europe)  
• Countries (country 1, country2, etc.)  
• Months since initial diagnosis calculated as: 
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Months since diagnosis =
(Date of randomization−Date of Initial IMNM Diagnosis1+1)
30.5
. 
1If the date of initial IMNM diagnosis is partial, it should be imputed to the most recent 
feasible date (i.e., last day of the month if only day is missing, or the last day of the year if 
day and month are missing). Note that if the date of randomization is missing then the 
duration of disease will be derived using the date of screening.  
• Age in years at initial diagnosis calculated as: Year of Initial IMNM Diagnosis −
 Year of Birth 
• HMGCR SRP Antibodies (positive/negative, positive/negative),  
• Muscle Biopsy performed (yes, no),  
− normal muscle biopsy  
− necrotic muscle fibers observed  
− complement C5b-9 or C9 staining performed  
− complement C5b-9 or C9 staining positive 
− complement C5b-9 or C9 staining negative 
• Electromyography performed (yes, no) 
− normal electromyography  
− increased insertional activity and spontaneous fibrillations   
− abnormal myopathic low-amplitude, short-duration polyphasic motor unit potential  
− complex repetitive discharges  
− other 
• MRI performed (yes, no) 
− normal MRI 
− muscle edema  
− muscle inflammation  
− muscle fibrosis  
− other 
• Extramuscular Manifestations of IMNM (yes, no) 
− skin  
− cardiac  
− skeletal 
− gastrointestinal  
− pulmonary  
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− constitutional  
• History of any statin use (yes, no) 
− Atorvastatin 
− Fluvastatin  
− Lovastatin  
− Pravastatin  
− Pitavastatin  
− Simvastatin 
− Rosuvstatin  
− other 
 
6.1.2 
Protocol deviations 
A listing of all protocol deviations will be provided based on the ITT and presented by IMP, 
indicating if PD is COVID-19 related or not.  
 
6.1.3 
Medical history 
Any medical condition reported on the Medical History form of the eCRF will be coded based on 
MedDRA dictionary. Medical History will be summarized by IMP and overall, by Primary 
System Organ Class (PSOC) and preferred term (PT) in the ITT. A participant will be counted 
only once for each PT. If a participant reports multiple PTs within the same PSOC then the 
participant will be counted only once for this PSOC. The summary will present the results 
alphabetically by PSOC and within each PSOC by decreasing frequency of the PT based on the 
active comparator. Summaries will be repeated by pre and during the COVID-19 era based on 
the enrollment date.   
A by-participant listing will be provided based on the ITT population. IMNM medical history 
will be listed separately in ITT as it is part of the baseline clinical characteristic. 
 
6.1.4 
Prior/concomitant Medications 
6.1.4.1 
Prior and Concomitant Medications (non – IMNM related) 
Prior and concomitant medications (prescriptions or over-the-counter medications) as recorded in 
the eCRF will be summarized on tables overall by IMPs in SS.  
A non – IMNM related medication is defined by the “indication” value on the Prior and 
Concomitant Medication eCRF form not equal to “Therapy for IMNM”. 
Medications will be classified as follows based on imputed start and stop dates / times as 
outlined in Section 5.1.1.8. 
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• Past medications will include any medications that started and stopped before the first 
administration of study drug.  
• Prior medications will include any medications that started before the first administration of 
study drug. 
• Baseline medications will include any medications that started prior to dosing and continued 
after (classified as prior and concomitant medications). 
• Concomitant medications will include any medications that have been taken at least once 
after the first administration of study drug during the Main or the Extension Period.  
• Concomitant Only medications will include any medication that started after the first 
administration of study drug and continues during the Main or the Extension Period. Any 
medication with a start date on the first dosing date and time unknown, will be assumed to be 
concomitant only. 
Medications will be presented in alphabetical order by Anatomical Main Group (ATC Level 1), 
then by Pharmacological Subgroup (ATC level 3) and finally by decreasing frequency of PT 
within Zilucoplan group. In the case of ties, sort these alphabetically within the Zilucoplan. 
Summaries will include the overall number and percentage of participants receiving at least one 
treatment of a PT. 
 
6.1.4.2 
Prior and concomitant Medications (IMNM related) 
IMNM specific medication will be presented separately from the other prior and concomitant 
medications (for both tables and listings). An IMNM specific medication is defined by the 
“indication” value on the Prior and Concomitant Medication eCRF form =“Therapy for IMNM”.   
The following tables summarizing the IMNM medications received will be created based on the 
SS:  
• Past IMNM medications will include any IMNM medication that started and stopped before 
the first administration of study drug.  
• Prior IMNM medications will include any IMNM medication that started before the first 
administration of study drug. 
• Baseline IMNM medications will include any IMNM medication that started prior to dosing 
and continued after (classified as prior and concomitant IMNM medications). 
• Concomitant IMNM medications will include any IMNM medication that have been taken 
at least once after the first administration of study drug during the Main or the Extension 
Period.  
Where an IMNM medication start date is partially or fully missing, and it is unclear as to 
whether the medication is prior or taken at baseline, it will be assumed that it is taken at baseline. 
Of note, an IMNM medication may be considered in both of these categories.  
• Additionally, the number and percentage of participants who have ever received one or more 
of the IMNM specific medications presented below will be summarized accordingly (eCRF 
form = “IMNM Treatment History”:Prednisone for IMNM (yes/no)  
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• Azathioprine for IMNM (yes/no)  
• Mycophenolate mofetil for IMNM (yes/no)  
• Cyclosporine for IMNM (yes/no)  
• Cyclophosphamide for IMNM (yes/no)  
• Methotrexate for IMNM (yes/no)  
• Tacrolimus for IMNM (yes/no) 
• Rituximab for IMNM (yes/no) and number of cycles the past 24 months (continuous) 
• Plasma Exchange for IMNM (yes/no) and number of cycles the past 24 months (continuous) 
• IVIG for IMNM (yes/no) and number of cycles the past 24 months (continuous) 
• scIG for IMNM (yes/no) and number of cycles the past 24 months (continuous) 
• Other (yes/no) 
 
6.1.5 
Data derivation rules 
6.1.5.1 
Triple timed up and go test 
The triple timed up and go test (3TUG) is a non-invasive and reproducible measure, which 
measures clinically important muscle weakness that impairs participant’s ability to walk, climb 
stairs and stand up from a chair. The test will only be performed in participants who are 
ambulatory. The 3TUG test involves the participant getting up from a seated position in a chair, 
walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting 
down. This sequence is repeated 3 times without rest. Sites will record each lap time rounded to 
the nearest second, and the 3TUG time is the average of the 3 lap times. The average of the 3 lap 
times will be calculated to the nearest tenth place (Sanders, et al. 2018). If 2 or more of the lap 
times are missing, the 3TUG time will be set to missing. 
 
6.1.5.2 
Proximal Manual Muscle Testing   
The proximal manual muscle testing (MMT) assesses muscle strength using manual muscle 
testing in 7 muscle groups. A zero to 10-point scale based on standard MMT grades will be used 
of 7 proximal, distal, and axial muscles (Kendall et al. 1993; Rider, Koziol, et al. 2010).   
The 7 muscle groups are:  
1. Trapezius  
2. Deltoid middle 
3. Biceps brachii  
4. Gluteus maximus  
5. Gluteus medius  
6. Iliopsoas  
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7. Quadriceps.  
The total score is the sum of the 7 muscle group scores with a range of 0−140 (i.e., each of the 7 
muscle groups are scored on the left and right sides on a 0−10 point scale) with a higher score 
indicating higher muscle strength. If any of the individual items are missing the total score will 
be set to missing. 
 
6.1.5.3 
Physician Global Activity Visual Analogue Scale  
The Physician Global Activity visual analogue scale (VAS) score, measures the global 
evaluation by the treating physician of the overall disease activity of the patient at the time of 
assessment using a 10 cm visual analogue scale (with a lower score indicating less disease 
activity and a higher score indicating greater disease activity) and a 0-4 point disease activity 
scale with 0=none and 4=extremely severe activity (Rider, Werth, et al. 2011). The VAS score 
will be the number of centimeters rounded to the nearest tenths place.  
 
6.1.5.4 
Patient Global Activity Visual Analogue Scale  
The Patient Global Activity VAS score measures the global evaluation by the patient of the 
patient's overall disease activity at the time of assessment using a 10 cm visual analogue scale 
with a lower score indicating less disease activity and a higher score indicating greater disease 
activity (Rider, Werth, et al. 2011). The score will be the number of centimeters rounded to the 
nearest tenths place. 
 
6.1.5.5 
Health Assessment Questionnaire (HAQ) 
The HAQ is a participant related outcome measure that assesses physical function.  
There are 8 sections:   
1. Dressing and Grooming 
2. Arising 
3. Eating 
4. Walking 
5. Hygiene   
6. Reach 
7. Grip 
8. Activities 
There are 2 or 3 questions for each section. Scoring within each section is based on the following 
response scales:  
• Without ANY difficulty = 0  
• With SOME difficulty = 1  
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• With MUCH difficulty =2  
• UNABLE to do =3  
• Answer Missing  
• Answer Ambiguous 
For each of the 8 sections, the score given to that section is the worst score within the section, i.e. 
if one question is scored 1 and another 2, then the score for the section is 2.  
In addition, if an aide or device is used or if help is required from another individual, then the 
minimum score for that section is 2 (note: questions regarding aids or devices are requested after 
the Walking and Activities items).  
If the section score is already 2 or more then no modification is made.  
If a component question is left blank (i.e., “Answer Missing”) or the response is too ambiguous 
(i.e., “Answer Ambiguous”) to assign a score, then the score for that category is determined by 
the remaining completed question(s).  
A HAQ overall score is calculated using by summing the 8 scores (i.e., from the 8 sections) and 
dividing by 8. In the event that one section is not completed by a subject, the summed score 
would be divided by 7. If more than one section is not completed the summed score would be set 
to missing.   
 
6.1.5.6 
Myositis Disease Activity Assessment Tool (MDAAT) 
The MDAAT measures the degree of disease activity of extra-muscular organ systems and 
muscle. This is a combined tool that includes the myositis disease activity assessment visual 
analogue scales (MYOACT), which is a series of physician's assessments of disease activity of 
various organ systems modified from the Vasculitis Activity Index (Whiting-O'Keefe, Stone and 
Hellmann 1999), and the Myositis Intention to Treat Activity Index (MITAX).   
The following ten MDAAT 0-10 VAS Scores will be summarized with descriptive statistics for 
each IMP:   
1. Constitutional Disease Activity  
2. Cutaneous Disease Activity  
3. Skeletal Disease Activity 
4. Gastrointestinal Disease Activity  
5. Pulmonary Disease Activity  
6. Cardiovascular Disease Activity  
7. Other Disease Activity   
8. Extramusular Disease Activity (note: this is the secondary efficacy endpoint: MDAAT 
Score).  
9. Muscle Disease Activity  
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10. Global Disease Activity 
The following MDDAAT items are scored on a 0 - 4 scale (or NA), based on worsening or 
improvement in specific clinical features, as described below. 
• 0 = Not present in the last 4 weeks  
• 1 = Improving - clinically significant improvement in the last 4 weeks compared to the 
previous 4 weeks  
• 2= The same - manifestations that have been present for the last 4 weeks without significant 
improvement or deterioration compared to the previous 4 weeks  
• 3= Worse - clinically significant deterioration over the last 4 weeks compared to the previous 
4 weeks  
• 4= New - in the last 4 weeks (compared to the previous 4 weeks)  
• NA = Cannot be assessed 
The following are the set of MDAAT items scored using this 0-4 (NA) scale: 
• Pyrexia – documented fever > 38o Celsius   
• Weight loss – unintentional > 5%  
• Fatigue / malaise / lethargy  
• Cutaneous ulceration  
• Erythroderma   
• Panniculitis  
• Erythematous rashes: a. with secondary changes (e.g. accompanied by erosions, 
vesiculobullous change or necrosis)  
• Erythematous rashes: Alopecia: b. Focal, patchy with erythema  
• Heliotrope rash  
• Gottron’s papules / sign  
• Periungual capillary changes  
• Alopecia: a. Diffuse hair loss 
• Alopecia: b. Focal, patchy with erythema  
• Mechanics hands  
• Arthritis: a. Severe active polyarthritis  
• Arthritis: b. Moderately active arthritis  
• Arthritis: c. Mild arthritis  
• Arthralgia Dysphagia: a. Moderate / severe dysphagia  
• Dysphagia: b. Mild dysphagia  
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• Abdominal pain related to the myositis disease process: a. Severe  
• Abdominal pain related to the myositis disease process: b. Moderate  
• Abdominal pain related to the myositis disease process: c. Mild  
• Respiratory muscle weakness without interstitial lung disease (ILD): a. Dyspnea at rest  
• Respiratory muscle weakness without interstitial lung disease (ILD): b. Dyspnea on exertion 
• Active reversible ILD (i.e. not just ventilatory abnormalities due to pulmonary fibrosis): a. 
Dyspnea or cough due to ILD  
• Active reversible ILD (i.e. not just ventilatory abnormalities due to pulmonary fibrosis): b. 
Parenchymal abnormalities on chest x-ray or high resolution CT scan (HRCT) and / or 
ground glass shadowing on HRCT  
• Active reversible ILD (i.e. not just ventilatory abnormalities due to pulmonary fibrosis): c. 
Pulmonary Function Tests: > 10% change in FVC OR > 15% change in DLCO  
• Dysphonia: a. Moderate to severe  
• Dysphonia: b. Mild  
• Pericarditis  
• Myocarditis  
• Arrhythmia: a. Severe arrhythmia  
• Arrhythmia: b. Other arrhythmia, except sinus tachycardia 
• Sinus tachycardia  
• Other Myositis: a. Severe muscle inflammation  
• Myositis: b. Moderate muscle inflammation  
• Myositis: c. Mild muscle inflammation 
• Myalgia 
 
6.1.5.7 
ACR/EULAR Response Criteria  
The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 
scale was created to develop a response criterion for patients with myopathy. The scale utilizes a 
conjoint analysis-based continuous model using absolute percent change in core set measures 
(physician, patient, and MDAAT; muscle strength; Health Assessment Questionnaire; and 
muscle enzyme levels). A total improvement score (range 0-100) is determined by summing 
scores for each core set measure and comparing improvement in each respective core set 
measure. Thresholds for minimal, moderate, and major improvement are ≥20, ≥40, and ≥60 
points in the total improvement score (Aggarwal, et al. 2017). The total improvement score will 
be calculated based on the core set measures as recorded in the eCRF and from central laboratory 
results as defined below in the following table. 
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Table 6‒1: 
ACR/EULAR Response Criteria 
Six Item with Improvement Score Scales 
1: Physician global activity 
Improvement 
Score 
4: Health Assessment 
Questionnaire 
Improvement 
Score 
From the Physician Global Activity Visual 
Analogue Scale  
From the Health Assessment Questionnaire  
Worsening to 5% 
improvement 
0 
Worsening to 5% improvement 
0 
>5–15% improvement 
7.5 
>5–15% improvement 
5 
>15–25% improvement 
15 
>15–25% improvement 
7.5 
>25–40% improvement 
17.5 
>25–40% improvement 
7.5 
>40% improvement 
20 
>40% improvement 
10 
2: Patient global activity 
 
5: Enzymea (most abnormal) 
 
From the Patient Global Activity VAS 
From the clinical laboratory data 
Worsening to 5% 
improvement 
0 
Worsening to 5% improvement 
0 
>5–15% improvement 
2.5 
>5–15% improvement 
2.5 
>15–25% improvement 
5 
>15–25% improvement 
5 
>25–40% improvement 
7.5 
>25–40% improvement 
7.5 
>40% improvement 
10 
>40% improvement 
7.5 
3: Manual muscle testing 
 
6: Extramuscular Disease 
Activity 
 
From the Proximal Manual Muscle Testing  
From the Extramuscular Disease Activity VAS 
component of the MDAAT  
Worsening to 2% 
improvement 
0 
Worsening to 5% improvement 
0 
>2-10% improvement 
10 
>5–15% improvement 
7.5 
>10–20% improvement 
20 
>15–25% improvement 
12.5 
>20–30% improvement 
27.5 
>25–40% improvement 
15 
>30% improvement 
32.5 
>40% improvement 
20 
Note: this table is from Table 3 in Aggarwal, et al. (2017). 
a For muscle enzymes, the most abnormal serum muscle enzyme value at baseline (creatine kinase, aldolase, alanine 
transaminase, aspartate aminotransferase, lactate dehydrogenase) is used to determine % improvement. Most 
abnormal will be defined as enzyme with the highest % above the ULN. 
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The total improvement score is the sum of all 6 improvement scores associated with the change 
in each core set measure. The score is between 0 and 100 corresponds to the degree of 
improvement, with higher scores corresponding to a greater degree of improvement.  
A total improvement score of ≥20 represents minimal improvement, a score of ≥40 represents 
moderate improvement, and a score of ≥60 represents major improvement.   
 
6.1.5.8 
FACIT-Fatigue Scale  
The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale is a 13-
item, easy to administer tool that measures an individual’s level of fatigue during their usual 
daily activities over the preceding week. The level of fatigue is measured on a five point ordinal 
scale (4 = not at all fatigued to 0 = very much fatigued) (Webster, Cella and Yost 2003). The 
items of the FACIT-Fatigue Scale are given in the table below. 
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Note that for the analyses, FACIT values coded as “ambiguous” are mapped to “missing” category. 
 
6.1.6 
AEs of Special Interest 
Not applicable. 
 
6.1.7 
Markedly Abnormal (MA) Criteria for Safety Endpoints 
Criteria listed in Table 6‒3 will be applied for the determination of MA values in laboratory 
parameters. They are based on the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5, November 17, 2017. The MA criterion is defined as the incidence of at least Grade 3 
CTCAE, unless otherwise noted.  
If both high and low criteria are shown for a parameter, then criteria should be summarized 
separately in tabular summaries. 
Table 6‒3: 
CTCAE v5.0 grades for laboratory assessments to be analyzed 
Parameter 
Unit 
(conventional) 
Unit 
(Standard) 
Marked Abnormality Criteria 
Hemoglobin 
g/dL 
g/L 
< 8.0 g/dL; <80g/L  
WBC 
(Leukocytes) 
109/L 
109/L 
Low: <2.0 x 109/L; 
High: >100 x 109/L 
Lymphocytes 
Absolute 
109/L 
109/L 
Low: <0.5 x 109/L 
High>20 x 109/L 
Neutrophils 
Absolute 
109/L 
109/L 
<1.0 x 109/L 
Platelets 
109/L 
109/L 
<50.0 x 109/L 
AST 
U/L 
U/L 
>5.0xULN if Baseline value is normal; > 
5.0x Baseline value if Baseline is abnormal 
ALT 
U/L 
U/L 
>5.0xULN if Baseline value is normal; > 
5.0x Baseline value if Baseline is abnormal 
ALP 
U/L 
U/L 
5.0xULN if Baseline value is normal; > 
5.0x Baseline value if Baseline is abnormal 
γ-GT 
U/L 
U/L 
>5.0xULN if Baseline value is normal; > 
5.0x Baseline value if Baseline is abnormal 
TBL 
mg/dL 
μmol/L 
>3.0xULN if baseline value is normal 
> 3.0xbaseline value if baseline is abnormal 
Albumin 
g/dL 
g/L 
<2g/dL; <20g/L 
Creatinine 
mg/dL 
μmol/L 
>3.0x ULN 
CRPa 
mg/dL 
mg/L 
>10mg/dL >100 mg/L 
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Table 6‒3: 
CTCAE v5.0 grades for laboratory assessments to be analyzed 
Parameter 
Unit 
(conventional) 
Unit 
(Standard) 
Marked Abnormality Criteria 
Corrected 
Calcium (Ca)b  
mg/dL 
mmol/L 
High: Corrected serum calcium of >12.5 
mg/dL; >3.1 mmol/L 
Low: Corrected serum calcium of <7.0 
mg/dL; <1.75 mmol/L 
Potassium 
mEq/L 
mmol/L 
Low: <3.0 mmol/L 
High: > 6.0 mmol/L 
Sodium 
mEq/L 
mmol/L 
Low: <125 mmol/L 
High: >155 mmol/L 
Glucosec 
mg/dL 
mmol/L 
Low: <40mg/dL; < 2.2 mmol/L 
High: >250 mg/dL; >13.9 mmol/L 
eGFRd 
mL/min/1.73 m2 
mL/min/1.73 m2 
eGFR <29 mL/min/1.73 m2 
a Includes CRP and High Sensitivity (HS) CRP. Reference for marked abnormality criteria: Nehring, S.M.; Goyal, 
A.; Patel, B.C. (2020). StatPearls Publishing, web link: https://www.ncbi.nlm.nih.gov/books/NBK441843/ 
b Corrected Ca (mg/dl) = Ca (mg/dl) + (0.8 [4 - measured albumin (g/dl)]);  Corrected Ca = [0.8 x (normal albumin - 
patient's albumin)] + serum Ca, Karbhari, D.S.; Karbhari, S.; Karbhari, N.S.; Patel, S. (2017).  
c Glucose high criterion defined by Grade 3 and higher events according to CTCAE, Version 4.03, June 14, 2010 
d GFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration or CKD-EPI formula 
(https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi) which is eGFR = 141 * min(Scr/κ,1)α * 
max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black]; where Scr is serum creatinine (mg/dL), κ is 
0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of 
Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. For derivation from values in standard units (umol/L) 
the κ values are 61.9 for females and 79.6 for males. 
 
The table for the markedly abnormal liver function tests will contain data beyond the CTCAE 
v5.0 Grade 3 thresholds as outlined in Table 6‒4 above, in order to allow for a more thorough 
review of elevated liver function tests.  
There will be one table by IMP in the SS, which will display the count and percentage of 
participants meeting the criteria mentioned in Table 6‒4 at any visit during the study (including 
unscheduled visits). For the combined criteria to be fulfilled the conditions should be present in 
the same visit. 
The liver function results for study participants with markedly abnormal criteria will be listed for 
all study visits (that is including the not on treatment assessments).  
 
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Table 6‒4: 
Markedly Abnormal Criteria for Liver Function Tests  
Category 
Parameter 
Criteriona 
Drug Hepatic 
disorders TEAEs 
TEAEs in 
MedDRA SMQ 
“Drug related hepatic disorders - comprehensive search 
(SMQ-narrow scope)”  
excluding the 2 sub-SMQs of “Liver neoplasms, benign (incl 
cysts and polyps) (SMQ)” and “Liver neoplasms, malignant 
and unspecified (SMQ)” 
Elevated Liver 
Function Tests 
AST 
>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN 
ALT 
>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN 
AST or ALT 
>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN 
TBL 
>1.5 x ULN, >2 x ULN 
ALP 
1.5 x ULN 
Potential drug-
induced liver injury 
(DILI) criteria 
AST or ALT 
>3xULN with TBL >1.5xULN 
AST or ALT 
>3xULN with TBL >2xULN 
Hy’s Law 
AST or ALT > 3×ULN with concurrent ALP < 2 × ULN and 
concurrent TBL > 2×ULN  
a Meeting the criteria at any post-baseline visit after the first infusion of study medication and within 40-days of the 
last injection and not meeting the same criteria during baseline  
 
Criteria listed in Table 6‒5 will be applied in the determination of PCSA (Potentially Clinically 
Significant Abnormalities) in vital signs of the study participants. 
Table 6‒5: 
Abnormality Criteria in Vital Signs 
Parameter 
Criteriona 
Systolic Blood 
Pressure (mmHg) 
≤ 90 mmHg and a decrease from Baseline of ≥20 mmHg 
≥ 160 mmHg and an increase from Baseline of ≥20 mmHg 
Diastolic Blood 
Pressure (mmHg) 
≤50 mmHg and a decrease from Baseline of ≥15 mmHg 
≥105 mmHg and an increase from Baseline of ≥ 15 mmHg 
Pulse rate (bpm) 
≤50 mmHg and a decrease from Baseline of ≥15 mmHg 
≥120 mmHg and an increase from Baseline of ≥15 mmHg 
a Meeting the criteria at any post-baseline visit after the first infusion of study medication and within 40-days of the 
last injection and not meeting the same criteria during baseline  
 
Criteria listed in Table 6‒6 will be applied in the determination of abnormalities in ECG of the 
study participants. 
Table 6‒6: 
Abnormality Criteria in ECG 
Parameter 
Criteriona 
QT interval (ms) 
≥500ms;   ≥60ms increase from Baseline 
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Parameter 
Criteriona 
QTc(F) (ms) 
≥500ms;   ≥60ms increase from Baseline 
PR interval (ms) 
Treatment-emergent value >200ms 
QRS interval (ms) 
Treatment-emergent value >100ms 
Heart Rate (bpm) 
<50bpm;  >120bpm 
a Meeting the criteria at any post-baseline visit after the first infusion of study medication and within 40-days of the 
last injection and not meeting the same criteria during baseline  
 
6.1.8 
Compliance 
Not Applicable. The number of doses missed will be recorded as detailed in Section 5.6.1.  
 
6.2 
Appendix 2: MedDRA Algorithmic Approach to Anaphylaxis 
The SMQ Anaphylactic reaction consists of three parts:  
• A narrow search containing PTs that represent core anaphylactic reaction terms: 
Preferred Terms:  
− Anaphylactic reaction  
− Anaphylactic shock 
− Anaphylactic transfusion reaction 
− Anaphylactoid reaction 
− Anaphylactoid shock 
− Circulatory collapse 
− Dialysis membrane reaction 
− Kounis syndrome 
− Shock 
− Shock symptom 
− Type I hypersensitivity 
 
• A broad search that contains additional terms that are added to those included in the narrow 
search. These additional terms are signs and symptoms possibly indicative of anaphylactic 
reaction and categorized in B, C or D: 
Category B Preferred Terms:  
− Acute respiratory failure 
− Asthma 
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− Bronchial oedema 
− Bronchospasm 
− Cardio-respiratory distress 
− Chest discomfort 
− Choking 
− Choking Sensation 
− Circumoral oedemia 
− Cough 
− Cyanosis 
− Dyspnoea 
− Hyperventilation 
− Irregular Breathing 
− Laryngeal dyspnea 
− Laryngeal oedema 
− Laryngospasm 
− Laryngotracheal oedema 
− Mouth swelling 
− Nasal obstruction 
− Oedema mouth 
− Oropharyngeal spasm 
− Oropharyngeal swelling 
− Respiratory arrest 
− Respiratory distress 
− Respiratory dyskinesia 
− Respiratory failure 
− Reversible airways obstruction 
− Sensation of foreign body 
− Sneezing 
− Stridor 
− Swollen tongue 
− Tachypnoea 
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− Throat tightness 
− Tongue oedema 
− Tracheal obstruction 
− Tracheal oedema 
− Upper airway obstruction 
− Wheezing. 
 
Category C Preferred Terms:  
− Allergic oedema 
− Angioedema 
− Erythema 
− Eye oedema 
− Eye pruritus 
− Eye swelling 
− Eyelid oedema 
− Face oedema 
− Flushing 
− Generalised erythema 
− Injection site urticaria 
− Lip oedema 
− Lip swelling 
− Nodular rash 
− Ocular hyperaemia 
− Oedema 
− Periorbital oedema 
− Pruritus 
− Pruritus allergic 
− Pruritus generalized 
− Rash 
− Rash erythematous 
− Rash generalized 
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− Rash pruritic 
− Skin swelling 
− Swelling 
− Swelling face 
− Urticaria 
− Urticaria papular 
 
Category D Preferred Terms:  
− Blood Pressure decreased 
− Blood Pressure diastolic decreased 
− Blood Pressure systolic decreased 
− Cardiac arrest 
− Cardio-respiratory arrest 
− Cardiovascular insufficiency 
− Diastolic hypotension 
− Hypotension 
 
• An algorithmic approach which combines anaphylactic reaction symptoms in order to 
increase specificity. A potential anaphylactic reaction is defined as meeting at least one of the 
following criteria:  
− A narrow term or a term from Category A;  
− A term from Category B - (Upper Airway/Respiratory) AND a term from Category C - 
(Angioedema/Urticaria/Pruritus/Flush), when both TEAEs occur on two consecutive 
days, under the condition that Zilucoplan treatment is still ongoing at the first of these 
two days (both TEAEs will be flagged as anaphylactic reactions) 
− A term from Category D - (Cardiovascular/Hypotension) AND [a term from Category B - 
(Upper Airway/Respiratory) OR a term from Category C - (Angioedema/Urticaria/ 
Pruritus/Flush)], when both TEAEs occur on two consecutive days, under the condition 
that Zilucoplan treatment is still ongoing at the first of these two days (both TEAEs will 
be flagged as anaphylactic reactions) 
 
6.3 
Appendix 2: Changes to Protocol-Planned Analyses 
No changes as per study protocol amendment 2, 16 February 2021. 
 
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7 
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2016 American College of Rheumatology/European League Against Rheumatism Criteria for 
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Arthritis & Rheumatology 898-910. Kendall, FP, and et. al. 1993. Muscles, testing and function: 
With Posture and pain.   
Fay MP, Feuer EJ. Confidence intervals for directly standardized rates: a method based on the 
gamma distribution. Stat Med. 1997 Apr 15;16(7):791-801.  
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical Principles of Clinical Trials E9 [Last accessed on 
2020 Oct 10]. Available from: https://database.ich.org/sites/default/files/E9_Guideline.pdf 
International Council for Harmonisation of Technical Requirements for Registration of 
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UCB 
 
09 June 2021 
Statistical Analysis Plan Amendment 2 
Zilucoplan 
RA101495-02.202 (UCB study IMNM01)
 
 
 
Confidential 
Page 75 of 75 
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Approval Signatures
Name:
IMNM01-sap-amendment-2
Version:
1. 0
Document Number:
CLIN-000174682
Title:
IMNM01-sap-amendment-2
Approved Date:
09 Jun 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Jun-2021 12:09:30 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Jun-2021 15:04:59 GMT+0000
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